Journal articles on the topic 'CAS PO 223'

Abstract Cancer metastasis is a complex cascade that involves activation of cancer cell invasion and migration. This activation is greatly attributed by multiple factors, including the tumor-microenvironment (TME). Cancer-associated fibroblasts (CAF), a prominent cell type within the TME, have been shown to promote cancer cell invasion and migration, causing metastasis in various cancers including head and neck squamous cell carcinoma (HNSCC). The molecular mechanisms of how CAFs promote HNSCC invasion remain elusive. Our research goal is to understand how CAFs influence HNSCC cells to become invasive and potentially metastatic. Using a top-down research approach, our aim is to identify novel therapeutic chemical probe/drug regimens that potentially target CAF-dependent HNSCC cancer cell-invasion. In-order to perform high-throughput small molecule screens, we have established a 384-well format, three-dimensional (3D) spheroid invasion assay, as a powerful tool to study CAF-dependent HNSCC cancer cell invasion. This platform is currently being used to screen small molecule libraries and identify putative molecular targets, providing insights into underlying mechanisms of CAF-induced cancer cell invasion and candidate therapeutic strategies. Citation Format: Kunal Karve, Stephanie Poon, Panagiotis Prinos, Laurie Ailles. High-throughput 3D-spheroid invasion assay: A powerful tool to identify novel drugs targeting tumor micro-environment in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-077.

The voltage- and Ca2+-dependent gating mechanism of large-conductance Ca2+-activated K+ (BK) channels from cultured rat skeletal muscle was studied using single-channel analysis. Channel open probability (Po) increased with depolarization, as determined by limiting slope measurements (11 mV per e-fold change in Po; effective gating charge, qeff, of 2.3 ± 0.6 eo). Estimates of qeff were little changed for intracellular Ca2+ (Ca2+i) ranging from 0.0003 to 1,024 μM. Increasing Ca2+i from 0.03 to 1,024 μM shifted the voltage for half maximal activation (V1/2) 175 mV in the hyperpolarizing direction. V1/2 was independent of Ca2+i for Ca2+i ≤ 0.03 μM, indicating that the channel can be activated in the absence of Ca2+i. Open and closed dwell-time distributions for data obtained at different Ca2+i and voltage, but at the same Po, were different, indicating that the major action of voltage is not through concentrating Ca2+ at the binding sites. The voltage dependence of Po arose from a decrease in the mean closing rate with depolarization (qeff = −0.5 eo) and an increase in the mean opening rate (qeff = 1.8 eo), consistent with voltage-dependent steps in both the activation and deactivation pathways. A 50-state two-tiered model with separate voltage- and Ca2+-dependent steps was consistent with the major features of the voltage and Ca2+ dependence of the single-channel kinetics over wide ranges of Ca2+i (∼0 through 1,024 μM), voltage (+80 to −80 mV), and Po (10−4 to 0.96). In the model, the voltage dependence of the gating arises mainly from voltage-dependent transitions between closed (C-C) and open (O-O) states, with less voltage dependence for transitions between open and closed states (C-O), and with no voltage dependence for Ca2+-binding and unbinding. The two-tiered model can serve as a working hypothesis for the Ca2+- and voltage-dependent gating of the BK channel.

Purpose To evaluate the efficacy and tolerability of dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance. Patients and Methods In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m2) and fluorouracil (500 mg/m2) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable. Results ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin. Conclusion Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.

