Journal articles on the topic 'JI. Circulation'

This article examines the “playful eight-legged essay” as a form of literary parody and discusses its circulation in printed editions of The Story of the Western Wing and The Story of the Lute in late imperial China. The rise of the playful eight-legged essay was part of a philosophical and literary tradition of “game-playing,” and occurred in the context of publications that appropriated canonical genres for fashionable entertainment. Reading the playful compositions against the generic conventions of the standard examination essay, on the one hand, and the original drama commentary, on the other, the author explores the playful eight-legged essay as an increasingly autonomous mode of critical commentary that was independent from, yet still associated with, the dramatic text. Employing dramatic impersonation, the essays opened up a playful space for the staging of passion and extended the appeal of the original play by involving the reader in its imaginative performance. Cet article étudie les adaptations plaisantes des “dissertations en huit jambes” comme forme de parodie littéraire et en examine la diffusion à travers les éditions imprimées du Pavillon de l’ouest et de l’Histoire du luth à la fin de l’empire. L’émergence de telles adaptations, inscrites dans une tradition ludique à la fois philosophique et littéraire, est contemporaine de la parution d’ouvrages qui détournaient les genres canoniques à des fins de récréation élégante. La lecture de ces dissertations amusantes que propose l’auteur se réfère à la fois aux conventions présidant à la composition des dissertations d’examen et aux commentaires d’œuvres théâtrales proprement dits. Il en ressort que le genre de la dissertation parodique a acquis une autonomie croissante en tant que commentaire critique indépendant des œuvres dramatiques tout en y restant associé. En s’appropriant la voix des personnages des pièces, de tels textes ouvrent un espace de fantaisie propice à la mise en scène des passions et renforcent l’attrait des œuvres originales en impliquant le lecteur dans leur réalisation imaginée.

AbstractThis paper explores the role of women as alleged sources for Qing dynasty zhiguai (tales of the strange) collections, particularly Ji Yun's (1724-1805) Yuewei caotang biji (Jottings from the Cottage of Close Scrutiny). Tracing circulation of narratives across both single-sex and mixed-sex networks sheds light on those networks, and on shared or divergent lore and interpretations as tales are cooperatively assembled. The absence or presence of female narrators or listeners in tales focused on women's behavior also reveals differing articulations of vice and virtue.

The distinction between convective and stratiform precipitation profiles around various precipitating systems existent in tropical regions is very important to the global atmospheric circulation, which is extremely sensitive to vertical latent heat distribution. In South America, the convective activity responds to the Intraseasonal Oscillation (IOS). This paper analyzes a disdrometer and a radar profiler data, installed in the Ji-Paraná airport, RO, Brazil, for the field experiment WETAMC/LBA & TRMM/LBA, during January and February of 1999. The microphysical analysis of wind regimes associated with IOS showed a large difference in type, size and microphysical processes of hydrometeor growth in each wind regime: easterly regimes had more turbulence and consequently convective precipitation formation, and westerly regimes had a more stratiform precipitation formation.

In recent years, sandy coasts are suffering from erosion. It is of great importance to evaluate the state of coasts and assure the achievement of coastal protection measures. Therefore, a three-dimensional numerical model of sandy beach response was developed based on unstructured grids and with capability of describing nearshore hydrodynamics and sediment transports. A three-dimensional hydrodynamic model was first developed based on a coupled wave-current model system that included the Simulating Waves Nearshore (SWAN) wave model and the Finite Volume Community Ocean Model (FVCOM) circulation model. Information exchange between the two models used Model-Coupling Toolkit (MCT) software following Chen et al. (2018). The new three-dimensional radiation stress including the bottom slope effects was employed (Ji et al. 2017). Based on the hydrodynamic model, a numerical model of sediment transport and morphological evolution on sandy beach was developed.Recorded Presentation from the vICCE (YouTube Link): https://youtu.be/BVVn1kfViH0

Abstract. El Niño events differ widely in their patterns and intensities. The regional climate anomalies caused by different types of El Niño events likely lead to various impacts on winter haze pollution in China. Based on long-term site observations of haze days in China from 1961 to 2013, this study explores the effects of eastern Pacific (EP) and central Pacific (CP) types of El Niño events on the number of winter haze days (WHDs) in China's Jing-Jin-Ji (JJJ) region and the physical mechanisms underlying WHD changes. The results show statistically significant positive and negative correlations, respectively, between WHDs in the JJJ region and EP and CP El Niño events. At most sites in the JJJ region, the average WHD increased in all EP El Niño years, with the maximum change exceeding 2.0 d. Meanwhile, the average WHD decreased at almost all stations over this region in all CP El Niño years, with the largest change being more than −2.0 d. The changes in large-scale circulations indicate obvious positive surface air temperature (SAT) anomalies and negative sea level pressure (SLP) anomalies over North China, as well as southerly wind anomalies at the middle to low troposphere over eastern China in the winters of EP El Niño years. These anomalies are conducive to increases in WHDs in the JJJ region. However, there are significant northerly and northwesterly wind anomalies at the middle to low troposphere over eastern China, as well as stronger and wider precipitation anomalies in the winters of CP El Niño years, which contribute to decreased WHDs over the JJJ region. Changes in local synoptic conditions indicate negative SLP anomalies, positive SAT anomalies, and weakened northerly winds over the JJJ region in the winters of EP El Niño years. The total occurrence frequency of circulation types conducive to the accumulation (diffusion) of aerosol pollutants is increased (decreased) by 0.4 % (0.2 %) in those winters. However, the corresponding frequency is decreased (increased) by 0.5 % (0.6 %) in the winters of CP El Niño years. Our study highlights the importance of distinguishing the impacts of these two types of El Niño events on winter haze pollution in China's JJJ region.

The number of legal journals published in Estonia has always been limited. On the one hand, the reasons for such scarcity have always rested with the small population, which limits the size of the Estonian legal audience and thus the potential number of readers. On the other hand, the twists and turns of (recent) history have always meant interruptions in the publication of legal journals. Publishing two, three or even four journals at the same time has proven possible only in a very limited number of years. There is usually no reason to talk about decades in this context. All the more reason for us, as the publishers and authors of this journal, to be proud of the publication of yet another issue of our magazine. The first issue of Juridica International – the foreign language companion to the Estonian language journal Juridica, which has been published since 1993 – appeared twenty years ago, in 1996. Professor Paul Varul, Editor-in-Chief of Juridica International from 1996–2015, took a look back at these first twenty years in the editor’s column of our last issue. Juridica International has acted like a seismograph when it comes to reflecting reforms in Estonian law and legal education. When Estonia joined the European Union in 2004, new and significantly more international challenges alreadly came along during the preparatory stage, not to mention the subsequent active participation in the harmonisation processes of European Union law. The foreign language journal, published at and with the means of the Faculty of Law of Estonia’s own national university, the University of Tartu, has given our legal practitioners a chance to express their views among an international community of scholars in a highly visible manner. Juridica International has also played an important part in publishing materials from legal conferences and seminars held in Estonia. Juridica International has become an attractive international journal that reaches well beyond the borders of Estonia and the European Union. This widespread circulation has been assisted by free access online – a decision made by Juridica International years before “open access” became a keyword of global research policy. In the span of only a couple of decades, the journal that first started as the “calling card” of the Faculty of Law at the University of Tartu, mainly introducing and analysing Estonia’s own legal developments, has become an internationally open, peer-reviewed legal journal that is represented in the most acknowledged databases. Since Juridica International is a universal legal journal by its very essence, and this number is not a topically focused conference issue, the geography of both the authors and the topics covered reflect points of interest and concern in the legal science of our region. A special place is reserved for the principal foundations of the European Union and European legal culture in general, and the latest developments in the law of Europe, Estonia, and other countries are addressed as always. One of the obvious causes for concern is Russia’s legal concept, and the legal situation of both it and its neighbours deserves an observant analysis. As the new Editor-in-Chief of the journal, I thank all the editors, colleagues at the editorial board, and the technical team for their continued energy and hard work. For our readers, as well as current and future authors, I hope this issue will be thought-provoking, give you topics to reflect on, and a reason to join us time and again.

Abstract We have established and optimized a robust tumor bone metastasis mouse model, which recapitulates the tumor metastasis progression from circulation to bone colonization, and provides windows for both prophylaxis and treatment. Specifically, we inoculated two breast cancer cell lines, JIMT-1 and MDA-MB-231, each with high metastatic potential, into mouse intra-caudal artery. By detection of steadily incremental bioluminescence signal, prophylaxis was observed to precede metastases, which were found exclusively on mouse hind limbs. These mouse models exhibited swollen hind limbs and even paralysis at late stage. Gross necropsy and pathology analysis confirmed the exclusive hind limb localization, the invasion and spreading of tumor cells to muscles and bone marrows, and the lesions in tibias and femurs. Our robust bone metastases models thus imitate the multiple stages of tumor metastasis, leading to exclusion bone metastasis and opening up windows for prophylaxis and treatment. Citation Format: Yao Shuai, Chaomeng Wang, Ling Tong, Qiao Liu, Jie Xu, Qunsheng Ji. Mouse hind limb tumor metastatic model to evaluate prophylaxis and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6010.

The metabolic syndrome (MS), a predisposing condition for cardiovascular disease, presents disturbances in hemodynamics; impedance cardiography (ICG) can assess these alterations. In subjects with MS, the morphology of the pulses present in the ICG time series is more irregular/complex than in normal subjects. Therefore, the aim of the present study was to quantitatively assess the complexity of ICG times series in 53 patients, with or without MS, through a nonlinear analysis algorithm, the approximate entropy, a method employed in recent years for the study of several biological signals, which provides a scalar index, ApEn. We correlated ApEn computed from ICG times series data during fasting and postprandial phase with the presence of alterations in the parameters defining MS [Adult Treatment Panel (ATP) III (Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; National Heart, Lung, and Blood Institute; American Heart Association. Circulation 109: 433–438, 2004) and the International Diabetes Federation (IDF) definition]. Results show that ApEn was significantly higher in subjects with MS compared with those without (1.81 ± 0.09 vs. 1.65 ± 0.13; means ± SD; P = 0.0013, with ATP III definition; 1.82 ± 0.09 vs. 1.67 ± 0.12; P = 0.00006, with the IDF definition). We also demonstrated that ApEn increase parallels the number of components of MS. ApEn was then correlated to each MS component: mean ApEn values of subjects belonging to the first and fourth quartiles of the distribution of MS parameters were statistically different for all parameters but HDL cholesterol. No difference was observed between ApEn values evaluated in fasting and postprandial states. In conclusion, we identified that MS is characterized by an increased complexity of ICG signals: this may have a prognostic relevance in subjects with this condition.

In the 1910s, the trend of “creating through translation” emerged in fiction by female Chinese writers. This concept, similar to that of “covert translation,” introduced by the contemporary Western translation theorist Juliane House, sprang up from the early stages of new literary forms that developed in the context of changes in early modern Chinese literature. The works of female Chinese authors were influenced by the plot, characters, and narrative techniques in Western literary works from which they consciously or subconsciously took inspiration, passing from the imitation of foreign novels to “creation through translation.” The arrival of this phenomenon is closely connected to the increased dissemination of Western knowledge and to a wider circulation of foreign novels among female writers in China. When reading and translating foreign literature, female authors transposed, filtered, and rewrote it into new texts that featured local elements. Ideologically and artistically, the practice of “creating through translation” provided enlightening guidance for modern women’s fiction in that it broadened the means of learning from Western literature, proving beneficial to China’s literary and cultural development. The same trend appears in early vernacular poetry during the May Fourth era, from which it can be traced further back to scholarly texts of the early modern period, such as Wei Yuan’s Illustrated Treatise on the Maritime Kingdoms (Haiguo tuzhi 海國圖志) or Wang Tao’s Report on the Franco-Prussian War (Pu-fa zhan ji 普法戰紀). Also Liang Qichao’s writings on Western thought and culture, for example, his Notes on Rousseau (Lusuo xue’an 盧梭學案), are written in a similar form. The emergence of “creation through translation” therefore evidently represents both a conscious, active effort by a generation’s intellectual elite to seek knowledge and truth from cultural exchange between China and the West, and a new exploration and practice under Western influence that had a positive impact on China’s literary and academic history, in that it broadened cultural/academic perspectives and stimulated the development of Chinese literature and culture.

Sigitas Urbonavičius, Mindaugas Trumpickas, Arūnas GrinkevičiusKauno medicinos universiteto Kardiochirurgijos klinikosAngiochirurgijos skyrius, Eivenių g. 2, LT-50009 KaunasEl. paštas: sigisu@takas.lr, sigisu@one.lt Tikslas Įvertinti Cyclo 3 Fort poveikį, gydant lėtinį venų nepakankamumą ir jo klinikinius simptomus. Ligoniai ir metodai Cyclo 3 Fort yra palyginti neseniai Lietuvoje pasirodęs preparatas, kuris susideda iš Ruscus aculeatus ekstrakto, flavonoido hesperidino bei askorbo rūgšties. Užsienyje jis gerai įvertintas gydant galūnių edemą, kai ji atsiranda dėl venostazės ar limfostazės. Pateikiama retrospektyvinė 35 ligonių tyrimo duomenų analizė. Dvidešimt ligonių keturias savaites buvo gydomi Cyclo 3 Fort (po 2 kapsules per dieną), o kiti 15 jokių venotonikų nevartojo. Kojos edema buvo vertinama matuojant blauzdos ir kulkšnies perimetrą bei tūrio kitimus. Skausmas ir galūnės diskomfortas buvo vertintas pagal sudarytą klausimyną. Rezultatai Šio tyrimo rezultatai parodė, kad po 4 savaičių ligoniams, kurie vartojo Cyclo 3 Fort, visi tirtieji veiksniai (kojos edema, skausmas, dienos ir nakties mėšlungis, diskomfortas, kojų sunkumas, parestezijos) buvo ženkliai mažesni negu jokių venotonikų nevartojusiems ir tik veninę kraujotaką gerinančius fizinius pratimus dariusiems ligoniams. Išvados Venotonikas Cyclo 3 Fort ženkliai mažina kojos edemą bei lėtinio venų nepakankamumo klinikinius simptomus. Reikšminiai žodžiai: lėtinis venų nepakankamumas, kojos edema, venotonikai The treatment of chronic venous insufficiency and it’s clinical symptoms with phflebotonic Cyclo 3 Fort Sigitas Urbonavičius, Mindaugas Trumpickas, Arūnas Grinkevičius Objective To evaluate the effectiveness of the phlebotonic Cyclo 3 Fort for the outpatient treatment of chronic venous insufficiency and its clinical symptoms. Patients and methods Cyclo 3 Fort is a quite new in Lithuania composite medicine containing Ruscus aculeatus, hesperidin and ascorbic acid. In some western countries it had a good approvement in the treatment of leg edema. There are retrospective data on 35 patients with chronic venous insufficiency (CVI). Twenty patients were treated with Cyclo 3 Fort for 4 weeks, and the other 15 patients for various reasons underwent physical examinations for venous circulation improvement in the same period. Leg edema was assessed by measuring the calf and ankle perimeters. Pain and leg discomfort was estimated by asking special questions. Results After four weeks all the study parameters (edema of legs, day and night cramps, discomfort, heaviness and parasthesias) were significantly better in the Cyclo 3 Fort group vs. the control group. Conclusion The use of phlebotonic Cyclo 3 Fort statistically significantly reduced the volume of the legs and symptoms of CVI. Keywords: chronic venous insufficiency, phlebotonics, oedema of the leg

BackgroundIn Korea, it has been reported that the incidence of some respiratory diseases and Kawasaki diseases has decreased compared to the previous year along with active non-pharmaceutical interventions in the early stages of the COVID-19 pandemic. Autoimmune inflammatory rheumatic disease (AIIRD) is mainly affected musculoskeletal organs and connective tissues due to impaired immune regulation. Although gout and osteoarthritis are rheumatic diseases, they are not a disease of the immune system, and are not included in the AIIRD.ObjectivesIn this study, we investigated the change and difference in the incidence rate of various rheumatic diseases during the COVID-19 pandemic after 2020.MethodsThe number of patients for each disease from January 2016 to December 2020 was obtained from the Korea Health Insurance Review and Assessment Service database. We compared the incidence of 9 rheumatic diseases [systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), Sjogren syndrome (SJS), Behcet’s disease (BD), inflammatory myositis (IIM), scleroderma, polymyalgia rheumatica (PMR), and gout] and hypertension before and after the COVID-19 outbreak. The incidence rates of patients before and after the COVID-19 outbreak were compared using the Poisson test.ResultsFrom 2016 to 2019, the prevalence of rheumatic diseases showed gradually increased. In 2020, the incidence of SLE, AS, SJS, BD, and IIM were significantly decreased compared to the previous 4 years. In contrast, the incidences of gout and hypertension during the COVID-19 pandemic period were significantly increased from the predicted values.ConclusionIn conclusion, we found that the incidence of many AIIRDs, including SLE, AS, SJS, BD, and IIM decreased despite the increased incidence of hypertension and gout during the COVID-19 pandemic.References[1]Huh K, Kim YE, Ji W et al. Decrease in hospital admissions for respiratory diseases during the COVID-19 pandemic: a nationwide claims study. Thorax 2021;76:939-41.[2]Kang JM, Kim YE, Huh K et al. Reduction in Kawasaki Disease After Nonpharmaceutical Interventions in the COVID-19 Era: A Nationwide Observational Study in Korea. Circulation 2021;143:2508-10.Table 1.Cumulative incidence of rheumatic diseases and HTN (by Poisson test)Mean (2016-2019)Observed (2020.1~12)Rate ratio (95%CI)P valueSLE5371.34541.00.844 (0.811, 0.878)<0.001BD3598.33057.00.848 (0.808, 0.890)<0.001AS11679.510934.00.935 (0.910, 0.959)<0.001SJS7913.57280.00.918 (0.890, 0.948)<0.001IIM839.8397.00.472 (0.418, 0.532)<0.001RA17490.317342.00.990 (0.969, 1.011)0.343SSc592.8557.00.938 (0.834, 1.054)0.288PMR1072.01152.01.073 (0.986, 1.167)0.098Gout129543.0131133.01.011 (1.003, 1.018)0.007HTN680943.2696391.01.021 (1.018, 1.024)<0.001SLE; systemic lupus erythematosus, BD; Behçet disease, AS; ankylosing spondylitis, SSc; systemic sclerosis, IIM; idiopathic inflammatory myositis, RA; rheumatoid arthritis, SJS; Sjogren syndrome, PMR; polymyalgia rheuamtica, HTN; hypertension, CI; confidence interval.Disclosure of InterestsNone declared