Ion channels in endosomal membranes from rabbit kidney cortex were studied after reconstitution into planar lipid bilayers. The most frequently observed ion channel was anion selective (PCl/PK = 13) and had a single-channel conductance of 116 pS when the cis and trans solutions contained 410 and 150 mM KCl, respectively, and a conductance of 90 pS in symmetrical 150 mM KCl solutions. The anion selectivity sequence of the channel was NO3- > F- > Br- > Cl- >> I-. The activity of the channel was voltage dependent such that hyperpolarization of the cis, or cytoplasmic, surface of the channel increased the open probability (Po). The activity of the channel was also highly dependent on the calcium activity of the cis but not the trans solution. Channels were fully active (Po > 0.7) at Ca2+ concentration > 1 microM, but channel activity was completely absent (Po < 0.001) at Ca2+ concentration < 250 nM. The effects of calcium on Po were not voltage dependent. The Cl(-)-channel blocker 2-[(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden -5- yl)oxy]-acetic acid (IAA-94/95) produced a concentration-dependent reversible flickering block of the endosomal channel with a Ki of 15 microM. 4,4'-Dinitrostilbene-2,2'-disulfonic acid, a disulfonic stilbene, also produced a flickering block of the channel with a Ki of approximately 5 microM. Because endosomal Cl- channels are believed to facilitate endosomal acidification, we tested the effects of IAA-94/95 and deletion of Ca2+ on the rate of acidification of intact endosomes. Because neither maneuver affected acidification, we conclude that the 116-pS channel does not participate in endosomal acidification. This channel may be involved in other endosomal processes, e.g., cell volume regulation and control of membrane trafficking.

BK channels are activated by intracellular Ca2+ and Mg2+ as well as by depolarization. Such activation is possible because each of the four subunits has two high-affinity Ca2+ sites, one low-affinity Mg2+ site, and a voltage sensor. This study further investigates the mechanism of Mg2+ activation by using single-channel recording to determine separately the action of Mg2+ on the open and closed states of the channel. To limit Mg2+ action to the Mg2+ sites, the two high-affinity Ca2+ sites are disabled by mutation. When the voltage is stepped from negative holding potentials to +100 mV, we find that 10 mM Mg2+ decreases the mean closed latency to the first channel opening 2.1-fold, decreases the mean closed interval duration 8.7-fold, increases mean burst duration 10.1-fold, increases the number of openings per burst 4.4-fold, and increases mean open interval duration 2.3-fold. Hence, Mg2+ can bind to closed BK channels, increasing their opening rates, and to open BK channels, decreasing their closing rates. To explore the relationship between Mg2+ action and voltage sensor activation, we record single-channel activity in macropatches containing hundreds of channels. Open probability (Po) is dramatically increased by 10 mM Mg2+ when voltage sensors are activated with either depolarization or the mutation R210C. The increased Po arises from large decreases in mean closed interval durations and moderate increases in mean open interval durations. In contrast, 10 mM Mg2+ has no detectable effects on Po or interval durations when voltage sensors are deactivated with very negative potentials or the mutation R167E. These observations are consistent with a model in which Mg2+ can bind to and alter the gating of both closed and open states to increase Po, provided that one or more voltage sensors are activated.

Abstract Background: Ozuriftamab vedotin (BA3021) is a conditionally active biologic (CAB) anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) using a cleavable linker (CAB ROR2 ADC) (Short, et al., 2014, Chang, et al. 2021). Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics (PK). ROR2 is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including head and neck squamous cell cancer (HNSCC). Increased ROR2 expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy. A pronounced unmet need exists as the majority of patients with recurrent or metastatic HNSCC experience disease progression with existing therapies (Chow 2020). Trial Design: BA3021-002 is a multi-center, open-label, single-arm Phase 2 study (n=40) designed to evaluate the efficacy and safety of BA3021 in patients previously treated with PD-(L)1 with ROR-2 expressing recurrent or metastatic HNSCC. Eligible patients include those with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Failure to prior treatment is defined as documented disease progression after no more than one PD-1/L1 inhibitor either administered as monotherapy or in combination therapy. Pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and biomarker assessments will be performed. Enrollment is ongoing (NCT05271604) References Chang, H.W., Frey, G., Liu, H., Steinman, L., Boyle, W.J. and Short, J.M. Proc. Natl. Acad. Sci. 2021 Mar. 2; 118(9). Chow LQ. Head and neck cancer. N Engl J Med. 2020 Jan 2;382(1):60–72. doi: 10.1056/NEJMra1715715 Short, J.M. Nature Biotechnology 2014 Nov 8, 13(20). Citation Format: Alan L. Ho, Douglas R. Adkins, Jochen Lorch, Jacob S. Thomas, Jaspreet S. Grewal. A phase 2 open-label study of conditionally active biologic, ozuriftamab vedotin (BA3021) in PD-1/L1 failure patients with recurrent or metastatic squamous cell carcinoma of the head and neck [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-007.

Wraz z wprowadzeniem narzędzi CAD, a potem BIM, architekci zaczęli dostrzegać, że narzędzia, których używają, mają wpływ na ich twórczość. Obecnie architekci zaczynają używać narzędzi AI umożliwiających eksplorację koncepcji projektowych poprzez generowanie obrazów. Te narzędzia, zwane generatorami obrazów AI, generują obrazy na podstawie opisów tekstowych oraz dowolnych wczytanych obrazów, w tym szkiców lub zdjęć. Na rynku dostępne są zarówno narzędzia przeznaczone bezpośrednio do projektowania architektonicznego, jak i narzędzia o charakterze ogólnym, służące do generowania dowolnych obrazów, od fotorealistycznych po malarskie i graficzne. Wszystkie te narzędzia są we wstępnych fazach rozwoju. Artykuł analizuje przydatność i ograniczenia tych narzędzi z perspektywy architekta, biorąc pod uwagę stan technologii na koniec 2023 roku.

Le présent travail vise à apprécier la qualité physico-chimique des eaux de l’Ouémé supérieur au Bénin. L’étude concerne quatre (04) communes. Les données ont été collectées en octobre 2021 et en mars 2022. Les paramètres physiques in-situ et les paramètres chimiques au laboratoire ont été étudiés. La description par les box plots (Boîtes à moustaches), le test de Shapiro-Wilk et celui de Kruskall Wallis au seuil α = 5% ont été utilisés. Les paramètres tels la salinité, T°C,〖 NO〗_2^-, NO_3^-, NH_4^+, PO_4^(3-), Ca2+, Mg2+, Fe2+ et le Cl- sont significativement différents des autres paramètres et ne respectent pas les normes des eaux de surface. Les résultats de la Classification Hiérarchique Ascendante (CAH) ont permis d’identifier trois groupes. Le groupe 1, constitué de : pH, OD, Salinité,〖 NO〗_2^-, NO_3^-,〖 NH〗_4^+,〖 PO〗_4^(3-), Ca2+, Mg2+, Fe2+ et le Cl- ; proviennent principalement des activités agricoles et des eaux usées. Le groupe 2, constitué de : T°C, STD et la DCO ; proviennent des différents éléments chimiques solubles dans l’eau. Le groupe 3, constitué de : CE, provient de la minéralisation globale de l’eau. L'eau est alors contaminée à travers les constituants physico-chimiques évalués. This work aims to assess the physico-chemical quality of the waters of the upper Ouémé in Benin. The study covered four (04) communes. The data was collected in october 2021 and march 2022. The in-situ physical parameters and the chemical parameters in the laboratory were studied. The description by the box plots, the Shapiro-Wilk test and the Kruskall Wallis test at the threshold α = 5% were used. The parameters such as salinity, NO_2^-, NO_3^-, NH_4^+, PO_4^(3-), Ca2+, Mg2+, Fe2+ and the Cl- are significantly different from the other parameters and do not respect the standards of the surface water. The results of the Hierarchical Ascending Classification (HAC) have helped us to identify three groups. The group 1, made up of: pH, DO, Salinity, 〖 NO〗_2^-, NO_3^-,〖 NH〗_4^+,〖 PO〗_4^(3-), Ca2+, Mg2+, Fe2+ and the Cl-; come mainly from agricultural activities and wastewater. The group 2, made up of: T°C, STD and COD; come from the different chemical elements that are soluble in water. The group 3, made up of: CE, comes from the global mineralization of water. The water is then contaminated through the physico-chemical constituents which have been evaluated.