Povilas PauliukasVilniaus universiteto Neuroangiochirurgijos centras,Vilniaus greitosios pagalbos universitetinės ligoninėsAngiochirurgijos skyrius,Šiltnamių g. 29, LT-04130 VilniusEl paštas: povilas.pauliukas@mf.vu.lt Įvadas / tikslas Poraktinių arterijų sužalojimai lūžus raktikauliui nėra dažni. Aprašomi du skirtingi klinikiniai atvejai, jų ypatumai, teikiamos rekomendacijos, kaip turi būti gydomi ir operuojami šie ligoniai. Pirmas atvejis Ligonis tris kartus operuotas VMUL Angiochirurgijos centre dėl besikartojančios kairės poraktinės arterijos trombozės. Du kartus buvo atlikta trombektomija Fogarty kateteriu, o trečią kartą į poraktinę arteriją įstatytas stentas, po to poraktinė arterija visiškai užsikimšo, pasireiškė kritinė kairės rankos išemija ir ligonis skubiai perkeltas į VGPUL Angiochirurgijos skyrių, kuriame atlikta skubi operacija. Rooso metodika pašalintas pirmas šonkaulis, naudojant kaulinį transplantatą ir metalinę plokštelę atlikta raktikaulio osteosintezė, suformuota autovenos jungtis iš kairės bendrosios miego arterijos į kairę žastinė arteriją. Pooperacinis laikotarpis sklandus. Po 4 metų raktikaulis gerai suaugęs, rankos kraujotaka normali. Pacientas dirba fizinį darbą. Antras atvejis Aprašoma dėl raktikaulio lūžimo ir jo osteomielito susidariusi mikozinė poraktinės arterijos pseudoaneurizma. Ji buvo sėkmingai pašalinta chirurginiu būdu, išsaugota slankstelinė arterija ir atkurta normali rankos kraujotaka. Išvados Poraktinės arterijos pažeidimų pobūdis abiem atvejais skirtingas. Pirmuoju atveju poraktinės arterijos trombozės priežastis buvo jos suspaudimas tarp dviejų kaulų: raktikaulio pseudoartrozės gumbo ir pirmo šonkaulio. Tokiais atvejais reikia šalinti vieną iš kaulinių struktūrų – raktikaulį arba pirmą šonkaulį, ir paskui rekonstruoti poraktinę arteriją. Antru atveju supūliavę osteomielitiniai raktikaulio lūžgaliai buvo rezekuoti, išsaugota poraktinės arterijos pradinė dalis su slanksteline arterija ir kitomis jos šakomis. Reikšminiai žodžiai: poraktinės arterijos sužalojimai, raktikaulio lūžimas Subclavian artery lesions due to clavicular fracture Povilas PauliukasVilnius University Center of Neurovascular Surgery,Vilnius University Emergency Hospital,Department of Vascular Surgery,Šiltnamių str. 29, LT-04130, Vilnius, LithuaniaE-mail: povilas.pauliukas@mf.vu.lt Background/objective Subclavian artery lesions complicating a clavicular fracture are not frequent, that’s why even vascular surgeons make tactical mistakes while operating on them as described in the first clinical case. The author presents two different cases from his personal experience, analyzes their peculiarities and gives recommendations how to treat and operate on these lesions. First case A 33-year-old male was three times operated on at Vilnius City University Hospital Vascular Surgery Center for recurrent thrombosis of the left subclavian artery: two times thrombectomy with the Fogarty catheter was performed, and during the third procedure the intraarterial stent was introduced into the subclavian artery. Soon after the insertion of the stent, the subclavian artery thrombosed from the aorta up to the axillary fossa, occluding all the subclavian artery branches, including the vertebral artery, and eliminating collateral circulation to the hand. Critical ischemia of the hand developed and the patient was transferred to the Vilnius University Emergency Hospital Vascular Surgery Department. An emergency operation was performed: the left first rib was resected through the axilla using the Roos technique, the clavicle pseudoarthrosis was resected and osteosynthesis of the clavicle using a bone transplant and a metallic plate was performed and then an autologous vein shunt from the common left carotid artery to the brachial artery was created. The postoperative period was uneventful. After 4 years the patient is healthy with a good reunion of the clavicle and normal left hand circulation. Second case The subclavian artery mycotic pseudoaneurysm caused by the fractured left clavicle was surgically eliminated preserving the vertebral artery and restoring the blood flow to the hand by a carotico-axillary autovenous shunt. Conclusions Both clinical cases differ, different were also the lesions of the subclavian artery. In the first case the cause of subclavian artery thrombosis was its compression between two bones: the callus of the clavicle pseudoarthrosis and the first rib. A misunderstanding of the ethiology of the subclavian artery thrombosis led to ineffective palliative procedures instead of eliminating one blade of the bone scissors: the first rib or the clavicle. There were no tactical mistakes made in the second case. Purulent osteomyelitic ends of the fractured clavicle were resected. The proximal part of the subclavian artery with all its branches including the vertebral artery was preserved. Keywords: subclavian artery lesions, clavicular fracture

Abstract Traditional antibody-drug conjugates (ADCs) selectively deliver cytotoxic payloads to tumor-associated antigen (TAA)-expressing tumor cells, thereby limiting healthy cell damage and toxicities associated with systemic administration. Analogously, a novel class of immune-stimulating antibody conjugates (ISACs) has recently emerged to achieve tumor-targeted activation of anti-tumor immune responses, avoiding dose-limiting immunotoxicities seen with the systemic immune agonist delivery. Most of the ADC or ISAC to date utilize random payload conjugation to native surface-exposed lysines or cysteines, and relatively labile linkage chemistries, leading to conjugation site and drug-to-antibody ratio (DAR) heterogeneity, and ADC/ISAC instability in systemic circulation. In particular, the presence of high-DAR species and linker instability can lead to off-tumor toxicity, thus limiting the therapeutic window. Here we describe the generation and preclinical characterization of a site-specific TLR7-agonist (TLR7a) ISAC targeting an undisclosed TAA1. To specify the conjugation site and DAR, a non-natural amino acid (nnAA), para-acetyl-L-phenylalanine (pAF) was genetically incorporated at defined sites within the anti-TAA1 antibody, providing an orthogonal chemical handle for covalent TLR7 agonist payload conjugation through a highly stable oxime bond. Using this site-specific, homogenous ISAC platform, we systematically screened different conjugate sites and TLR7 agonist payloads to obtain an optimized TAA1-TLR7a ISAC drug candidate. ISAC platform stability, homogeneity, and flexibility were critical, because conjugation site and payload structure dramatically influenced ISAC in vitro activity, PK profile and in vivo efficacy. Using in vitro co-culture assays with human immune cells and tumor cell lines, we showed that the optimized TAA1 ISAC can induce multiple anti-tumor immune mechanisms, including proinflammatory cytokine production, the myeloid cell activation markers induction and enhanced ADCC mediated tumor cell killing. The TAA1 ISAC is 100-fold more active than the free, unconjugated TLR7 agonist, and all activity is conditional on the presence of TAA1-expressing tumor cells. Finally, we demonstrated in vivo efficacy in both xenograft and syngeneic tumor models. In a syngeneic MC38-tumor model expressing human TAA1, ISAC treatment led to complete tumor regression and formation of immunologic memory. These results provide a strong rationale for site-specific TLR7 agonist ISAC as a next generation platform for tumor-targeted, innate immune agonist immunotherapy. Citation Format: Mingchao Kang, Sung-Ju Moon, Ji Young Kim, Andy Beck, Molly Allen, Jay Nelson, Keith Tatsukawa, Hon Tran, Manoj Pal, Michael Gray, Nick Knudsen, Lillian Skidmore, David Mills, Yingchun Lu, Ying Buechler, Sukumar Sakamuri, Shawn Zhang, Feng Tian. Tumor-targeted immune activation via a site-specific TLR7-agonist antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5616.

Background: Vaccinia is known to induce antibody and cellular responses. Plasmablast, circulating follicular helper T (cTFH) cells, cytokine-expressing CD4 T cells, and memory B cells were compared between subcutaneous (SC) and needle-free jet injection (JI) recipients of non-replicating modified vaccinia Ankara (MVA) vaccine. Methods: Vaccinia-naïve adults received MVA SC or by JI on Days 1 and 29. Vaccinia-specific antibodies were quantified by plaque reduction neutralization test (PRNT) and enzyme-linked immunosorbent assay. Plasmablast, cTFH, and cytokine-expressing CD4 T cells were assessed on Days 1, 8, 15, 29, 36, 43 (cTFH and CD4+ only) and 57. Memory B cells were measured on Days 1 and 57. Results: Of the 36 enrolled subjects, only 22 received both vaccinations and had evaluable specimens after the second vaccine. Plasmablasts peaked one week after each vaccine. Day 15 plasmablasts correlated with peak PRNT titers. cTFH peaked on Days 8 and 36 and correlated with Day 36 plasmablasts. CD4+ peaked at Day 29 and one-third produced ≥2 cytokines. Day 57 memory B cells ranged from 0.1% to 0.17% of IgG-secreting B cells. Conclusions: This study provides insights into the cellular responses to non-replicating MVA, currently used as a vector for a variety of novel vaccines.

Abstract Background Rapid mobilization of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to the peripheral blood by anti-CXCR4 agents such as AMD3100 is a complex process, which requires CXCL12 secretion, activation of proteolytic enzymes and supporting cellular compartments (Dar et. al, Leukemia 2011). Notably, components of innate immune system were also shown to be involved (Ratajczak et. al, Leukemia 2010). Human β-defensin-3 (hBD3) is an antimicrobial peptide possessing also anti-CXCR4 effects on human T cells in vitro (Feng et. al, JI 2006), suggesting its HSPC mobilizing potential. Here, we describe a novel approach for targeting CXCR4 in vivo by utilizing β-defensin-derived peptides, resulting in rapid HSPC mobilization. Results While AMD3100 blocked CXCL12-mediated signaling and migration of enriched BM mononuclear cells (MNCs) in vitro, we unexpectedly detected rapid phosphorylation of AKT, p38 and ERK1/2 in BM stromal cells (BMSCs). Interestingly, single administration of AMD3100 to mice resulted in enhancement of CXCR4 phosphorylation within minutes in both BM residing mesenchymal stem/progenitor cells (MSCs) and HSPCs, thus suggesting a CXCR4 agonistic activity. Aiming to test HSPC mobilizing potential of hBD3 and avoiding potential toxicity of systemic administration, we synthesized short linear peptides, comprising the C-terminal parts of hBD3 and the murine ortholog β-defensin-14 (mBD14), as well as a cyclic peptide of hBD3, comprising the same amino acids as the linear one, to serve as a control. All full-length β-defensins and tested peptides (both linear and cyclic) specifically bound CXCR4 (demonstrated by docking approach and anti-CXCR4 antibody competition assay) and efficiently blocked CXCL12-mediated activity of enriched BM MNCs in vitro including cell migration and CXCR4-dependent HIV infection. Intriguingly, full-length β-defensins and derived linear peptides (but not cyclic) revealed a strong stimulatory effect on BMSCs in vitro: triggering phosphorylation of AKT, p38 and ERK1/2 along with enhancing secretion of functional CXCL12. Administration of linear peptides to mice led to a fast activation of CXCR4 signaling in BMSCs and MSCs as well as in HSPCs accompanied by CXCL12 release to the circulation, increased activity of proteolytic enzymes and consequent rapid mobilization of progenitors as well as long-term repopulating stem cells. In addition, linear peptides augmented AMD3100-induced rapid mobilization. Importantly, the control cyclic peptide, which bound CXCR4 but failed to activate BMSCs in vitro, did not induce HSPC mobilization in vivo. Moreover, it inhibited both steady-state egress and AMD3100-induced mobilization of HSPCs. A series of in vivo inhibitory analyses confirmed dependence of hBD3- and mBD14-derived peptide-induced HSPC mobilization on the activation of CXCL12/CXCR4 axis and revealed involvement of uPA and JNK signaling as well as ROS generation. Conclusions Our study demonstrated for the first time the capability of β-defensin-derived peptides to activate in vivo CXCL12/CXCR4 signaling in both hematopoietic and non-hematopoietic BM cells, leading to rapid HSPC mobilization. We suggest that activation of CXCR4 signaling in non-hematopoietic BM cells is crucial for inducing HSPC mobilization. Accordingly, CXCR4-binding agents capable of triggering CXCR4 signaling in non-hematopoietic BM cells in vitro, would induce rapid HSPC mobilization. The results presented here help to better understand the mechanisms of rapid HSPC mobilization and have the potential of improving existing clinical protocols to increase the yield of HSPC harvest for transplantation. Disclosures: Scadden: Fate Therapeutics: Consultancy, Equity Ownership.

Saulius Cicėnas, Arnoldas Krasauskas, Renatas Aškinis, Vladislavas Vencevičius, Valdas PuodžiūnasVilniaus universiteto Onkologijos instituto Krūtinės chirurgijos ir onkologijos skyrius,Santariškių g. 1, LT-08660 VilniusEl paštas: cicenas@loc.lt Tikslas Įvertinti vietiškai išplitusio plaučių vėžio (T4) (peraugančio gretimas krūtinės ląstos struktūras) ir didelių matmenų piktybinio tarpuplaučio naviko chirurginio gydymo galimybes, išanalizuoti komplikacijas ir ligonių vidutinę gyvenimo trukmę. Ligoniai ir metodai Vilniaus universiteto Onkologijos instituto Krūtinės chirurgijos ir onkologijos skyriuje 2000–2003 m. buvo gydomi 84 ligoniai, sergantys vietiškai išplitusiu T4 plaučių vėžiu ir didelių matmenų piktybiniu tarpuplaučio naviku: 23 (27,4%) ligoniams rezekuotas kairysis prieširdis, nenaudojant dirbtinės kraujo apytakos, 2 (2,3%) ligoniams atlikta prieširdžio rezekcija ir aortos lanko rezekcija naudojant dirbtinę kraujo apytaką ir 59 (70,2%) ligoniai operuoti dėl didelių matmenų piktybinio tarpuplaučio naviko. Pašalinto piktybinio tarpuplaučio naviko masė svyravo nuo 5 iki 10 kg. Morfologiškai patvirtinta ligonių, sergančių plaučių vėžiu, diagnozė: 20 (80%) ligonių nustatytas plokščialąstelinis vėžys, 5 (20%) ligoniams – liaukinis vėžys. Ligoniams, sergantiems piktybiniu tarpuplaučio naviku, morfologiškai patvirtinta: 10 (17%) ligonių – limfogranuliomatozė (LGR), 9 (15,2%) ligoniams – teratoblastoma, 10 (17%) ligonių – piktybinė tarpuplaučio ektopinė seminoma, 30 (50,8%) ligonių – piktybinė timoma. Plaučių vėžys pagal TNM: T4N0M0 – 18 (72%) ligonių, T4N1M0 – 5 (25%) ligoniams, T4N2M0 – 2 (8%) ligoniams. Kitos atliktos operacijos: kiekvienam ligoniui, sergančiam plaučių vėžiu, buvo atlikta sudėtinė pulmonektomija; iš ligonių, kuriems buvo tarpuplaučio piktybinis navikas 20-iai (33,9%) ligonių tarpuplaučio navikas pašalintas atlikus sternotomiją (iš jų 12 (60%) ligonių atlikta tuščiosios venos rezekcija, 2 atvejais ji pakeista protezu), 10 (17%) ligonių – atlikus torakotomiją (kartu su pulmonektomija), 29 (49,1%) ligoniams – atlikus išilginę ir skersinę sternotorakotomiją. Rezultatai Atlikus 25 sudėtines operacijas dėl T4 plaučių vėžio pasireiškė pooperacinės komplikacijos: broncho fistulė – 2 (8%) ligoniams, širdies kraujagyslių nepakankamumas – 3 (12%) ligoniams, kraujavimas – 2 (8%) ligoniams. Du (8%) ligoniai mirė po operacijos. Operacijos metu atliekant piktybinio tarpuplaučio naviko pašalinimo operaciją pasireiškė komplikacijos: broncho fistulė – 1 (10%) ligoniui, poopercinis kraujavimas – 2 (3,4%) ligoniams, mediastinitas – 1 (1,7%) ligoniui. Trys (5,1%) ligoniai mirė po operacijos. Dvylikai (48%) ligonių, sergančių plaučių vėžiu, prieš operaciją buvo taikoma chemoterapija ir radioterapija. 34% šių ligonių išgyveno 3 metus. 22 (37,3%) ligoniams, sergantiems piktybiniu tarpuplaučio naviku, buvo taikyta priešoperacinė ir pooperacinė chemoterapija ir radioterapija. Penkerius metus išgyveno 48% ligonių. Išvados Chirurginis vietiškai išplitusio plaučių vėžio (T4) ir piktybinio tarpuplaučio naviko gydymas yra efektyvus ir pailgina ligonių gyvenimo trukmę. Pooperacinių komplikacijų skaičius ligoniams po plaučių vėžio operacijos siekė 28%, pooperacinis mirštamumas – 2%. Po tarpuplaučio piktybinio naviko operacijos komplikacijų skaičius sudarė 6,8%, pooperacinis mirštamumas – 5,1%. Priešoperacinė ir pooperacinė chemoterapija bei radioterapija pailgino ligonių gyvenimo trukmę: 3 metus išgyveno 34% ligonių, sergančių plaučių vėžiu (T4), o 5 metus išgyveno 48% ligonių, sergančių tarpuplaučio piktybiniu naviku. Pagrindiniai žodžiai: vietiškai išplitęs plaučių vėžys (T4), didelių matmenų piktybinis tarpuplaučio navikas, chirurginis ir sudėtinis gydymas, ligonių gyvenimo trukmė Surgery for lung cancer T4 tumours and malignant mediastinal masses Saulius Cicėnas, Arnoldas Krasauskas, Renatas Aškinis, Vladislavas Vencevičius, Valdas PuodžiūnasVilnius University, Institute of Oncology, Department of Thoracic Surgery and Oncology,Santariškių str. 1, LT-08660 Vilnius, LithuaniaE-mail: cicenas@loc.lt Objective To evaluate the results of surgical treatment for lung cancer T4 tumours and malignant mediastinal masses, the rate of complications and median survival. Patients and methods In 2000–2003, 84 patients (pts) with T4 lung cancer and “king” size mediastinal tumours underwent surgery at Department of Thoracic Surgery and Oncology, Institute of Oncology, Vilnius University. Twenty-five (29.7%) pts with T4 tumours were operated on: 23 (27.4%) pts with left atrium resections with no artificial blood circulation, and in 2 (2.3%) pts aortic arch and atrium resection were performed using artificial blood circulation. Fifty-nine (70.2%) pts were operated on due to “king“ size malignant mediastinal masses, their weight ranging within 5–10 kg. The morphology for the pts with lung cancer: 20 (80%) pts – epidermoid cancer, 5 (20%) pts – adenocarcinoma; for the pts with mediastinal masses: 10 (17%) pts LGR, 9 (15.2%) pts – teratoblastoma, 10 (17%) pts – ectopic seminomas and 30 (50.8%) – malignant thymomas. Lung cancer TNM: T4N0M0 – 18 (72%) pts, T4N1M0 – 5 (25%) pts, T4N2M0 – 2 (8%) pts. Other operations: all pts with lung cancer underwent pneumonectomies and for mediastinal masses: 20 (33.9%) pts – sternotomies (12 pts (60%) v. cava resections, 2 pts v. cava replacement), 10 (17%) pts – thoracotomies with pneumonectomy, 29 (49.1%) pts – sternothoracotomies. Results Postoperative complications in the lung cancer group were: bronchial fistula – 2 (8%) pts, heart – lung insufficiency – 3 (12%) pts, bleeding – 2 (8%) pts; two (8%) pts died after operation. In the mediastinal masses group: bronchial fistula – 1 (10%) pt; postoperative bleeding – 2 (3.4%) pts, mediastinitis – 1 (1.7%) pts; three (5.1%) pts died after operation. 12 (48%) pts with lung cancer underwent chemoradiation before operation. Three-year survival of these pts was 34%. For tventy-two (37.3%) pts with mediastinal tumours, chemoradiation was used before and after surgery. The 5-year survival of these pts was 48%. Conclusions Surgery for lung cancer T4 tumours and malignant mediastinal masses is an effective treatment and prolongs the patients’ survival. Postoperative complications in the lung cancer group reached 28% and postoperative mortality 2%. In the mediastinal tumous group, postoperative complications comprised 6.8% and mortality 5.1%. Induction and postoperative chemoradiation prolong the patients’ survival: in the lung cancer group, three-year survival was 34% and in the mediastinal masses group 5-year survival reached 48%. Keywords: locally advanced T4 lung cancer, “king size” mediastinal tumours, surgical and combined treatment, survival

Yang L, Ruan L-M, Ye H-H, Cui H-B, Mu Q-T, Lou Y-R, Ji Y-X, Li W-Z, Sun D-H, Chen X-B. Depression is associated with lower circulating endothelial progenitor cells and increased inflammatory markers.Objective: To test the hypothesis that depression status in subjects without cardiovascular diseases (CVD) or diabetes is associated with depletion of circulating endothelial progenitor cells (EPCs) and impaired endothelial function.Method: Thirty depressive persons with the first episode of depression (case group) diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and 30 healthy people (control group) were investigated. The depression status was estimated using Hamilton Rating Scale of Depression from which the criteria of depression are determined to be >21 score. EPCs labeled with CD34-ECD, CD133-phycoerythrin and kinase insert domain receptor (KDR)-fluorescein isothiocyanate antibodies were counted by flow cytometry in the peripheral blood of patients and control subjects. Mononuclear cells that were positive for CD34/KDR, CD133/KDR and CD34/CD133/KDR within the lymphocyte population were characterised as different phenotypes of EPCs.Results: There were no significant differences in baseline clinical characteristics between patients and healthy individuals (all p > 0.05). However, patients with depression had significantly lower levels of circulating CD34+CD133+KDR+ EPCs (132.20 ± 17.27 vs. 225.93 ± 9.88, p = 0.000) and endothelial colony-forming units (26.40 ± 3.79 vs. 36.60 ± 2.88, p = 0.000) than that of healthy subjects. Furthermore, CD34+CD133+KDR+ EPCs had a negative correlation with tumour necrosis factor-α (Spearman's ρ = 0.433, p = 0.000) and interleukin-6 (Spearman's ρ = 0.441, p = 0.032).Conclusion: Our result shows that depression was associated with lower levels of circulating EPCs, which may contribute to the development of endothelial dysfunction and atherosclerosis.

486 Background: Recent studies have suggested the predictive value of liquid biopsies for immune checkpoint inhibitors. NCT03113266 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-PD-1) in metastatic urothelial carcinoma (mUC). Here we report the initial circulating tumor DNA (ctDNA) analysis of genomic alterations from a single-institution biomarker cohort. Methods: Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled and consented to Institutional Review Board-approved protocols permitting biomaterial collection and genetic sequencing. Serial plasma specimens were obtained at baseline and every two cycles. The 600-gene panel (PredicineATLAS) liquid biopsy assay was applied to assess somatic variants and blood tumor mutational burden (bTMB). Results: The ctDNA assays were performed successfully for 100% of baseline samples (n = 27) with average read depth of 24,389 (range 14,000-31,700). A total of 571 non-synonymous mutations were identified, demonstrating prevalent aberrations in TP53 (63%), TERT promoter (30%), KDM2D (26%), PPM1D (26%), and KDM6A (26%). In 5 patients, FGFR3 variants were detected, including 6 missense sites and 4 FGFR3- TACC3 fusion events. Copy number gain ( FGFR1, ERBB2) and loss ( PTEN, BRCA2, CDKN2A) were pinpointed. TMB estimation revealed one case with an exceptionally high bTMB (62.6 mutations/Mb) and genomic features of microsatellite instability (MSI). Concordance with tumor-based genotyping and ctDNA kinetics during toripalimab treatment are being determined. Conclusions: Prospective ctDNA analysis using the PredicineATLAS liquid biopsy assay is feasible and represents a minimally invasive approach to detecting cancer-specific genetic landscape and potentially guiding personalized therapeutic decisions in mUC patients. Clinical trial information: NCT03113266 . Research Sponsor: Shanghai Junshi BioSciences; Huidu Shanghai Medical Sciences Ltd

Abstract The ability of humans and rodents to mount effective immune responses declines with age. Yet, when old baboons (19-24 years) were immunized with LcrV, a protective antigen from Y. pestis, antibody titers were significantly higher than in immunized young animals (2½ years) [JI 181:109]. It may be that baboons are unusual, aging without losing immune competence or alternatively, that LcrV is enhancing humoral immunity in older animals. To address this, a second NHP species was tested; young (4 years), middle-age (11 years), and older (18-24 years) rhesus macaques were immunized with LcrV. Significant humoral responses were observed in all age groups, so like baboons, there was no loss of immune reactivity with aging. However, the greatly enhanced response in older baboons was not recapitulated in rhesus. To test the possibility that LcrV is unique, young (6 years), middle-age (12-13), and older (21-23) baboons were immunized with a second plague antigen, F1; a more typical response was seen whereby F1 antibody titers elicited in younger baboons were higher than those seen in the older cohorts. T cell proliferative and cytokine responses to these antigens have been assessed and no definitive age-associated changes were noted. On the other hand, circulating Tregs and some serum cytokines were higher in older NHPs. These experiments provide novel insights into aging effects on primate immunity and suggest a unique function for plague LcrV in enhancing responses in old animals.

Abstract [Background] As the development of endocrine resistance and late recurrences are the major clinical concerns in hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC) patients, biomarkers to predict the occurrence of endocrine resistance or disease progression are crucial for improving patient outcomes. Aberrant HGF/c-MET signaling pathway has been reported to play a role in various cellular processes in cancer. Estrogen Receptor 1 (ESR1) mutations, encoding estrogen receptor α, are associated with endocrine resistance in HR+ breast cancer. PIK3CA hotspot mutations that induce hyperactivation of the PI3K are found in 30-40% of HR+ advanced breast cancers. In this context, we evaluated the prognostic values of c-MET-enriched CTC, ESR1 mutations, PIK3CA mutations, and cfDNA concentrations detected in the blood of HR+HER2- MBC patients. [Methods] MBC patients were prospectively enrolled during standard treatments at Samsung Medical Center (IRB No.2019-08-119). Circulating tumor cells (CTCs) were isolated using the GenoCTC® with c-MET-enriched or EpCAM-enriched CTC isolation kits (Genobio Corp., South Korea) from 4mL of blood each. PIK3CA and ESR1 hotspot mutations were analyzed by droplet digital PCR kits (Gencurix Inc., South Korea). cfDNA concentrations were calculated using ESR1 gene copy numbers from plasma. To compare the proportion of c-MET overexpression between primary breast tumors and metastatic sites in HR+HER2- breast cancer patients, primary breast (n=358) and metastatic sites (n=27) were independently collected. c-MET expression was evaluated by an immunohistochemistry assay using an anti-total c-MET (SP44) antibody with a Ventana Discovery XY automated system according to the manufacturer’s instruction. c-MET overexpression was defined if the staining was scored as 2+ or 3+. Progression-free survival (PFS) was defined as the time from blood draw to the first of either disease progression or death during standard therapy. [Results] Out of 93 patients with HR+ MBC, analysis was performed in 63 HR+HER2- MBC patients. Seventeen patients (27%) had one or more EpCAM-enriched CTCs, and fourteen patients (22%) had one or more c-MET-enriched CTCs detected in their blood. The median follow-up time and median time to censoring were 8.4 months and 18.7 months, respectively. According to the Kaplan-Meier survival analysis by log-rank test, c-MET-enriched CTCs, cfDNA concentrations, and ESR1 mutations were significantly associated with PFS (p=0.0026, 0.0064, and 0.011, respectively). However, PIK3CA mutations and EpCAM-enriched CTCs were not statistically significant with PFS (p=0.38 and 0.86, respectively). Multivariate analysis showed that both c-MET-enriched CTCs (HR=3.5, p=0.014) and cfDNA concentrations (HR=2.2, p=0.031) were independent predictors for PFS in HR+HER2- MBC. The proportion of c-MET overexpression was significantly higher in metastatic sites (22.2%) than in primary breast tumors (4.7%) in HR+HER2- breast cancer patients (p=0.00002). As c-MET-enriched CTCs and cfDNA concentrations were independent predictors of disease progression, patients were divided into two groups depending on the result of c-MET-enriched CTCs and cfDNA concentration. When patients with low c-MET-enriched CTC and cfDNA concentrations were classified as a low-risk group and other patients into a high-risk group, the high-risk group had a shorter PFS than the low-risk group (p=0.003). [Conclusion] This study provided c-MET-enriched CTCs and cfDNA concentrations calculated by ESR1 copy numbers in patient blood were significant independent predictors of disease progression in HR+HER2- MBC. The poor prognosis in the c-MET-enriched CTC-high group and the difference in the c-MET overexpression rate between the primary breast and metastatic sites suggested the importance of monitoring c-MET-enriched CTCs in the blood of HR+HER2- MBC patients. Citation Format: Jieun Park, Eun Sol Chang, Ji-Yeon Kim, Chaithanya Chelakkot, Minjung Sung, Ji-Young Song, Kyungsoo Jung, Na Young Kim, Hyegyeong Lee, Mi-Ran Kang, Yeon Hee Park, Young Kee Shin, Yoon-La Choi. The prognostic value of c-MET monitoring by using c-MET-enriched circulating tumor cells in HR-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-06-04.

Abstract Background BRII-196 and BRII-198 are human monoclonal antibodies (mAb) with an extended half-life targeting distinct epitopes of the spike protein on SARS-CoV-2. Mutations in these epitope regions are continuously emerging, potentially conferring resistance to COVID-19 therapeutics in development. Individual phase I studies showed that BRII-196 or BRII-198 alone were safe and well tolerated in healthy subjects. The BRII-196 and BRII-198 cocktail is currently under evaluation in Phase 2/3 studies for the treatment of COVID-19. Methods Preclinical study: BRII-196 and BRII-198 were evaluated in the microneutralization assay using pseudo-viruses encoding mutations identified in the spike protein of a panel of SARS-CoV-2 variants of concerns, including strains originating in UK, SA, BR, CA, and India. The fold-change in neutralization IC50 titers relative to wild-type virus was calculated. Phase 1 study: healthy adults received sequential IV BRII-196 and BRII-198 (n=9) or placebo (n=3); and were followed for 180 days. Two dose levels (750mg/750mg and 1500mg/1500mg) were evaluated for safety, pharmacokinetics and immunogenicity. Interim analysis results are presented. Results Preclinical: BRII-196 and BRII-198 exhibited neutralizing activity against pseudo-virus variants that contained spike mutations of a panel of variants including B.1.1.7 (UK), B.1.351(SA), P.1(BR), B.1.427/429 (CA), B.1.526 (NY), and B.1.617 (IN), comparable to that against wild-type virus. Phase I study: BRII-196 plus BRII-198 was well tolerated with no dose-limiting adverse events (AEs), deaths, serious adverse events, or infusion reactions. The majority of AEs were isolated asymptomatic grade 1-2 laboratory abnormalities. (Table 1). Each mAb displayed pharmacokinetic characteristics expected of extended half-life YTE-antibodies. Conclusion The BRII-196 and BRII-198 cocktail was well-tolerated, and maintains neutralization against currently reported circulating variants of concern. These preclinical and clinical results support further development of BRII-196 and BRII-198 as a therapeutic or prophylactic option for SARS-CoV-2. Disclosures David A. Margolis, MD MPH, Brii Biosciences (Employee) Yao Zhang, MD, Brii Biosciences (Employee) Yun Ji, PhD, Brii Biosciences (Employee, Shareholder)

Abstract Background: HER2+ breast cancer is treated with anti-HER2 IgG monoclonal antibody therapies such as trastuzumab and pertuzumab. These antibodies inhibit HER2-driven intracellular signaling and can also be described as a form of passive immunotherapy, engaging effector immune cells in antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). Tumor-associated autoantibodies (AAbs) to tumor neo-antigens can be generated by the adaptive immune response before, or in response to, therapy. There is growing evidence of a functional role for tumor-associated AAbs in the immune response to tumors, with IgG and IgA AAbs capable of mediating ADCC and ADCP. Using the innovative Nucleic Acid-Programmable Protein Array (NAPPA) platform we examined the levels and targets of circulating AAbs to ~1700 human proteins before, during and after treatment in HER2+ breast cancer treated in the neo-adjuvant setting. . Methods: Pre-treatment, On-treatment (pre- Cycle 2) and Post-treatment (post-Cycle 6) serum samples were obtained from HER2+ breast cancer patients (n=19) treated on the ICORG 10-05 clinical trial. Patients were treated with neo-adjuvant chemotherapy (docetaxel (T)/carboplatin (C)) +/- trastuzumab (H), lapatinib (L) or HL, TCH n=9, TCHL n= 7, TCL n=3. Patients were classified as having a pathological complete response (pCR, n=6), a partial response (PR, n=6) or a non-response (NR, n=7) to treatment. IgG and IgA autoantibody levels were determined using the HD-NAPPA system, focussing on a subset of ~ 1700 human protein targets. A normalised intensity score of &gt 5 was utilised as a cut-off for detection. Results: 92 IgG AAbs and 29 IgA AAbs were detected in all samples, across all timepoints (n=57). When IgG AAbs were divided by patient response, 26 AAbs unique to pCR, 26 AAbs unique to PR and 16 AAbs unique to NR were detected. 5 IgG AAbs (BCL11B, MAP6, PRDM8, SYTL2, TP53BP2) were common to all HER2+ breast cancer patients. When IgA AAbs were divided by patient response, 11 AAbs unique to pCR, 6 AAbs unique to PR and 7 AAbs unique to NR were detected. 2 IgA AAbs (TDP1 and MAP6) were common to all HER2+ breast cancer patients. Treatment-induced AAbs were detected in On-treatment and Post- treatment samples in 16/19 patients examined. Conclusions: Our results suggest HER2+ BC patients have unique circulating AAbs associated with treatment response and AAb levels change in response to treatment. Further investigation of AAb levels as biomarkers of response in HER2+ BC is warranted in a larger cohort of patients. Citation Format: Denis Martin Collins, Ji Qiu, Jaine Blayney, Nuala McCabe, Richard Kennedy, Joshua LaBaer, John Crown. Investigation of autoantibodies (AAbs) in HER2+ breast cancer (BC) patients treated in the neo-adjuvant setting [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-09.

Abstract Background: In recent clinical trials for EGFR-mutant lung cancer acquiring MET amplification as resistance to EGFR inhibitor, two-drug combination treatment showed promising anti-tumor activity. However, these combination treatments also resulted in increased toxicity with intolerability. Thus, this study evaluated the possible role of single MET inhibition in these distinct tumors. Methods: Using gefitinib-resistant MET-amplified lung cancer cells (HCC827GR), we tested the sensitivity to single MET inhibitor with various conditions. Supporting preclinical data with cell lines, the matched case reports and drug-sensitivity tests using patient-derived cells were presented. Furthermore, we chronically treated HCC827GR with single MET inhibitor to establish MET inhibitor-resistant cell line (HCC827GR_PR). And then, we explored putative resistance mechanisms of the HCC827GR_PR cells. Results: The HCC827GR cells were partially inhibited by single MET inhibitor regardless of gefitinib-free duration or drug exposure time. Three patients with stage IV MET-amplified and EGFR-mutant lung cancer resistant to EGFR inhibitor showed initially definite response to single crizotinib treatment but their disease progressed within two or three months. The copy number of MET gene in plasma circulating tumor DNA was decreased significantly during crizotinib treatment and not increased even after progression to crizotinib. In their post-crizotinib tumor, MET amplification was disappeared in fluorescence in situ hybridization test. In vitro drug test using patient-derived cells revealed the sensitivity to EGFR inhibitor was recovered after single crizotinib treatment. We established HCC827GR_PR resistant to single MET inhibitor. In the major clones of HCC827GR_PR cells, EGFR signaling pathway was reactivated and gefitinib successfully suppressed their survival. Furthermore, increased MET gene copy number or bypass activation of FGFR1 were observed as resistance mechanism in the minor clones of HCC827GR_PR cells. Conclusions: Single MET inhibitor could be effective but its efficacy could not durable in patients with MET-amplified and EGFR-mutant lung cancer resistant to EGFR inhibitors because these resistant cells might be subclones. A novel combination strategy is needed to get both long-term efficacy and less toxicity in these lung cancer patients. Citation Format: Youngjoo Lee, Yu-Ra Choi, Eun Hye Kang, Sunshin Kim, SeogYun Park, Ji-Youn Han. The role of transient single MET inhibition in MET-amplified and EGFR-mutant nonsmall cell lung cancer resistant to EGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5235.

2605 Background: AKT plays a key role in the survival, resistance, and overall aggressive pathogenesis of HER2+ malignancies, suggesting that AKTis may be of therapeutic value. MK2206 is a selective allosteric AKTi that has demonstrated synergy in combination with both H and P in preclinical studies. Methods: We conducted a phase 1b study of MK2206 in combination with weekly P 80 mg/m2 and H 2 mg/kg in pts with HER2+ solid tumors. MK2206 was given orally at a starting dose of 135 mg once a week (QW). Dose escalation was performed using a modified Ji method. The maximum tolerated dose (MTD) was defined as the dose level resulting in 3 or fewer dose limiting toxicities (DLTs) in 11 pts, then confirmed in 4 additional pts. Circulating tumor cells and PK samples were collected for all pts. Results: A total of 17 pts were enrolled, and 15 pts were evaluable for toxicity. All pts had HER2+ tumors (11 breast, 3 gastric, 1 esophageal). Based on interim toxicity data from other studies, the dose of MK2206 was not escalated beyond 135 mg QW. All 15 pts were treated at this dose level which was determined to be tolerable. Two DLTs were observed including grade 3 rash and grade 3 neutropenia resulting in a >7 day treatment delay. There were no severe adverse events (AEs) related to study treatment. Other grade 3/4 AEs were neutropenia (6 pts), febrile neutropenia (1 pt), peripheral neuropathy (1 pt), and depression (1 pt). The most common all-grade AEs include rash (13 pts), hyperglycemia (13 pts), neutropenia (13 pts), peripheral neuropathy (10 pts), diarrhea (9 pts), fatigue (9 pts), anorexia (9 pts), stomatitis (7 pts). Of the 14 pts evaluable for response, 9 pts (64%) had tumor response (2 CR, 7 PR), and 4 pts had SD. The median duration of response was 5.5 months. Pts were heavily pretreated (median lines of prior therapy 3, 11 prior taxane, 12 prior H). Conclusions: MK2206 at a dose of135 mg QW in combination with weekly P and H is safe and well-tolerated. 135 mg QW is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in pts with HER2+ tumors despite extensive prior therapy. MK2206 is now being tested in the neoadjuvant ISPY2 trial. Clinical trial information: NCT01235897.