BackgroundCD38 is a NAD+ consuming enzyme ubiquitously expressed on immune cells and its expression increases in several pathological conditions, including Rheumatoid Arthritis (RA) [1, 2]. Pre-clinical studies in CD38knock-outmodels have demonstrated that CD38 deficient animals develop an attenuated form of Collagen-Induced-Arthritis (CIA) characterized by reduced inflammation and damage at the joint level suggesting a causal role of CD38 in the pathogenesis of CIA and, potentially, RA [3-5].ObjectivesThis study investigated the efficacy of NTX-748, a newly developed, potent and orally available small molecule inhibiting the enzymatic activity of CD38, in reducing the inflammation, cartilage destruction, pannus formation, and bone resorption associated with developing CIA in mice, a well-established animal model for the study of RA.MethodsMice were injected intradermally (ID) with Freund’s complete adjuvant (CFA) containing bovine type II collagen to induce arthritis on study days 0 and 21. Beginning on study day 18, the animals were dosed twice daily (BID) by the oral route (PO) with vehicle or NTX-748 (3, 10, or 30 mg/kg), or dosed PO once daily (QD) with Methotrexate (1 mg/kg) (n=12/group) for 18 days. One group served as a naïve control group (n=4). Efficacy evaluation was based on animal body weights, clinical arthritis scores (CAS) based on daily clinical scores of the paws (right front, left front, right rear, left rear) expressed as area under the curve (AUC), summed histopathology scores based on histopathologic evaluation performed on fore paws, hind paws, and knees, analysis of NTX-748 plasma concentrations and tissue metabolomic profile. The primary endpoint was day 36 CAS.ResultsTreatment with NTX-748 at 10 and 30mg/kg showed a statistically significant dose-dependent beneficial effect reducing day 36 CAS by 37% and 50% respectively relative to vehicle (p=0.13 and p=0.047), without showing any toxicity, including body and spleen weights. Histopathology analysis of joints, paws and knees confirmed NTX-748 efficacy. Strikingly, NTX-748 reduces incidence of CAS up to 50% in a dose-dependent manner (p = 0.0015). Plasma concentrations of NTX-748 increased approximately in proportion to dose. Mass Spectrometry-based tissue metabolomic analysis (liver and spleen) confirmed target engagement with dose dependent increases of NAD+ levels, the main substrate of CD38-mediated NAD+ hydrolysis, and decreases of NAM and ADPR, both products of the same enzymatic reaction. Methotrexate 1mg/kg also demonstrated efficacy (98% reduction in CAS) however significant splenomegaly (3-fold increase) indicated toxicity at this dose.ConclusionOur results demonstrated that NTX-748, a small molecule inhibiting the NADase enzymatic activity of CD38, is efficacious in the mouse CIA model, and thus potentially RA. These data confirm the potential of CD38 as druggable target in the treatment of inflammation-driven autoimmune diseases such as RA.References[1] Cole, S., et al.,Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.Arthritis Res Ther, 2018.20(1): p. 85.[2] Thevissen, K., et al.,Diagnostic and prognostic value of synovial biopsy in adult undifferentiated peripheral inflammatory arthritis: a systematic review.J Rheumatol Suppl, 2011.87: p. 45-7.[3] Postigo, J., et al.,Mice deficient in CD38 develop an attenuated form of collagen type II-induced arthritis.PLoS One, 2012.7(3): p. e33534.[4] Rosal-Vela, A., et al.,Identification of multiple transferrin species in the spleen and serum from mice with collagen-induced arthritis which may reflect changes in transferrin glycosylation associated with disease activity: The role of CD38.J Proteomics, 2016.134: p. 127-137.[5] Du, Y., et al.,CD38 Deficiency Downregulates the Onset and Pathogenesis of Collagen-Induced Arthritis through the NF-kappaB Pathway.J Immunol Res, 2019.2019: p. 7026067.AcknowledgementsWe thank Dr. Peter Bungay (Sympetrus Ltd) for the support with the pharmacokinetic analysis.Disclosure of InterestsRosalba Perrone Consultant of: Juvenescence Ltd, a company owning shares of Napa Therapeutics Ltd., Prasanna Vadhana Ashok Kumaar: None declared, Katrina Gore: None declared, Jacob Favret: None declared, Eric Verdin Shareholder of: Napa Therapeutics Ltd, Steve Felstead Employee of: Juvenescence Ltd, a company owning shares of Napa Therapeutics Ltd.