9553 Background: Resistance to BRAF+MEK inhibitors(i) in BRAF-mutant melanoma is common. Multiple resistance mechanisms involve HSP90 clients, and a phase 1 study of VEM with XL888 showed PFS rates similar to the combination of BRAF+MEKi (Eroglu, CCR, 2018). Methods: Combination of VEM (960 mg PO BID) and COB (60 mg QD for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60 or 90 mg PO twice weekly) was investigated in a phase 1 study of advanced melanoma, with a modified Ji dose escalation design. Dose-limiting toxicity (DLT) was defined as related grade ≥3 adverse event or inability to deliver 75% of XL888 in first 4 weeks. Results: 25 pts (9 female, median age 62, 15 with M1C disease, 6 with prior anti-PD-1 therapy) were enrolled. After 2 DLTs (rash and acute kidney injury) in first cohort, a lower dose of VEM 720 mg BID and COB 40 mg, with the same XL888 cohorts was investigated. 3 DLTs (rash) in 12 pts were observed in the XL888 60 mg cohort, which was determined as the maximum tolerated dose. Most common grade 3 toxicities included diarrhea (8), hypertension (6), rash (5), alkaline phosphate/GGT elevation (4). 11 patients required dose reductions of VEM and/or COB. Objective responses (PR/CR) were observed in 18 of 25 pts (72%; 95% CI: 51-88%). Median PFS was 8.1 months (4.7 – NA); median overall survival was not reached, with 1-year OS of 71% (45-86%). Single cell RNA-Seq (10X genomics) was performed on baseline and on-treatment tumor biopsies; 8 days of treatment was associated with an increase in immune cell influx (CD4+ and CD8+) and a decrease in number of melanoma cells. At day 8, one patient (now without progression for nearly 2 years) had no tumor cells remaining with only immune cells and stromal fibroblasts left. Further analyses will be presented. Serial plasma BRAF circulating tumor (ct)DNA levels were obtained, with decrease in ctDNA levels corresponding with response and 83% of patients with disease progression showing an elevation in ctDNA from baseline. Conclusions: VEM/COB plus XL888 had significant toxicity, requiring dose-reductions that may have contributed to the low PFS rate despite high response rate. Caution must be used in combination of BRAF+MEKi with other agents. Clinical trial information: NCT02721459.

Abstract Background Previous studies proposed low-pass whole genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis as a versatile tool for genomic profiling and therapeutic monitoring of cancer patients. Here we demonstrate LP-WGS ctDNA genomic profiles and its clinical significance in metastatic breast cancer patients. Patients and methods This prospective exploratory study enrolled 207 treatment-naïve metastatic breast cancer patients from Feb 2017 to September 2020 in Yonsei Cancer Center. The median follow-up duration of patients was 35 months. The baseline (n=207) and post-progression (n=48) plasma samples were prospectively collected on first-line systemic therapy, and LP-WGS was employed for ctDNA somatic copy number alteration (CNA) analysis. The CNA burden of ctDNA was scored by “I-score” method, which was developed to measure genome-wide chromosomal instabilities, to be matched with therapy response. The unsupervised molecular clustering and homologous recombination deficiency (HRD) estimation by shallowHRD algorithm were performed using locus-level CNA profiles with 1 mega base pair resolution. Results The baseline I-score ctDNA CNA burden was highest in triple-negative breast cancer (TNBC) patients among subtypes, and the patients were dichotomized by median I-score level 5.54 (range 2.55 to 12.98). The high baseline ctDNA I-score was independently associated with poor overall survival (hazard ratio [HR] = 3.98, p &lt; 0.001) with adjustment of tumor subtype, visceral metastasis, and disease status (de novo stage IV versus recurrent). The progression-free survival (PFS) on endocrine plus CDK4/6 inhibitors (HR = 2.75, p = 0.005), anti-HER2 therapy (HR = 2.52, p = 0.032), and cytotoxic chemotherapy (HR = 2.33, p = 0.012) was also shorter in high baseline I-score patients than in low I-score patients. The locus-level CNA profile was analyzed in high I-score patients (n=103), and the patients were classified into five molecular clusters with distinct overall survival by unsupervised k-means clustering of CNA profile: basal-like, EGFR-high basal-like, CCND1-high, luminal, and HER2-enriched clusters. Patients with BCL6 (p = 0.009) and PIK3CA amplification (p &lt; 0.001) on baseline ctDNA showed significantly shorter PFS on CDK4/6 inhibitor treatment. The matched baseline and post-progression ctDNA analysis found emergence of FGFR1 amplification and MYC amplification after CDK4/6 inhibitor treatment (n=1, each). The ctDNA shallowHRD score was highest in TNBC patients among subtypes, and TNBC patients with high shallowHRD score (≥10) showed high response rate on (58.3% versus 28.6%) on platinum-based chemotherapy. Conclusion LP WGS-based ctDNA analysis provides a robust tool for non-invasive genomic clustering, therapy response prediction, and HRD estimation in metastatic breast cancer patients. All patients (n=207)Low I-score (n=104)High I-score (n=103)N (%)N (%)N (%)Age, Median (Interquartile range)54 (46-62)53 (47-60)54(44-62)GenderFemale205 (99)102 (98.1)103Male2 (1)2 (1.9)0SubtypeHR+ HER2-106 (51.2)61 (58.7)45 (43.7)HR- HER2+33 (15.9)14 (13.5)19 (18.4)HR+ HER2+22 (10.6)11 (10.6)11 (10.7)HR- HER2- (TNBC)46 (22.2)18 (17.3)28 (27.2)Disease statusDe novo stage IV74 (35.7)31 (29.8)43 (41.7)Recurrent133 (64.3)73 (70.2)60 (58.3)Primary therapyEndocrine + CDK 4/6 inhibitor97 (46.9)55 (52.9)42 (40.8)Anti-HER2 based therapy54 (26.1)24 (23.1)30 (29.1)Chemotherapy45 (21.7)16 (15.4)29 (28.2)Others11 (5.3)9 (8.7)2 (1.9)Visceral metastasisYes142 (68.6)60 (57.7)82 (79.6)No65 (31.4)44 (42.3)21 (20.4)Metastasis SitesLung89 (43)43 (41.3)46 (44.7)Brain19 (9.2)4 (3.8)15 (14.6)Liver59 (28.5)13 (12.5)46 (44.7)Bone120 (58)47 (45.2)73 (70.9)Lymph node90 (43.7)32 (30.8)58 (56.9)Pleura33 (15.9)17 (16.3)16 (15.5) Citation Format: Joohyuk Sohn, Min Hwan Kim, Jin Mo Ahn, Won-Ji Ryu, Seul-Gi Kim, Jee Hung Kim, Tae Yeong Kim, Hyun Ju Han, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Eun Hae Cho, Gun Min Kim. Whole genome sequencing-based circulating tumor DNA profiling of metastatic breast cancer patients for molecular characterization and therapy response prediction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-07.

Background:Patients with systemic lupus erythematosus (SLE) suffer from severe morbidity and mortality1-4, either from the disease itself or from side effects of immunosuppression5. Discovery of novel effective therapies with less toxicity is an urgent need.Objectives:The aim of this study is to elucidate the therapeutic potential and working mechanism of cytokine CXCL5 in lupus mice.Methods:Treatment with CXCL5, bone marrow (BM)-MSCs, standard of care (SOC) with combination of methylprednisolone and cyclophosphamide was given to 16-week-old Faslprmice. Mice were monitored for 10 weeks. Splenic immune cell subsets were measured by flow cytometry. Circulating cytokine and immunoglobulin were detected by Luminex technology. Renal function was evaluated by urinary spot albumin creatinine ratio. In situ renal immune cell infiltration and complement 3 deposition were detected by Haematoxylin and Eosin (H&E) staining and immunohistochemistry.Results:CXCL5 demonstrated consistent and potent immunosuppressive capacity in suppressing SLE with reduced autoantibody secretion, lymphoproliferation and preserved kidney function. With further exploration, we proved that CXCL5 reduced the proliferation of helper T cells (TH1 and TH2) in thein vitrofunctional assay. When we administrated CXCL5 to lupus mice, it promoted the proliferation of regulatory T cells and reduced the proliferation of TH17 cells, macrophages and neutrophils. Multiple proinflammatory cytokines including IL-2, IL-6, IL-12, IL-17A, KC/CXCL1, MIP-1β/CCL4 and TNF-α were also reduced. When combined with SOC, CXCL5 boosted its therapeutic effect and reduced the relevant indices of disease activity. When we correlated the effect of four different treatment groups (CXCL5, BM-MSCs, SOC, and CXCL5 plus SOC) on mice survival and target cell changes, we found that TH17 cells were the key effector cells involved in the pathogenesis of SLE.Conclusion:These findings demonstrated that CXCL5 dampens inflammation in the pre-clinical model of systemic lupus erythematosus via the orchestral effect of regulating neutrophil trafficking and suppressing helper T cell-mediated immune response. Administrating exogenous CXCL5 might be an attractive option to treat patients with lupus.References:[1]Ji S, Guo Q, Han Y, Tan G, Luo Y, Zeng F. Mesenchymal stem cell transplantation inhibits abnormal activation of Akt/GSK3beta signaling pathway in T cells from systemic lupus erythematosus mice.Cell Physiol Biochem.2012;29(5-6):705-712.[2]Peng SL. Altered T and B lymphocyte signaling pathways in lupus.Autoimmun Rev.2009;8(3):179-183.[3]Ferucci ED, Johnston JM, Gaddy JR, et al. Prevalence and incidence of systemic lupus erythematosus in a population-based registry of American Indian and Alaska Native people, 2007-2009.Arthritis Rheumatol.2014;66(9):2494-2502.[4]Jakes RW, Bae SC, Louthrenoo W, Mok CC, Navarra SV, Kwon N. Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality.Arthritis Care Res (Hoboken).2012;64(2):159-168.[5]Sattwika PD, Mustafa R, Paramaiswari A, Herningtyas EH. Stem cells for lupus nephritis: a concise review of current knowledge.Lupus.2018;27(12):1881-1897.Acknowledgments:The work was supported by SMART II Centre Grant (NMRC/CG/M011/2017_SGH) and SingHealth Foundation (SHF/FG638P/2016).Disclosure of Interests:None declared

Abstract PURPOSE:Previous studies supported combining PD-1 inhibitors with trastuzumab to treat HER2-positive cancers. Yet proper biomarkers for response/resistance prediction remain unveiled. METHODS: Eligible patients were 18 years of age or older and had histologically confirmed gastric cancer (GC) or gastro-esophageal junction cancer (GEJ). The HER2 status was evaluated with tissue assay, including IHC and FISH. Paired plasma-white blood cell samples were collected prior treatment and assessed with targeted next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Different therapeutic regimens and ctDNA biomarkers were explored in HER2-positive patients, who received combining therapeutics containing trastuzumab and anti-PD-1 agents. The HER2-positive status was defined as IHC 3+ or IHC 2+/FISH-positive. RESULTS: A total of 49 patients were included. Four patients were excluded due to fail in the quality control for NGS. The HER2 status of tumor tissue and matched plasma ctDNA at baseline display a high concordance of 84.4% (38/45). NGS ctDNA method demonstrated an 84.2% (33/40) sensitivity and a 100% (5/5) specificity to detect HER2 amplification. Among HER2-positive patients, nineteen and eighteen patients were administrated trastuzumab+anti-PD-1±anti-vascular (chemo-free) and trastuzumab+anti-PD-1+chemotherapy (chemo-containing) respectively. Compared to Chemo-free subgroup, the chemo-containing subgroup had numerically higher ORR (61.11% vs 31.58%, p = 0.10) and longer median PFS (8.98 vs 5.43 months, p = 0.54, HR 0.78, 95%CI: 0.35-1.73). Patients with HER2 amplification in ctDNA had higher ORR than those without amplification (56.67% vs 0%, p = 0.009). Besides, an immune-related negative gene set (PTEN mutations, MDM2 amplification and FGF3/4/19 amplification) was also explored. The patients carrying immune-related negative gene alterations achieved decreased ORR (0% vs 54.8%, p = 0.02) and shorter PFS (2.1 vs 6.9 months, p&lt;0.0001, HR 8.21, 95%CI: 2.76-24.48), compared to that of wild type. CONCLUSIONS: The ctDNA display a high consistency with tumor tissue for HER2 status. Compared to chemo-free regimens, chemo-containing regimens trend to demonstrate improved PFS and ORR in HER2-postive GC/GEJ, though no statistically significant. The HER2 amplification and immune-related negative gene alterations in ctDNA might be used as alternative biomarkers for predicting the efficacy of combining therapeutics containing trastuzumab and anti-PD-1 agents. Further studies are warranted to confirm our observation for better management of HER2-positive GC/GEJ. Citation Format: Xiaoyi Chong, Zhengqing Yan, Hua Liu, Lin Cong, Fangli Jiang, Chenhui Xu, Yan Li, Hui Chen, Yanyan Li, Congcong Ji, Shiqing Chen, Xiaochen Zhao, Xiaotian Zhang. Clinical implication of plasma ctDNA features in HER2-positive gastric cancer treated with combinations of trastuzumab & anti-PD-1 agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5129.

Abstract Introduction: Genomic scale copy number, methylation, and fragmentation aberrations are proven genetic and epigenetic biomarkers of circulating tumor DNA (ctDNA). We developed a novel cell-free DNA (cfDNA) methylome sequencing assay that allows for integrative analysis of these genomic features for sensitive detection of multiple types of cancer. Methods: Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA. Low-pass (~2X) paired-end NGS sequencing was performed on WMS libraries and paired whole genome sequencing (WGS) libraries of unconverted cfDNA for technical comparison and analytical validation. For development of cancer detection models, we profiled the genome-wide methylation density (MD), fragment size index (FSI), fragment end motif (motif) and chromosome instability (CIN) based on WMS data from a discovery cohort of 352 healthy controls and 559 newly diagnosed cancer patients (45 breast, 105 colorectal, 44 esophageal, 79 gastric, 79 liver, 110 lung, 83 pancreatic, and 14 others), 34.5% of which were at stage I or II. Machine learning models, including KNN, SVM, LR, GBDT, and random forest were trained and tested for individual biomarker types, with a final ensemble classifier to integrate all biomarkers. Performance of the predictive model was confirmed on an independent validation cohort consisting of 145 healthy controls and 236 cancer patients (21 breast, 45 colorectal, 18 esophageal, 35 gastric, 34 liver, 47 lung, and 36 pancreatic), among which 31.8% were at early stages (I or II). Results: WMS and WGS data from 512 cfDNA samples showed high concordance in CIN (R=0.988, 95% CI: 0.986-0.990) and FSI (R=0.961, 0.954-0.967) profiles. On the independent validation cohort, the optimal model selected for each of individual genomic features achieved following area under the ROC curve (AUC) values for cancer detection: MD-KNN, 0.830 (0.789-0.870); FSI-SVM, 0.904 (0.874-0.933); motif-SVM, 0.943 (0.920-0.966); and CIN-PAscore, 0.812 (0.770-0.854). The ensemble classifier based on linear SVM outperformed individual biomarkers, with an AUC value of 0.952 (0.934-0.971), which translated to, at 95% specificity, detection sensitivity of 66.7% for breast, 77.8% for colorectal, 83.3% for esophageal, 62.9% for gastric, 82.4% for liver, 66.0% for lung, and 77.8% for pancreatic cancers. Noteworthily, the overall sensitivity on early-stage cancer was 74.7%. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers on the same WMS technical platform. Low-pass WMS on plasma cfDNA from 10ml of blood with integrative multimodal analysis of methylation, fragmentation, and CNV profiles yields in satisfactory sensitivity and specificity for detection of multiple types of cancer, warranting a forthcoming prospective study to further assess its clinical performance in a larger cohort. Citation Format: Yulong Li, Fenglong Bie, Fengwei Tan, Tiancheng Han, Shunli Yang, Fang Lv, Peiyao Nie, Qi Zhang, Yuanyuan Hong, Zhijie Wang, Ji He, Weizhi Chen, Liang Zhao, Shugeng Gao. Multimodal analysis of plasma cell-free DNA methylome for sensitive multi-cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5150.

Abstract Introduction: Regorafenib is a multikinase inhibitor which showed clinical benefit in patients with treatment refractory metastatic colorectal cancer. However, as only a subset of patients derives clinical benefit from regorafenib, it is essential to identify biomarker to predict therapeutic response. Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in patients with metastatic colorectal cancer treated with regorafenib. Methods: This is a prospective biomarker study including patients with refractory metastatic colorectal cancer treated with regorafenib (ClinicalTrial.gov Identifier: NCT01996969). Patients with metastatic colorectal cancer who were refractory to standard therapies (fluoropyrimidine, oxaliplatin, and irinotecan) were eligible for the current study. Patients received oral regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle and were treated until disease progression, death, unacceptable toxicity, or decision by the treating physicians. Blood samples were obtained prior to regorafenib treatment and after every two cycles of regorafenib treatment until disease progression. ctDNA was detected by AlphaLiquid® 100 target capture panel (IMBdx, Inc., Seoul, South Korea). Alphaliquid® 100 is a tumor agnostic panel consist of 106 genes, including 10 gene fusion and MSI. Variant allele frequency (VAF) amount was calculated by adding the VAF value of all altered genes. Results: A total of 110 patients were included in the present study. Baseline blood samples were successfully acquired in 107 patients (97.3%) with a total of 713 genetic alteration. Mutation was most frequently found in TP53 (76.6%) followed by APC (75.7%), KRAS (43.0%), PIK3CA (17.8%), and SMAD4 (17.8%). BRAF mutation was found in 8.4% of patients and NRAS was detected in 3.7% of patients. Blood samples after two cycle of regorafenib was acquired in 106 patients, and was acquired in 95 patients after disease progression. Among 104 patients with baseline and follow-up cfDNA, the mean VAF at baseline was 12.8% and 7.2% in follow-up. This resulted in a mean VAF change of -5.61% (absolute value) and -43.7% (relative change). VAF decreased markedly after 2 cycles of regorafenib in several genes, including CSF1R, JAK3, KIT, ROS1, and TERT. Although, VAF change of specific gene was not associated with regorafenib outcome, VAF change of whole gene was an early predictive marker for regorafenib. Reduction in VAF amount of ≥ 50% after two cycles of regorafenib were associated with a significantly improved PFS (6.1 vs. 2.7 months, p = 0.002), OS (11.3 vs. 5.9 months, p = 0.001), and higher disease control rate (86.3% vs. 51.1%, p &lt; 0.001). Conclusions: Serial ctDNA could be used as an early predictive biomarker in metastatic colorectal cancer treated with regorafenib. Citation Format: Dae-Won Lee, Sae-Won Han, Yoojoo Lim, Hwang-Phill Kim, Hanseong Roh, Min Jung Kim, Seung-Bum Ryoo, Ji Won Park, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae-You Kim. ctDNA change predicts treatment outcome of regorafenib in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5157.