Vulnus morsum adalah luka yang disebabkan oleh gigitan. Vulnus morsum yang tidak ditangani secara cepat dan tepat dapat menimbulkan infeksi. Seekor kucing lokal betina steril berumur satu tahun dengan bobot badan 2,3 kg diperiksa karena adanya luka gigitan pada daerah tulang belikat bagian kiri yang telah berlangsung lebih dari dua minggu. Hasil pemeriksaan klinis menunjukkan adanya dua luka terbuka, salah satu luka sudah mengalami nekrosis dan luka lainnya terlihat dalam. Mukosa mulut tampak pucat dengan capillary fill time (CRT) lebih dari dua detik, serta nafsu makan dan minum yang berkurang. Pemeriksaan hematologi menunjukkan polisitemia dan trombositopenia, sedangkan parameter lainnya menunjukkan hasil yang normal. Kasus kucing didiagnosis mengalami vulnus morsum stadium III dan IV dengan prognosis fausta. Kucing ditangani dengan operasi penutupan luka menggunakan tiga prinsip penanganan luka, yaitu pembersihan luka ( cleansing ) , transmisi jaringan yang mati dan rusak ( debridement ) , dan penutupan luka dengan jahitan ( penjahitan ). Luka diberikan iodin dan ditutup menggunakan kasa yang mengandung antibiotik framycetin sulfate . Pasca operasi diberikan cefotaxime 20 mg/kg BB (IM q12h) selama tiga hari dan cefixime 10 mg/kg BB (PO q12h) selama empat hari serta dexamethasone 0,5 mg/ekor (PO q12h) selama tiga hari. Pada hari ke-10 pascaoperasi, kucing menunjukkan kesembuhan secara klinis yang ditandai dengan menyatunya luka, nafsu makan dan minum yang baik, serta adanya peningkatan bobot badan.