Abstract Background: AAC-HPV consists of autologous RBCs engineered using Cell Squeeze® technology to deliver synthetic long peptides (SLP) of HPV16 E6, E7 and the adjuvant, poly I:C. After intravenous (IV) administration, the AACs are designed to be phagocytosed by endogenous antigen presenting cells (APCs) and the E6 and E7 antigens presented on the APC’s major histocompatibility complexes (MHCs). The concurrent delivery of antigen and adjuvant to the APCs is designed to elicit a potent antitumor T cell response to drive HPV16+ tumor killing. Preclinical experiments demonstrated that post IV administration of mouse AAC-HPV in a HPV16 E7-expressing TC-1 mouse model, E7 specific CD8+ T cells are recruited to the tumor, inhibiting tumor growth, prolonging survival, and forming immunological memory. Murine AAC-HPV treatment was also shown to be synergistic with cisplatin combinations. In vitro studies with human volunteer derived SQZ-AAC-HPV demonstrated to be endocytosed by dendritic cells and drive IFN-gamma production by T cell clones specific to human E7. The Phase 1/2 study’s biomarker program investigates whether pharmacodynamic effects observed in nonclinical studies correlate with potential clinical benefit. Immunogenic and pharmacodynamic endpoints include quantification and characterization of TILs and tumor microenvironment, changes in numbers and functions of circulating blood cells. In addition, cytokine responses and cell-free HPV16 DNA will be measured. Methods: ENVOY-001 (NCT04892043) is open for enrollment to HLA A*02+ patients with HPV16+ recurrent, locally advanced, or metastatic solid tumors and includes escalation cohorts for monotherapy and in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitors. The study is divided in two parts, the first will assess the safety in monotherapy dose-escalation following a Bayesian Optimal Interval approach. The second part of the study will assess the safety of SQZ-AAC-HPV when combined with nivolumab 360 mg q3w and/or ipilimumab 3 mg/kg q3w x4 or 1 mg/kg q6w when combined with nivolumab. The cycle length is 3 weeks, and patients will receive SQZ-AAC-HPV for up to 1 year or until available autologous drug product is exhausted. Eligible patients including but not limited to anal, cervical and head and neck tumors will undergo a 200 mL whole blood collection at the study site. The manufacturing process takes less than 24 hours to produce multiple cryopreserve patient doses and this therapy does not necessitate pre-conditioning. The vein-to-vein time for the 1st administration is approximately one week. Patients must have a lesion that can be biopsied with acceptable clinical risk and agree to have a fresh biopsy at Screening and on study. A Data Monitoring Committee is in place. No formal statistical hypothesis testing will be performed. Results: N/A Conclusions: N/A Citation Format: Victoria Villaflor, Rajwanth Veluswamy, Elena Garralda, Richard Maziarz, Emese Zsiros, Anthony Shields, Mariano Ponz-Sarvise, Martijn Lolkema, Mehdi Brahmi, Julia Jennings, Nathan Miselis, Lindsay Moore, Katarina Blagovic, Rui-Ru Ji, Scott Loughhead, Ricardo Zwirtes, Sandip Patel. ENVOY-001: A phase 1, multicenter, open-label study of SQZ-AAC-HPV as monotherapy and in combination with immune checkpoint inhibitors in HLA-A*02+ patients with HPV16+ recurrent, locally advanced, or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT241.

Audrius Andrijauskas1, Juozas Ivaškevičius1, Manvilius Kocius2, Narūnas Porvaneckas2, Darius Činčikas1, Jeugenija Olševska11 Vilniaus universiteto Anesteziologijos ir reanimatologijos klinika,Šiltnamių g. 29 LT-04130 Vilnius2 Vilniaus universiteto Reumatologijos, ortopedijos, traumatologijos,plastinės ir rekonstrukcinės chirurgijos klinika, Šiltnamių g. 29 LT-04130 VilniusEl paštas: Audrius.Andrijauskas@mf.vu.lt Kontroliuojama hipotenzinė anestezija jau ilgą laiką taikoma siekiant sumažinti kraujo netektį ir kraujo perpylimo poreikį. Be to, sumažinus arterinį kraujo spaudimą, pagerėja operavimo sąlygos („sausas operacinis laukas“). Atsiranda galimybė sumažinti išorinį mechaninį spaudimą, taikomą operuojamos galūnės kraujotakai sustabdyti atliekant kelio sąnario endoprotezavimą, arba net visai jo netaikyti. Šiuolaikiniai metodai grindžiami įvairiais valdomą hipotenziją sukeliančiais veiksniais, kaip pavyzdžiui, tai gali būti (a) kraujagysles plečiantys vaistai, (b) centrinė simpatinė blokada ir (c) stiprų kardiodepresinį-vazopleginį poveikį turintys inhaliaciniai anestetikai. Taikant hipotenzinę anesteziją, didžiausią rūpestį kelia paciento saugumo užtikrinimas. Ypatingą pavojų kelia „nebyli“ organų išemija dėl nepakankamo jų aprūpinimo krauju, nes ji gali sutrikdyti audinių ir organų funkciją ar net sukelti žūtį. Taigi, užtikrinant metodo saugumą lemiama reikšmė tenka efektyvaus cirkuliuojančio tūrio (normovolemijos) palaikymui arterinės hipotenzijos sąlygomis. Deja, iki šiol nėra paprasto, patikimo ir veiksmingo metodo, kuris leistų užtikrinti šią ypač svarbią paciento saugumo sąlygą. Tradicinius kraujotakos optimizavimo metodus šiuo metu keičia skysčių terapijos metodai, grindžiami į tikslą nukreiptų priemonių taikymo koncepcija. Remdamiesi šia koncepcija autoriai sukūrė klinikinį TNP algoritmą, kuris skirtas normovolemijai užtikrinti, atliekant kelio ir klubo sanario planinį endoprotezavimą hipotenzinės anestezijos sąlygomis. Algoritmas pateikiamas kartu su svarbiausių hemodinamikos parametrų taikymo ir klinikinio interpretavimo ypatumų apžvalga. Reikšminiai žodžiai: hemodinamika, į tikslą nukreipta skysčių terapija, skysčiai, transfuzija, algoritmas Hypotensive anaesthesia in total hip and knee arthroplasty: algorithm for the goal-directed fluid management Audrius Andrijauskas1, Juozas Ivaškevičius1, Manvilius Kocius2, Narūnas Porvaneckas2, Darius Činčikas1, Jeugenija Olševska11 Vilnius University Clinic of Anaesthesiology and Intensive Care,Šiltnamių str. 29 LT-04130 Vilnius, Lithuania2 Vilnius University Clinic of Rheumatology, Orthopaedics, Traumatology, Plastic and Reconstructive Surgery, Šiltnamių str. 29, LT-04130 Vilnius, LithuaniaE-mail: Audrius.Andrijauskas@mf.vu.lt Hypotensive anaesthesia is a technique that deploys the controlled reduction of mean arterial pressure. It has been used for decades to reduce intraoperative blood loss and related blood transfusions, also to ensure the ‘dry operating field’ and minimize the tourniquet inflation pressure in patients undergoing total hip (THA) and knee (TKA) arthroplasty. Hypotensive anesthesia can be achieved in different ways such as (a) by decreasing cardiac output with vasodilatory agents, (b) inducing the sympathetic block by spinal and/or epidural anaesthesia, and/or (c) by using potent anesthetic gases in general anaesthesia. The major concern in the method’s clinical applicability is the patient’s safety. Inherent risks related to hypotensive anaesthesia are mainly associated with the concern of occult tissue hypoperfusion resulting from inadequately compensated relative hypovolemia. Therefore, maintaining an effective circulating volume (normovolemia) is crucial for the safe management of controlled arterial hypotension. However, the lack of a simple, reliable and effective method for the guidance of appropriate measures is an ongoing deficiency. Conventional strategies aiming to establish, monitor and maintain normovolemia are currently replaced by the goal-directed management (GDM) in fluid therapy. It has already become a standard of care in selected patients such as those undergoing major abdominal surgery. On the basis of goal-directed fluid management, authors have developed a GDM algorithm for the optimization of fluid status, aiming to secure normovolemia during hypotensive anaesthesia. The new algorithm is highlighted along with a review of related issues of its clinical application. Key words: hemodynamics, goal-directed-management, fluid, transfusion, algorithm

Background:Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that is potentially fatal. There is an unmet need to improve current therapies. In patients with SLE, we observed that serum CXCL5 levels were significantly lower than healthy control subjects and negatively correlated with disease activity(1-9).Objectives:The aim of this study is to elucidate the effect of supplemental serum CXCL5 in abrogating the pathological processes of SLE.Methods:Ten doses of exogenous CXCL5 (3µg/kg) was administered to 16-week-old Faslpr mice weekly by intravenous injection. Mice were monitored for 10 weeks. Splenic immune profile was measured by flow cytometry. Circulating cytokine and immunoglobulin profile were detected by Luminex technology. Renal function was evaluated by urinary spot albumin creatinine ratio. In situ renal immune cell infiltration and complement 3 deposition were detected by Haematoxylin and Eosin (H&E) and immunohistochemistry staining. The molecular pathways involved were examined by RNA sequencing.Results:In Faslpr mice, intravenous administration of exogenous CXCL5 significantly improved mouse survival with concomitant reduction of autoantibody secretion, proteinuria, complement 3 deposition, neutrophil infiltration and lupus nephritis classes. Through evaluating the changes of immune profile, cytokine profile and molecular pathways, we found that intravenous CXCL5 reduced inflammation via an orchestral effect of regulating neutrophil trafficking and modulating helper T cell-mediated immune response. Pharmacokinetic and real-time Polymerase Chain Reaction studies further demonstrated that this orchestration was triggered by a cascade reaction - restoring vascular under-expressed CXCL5 by an exogenous stimulation, re-establishing the normal serum levels of endogenous CXCL5 and reverting the CXCL5 chemokine gradient between inflamed tissues and blood circulation.Conclusion:Managing the dysregulation of CXCL5 by exogenous supplement may provide a new option for SLE therapy.References:[1]Dufies M, Grytsai O, Ronco C, et al. New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments. Theranostics. 2019;9(18):5332-5346. doi:10.7150/thno.34681[2]Yildirim K, Colak E, Aktimur R, et al. Clinical Value of CXCL5 for Determining of Colorectal Cancer. Asian Pac J Cancer Prev. Sep 26 2018;19(9):2481-2484. doi:10.22034/apjcp.2018.19.9.2481[3]Wu K, Yu S, Liu Q, Bai X, Zheng X. The clinical significance of CXCL5 in non-small cell lung cancer. Onco Targets Ther. 2017;10:5561-5573. doi:10.2147/ott.s148772[4]Zhao J, Ou B, Han D, et al. Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3beta/beta-catenin pathways. Mol Cancer. Mar 29 2017;16(1):70. doi:10.1186/s12943-017-0629-4[5]Han KQ, Han H, He XQ, et al. Chemokine CXCL1 may serve as a potential molecular target for hepatocellular carcinoma. Cancer Med. Oct 2016;5(10):2861-2871. doi:10.1002/cam4.843[6]Pappa CA, Tsirakis G, Kanellou P, et al. Monitoring serum levels ELR+ CXC chemokines and the relationship between microvessel density and angiogenic growth factors in multiple myeloma. Cytokine. Dec 2011;56(3):616-20. doi:10.1016/j.cyto.2011.08.034[7]Zhang L, Li H, Ge C, et al. CXCL3 contributes to CD133(+) CSCs maintenance and forms a positive feedback regulation loop with CD133 in HCC via Erk1/2 phosphorylation. Sci Rep. Jun 3 2016;6:27426. doi:10.1038/srep27426[8]Matsubara J, Honda K, Ono M, et al. Reduced plasma level of CXC chemokine ligand 7 in patients with pancreatic cancer. Cancer Epidemiol Biomarkers Prev. Jan 2011;20(1):160-71. doi:10.1158/1055- 9965.epi-10-0397[9]Ma Y, Ren Y, Dai ZJ, Wu CJ, Ji YH, Xu J. IL-6, IL-8 and TNF-alpha levels correlate with disease stage in breast cancer patients. Adv Clin Exp Med. May-Jun 2017;26(3):421-426. doi:10.17219/acem/62120Disclosure of Interests:None declared

BackgroundNK cells expanded on membrane-bound (mb) IL-15 and 41BBL expressing K562 stimulatory cells (NKSTIM) for clinical use can be genetically modified to express activating chimeric receptors.1 2 3 NK cells activated in the presence of IL-12, IL-15 and IL-18 develop cytokine induced memory-like (CIML) phenotype and function; these cells have shown clinical promise.4 Additionally, HSCT AML transplants using NK KIR Haplotype Group B donors with better and best Group B profiles (≥2 activating genes) show better survival.5 6 Here we investigate whether KIR profiles impact healthy allogeneic donor NK cell function and phenotype when these cells are expanded on NKSTIM in the presence of IL-12 and IL-18 (12–18).MethodsHealthy donor PBMC NK were genotyped for HLA and KIR and expanded on K562-mbIL15-41BBL stimulatory cells with IL-2 alone or with IL-2 plus IL-12 and IL-18 (12–18). Expanded NK were transduced with CAR constructs including CD19, and then evaluated for NK cell expansion, cytokine secretion, RNA profiles, cytotoxicity against tumor lines, and cell surface phenotypes. Expanded CD19 NK donors with varying numbers of activating KIR vs inhibitory KIR were tested for effector function, and these donors were then tested for in vivo efficacy and pharmacokinetics. A KIR ranking score was developed by considering both the number of activating and inhibitory KIR genes expressed by each donor. This score was correlated with functional properties of CAR NK cells.ResultsAddition of 12–18 to the K562-mbIL15-41BBL stimulatory cells improves CD19-CAR NK potency 2-fold relative to the stimulatory cell line alone (P=.02) while NK cell expansion is unchanged. 12–18 also drove an increase in effector cytokine accumulation on exposure of CAR-NK to CD19 tumor. CIML CAR NK cells from donors with higher KIR scoring also had higher cytotoxicity (Pearson’s R=0.74, P=0.006); this correlation was not observed following expansion in the absence of 12–18. 12–18 also drove more potent in vivo activity against tumor with an increased presence of circulating NK cells over 4 weeks in the mice.ConclusionsCIML CAR NK cells derived from donors with favorable KIR scoring have greater cytotoxic activity, effector cytokine production, and in vivo pharmacokinetics and efficacy. These findings may provide an important criterion for donor selection in the development of more robust and potent engineered NK cells for clinical use.ReferencesLapteva N, Durett AG, Sun J, Rollins LA, Huye LL, Fang J, Dandekar V, Mei Z, Jackson K, Vera J, Ando J, Ngo MC, Coustan-Smith E, Campana D, Szmania S, Garg T, Moreno-Bost A, Vanrhee F, Gee AP, Rooney CM. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy 2012;14(9):1131–1143.Chihaya I, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 2005;106:376–383.Yang Y, Connolly J, Shimasaki N, Mimura K, Kono K, Campana D. A Chimeric Receptor with NKG2D Specificity Enhances Natural Killer Cell Activation and Killing of Tumor Cells. Cancer Res 2013;73(6):1777–1786.Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, Leong JW, Abdel-Latif S, Schneider SE, Willey S, Neal CC, Yu L, Oh ST, Lee YS, Mulder A, Claas F, Cooper MA, Fehniger TA. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Trans Med 2016;8(357): 357ra123.Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, Marsh SGE, Geraghty D, Spellman S, Haagenson MD, Ladner M, Trachtenberg E, Parham P, and Miller JS. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010;116(14):2414–2419.Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Marsh SGE, Spellman S, Haagenson MD, Saeturn K, Ladner M, Trachtenberg E, Parham P, and Miller JS. Donor Killer Cell Ig-like Receptor B Haplotypes, Recipient HLA-C1, and HLA-C Mismatch Enhance the Clinical Benefit of Unrelated Transplantation for Acute Myelogenous Leukemia. JI, 2014;192(10):4592–600.Ethics ApprovalAnimal studies were conducted with IACUC approval.