Abstract Background: The biology of head and neck cancer (HNC) has been explained by the field carcinogenesis theory in which accumulated abnormalities (mainly gene mutations) caused by environmental stresses promote carcinogenesis. However, as clearly demonstrated by recent studies (Yokoyama et.al, Nature 2019; Hedberg et.al, JCI 2016), the genetic landscape of HNC (i.e., the loss-of-function mutations in tumor suppressor genes) fails to account for the onset and metastatic ability of HNC. In addition to being mutagen, environmental stresses induce oncogenic transcriptional programs (e.g., tissue regeneration). In this context, we have advanced our study based on a perspective that HNC is a symbiotic evolving system, highly dependent on transcriptional reprograming. Recently we succeeded to develop an ultra-rapid mouse carcinogenesis model (4W) induced by a transcriptional coactivator YAP1 (Omori et al, Sci Adv 2020) and are conducting integrative epigenetic analyses to elucidate how YAP1-induced transcriptional reprogramming drives HNC. Material and methods: Mouse tumors and a cell line and human HNC cell lines and tissue samples were subject to WES, WGBS, RNA-seq, Chip-seq (H3K27ac, YAP1, H3K9me2/3), and IHC. Results: YAP1-induced mouse tumors and cell lines demonstrated that YAP1 epigenetically causes carcinogenesis without affecting genome-wide chromatin confirmation, but inducing hypomethylation on the super enhancers (SE) of genes related to tissue regeneration (i.e., recapitulation of wounds that don’t heal condition). Poor prognosis was associated with YAP1-induced carcinogenesis gene module in the TCGA data (p = 0.00033) and with the level of YAP1nuclear protein in the 119 HNC samples (p = 0.0116). RNA-seq and Chip-seq with HNC cell lines showed that YAP1 is essential for the assembly of SE and that YAP1-related SE module including IL6 was associated with unfavorable survival in the TCGA data (p = 0.031). The existence of IL6-YAP1 feed-forward loop was confirmed in vitro assays. EEM and motif assays revealed that YAP1, collaborating with PITX2 transcriptional factor (TF), regulates TGF-beta-induced EMT and CAF, suggesting the involvement of YAP1 and PITX2 in the partial-EMT process, which was reported to play an important role in the nodal metastases of HNC (Puram et.al, Cell 2017). In the TCGA data, YAP1 target module demonstrated a significant correlation with p-EMT score or TGF-beta induced LRRC15 expressing CAF module. In the invasion front, YAP1 positive cancer cells co-existed with LRRC15 positive CAF. In vitro assays and Chip-seq on human HNC samples support the significance of collaboration of YAP1 and PITX2 in SE for nodal metastases. Co-expression of YAP1 plus PITX2 or BRD4 further worsened the prognosis than the individual factor alone. Conclusions: Collectively, our data indicate that YAP1-induced transcriptional reprograming, triggered and activated in the HNC specific tumor microenvironment, may function as a potent engine and thereby drive symbiotic evolution of HNC. Citation Format: Muneyuki Masuda, Hirofumi Omori, Kuniaki Sato, Josef Penninger, Silvio Gutkind. Environment-induced YAP1 transcriptional reprogramming drives head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-063.

The response of coastal systems to global acidification depends strongly on river inputs, which can alter the total alkalinity (AT) and dissolved inorganic carbon (DIC) in seawater. The northern Adriatic Sea (NAd) is a shallow continental shelf region that currently receives about 15% of the total freshwater input in the Mediterranean Sea, where the role of riverine discharges on the carbonate system has been poorly studied. In particular, river discharges can alter the carbonate system in the sea, affecting both the equilibrium chemistry and biological processes. For the main rivers flowing into the NAd (the Po, Adige, Brenta, Piave, Livenza, Tagliamento, Isonzo, Timavo and Rižana), data were collected for the pH, concentrations of the total alkalinity (AT), Ca2+ and Mg2+ and the isotopic ratio of stable carbon in the dissolved inorganic carbon (δ13CDIC). The DIC fluxes were estimated using the THINCARB (THermodynamic modeling of INOrganic CARBon) model for the compilation of the AT and pH data. The results show that the total transport of the AT in the rivers was 205 Gmol yr−1 while the transport of the DIC was 213 Gmol yr−1, of which about 70% was from the Po River. About 97% of the DIC in the river waters was in the form of bicarbonates. The high Mg2+/Ca2+ ratios indicate that dolomite weathering is predominant in the Adige, Piave, and Livenza river basins, while lower ratios in the Timavo and Rižana rivers indicate a greater proportion of calcite. The mean δ13C-DIC value was estimated to be −10.0 ± 1.7 ‰, a value nowadays considered typical for the DIC flux inputs in oceanic carbon cycle modeling. The DIC flux depends on the mineral weathering and biological activity in each river basin. However, these natural processes can be modified by anthropogenic disturbances that should be better quantified.