Introducción: La enfermedad renal crónica asociada a la obesidad (ERC-AO) es una enfermedad con aumento en la prevalencia en las últimas décadas. Se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica. Propósito de la revisión: El objetivo de la revisión es delinear el papel de los diferentes mecanismos fisiopatológicos para el desarrollo de enfermedad renal funcional o anatómica en pacientes con obesidad. Buscamos reportes actualizados en donde se incluye los resultados de mejor supervivencia para los pacientes con ERC-AO. Recientes hallazgos: Actualmente sabemos la ERC-AO tiene un comportamiento pro inflamatorio crónico. La obesidad y sobrepeso se asocian alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Conclusiones: Clasificamos a la ERC-AO en Tipo 1: Obesidad y alteraciones funcionales potencialmente reversibles. Tipo 2: Obesidad y alteraciones estructurales histopatológicas potencialmente no reversibles (Incluye la Glomerulopatía asociada a obesidad y glomeruloesclerosis focal y segmentaria). Tipo 3: Obesidad en relacionada con enfermedades crónicas (Diabetes, Hipertensión, Hipertensión pulmonar. Insuficiencia Cardíaca). Tipo 4: Obesidad en el paciente con terapia sustitutiva de la función renal. Recibido: Agosto 03, 2022 Aceptado: Septiembre 30, 2022 Publicado: Septiembre 30, 2022 Editor: Dr. Franklin Mora Bravo. Introducción La obesidad es una enfermedad en crecimiento con un aumento en su prevalencia en las últimas décadas, asociándose a un elevada carga asistencial y económica para los sistemas sanitaros derivado de su relación con enfermedades cardiovasculares, endocrinas, psicológicas, renales entre otras [1, 2]. El incremento en las tasas de obesidad en distintos grupos etarios, desde niños hasta adultos jóvenes conlleva a asumir que en el futuro veremos más enfermedad renal relacionada con la obesidad (ERC-AO) en la población general, con implicaciones relevantes para los sistemas de atención [3]. Por ello el conocimiento y comprensión de esta interacción podría tener implicaciones en la prevención y tratamiento de las enfermedades renales. Dentro de la población general la obesidad se asocia a incremento en el riesgo de diversas condiciones patológicas, como la hipertensión arterial crónica (HTA), enfermedad renal crónica (ERC), artrosis, infecciones, síndrome de apnea hipopnea obstructiva del sueño (SAHOS) y diabetes mellitus (DM) entre otras [3]. No obstante, en el escenario de la ERC, la obesidad juega un rol dual y paralelo en el desarrollo de la enfermedad, tradicionalmente se ha denominado “paradoja de la obesidad”, donde por un lado actúa como un factor de riesgo modificable para el desarrollo de la enfermedad renal crónica (ERC) y por otro se ha asocia de manera consistente con mejores resultados de supervivencia en pacientes con enfermedad renal terminal [1]. Por lo anterior, en las próximas páginas describimos aspectos fisiopatológicos que involucran la obesidad en el desarrollo de la ERC. Definición y epidemiología La obesidad es una condición que se caracteriza por la acumulación anormal o excesiva de tejido adiposo con consecuencias patológicas adversas e incremento del riesgo cardiovascular [4]. Utilizando para su definición y diagnostico un indicador simple como es la relación entre el peso y la talla denominado índice de masa corporal (IMC), se calcula dividiendo el peso de una persona en kilos por el cuadrado de su talla en metros (kg/m2). Un IMC entre 18.5 y 25 kg/m2 es considerado por la Organización Mundial de la Salud (OMS) como peso normal, un IMC entre 25 y 30 kg/m2 como sobrepeso y un IMC > 30 kg/m2, como obesidad [5-7]. Además, la obesidad puede ser clasificada en tres niveles de severidad: clase I (IMC 30.0 – 34.9), clase II (IMC 35.0 – 39.9) y clase III (IMC > 40) [8]. Durante las últimas tres décadas, la prevalencia de adultos con sobrepeso y obesidad (IMC ≥ 25 kg/m2) en todo el mundo ha aumentado sustancialmente, convirtiendo a la obesidad en una epidemia y se prevé que su prevalencia crezca un 40% en la próxima década [6]. Actualmente, el problema de obesidad se ha visto en mayor aumento debido al incremento en la afectación en niños, lo que ocasiona una mayor prevalencia de patologías a edad temprana. En 2016, según las estimaciones de la OMS unos 41 millones de niños menores de cinco años tenían sobrepeso o eran obesos [7]. Esto afectando a todos los países, independiente de su nivel de ingresos [7]. La prevalencia del sobrepeso y la obesidad en niños y adolescentes (de 5 a 19 años) ha aumentado de forma espectacular, del 4% en 1975 a más del 18% en 2016. Este aumento ha sido similar en ambos sexos: un 18% de niñas y un 19% de niños con sobrepeso en 2016. Mientras que en 1975 había menos de un 1% de niños y adolescentes de 5 a 19 años con obesidad, en 2016 eran 124 millones (un 6% de las niñas y un 8% de los niños) [7]. La creciente prevalencia de la obesidad tiene implicaciones para las enfermedades cardiovasculares (ECV) y también para la ERC. Un IMC alto es uno de los factores de riesgo más fuertes para la ERC de nueva aparición [6]. Epidemiología de la enfermedad renal crónica asociada a obesidad (ERC-AO) La enfermedad renal crónica (ERC) es una condición de interés en salud pública, asociada a una elevada morbilidad y mortalidad a nivel mundial. Las guías KDIGO (Kidney Disease: Improving Global Outcomes), definen la ERC como la presencia de alteraciones en la estructura o función renal durante al menos tres meses y con implicaciones para la salud [9, 10]. Los principales elementos clasificatorios para definir la presencia de ERC son la tasa de filtración glomerular (TFG) estimada (G1 a G5) utilizando como umbral definitorio una TFG 60 ml/min/1,73m2 y la tasa de excreción de albúmina en orina (A1 a A3) según el cociente albúmina/creatinina en una muestra aislada de orina sea < 30, 30-300 o > 300 mg/g, respectivamente [9, 10]. Si bien inicialmente existía cierta controversia sobre el uso de la TFG para el diagnóstico de la ERC en fases iniciales, trabajos recientes han puesto en evidencia que tanto una TFG< 60 ml/min/1.73 m2 como un cociente albúmina/creatinina (CAC) ≥ 1.1 mg/mmol (10 mg/g) son predictores independientes del riesgo de mortalidad e insuficiencia renal terminal (IRT) en población general [11, 12]. En consecuencia, debido a estas categorías podemos determinar el pronóstico de cada paciente. Los datos globales sugieren que la prevalencia de la ERC se encuentra entre el 10 y el 16 %, pero la información sobre la prevalencia de la población por categoría de TFG y ACR es escasa [13]. La ERC es una afección asociada a una elevada carga de morbilidad, mortalidad y enfermedad cardiovascular (ECV). A medida que disminuye la función renal, surgen trastornos metabólicos y hemodinámicos que aumentan las tasas de hospitalización, ECV y muerte [4]. El conjunto de factores de riesgo conocidos para la progresión de la ERC es relativamente pequeño, y las terapias y estrategias efectivas para retrasar la progresión de la ERC son limitadas [14]. Por lo cual resulta necesario conocer y entender los diferentes factores de riesgo y su impacto en el daño renal, en aras de lograr minimizar la progresión del mismo, sobre todo en aquellos en los cuales se puede realizar intervenciones activas, evaluables, controlables y con seguimiento continuo como es la obesidad. A la fecha existe suficiente evidencia para asociar la obesidad con el desarrollo y progresión de la enfermedad renal crónica. Los datos granulares sobre la prevalencia de la obesidad en personas con ERC son limitados pero consistentes en todo el espectro de la enfermedad renal. En la Encuesta Nacional de Examen de Salud y Nutrición de 2011–2014, el 44.1 % de los pacientes con ERC en los Estados Unidos también tenían obesidad (21.9 % con obesidad de clase 1 y 11.1 % con clase 2 y obesidad clase 3, habiéndose incrementado el porcentaje global un 5% en los últimos 12 años [15]. La glomeruloesclerosis focal y segmentaria (GEFS) es el tipo de glomerulonefritis que se asocia con mayor frecuencia a la obesidad [16]. La enfermedad glomerular habitualmente asociada a la obesidad se denomina glomerulopatía relacionada con la obesidad (GRO). Esta condición suele presentarse con síndrome nefrótico y pérdida progresiva de la función renal. Con la epidemia mundial de obesidad, se produjo un aumento progresivo de la GRO del 0.2% entre 1986 y 1990 al 2% entre 1996 y 2000, y se ha convertido en un tema emergente en el ámbito de la nefrología [15]. Etiología y patogénesis de la ERC-AO La obesidad se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica [12]. Hay dos tipos de tejido adiposo presentes en los humanos: tejido adiposo blanco (WAT) y tejido adiposo marrón (BAT) [17-19]. El depósito de grasa ectópica primariamente ocurre en lugares donde no se almacena fisiológicamente, como el hígado, el páncreas, el corazón y el músculo esquelético; secundariamente hay un cambio en la distribución del tejido adiposo visceral con almacenamiento de tejido adiposo en los espacios intraperitoneal y retroperitoneal; luego se presenta la desregulación inflamatoria y de adipoquinas; y por último la resistencia a la insulina [20]. Tejido adiposo blanco (WAT) El tejido adiposo blanco (WAT) se caracteriza por ser un tejido blanco o amarillo con menor vascularización e inervación que el tejido marrón. Las células grasas tienen un tamaño que oscila entre 20 y 200 µm y contienen una única vacuola lipídica (uniloculares). En dicha vacuola se almacenan lípidos para su uso cuando hay demanda energética. De la totalidad de los lípidos que abarca la vacuola lipídica del adipocito blanco, del 90 al 99% son triacilgliceroles. El tejido adiposo blanco genera una gran cantidad de adipocinas y lipocinas. Las adipocinas son péptidos que actúan como hormonas o mensajeros que regulan el metabolismo. El tejido adiposo blanco se localiza en el tejido omental, mesentérico, retroperitoneal, perirrenal, gonadal y pericárdico [19]. Este tejido al igual que el tejido adiposo de otros sitios, está compuesto por una variedad de células que incluyen macrófagos, neutrófilos, células T CD4 y CD8, células B, neutrófilos, mastocitos, células T reguladoras y células T asesinas naturales (NK) [21, 22]. El tejido adiposo es responsable de la secreción de muchas moléculas de señalización, incluidas adipocinas, hormonas, citocinas y factores de crecimiento, como leptina, adiponectina, resistina, factor de necrosis tumoral-α (TNF-α), interleucina 6 (IL-6), monocito, proteína quimioatrayente-1 (MCP-1), factor de crecimiento transformante-β (TGF-β) y angiotensina II [23]. Tejido adiposo marrón o pardo (BAT) La coloración marrón del tejido adiposo se debe a que está más vascularizado y tiene un alto contenido de mitocondrias, las células grasas que componen el tejido adiposo pardo son multiloculares o tienen varias vacuolas lipídicas. Estas células tienen forma poligonal y miden de 15 a 50 µm. A diferencia del tejido adiposo blanco, el tejido marrón no tiene la función de almacenar energía, sino que la disipa a través de la termogénesis. Para lograr la regulación de la temperatura corporal, el tejido adiposo pardo se localiza en sitios superficiales y profundos [18]. Clasificación de la ERC-AO Se ha establecido que la obesidad es una enfermedad con un comportamiento pro inflamatorio crónico con múltiples comorbilidades asociadas [19]. El tejido adiposo como se describió previamente funciona como un órgano con actividad endocrina y esta infiltrado por diferentes poblaciones celulares que incluyen macrófagos y otras células con actividad inmune como linfocitos T, B y células dendríticas [19]. La mayor parte de la grasa corporal total, se considera como un sistema de órganos endocrinos, la perturbación de este tejido tiene como resultado una respuesta patológica al balance calórico positivo en individuos susceptibles que directa e indirectamente contribuye a la enfermedad cardiovascular y metabólica, se tiene conocimiento de tres principales mecanismos de disfunción del tejido adiposo “adiposopatía” [20]. Estos mecanismos incluyen alteraciones hemodinámicas, metabólicas e inflamatorias, lo que es la base de la clasificación de la ERC-AO propuesta en esta revisión (Tabla 1). ERC-AO tipo 1 La obesidad produce un daño renal de forma directa a través de alteraciones hemodinámicas, inflamatorias, y desregulación de factores de crecimiento y adipocitoquinas, además de aumento de leptina y disminución de adiponectina, aun cuando la función renal y las pruebas convencionales sean normales [16]. La obesidad desencadena una serie de eventos, que incluyen resistencia a la insulina, intolerancia a la glucosa, hiperlipidemia, aterosclerosis e hipertensión, todos los cuales están asociados con un mayor riesgo cardiovascular [4, 16] (Figura 1). La obesidad conduce a un incremento en la reabsorción tubular de sodio, alterando la natriuresis y provocando una expansión de volumen extracelular debido a la activación del sistema nervioso simpático (SNS) y el sistema renina-angiotensina-aldosterona (SRAA)(16). El aumento en la reabsorción tubular de sodio y la consiguiente expansión de volumen extracelular es un evento central en el desarrollo de HTA en la obesidad [4, 16]. Algunos estudios sugieren que se produce un aumento de la reabsorción de sodio en algunos segmentos además del túbulo proximal, posiblemente en el asa de Henle. Además, hay un aumento del flujo sanguíneo renal, la tasa de filtración glomerular (TFG) y la fracción de filtración [16]. La hiperfiltración glomerular, asociada con el aumento de la presión arterial y otras alteraciones metabólicas como la resistencia a la insulina y la DM, finalmente resultan en daño renal y disminución del filtrado glomerular [16]. Por otro lado, la activación del SNS también contribuye a la hipertensión relacionada con la obesidad [4]. Hay evidencia de que la denervación renal reduce la retención de sodio y la hipertensión en la obesidad, lo que sugiere que la activación del SNS inducida por la obesidad aumenta la presión arterial principalmente debido al estímulo de retención de sodio, más que a la vasoconstricción [16]. Los mecanismos que conducen a la activación del SNS en la obesidad aún no se conocen por completo, pero se han propuesto varios factores como desencadenantes de este estímulo, entre ellos la hiperinsulinemia, la hiperleptinemia, el aumento de los niveles de ácidos grasos, los niveles de angiotensina II y las alteraciones del reflejo barorreceptor. El aumento de los niveles de leptina está asociado a la activación del SNS y su efecto sobre el aumento de los niveles de presión arterial incluye también la inhibición de la síntesis de óxido nítrico (potente vasodilatador) [16, 24, 25].También se ha descrito un aumento de la producción de endotelina-1 en sujetos obesos, lo que contribuye aún más a la elevación de los niveles de presión arterial y, en consecuencia, a la disfunción renal. Estudios recientes han demostrado que la endotelina-1 está aumentada en pacientes con hipertensión intradiálisis, lo que sugiere que esta sustancia juega un papel clave en la génesis de la hipertensión en pacientes con ERC y posiblemente esté asociada con la hipertensión en pacientes obesos [16, 25]. Por lo anterior, las alteraciones hemodinámicas en los pacientes con obesidad conllevan a progresión de la ERC e incremento del riesgo cardiovascular derivado del desarrollo de enfermedades adicionales como la HTA, potencialmente estos cambios son reversibles con el control de la obesidad. ERC-AO Tipo 2 Mantener el estado de obesidad más allá de los efectos renales funcionales produce cambios estructurales irreversibles a nivel glomerular [25]. El estudio de pacientes con ERC y obesidad ha permitido identificar la presencia de enfermedad glomerular asociada a la obesidad, denominada glomerulopatía relacionada con la obesidad (GRO). En esta condición la hipertrofia glomerular parece ser la lesión inicial que estimula el borramiento de los podocitos y desencadena la respuesta inflamatoria local [25, 26]. Es relevante mencionar que las señales profibrogénicas inducen la formación de depósitos en la matriz extracelular de las nefronas, que conduce al engrosamiento de la membrana basal glomeruloesclerosis y fibrosis tubulointersticial [26]. Dentro del curso patogénico de la enfermedad la expansión de la superficie glomerular conduce a que los podocitos sean incapaces de cubrirla, esto lleva a disfunción y borramiento de los mismos, generando ruptura de la barrera de filtración glomerular con sobrecarga de las células restantes, lo que finalmente conduce a hiperfiltración y proteinuria [25, 26]. No obstante, no todos los pacientes con obesidad o IMC aumentado desarrollan ERC, lo cual sugiere que el incremento del IMC por sí solo no genera aumento en la incidencia o progresión de la ERC, ameritando alteraciones metabólicas adicionales. En los siguientes apartados se describen algunas de estas vías fisiopatológicas comunes a todos los tipos de ERC-AO. ERC-AO Tipo 3 La obesidad produce daño renal de forma secundaria ya que aumenta el riesgo de diabetes mellitus, hipertensión y daño cardiovascular, estas patologías causan enfermedad renal diabética (ERD), nefroangioesclerosis, y glomerulopatía asociada a hipertensión pulmonar e insuficiencia cardíaca. La mortalidad no solo se ve afectada por la presencia de la obesidad sino por la presencia de diabetes tipo 2, hipertensión arterial, hipertensión pulmonar e insuficiencia cardíaca. Los peores resultados en supervivencia lo padecen los pacientes con falla cardíaca, obesidad e insuficiencia renal. ERC-AO Tipo 4 En pacientes en hemodiálisis los niveles más elevados de adiponectina se asocian paradójicamente con tres veces más riesgo de muerte [24]. La obesidad se asocia a niveles muy bajos adiponectina por lo que la obesidad en el grupo poblacional que se realiza hemodiálisis es un fuerte factor protector con mejores resultados de supervivencia a 3 años comparados con pacientes con índice de masa corporal normal o baja. Mecanismos fisiopatológicos comunes en la ERC-AO Lipotoxicidad derivada del tejido adiposo En pacientes obesos el exceso de energía conduce a un microambiente sometido a estrés crónico, lo cual resulta en hipertrofia del tejido adiposo hasta que los adipocitos alcanzan su límite de crecimiento [25]. En ese momento, el exceso de especies toxicas lipídicas se acumula ectópicamente en diferentes órganos, induciendo un efecto nocivo conocido como lipotoxicidad; especialmente a nivel renal [27]. La lipotoxicidad se asocia a cambios estructurales y funcionales de las células mesangiales, podocitos y células tubulares proximales [28]. En los podocitos, esto interferiría con la vía de la insulina, crítica para la supervivencia y el mantenimiento de la estructura de los podocitos, lo que conduciría a la apoptosis de los podocitos e induciría una respuesta hipertrófica compensatoria en los podocitos restantes [25]. En el riñón, los depósitos de lípidos ectópicos contribuyen tanto a la inflamación local como al estrés oxidativo [27]. En modelos de ERD, la dislipidemia puede favorecer la acumulación de lípidos ectópicos e intermediarios lipídicos, no solo en el riñón sino también en tejidos extrarrenales como hígado, páncreas y corazón [27]. La acumulación de lípidos en el parénquima renal, genera daño en varias poblaciones celulares, incluídos podocitos, células epiteliales tubulares proximales y el tejido tubulointersticial a través de distintos mecanismos descritos en las siguientes apartados, pudiendo general compromiso a largo plazo de la función renal [27]. El tejido adiposo es una fuente importante de producción de diferentes factores proteicos activos, conocidos como adipocitocinas, las cuales participan en diferentes procesos metabólicos. Alteraciones en la secreción y señalización de moléculas derivadas del tejido adiposo durante la obesidad en gran medida puede mediar en la patogenia de los trastornos metabólicos [25]. A continuaciones se describe el rol de las adipocinas en la patogenia de la ERC y obesidad. Adiponectina La adiponectina es una proteína secretada principalmente por los adipocitos WAT, las principales funciones biológicas de la adiponectina incluyen una mayor biosíntesis de ácidos grasos y la inhibición de la gluconeogénesis hepática [17]. Es probablemente la adipocina secretada más abundantemente, forma alrededor del 0.05 % de las proteínas séricas y mide de 3 a 30 mg/ml en humanos, para su activación utiliza dos isoformas del receptor (AdipoR1 y AdipoR2) son receptores de siete transmembranas y tienen una homología del 66.7 % en su estructura [17]. Sin embargo, AdipoR1 y AdipoR2 son estructural y funcionalmente distintos de los receptores acoplados a proteína G porque su terminal N es intracelular, mientras que el terminal C es extracelular [29, 30]. La señalización de adiponectina se basa principalmente en interacciones de tipo receptor-ligando, en las que la adiponectina se une a sus receptores afines e inicia la activación de varias cascadas de señalización intracelular a través de las vías AMPK, mTOR, NF-κB, STAT3 y JNK [17]. La adiponectina inicia la activación de la señalización de AMPK mediada por la proteína adaptadora APPL1, que se une al dominio intracelular de AdipoR. Eso produce la activación de la biosíntesis de moléculas, otras proteínas reguladoras e importantes factores de transcripción. AMPK es un regulador que participa principalmente en la proliferación celular [17]. Hay dos tipos de macrófagos, M1 participan en la estimulación de los factores pro inflamatorios e induce la resistencia a la insulina y M2 bloquean una respuesta inflamatoria y promueve el metabolismo oxidativo; En los macrófagos, la adiponectina promueve la diferenciación celular de monocitos a macrófagos M2 y suprime su diferenciación a macrófagos M1, lo que muestra efectos pro inflamatorios y antiinflamatorios. Además, también activa los factores antiinflamatorios IL-10 pero reduce las citoquinas pro inflamatorias como IFN-γ, IL-6 y TNF-α en los macrófagos humanos [17]. Los pacientes con ERC muestran niveles elevados de proteína C reactiva (PCR), IL-6 y TNF-α y tienen una activación aberrante de receptor tipo toll (TLR)-4 [25]; en un estudio realizado en el año 2005 en 29 pacientes con ERC no diabéticos en etapa 5 y 14 controles sanos, se identificó que los pacientes con ERC tenían una expresión elevada del gen y la proteína TLR4, la estimulación de TLR-4 in vitro indujo la activación de TNF-α y NF-κB en células C2C12. Esto sugiere indirectamente que la activación de TLR-4 podría promover la inflamación muscular de los pacientes con ERC [31]. Los niveles de adiponectina se consideran predictivos de ERC, dado que estos se encuentran aumentados en pacientes con etapa pre diálisis [17, 29, 32]. Adicionalmente, en un estudio prospectivo realizado en el año 2008 en pacientes con ERC primaria no diabética identificó niveles elevados de adiponectina como un predictor novedoso de progresión de la ERC en hombres [33]. En estudios realizados en animales (ratones) muestran que la deficiencia de adiponectina se relaciona con varias alteraciones histológicas, incluida la fusión segmentaria procesos podocitarios, albuminuria y aumento del estrés oxidativo en los riñones [34]. Por otro lado, en pacientes obesos la producción de adiponectina se encuentra disminuida por lo que se cree que puede generar una función protectora sobre el riñón [29]. No obstante, paradójicamente, algunos estudios muestran que los pacientes con ERC y enfermedad renal crónica en diálisis (ERCT) tienen altos niveles de adipocinas, las explicaciones a esta situación son controversiales, se ha planteado podrían corresponder a un mecanismo compensatorio, otras consideraciones sugieren una disminución de la sensibilidad a la adiponectina o una reducción en el aclaramiento de la misma [35]. Leptina En pacientes con ERC independiente de la presencia de obesidad o no, se asocian a niveles elevados de leptina sérica. La leptina es una proteína de 167 aminoácidos, con una masa molecular de aproximadamente 16 kDa que está codificada por el gen LEP [23] secretada principalmente por los adipocitos, es una adipocina pleiotrópica. La leptina circulante llega a los órganos diana, donde se une a receptores específicos (conocidos como ObR, LR o LEPR), se conocen cinco isoformas del receptor de leptina en humanos (ObRa, ObRb, ObRc, ObRd y ObRe), de estas solo la isoforma ObRb (isoforma larga) se considera un receptor completamente activo, ya que es capaz de transducir completamente una señal de activación en la célula. Esta isoforma se encuentra altamente expresada en el sistema nervioso central (SNC), especialmente en el hipotálamo, donde participa en la regulación de la actividad secretora de este órgano. Los efectos de la leptina están mediados por cinco vías principales de señalización. Estas vías incluyen las vías de señalización JAK-STAT, PI3K, MAPK, AMPK y mTOR [23]. Por esta razón la principal función fisiológica de la leptina es transmitir información al hipotálamo sobre la cantidad de energía almacenada, como la masa de tejido adiposo, e influir en el gasto de energía al reducir el apetito. Regula el metabolismo energético, tiene efecto sobre la ingesta de alimentos, procesos de coagulación, angiogénesis, funciones relacionadas con la insulina y la remodelación vascular, además funciona como un pro inflamatorio molecular [36]. La leptina tiene efectos sobre el apetito y se ha demostrado que la hiperleptinemia contribuye a la hipertensión asociada a la obesidad por sobre activación del sistema nervioso simpático [37]. En cuanto al curso de la ERC, la leptina puede modular diferentes vías de señalización en el riñón, debido a que las células endoteliales glomerulares y mesangiales expresan abundantes receptores de leptina [25]. La leptina inducirá un incremento en la expresión de genes profibróticos, como TGF-β1 y citocinas pro inflamatorias [25]. El aumento en la expresión de TGF-β1, también contribuirá al desarrollarlo de la fibrosis renal, al unirse a receptores específicos a nivel renal, estimulara la expresión de factores profibróticos en un ciclo de retroalimentación positiva. Además, TGF-β1 es un potente iniciador de proliferación de células mesangiales renales [25]. Debido a su tamaño relativamente pequeño, la leptina atraviesa libremente el filtro glomerular de los riñones y luego se reabsorbe en la parte proximal de los túbulos contorneados [23]. Por lo que el estado elevado de leptina puede indicar una función renal deficiente [36]. Promueve la inflamación y trastorno de los lípidos, que contribuyen al riesgo de ERC [36]; se considera como “toxina urémica”, estando implicada tanto en la progresión de la enfermedad renal a través de efectos pro-hipertensivos y profibróticos, como en el desarrollo de complicaciones relacionadas con la ERC (inflamación crónica, pérdida de proteínas) [38]. Como se mencionó previamente, la leptina estimula la proliferación de células endoteliales glomerulares renales y aumenta la expresión de TGF-β1, un mediador clave de la hidrogénesis en estas células, el aumento de los niveles de leptina también contribuye al aumento de la expresión de colágeno tipo IV en el riñón, induce la proliferación de células mesangiales glomerulares mediante la activación de la vía PI3K, la hipertrofia de las células mesangiales aumenta la cantidad de proteína filtrada y albúmina que llega a las células del túbulo proximal y, como resultado, activa las vías inflamatorias y la fibrosis [23]. Puede presentarse un aumento en la síntesis del receptor TGFβ-1 secretado por las células endoteliales, este actúa de manera parácrina sobre el mesangio uniéndose a su receptor y activando la síntesis de proteínas de la matriz extracelular (ECM), incluyendo colágeno, fibronectina, tenazina y proteoglicanos; consiguientemente, un aumento en el nivel de TGFβ-1 conduce a la acumulación de MEC y, en consecuencia, a fibrosis glomerular y glomeruloesclerosis. En los podocitos, la leptina contribuye a la disminución de la expresión de las proteínas responsables de la filtración glomerular adecuada, incluidas la podocina, la nefrina, la podoplanina y la podocalixina. En las células del túbulo contorneado proximal (PTC), la leptina reduce la actividad metabólica de las células al activar la vía de señalización de mTOR [23]. Por otro lado, la leptina inhibe el apetito y aumenta el gasto de energía conduciendo a anorexia y desnutrición en pacientes con ERC, particularmente en casos de hemodiálisis de mantenimiento [36]. Por ende, una elevación de la leptina no solo nos indicaría daño renal, sino que además nos indica mayor progresión de complicaciones secundarias [39]. La obesidad aumenta la carga sobre los riñones y es un factor de riesgo de lesión renal, además de contribuir en los trastornos metabólicos asociados. Por lo que, teniendo en cuenta los efectos inhibitorios de la leptina sobre la obesidad, se puede considerar que puede proteger contra la lesión renal [39, 40]. Un estudio experimental publicado en el año 2017 demostró que la leptina disminuyó la ingesta calórica y los niveles de glucosa en ratas diabéticas [41], ese mismo año se publicó un estudio retrospectivo donde demostraron que la metreleptina, una metionil leptina humana recombinante, reduce el peso corporal y la dosis diaria de insulina en la diabetes mellitus tipo 1 [42]. La metreleptina ejerce efectos terapéuticos en la lipodistrofia [43], lo que indica que es probable que la leptina se aplique en los trastornos metabólicos [36]. Otras adipocinas Las principales adipocinas corresponden a la adiponectina y leptina como se ha descrito previamente. Además de estas, se distinguen la actividad de la visfatina y resistina, las cuales muestran propiedades pro-inflamatorias y efectos aterogénicos [25]. La visfatina estimula la expresión de TGF-β1, inhibidor del activador del plasminógeno-1 (PAI-1) y colágeno tipo I, los cuales han demostrado un rol importante como agentes profibróticos. Por otro lado, la resistina estimula la producción de las moléculas de adhesión como la molécula de adhesión intracelular 1 (ICAM-1) y la proteína de adhesión celular vascular 1 (VCAM-1) y promueve la activación del sistema renal simpático. Los niveles de estas adipocinas están marcadamente elevados en la obesidad y ERC correlacionándose con parámetros proinflamatorios y disminución de la tasa de filtración glomerular (TFG) [25, 37]. Durante el curso de la obesidad se presenta una sobre activación del SRAA, el tejido adiposo también estaría involucrado en la producción o estimulación de algunos de los componentes del RAS. Por ello la sobre estimulación del SRAA en obesos, asociado a la glomerulomegalia y desregulación de la reabsorción de sodio/glucosa, generalmente conlleva a hipertensión glomerular e hiperfiltración [25]. Otra adipocina a considerar, es la actividad de la adipocina proinflamatoria lipocalina 2 (LCN2), también denominada lipocalina asociada con la gelatinasa de neutrófilo (NGAL), estudiada como biomarcador funcional tanto para la enfermedad renal aguda como ERC(25). LCN2 es conocido por su papel en la respuesta inmune innata a través de su unión a sideróforos derivados de una infección bacteriana. Sin embargo, LCN2 no es secretada únicamente por neutrófilos sino también por otros tejidos como hígado, pulmones y de interés para este artículo, a nivel renal [25]. Se han informado niveles elevados de LCN2 en suero y orina en la lesión renal, debido a una expresión aumentada de LCN2 en el túbulo distal renal y una reabsorción alterada en el túbulo proximal [44]. El tejido adiposo, también puede producir factores angiogénicos como el factor de crecimiento del endotelio vascular (VEGF). Este elemento podría inducir la formación de novo de capilares glomerulares en gran parte defectuosos dentro del riñón, lo que contribuye a la hipertrofia glomerular característica de GRO [25] (Figura 2). Conclusiones La obesidad y el sobrepeso se asocian a alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Por lo tanto, los efectos renales de la obesidad son estructurales y funcionales. Hay varios mecanismos actualmente descritos que involucran a la obesidad como generador de alteraciones renales. Teniendo en cuenta las bases fisiopatológicas, proponemos una clasificación de la ERC-AO basadas en 4 tipos. Abreviaturas ERC: enfermedad renal crónica. ERC-AO: enfermedad renal crónica-asociada a enfermedad. VEGF: factor de crecimiento del endotelio vascular. OR: Odds ratio. Información suplementaria Materiales suplementarios no han sido declarados. Agradecimientos No aplica. Contribuciones de los autores Jorge Rico-Fontalvo: Conceptualización, Curación de datos, Análisis formal, Adquisición de fondos, Investigación, Metodología, Administración de proyecto, Recursos, Software, Escritura – borrador original. Rodrigo Daza-Arnedo: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Tomás Rodríguez-Yanez: Metodología, validación, supervisión, redacción: Revisión y edición. Washington Osorio: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Beatriz Suarez-Romero: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Oscar Soto: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Montejo-Hernandez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. María Cardona-Blanco: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Camilo Gutiérrez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Todos los autores leyeron y aprobaron la versión final del manuscrito. Financiamiento Los autores proveyeron los gastos de la investigación. Disponibilidad de datos o materiales Los conjuntos de datos generados y analizados durante el estudio actual no están disponibles públicamente debido a la confidencialidad de los participantes, pero están disponibles a través del autor correspondiente a pedido académico razonable. Declaraciones Aprobación del comité de ética y consentimiento para participar No aplica para revisiones narrativas. Consentimiento para publicación No aplica cuando no se publican imágenes o fotografías del examen físico o radiografías/tomografías/resonancias de pacientes. Conflictos de interés Los autores reportan no tener conflictos de interés. 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LANGUAGE NOTE | Document text in Chinese; abstract also in English. 萬曆七年少山堂《新刻考正古本大字出像釋義北西廂》二卷，現藏日本御茶水圖書館成簣堂文庫。少山堂本有眉批和少量旁批。該書不僅是現存最早的《西廂記》評點本，也是今存“最早的中國戲曲評點本”，在《西廂記》傳播史乃至中國戲曲史上具有非常重要的價值。少山堂本很可能是一個“原刻初印”本，也是一個“初評”本，在正文和批語兩方面實爲今存多種明刊《西廂記》之初祖。具體而言，少山堂本直接影響到徐士範本，又經過徐士範本間接影響到熊龍峰刊余瀘東訂本、三槐堂本等明刊《西廂記》評點本。 An edition of the Xixiang ji (Romance of the West Wing) published by Shaoshan tang in 1579, titled Xinke kaozheng ben dazi chuxiang shiyi bei Xixiang (A newly engraved redacted edition of the north edition of The Xixiang ji in large print, with illustrations and annotations) in two fascicles is preserved in Naruhodo Bunko of the Ochanomizu Library in Japan. This Shaoshan tang edition contains some “eyebrow” notes and a few notes next to the text. This edition is not only the earliest extant commentated edition of the Xixiang ji but also “the earliest extant commentated edition of Chinese dramatic texts; therefore, it is very significant in the circulation of the Xixiang ji and even in the history of classical Chinese drama. The Shaoshan tang edition is most likely the “first cut and first print” edition and the “first commentated” version, which contains the urtext and commentaries on which the extant Ming versions were based. In particular, the Shaoshan tang edition had a direct influence on the edition of Xu Shifan, who continued to exert influence on other Ming editions such as the one done by Yu Ludong and published by Xiong Longfeng, and the one with commentaries published by Sanhuai tang.

In the back light of the inspirational article of Kishor Patwardhan ji ‘The history of the discovery of blood circulation: unrecognized contributions of Ayurveda masters’ raising at most relevant issue of neglected Ayurvedic scholars’ contribution to the field of Anatomy-physiology well ahead of the contemporary developing sciences. Crawling in the same lines this article is dedicated for one such legendary Sharangadhara and his work related to Circulatory system. Structural entities play a major role in any of the system; especially in Medicine and that too in Ayurveda as it recommends ‘Rogam ado pareekshet’ shows how important the examination of a diseased person is considered by our Acharyas. The Circulatory System is one such structural physical entity, not only circulate but has additional Functions like Nutrition, Metabolism, Excretion system of body depends, endocrine etc. As early as 200 BC, works to understand this human body was initiated. In this article an attempt is made to sketch out the understanding of circulatory system as evident in 14th century in India through the prismatic view of Sharangadhara Samhita and its commentator.

Ethnopharmacology relevance: Yunnan Baiyao (YNBY), a traditional Chinese medicine formulae, has some significant properties including activating blood circulation to dissipate blood stasis (Huo-Xue-Hua-Yu), eliminating swelling and alleviating pain (Xiao-Zhong-Zhi-Tong), and eliminating necrotic tissues and promoting granulation (Qu-Fu-Sheng-Ji).Aim of this study: This paper intends to provide a comprehensive and critical analysis of studies on YNBY, proposing new possible therapeutic directions of this formula.Materials and methods: Relevant data on YNBY were retrieved from available databases and a hand-search by searching the keywords such as “Yunnan Baiyao,” “pharmacology,” “toxicity,” and “clinical applications.”Results: Traditionally, YNBY has been used to cure hemorrhage, bruises, swelling, and pain caused by injuries in the Chinese folk. Modern pharmacological studies show that YNBY possesses pharmacological activities including hemostasis, invigorating the circulation of blood, wound healing, anti-inflammation, analgesia, antibiosis, infection prevention, and other effects. Toxicological studies demonstrate that YNBY has a certain toxicology, which is mainly caused by Aconitum alkaloids from Cao-wu (CW, Aconiti Kusnezoffii Radix). The developmental non-toxic reaction dose (NOAEL) of YNBY for embryos and fetuses is 0.5 g/kg in rats. In addition, the NOAEL for fertility and early embryo development toxicity is 4.0 g/kg in rats. Clinical trials have confirmed the safety of YNBY in a large number of patients, and adverse drug reactions (ADRs) such as abdominal pain, diarrhea, allergy, and others in very few people. YNBY is routinely used in clinic to cure bleeding, pain, swelling, upper digestive tract ulcer, postoperative wound, arthritis, mouth ulcers, ulcerative colitis, etc.Conclusions: Hemostasis is a conspicuous effect of YNBY. Except for this effect, analgesia and anti-infection may be new research directions of this formula. In addition, the in vitro and in vivo pharmacology and mechanisms of action of YNBY are encouraged as well as the pharmacokinetics of this formulae. Furthermore, the material basis of the pharmacological effects of YNBY also needs clear identification.

Abstract Objective: The citation history of a published article reflects its impact on the literature over time. We conducted a comprehensive bibliometric analysis to identify the most cited papers on CHD in children. Methods: One-hundred and ninety journals listed in Journal Citation Reports were accessed via Web of Science. Publications with 250 or more citations were identified from Science Citation Index Expanded (1900–2020), and those relating to structural CHD in children were reviewed. Articles were ranked by citation count and the 100 most cited were analysed. Results: The number of citations ranged from 2522 to 309 (median 431, IQR 356–518), with 35 published since 2000. All were written in English, most originated from the United States (74%), and were published in cardiovascular journals, with Circulation (28%) the most frequent. There were 86 original research articles, including 50 case series, 14 cohort studies, and 10 clinical trials. The most cited paper was by Hoffman JI and Kaplan S on the incidence of CHD. Thirteen authors had 4 or more publications in the top 100, all of whom had worked in Boston, Philadelphia, San Francisco, or Dallas, and the most prolific author was Newburger JW (9 articles). Conclusions: Citation analysis provides a historical perspective on scientific progress by assessing the impact of individual articles. Our study highlights the dominant position of US-based researchers and journals in this field. Most of the highly cited articles remain case series, with few randomised controlled trials in CHD appearing in recent years.

Abstract Background BRII-732, a prodrug of islatravir (ISL), is a potent HIV-1 nucleotide reverse transcriptase translocation inhibitor. Following oral absorption, BRII-732 is rapidly converted to ISL, which is metabolized intracellularly to the active metabolite, ISL triphosphate (ISL-TP). Single doses of ISL as low as 0.5 mg significantly suppressed HIV-1 RNA by more than 1.0 log at day 7 in treatment-naive adults with HIV-1 infection. Current development work with BRII-732 is designed to provide optimal drug exposure to enable once weekly (QW) dosing, to be part of combination antiretroviral therapy to provide improved patient convenience and treatment adherence. Methods This was a Phase 1, randomized, double-blind, placebo-controlled study consisting of healthy adult subjects enrolled in five single ascending dose and two multiple ascending dose cohorts. The objectives of the study were to assess the safety, tolerability, and PK profiles of BRII-732 and ISL in plasma; ISL-DP and ISL-TP in human PBMCs. BRII-732 was orally administered in the fasted state using an oral solution formulation. Safety-related assessments included physical examinations, ECGs, vital signs, AEs, and standard clinical laboratory tests. Results BRII-732 as single dose or multiple doses was generally safe and well-tolerated when administered to healthy adult subjects. There were no Grade ≥ 3 AEs, SAEs, drug-related AEs leading to withdrawal or graded lymphocyte abnormalities. BRII-732 rapidly converted to ISL post BRII-732 oral administration with no detectable level (LLOQ = 1.0 ng/mL) of BRII-732 in systemic circulation at 0.5h. Dose proportional ISL exposure increases were observed over the dose range of 10 mg to 200 mg of BRII-732. No meaningful ISL accumulation in plasma was observed after 3 QW BRII-732 doses. ISL-DP and ISL-TP exposures in PBMC cells increased dose-dependently. Approximately 1.7-2.0 fold accumulation ratios for ISL-DP and ISL-TP are consistent with observed long terminal half-lives of 110-150 hours. Conclusion Safety, tolerability and PK profiles including ISL in plasma and ISL-TP in PBMC cells after single and multiple oral administrations of BRII-732 supports further development of BRII-732 as part of oral weekly combination antiretroviral therapy. Disclosures David A. Margolis, MD MPH, Brii Biosciences: Stocks/Bonds Ji Ma, PhD, Brii Biosciences: Stocks/Bonds Michael Watkins, PharmD, Brii Biosciences: Stocks/Bonds Yujin Wang, M.Sc., Brii Biosciences: Stocks/Bonds Chetana Trivedi, B.A., Brii Biosciences: Stocks/Bonds Chi-Chi Peng, PhD, Brii Biosciences: Stocks/Bonds Xuelian Wei, PhD, Brii Biosciences: Stocks/Bonds Lijie Zhong, PhD, Brii Biosciences: Stocks/Bonds Kamlesh Patel, PhD, Brii Biosciences: Stocks/Bonds Jean-Luc Girardet, PhD, Brii Biosciences: Stocks/Bonds Michael Wang, PhD MBA, Brii Biosciences: Stocks/Bonds Annalise VonderEmbse, PhD, Brii Biosciences: Stocks/Bonds Li Yan, MD PhD, Brii Biosciences: Stocks/Bonds Zhi Hong, PhD, Brii Biosciences: Ownership Interest Lianhong Xu, PhD, Brii Biosciences: Stocks/Bonds.

In 2007, Li Ke’s novel A Story of Lala’s Promotion (Du Lala Shengzhi Ji) became a bestseller among Chinese white-collar workers in foreign-owned (Western) companies and struck a chord with the Chinese middle class. The novel revolves around office politics, Western company culture and the white-collar lifestyle, the ‘shelved ladies’ phenomenon and middle-class aesthetics. To decipher the embedded cultural codes of this book, this study undertakes a textual analysis of the plots of A Story of Lala’s Promotion and its filmic adaptation, Go Lala Go! (Du Lala Shengzhi Ji dir. Xu Jinglei, 2010). This paper conducts a trans-media adaption study (from fiction to film) to examine three interrelated themes in the novel and the film. First, focusing on the influence of Western corporate culture on Chinese white-collar workers under economic globalisation, the widely circulating rules of Western workplaces are interpreted, clarifying the acculturating process of Western culture over its Chinese counterpart. The paper further explains that on the platform provided by foreign companies, and with the influence and training of Western corporate culture, intelligent and diligent young Chinese aspirational women struggle and realise their dreams in the workplace. Second, employing a feminist perspective, an attempt is made to address the situation of contemporary Chinese white-collar women represented by the contemporary social phenomenon of the ‘shelved ladies’, which also serves as an emblem of female independence and individualism. Third, through an analysis of the filmic adaptation, which focuses on the white-collar female’s lifestyle and consumption habits, the paper also highlights the contemporary Chinese population’s pursuit of a middle-class identity and aesthetic that mirrors the overwhelming consumerism of post-socialist China.

AbstractObjective. To describe the effects of wearing individual protection equipment against biological hazard when performing a simulated resuscitation.Methods. Uncontrolled quasi-experimental study involving 47 volunteers chosen by random sampling stratified by sex and professional category. We determined vital signs, anthropometric parameters and baseline lactate levels; subsequently, the volunteers put on level D individual protection equipment against biological hazard and performed a simulated resuscitation for 20 minutes. After undressing and 10 minutes of rest, blood was extracted again to determine lactate levels. Metabolic fatigue was defined as a level of lactic acid above 4 mmol/L at the end of the intervention.Results. 25.5% of the participants finished the simulation with an unfavorable metabolic tolerance pattern. The variables that predict metabolic fatigue were the level of physical activity and bone mass -in a protective formand muscle mass. People with a low level of physical activity had ten times the probability of metabolic fatigue compared to those with higher levels of activity (44% versus 4.5%, respectively).Conclusion. Professionals who present a medium or high level of physical activity tolerate resuscitation tasks better with a level D individual biological protection suit in a simulated resuscitation.Descriptors: cardiopulmonary resuscitation; personal protective equipment; anaerobic threshold; containment of biohazards; stress, physiological.How to cite this article: Martín-Rodríguez F. Metabolic fatigue in resuscitators using personal protection equipment against biological hazard. Invest. Educ. Enferm. 2019; 37(2):e04ReferencesBarsuk JH, Cohen ER, Wayne DB, Siddall VJ, McGaghie WC. Developing a Simulation-Based Mastery Learning Curriculum: Lessons from 11 Years of Advanced Cardiac Life Support. Simul. Healthc. 2016; 11(1):52–9. Kwon JH, Burnham CAD, Reske KA, Liang SY, Hink T, Wallace MA, et al. Assessment of Healthcare Worker Protocol Deviations and Self-Contamination During Personal Protective Equipment Donning and Doffing. Infect. Control Hosp. Epidemiol. 2017; 38(9):1077-83. Schoch-Spana M, Cicero A, Adalja A, Gronvall G, Kirk Sell T, Meyer D, et al. Global Catastrophic Biological Risks: Toward a Working Definition. Health Secur. 2017; 15(4):323-8. Millett P, Snyder-Beattie A. Existential Risk and Cost-Effective Biosecurity. Health Secur. 2017; 15(4):373-83. Fogel I, David O, Balik CH, Eisenkraft A, Poles L, Shental O, et al. The association between self-perceived proficiency of personal protective equipment and objective performance: An observational study during a bioterrorism simulation drill. Am. J. Infect. Control. 2017; 45(11): 1238-42. Calfee MW, Tufts J, Meyer K, McConkey K, Mickelsen L, Rose L, et al. Evaluation of standardized sample collection, packaging, and decontamination procedures to assess cross-contamination potential during Bacillus anthracis incident response operations. J. Occup. Environ. Hyg. 2016; 13(12): p. 980-92. Narayanan N, Lacy CR, Cruz JE, Nahass M, Karp J, Barone JA, et al. Disaster Preparedness: Biological Threats and Treatment Options. Pharmacotherapy. 2018; 38(2):217-34. Hunt L, Gupta-Wright A, Simms V, al. e. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect. Dis. 2015; 15(11):1292–9. Nicaise V. The Sensitivity And Specificity Of The IPAQ For Detecting Intervention Related Changes In Physical Activity. Med. Sci. Sports Exerc. 2011; 43(Sup. 1):607. van Poppel MNM, Chinapaw MJM, Mokkink LB, van Mechelen W, Terwee CB. Physical activity questionnaires for adults: A systematic review of measurement properties. Sports Med. 2010; 40(7):565-600. Baur DA, Bach CW, Hyder WJ, Ormsbee MJ. Fluid retention, muscle damage, and altered body composition at the Ultraman triathlon. Eur. J. Appl. Physiol. 2016; 116(3):447-58. Spartano LN, Lyass GA, Larson DM, Lewis SG, Vasan SR. Abstract 19256: Predicting Exercise Systolic Blood Pressure and Heart Rate at 20 Years of Follow-up: Correlates in the Framingham Heart Study. Circulation. 2015; 132(3):A19256-A19256. Jayasinghe S, Lambert G, Torres S, Fraser S, Eikelis N, Turner A. Hypothalamo-pituitary adrenal axis and sympatho-adrenal medullary system responses to psychological stress were not attenuated in women with elevated physical fitness levels. Endocrine. 2016; 51(2):369-79. Pattani R, Marquez C, Dinyarian C, Sharma M, Bain J, Moore JE, et al. The perceived organizational impact of the gender gap across a Canadian department of medicine and proposed strategies to combat it: a qualitative study. BMC Medicine. 2018; 16(1): p. 48. ¿Morales‐Alamo D, Losa‐Reyna J, Torres‐Peralta R, Martin‐Rincon M, Perez‐Valera M, Curtelin D, ¿et al. What limits performance during whole‐body incremental exercise to exhaustion in humans? J. Physiol. 2015; 593(20):4631–48. Hall MM, Rajasekaran S, Thomsen TW, Peterson AR. Lactate: Friend or Foe. PM R. 2016; 8(3):S8-S15. Ekkekakis P, Hall EE, Petruzzello SJ. Practical markers of the transition from aerobic to anaerobic metabolism during exercise: rationale and a case for affect-based exercise prescription. Prev. Med. 2014; 38(2):149-59. Vikmoen O, Raastad T, Seynnes O, Bergstrøm K, Ellefsen S, Rønnestad BR. Effects of Heavy Strength Training on Running Performance and Determinants of Running Performance in Female Endurance Athletes. PLoS One. 2016; 11(3):e0150. Devlin J, Paton B, Poole L, Sun W, Ferguson C, Wilson J, et al. d lactate clearance after maximal exercise depends on active recovery intensity. J. Sports Med. Phys. 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A 22-year-old man presented with a 3-week history of increased thirst, polydipsia, and polyuria. He described consuming large volumes of water and waking up multiple times throughout the night to drink and urinate. He also endorsed symptoms of fatigue and frequent headaches. Prior to this, he had been well. There was no history of diuretic use, lithium use, or renal disease. There was no prior head trauma, cranial irradiation, or intracranial pathology. He denied consumption of nutritional or protein supplements. Clinical exam revealed a well appearing young man with normal heart rate and blood pressure. Visual fields and general neurologic exam were grossly normal.Baselines investigations revealed serum sodium ranging from 141–142 mmol/L (reference range 133–145 mmol/L), creatinine 92 umol/L (50–120 umol/L), random glucose 5.4 mmol/L (3.3–11.0 mmol/L), potassium 4.0 (3.3–5.1 mmol/L) and ionized calcium 1.25 mmol/L (1.15–1.35 mmol/L). A 24-hour urine collection was arranged, and returned a urine volume of 5.6L (normal less than 3 litres/24 hours). Further investigations revealed a serum sodium of 142 mmol/L, serum osmolality 306 mmol/kg (280–300 mmol/kg), and urine osmolality of 102 mmol/kg (50–1200 mmol/kg). AM cortisol was 372 nmol/L (200–690 nmol/L).These results demonstrated inability to concentrate the urine, despite the physiologic stimulus of hyperosmolarity. Based on this, a presumptive diagnosis of diabetes insipidus was made. The patient was instructed to drink as much as he needed to satiate his thirst, and to avoid fluid restriction. The patient was started on DDAVP intranasal spray, which provided immediate relief from his symptoms. Magnetic resonance imaging of the brain revealed an unremarkable pituitary gland with abnormal thickening of the pituitary stalk and loss of the posterior pituitary bright spot. This confirmed the diagnosis of central diabetes insipidus, presumed secondary to infiltrative disease affecting the pituitary stalk.IntroductionPolyuria is defined as inappropriately high urine output relative to effective arterial blood volume and serum sodium. In adults, polyuria can be objectively quantified as urine output in excess of 3–3.5 L per day with a low urine osmolality (<300 mmol/kg).2Daily urine output is dependent on 2 major factors. The first is the amount of daily solute excretion, and the second is the urine concentrating capability of the nephron.3 Disturbances in either of these factors can occur by many different mechanisms, and can lead to a diuresis. This diuresis can be driven either by solute (solute diuresis), water (water diuresis) or a combination of these processes.4 A diagnostic algorithm for polyuria is outlined in Figure 1.Figure 1. Diagnostic Approach to Polyuria Solute DiuresisDaily solute intake varies between individuals, but typically averages about 10 mmol/kg or 500–800 mmol/day.2,3 Solute diuresis is the result of a higher solute load that exceeds the usual solute excretion. 4 Higher solute loads can be a consequence of either increased solute intake or increased solute generation through metabolism. High solute intake can occur from intravenous fluids, enteral or parental nutrition, and any other sources of exogenous protein, glucose, bicarbonate, or sugar alcohols.2,4 Metabolic processes leading to increased solute generation include hyperglycemia and azotemia. 2,4 Increased solute excretion drives urine output in a linear fashion.3 Furthermore, solute diuresis impairs the ability of the kidney to concentrate urine. Typically, in a pure solute diuresis, urine concentration is between 300 and 500 mmol/kg.2,4 The specific cause of solute diuresis can be further delineated with estimation of the urine electrolyte solute over 24 hours: 2(urine [Na]+urine [K]) ×24 hours.4 Values greater than 600 mmol/day suggest electrolytes are the solutes driving the diuresis, while values less than 600 mmol/day imply that the diuresis is due to a non-electrolyte solute, typically glucose or urea.Water DiuresisWater diuresis can occur due to excessive amounts of free water consumption (primary polydipsia) or impaired secretion or response to ADH (diabetes insipidus). In both cases, urine osmolality should be less than 100 mmol/kg.2 Primary polydipsia is characterized by excessive water consumption. This can be a result of compulsive water drinking (often observed in psychiatric disorders) or a defect in the thirst centre of the hypothalamus due to an infiltrative disease process.5,6The osmotic threshold for ADH release occurs at 280–290 mmol/kg. Failure to maximally concentrate the urine (1000–1200 mmol/kg in healthy kidneys) when serum osmolality rises above the osmotic threshold suggest diabetes insipidus.3 Diabetes insipidus (DI) can result from either insufficient ADH secretion from the posterior pituitary (central DI) or ADH resistance (nephrogenic DI).1Central DI can be caused by both congenital and acquired conditions known to affect the hypothalamic-neurohypophyseal system7,8 (Table 1). Polyuria occurs when 80% or more of the ADH secreting neurons are damaged 7. Metastatic disease has a predilection for the posterior pituitary, as its blood supply is derived from the systemic circulation, in contrast to the anterior pituitary which is supplied by the hypophyseal portal system.9 Rapid onset of polydipsia and polyuria in a patient older than 50 years of age should therefore raise immediate suspicion for metastatic disease.9 Treatment of adrenal insufficiency may “unmask” or exacerbate central DI, as normalization of blood pressure following glucocorticoid replacement inhibits ADH release.10 In the pregnant state, ADH degradation is increased due to placental production of vasopressinase. Any mechanism of hepatic dysfunction that occurs in pregnancy (pre-eclampsia, HELLP, acute fatty liver) will augment this normal physiology by reducing vasopressinase clearance, and can subsequently lead to transient DI 11In nephrogenic DI, ADH is present but the kidneys are unable to respond appropriately.8 In normal physiology, ADH acts to concentrate the urine via activation of the vasopressin V2 receptor, which leads to insertion of aquaporin-2 water channels in the collecting duct. 3,12 Nephrogenic DI can be primary (genetic) or secondary (acquired). Primary nephrogenic DI occurs as a result of genetic mutations affecting either the vasopressin 2 receptor or aquaporin-2 water channels; typically, such conditions present in infancy.12 Secondary nephrogenic DI can occur by a variety of mechanisms; the most common is chronic lithium administration. Lithium enters the principal cell in the collecting duct via epithelial sodium channels, and is thought to impair urinary concentrating ability via reduction in the number of principal cells and interference in signalling pathways involved in aquaporin. 12,13 Hypercalcemia, hypokalemia, obstructive uropathy, and pregnancy can lead to transient nephrogenic DI. 12,13 Hypercalcemia can lead to nephrogenic DI by causing a renal concentrating defect when calcium levels are persistently above 2.75 mmol/ L.14 Increased hydrostatic pressure from obstructive uropathy may lead to suppression of aquaporin-2 expression, resulting in transient nephrogenic DI.12 Nephrogenic DI can be caused by various renal diseases due to impairment of renal concentrating mechanisms, even before glomerular filtration rate is impaired. Polycystic kidney disease causes anatomic disruption of the medullary architecture. Polyuria in sickle cell disease results from a similar mechanism, as sickling in the vasa recta interferes with the countercurrent exchange mechanisms 16. Infiltrative renal disease including amyloid and Sjogren’s syndrome impair renal tubular function due to amyloid deposition and lymphocytic infiltration.17,18Mixed Water-Solute DiuresisIn some cases, polyuria can be caused by a combination of both mechanisms. The linear relationship between solute excretion and urine output described above is strongly influenced by ADH. In the setting of a solute diuresis, absence or deficiency of ADH can augment the degree of polyuria quite dramatically.14,19 Clinical examples of mixed diuresis include concurrent loading of both water and solute, chronic renal failure or infiltrative renal disease, relief of prolonged urinary obstruction, and partial DI.2,4 Typically in such scenarios, urine osmolality ranges from 100–300 mmol/kg.2 Conclusion Polyuria has a broad range of causes and can be a diagnostic challenge for clinicians. Understanding the pathophysiology that underpins the different mechanisms of polyuria is essential to appropriate workup, diagnosis, and treatment of this condition. If this is a complaint, the first step is to quantitate the 24-hour urine volume. We recommend referral to endocrinology when there is evidence of hypothalamic or pituitary disease, when a water deprivation test is required, or in cases where the diagnosis is unclear. DisclosureFunding sources: None.Conflicts of interest: None. References 1. Leung AK, Robson WL, Halperin ML. Polyuria in childhood. Clin Pediatr (Phila) 1991;30(11):634–40.2. Bhasin B, Velez JC. Evaluation of polyuria: the roles of solute loading and water diuresis. Am J Kidney Dis 2016;67(3):507–11.3. Rennke HG, Denker BM. Renal pathophysiology: the essentials. 4th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2014.4. Oster JR, Singer I, Thatte L, Grant-Taylor I, Diego JM. The polyuria of solute diuresis. Arch Intern Med 1997;157(7):721–9.5. Grois N, Fahrner B, Arceci RJ, Henter JI, McClain K, Lassmann H, et al. Central nervous system disease in Langerhans cell histiocytosis. J Pediatr 2010;156(6):873–81, 81.e1.6. Stuart CA, Neelon FA, Lebovitz HE. Disordered control of thirst in hypothalamic-pituitary sarcoidosis. N Engl J Med 1980;303(19):1078–82.7. Di Iorgi N, Napoli F, Allegri AE, Olivieri I, Bertelli E, Gallizia A, et al. Diabetes insipidus--diagnosis and management. Horm Res Paediatr 2012;77(2):69–84.8. Mahzari M, Liu D, Arnaout A, Lochnan H. Immune checkpoint inhibitor therapy associated hypophysitis. Clin Med Ins Endocrin Diabet 2015;8:21–8.9. Hermet M, Delévaux I, Trouillier S, André M, Chazal J, Aumaître O. Diabète insipide révélateur de métastases hypophysaires : quatre observations et revue de la littérature. La Revue de Médecine Interne 2009;30(5):425-9.10. Martin MM. Coexisting anterior pituitary and neurohypophyseal insufficiency: A syndrome with diagnostic implication. Arch Intern Med 1969;123(4):409–16.11. Aleksandrov N, Audibert F, Bedard MJ, Mahone M, Goffinet F, Kadoch IJ. Gestational diabetes insipidus: a review of an underdiagnosed condition. J Obstet Gynaecol Can 2010;32(3):225–31.12. Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol 2015;11(10):576–88.13. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009;5(5):270.14. Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders. 5th ed. New York: McGraw-Hill, Medical Pub. Division; 2001, 754.15. Gabow PA, Kaehny WD, Johnson AM, Duley IT, Manco-Johnson M, Lezotte DC, et al. The clinical utility of renal concentrating capacity in polycystic kidney disease. Kidney Internat 35(2):675–80.16. Hatch FE, Culbertson JW, Diggs LW. Nature of the renal concentrating defect in sickle cell disease. J Clin Invest 1967;46(3):336–4517. Carone FA, Epstein FH. Nephrogenic diabetes insipidus caused by amyloid disease: Evidence in man of the role of the collecting ducts in concentrating urine. Am J Med 1960;29(3):539–44.18. Shearn MA, Tu W-H. Nephrogenic diabetes insipidus and other defects of renal tubular function in Sjögren's syndrome. Am J Med 1965;39(2):312–8.19. Rennke HG, Denker BM. Renal pathophysiology: the essentials. 4th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2014. Figure 3.7, effects of ADH and solute excretion on urine volume, 88.