This study was conducted in a reservoir located in Mbiabet Ikot Udo community, Northern Akwa Ibom State, Nigeria, to assess the physicochemical status, composition and abundance of aquatic insects. Samples were collected from June 2022 to January 2023 and all the parameters were evaluated using standard methods. The results revealed that temperature ranged from 22.7 to 30.6°C, TDS (153 – 238 mgL-1), EC (153 – 238μScm-1), TDS (97.9 –152.3mgL-1), pH (6.3 – 8.1), DO (2.22 – 5.14 mgL-1), TSS (1.62 – 6.34 mgL-1), NO-3 (1.53 – 5.68 mgL-1), PO-4 (2.18 – 4.16 mgL-1), Mg2+ (3.92 – 5.36 mgL-1), Ca2+ (5.39 – 8.13 mgL-1), Na+ (0.72 – 2.37 mgL-1), K+ (0.68 – 1.48 mgL-1), BOD (1.34 – 6.46mgL-1), Ni (0.001 – 0.08 mgL-1), Fe (0.1 – 0.3 mgL-1), Pb (0.003 – 0.008 mgL-1), Cu (0.01 – 1.3 mgL-1) and Cd (0.002 – 0.008). There were significant temporal variations in some of these parameters. However, all the parameters were within the acceptable limits, except for TSS, BOD, DO, Ni, Cu and Fe. A total of 185 species of aquatic insects, in five taxonomic orders and 10 families, were recorded. Odonata had the highest percentage (40.5%), followed by Hemiptera (25.0%), and Diptera had the lowest percentage (8.6%). The dominant family was Aeshnidae (18.9%) while the least percentage was from Pleidae (1.1%). The analysis revealed that parameters such as temperature, DO, pH, Ca2+, EC, TDS and Cu negatively influenced the abundance of aquatic insects coupled with seasonal influence.

Groundwater is a primary drinking, agricultural, domestic, and nondomestic water source in Ethiopia’s Yisr River watershed of the Blue Nile River basin. There has been no systematic investigation of the hydrogeochemical properties of groundwater in the research area. The study investigated the hydrogeochemical parameters of groundwater in the catchment to find out if it is fit for drinking and irrigation. A total of 26 samples of groundwater were collected and analyzed for seventeen parameters, including pH, temperature, EC, TDS, TH, K+, Na+, Ca2+, Mg2+, Fe2+, Cl−, HCO 3 − , CO 3 2 − , SO 4 2 − , F−, PO 4 2 − , and NO 3 − . The data were processed and evaluated using integrated hydrogeochemical techniques, including individual ionic signatures, interionic ratios, and multivariate statistical methods, such as multiple correlation analysis, principal component analysis, and hierarchical cluster analysis. The water quality index (WQI) and Na%, PI, RSC, SAR, EC, TDS, and MH were used to judge the quality of water for drinking and irrigation, respectively. The box plot diagram shows the dominant ions in descending order of Ca2+ > Mg2+ > Na+ > K+ and HCO 3 2 − > Cl- > SO 4 2 − > NO 3 − > F− for cations and anions, respectively. The chemical composition of shallow wells and springs indicates freshwater. At the same time, the deep groundwater wells are brackish. The two-factor loadings (principal component analysis) were used to explain the existence of anthropogenic and geogenic sources. Three clusters are identified in the dendrogram. The third cluster has the most significant linkage distance among all the clusters. This means that the groundwater sample in this cluster is geochemically different from the other two clusters, and that this cluster is made up of only deep wells. Water quality indices showed that water quality ranged from excellent to very poor, with the majority (53.85%) being excellent and 26.9% being good. The results of the calculated indices for agricultural water quality indicated that the water quality in most collected samples was in the good and excellent categories; however, the EC, RSC, MH, and TDS indices in deep groundwater wells were found to be hazardous. The findings of this study are useful for understanding groundwater sustainability for various reasons. However, they are also helpful in supporting water management and protection in the future.

Abstract Background: Present line indications for pembrolizumab are for patients with metastatic or unresectable recurrent (i.e. incurable) head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients on immunotherapy will realize a durable survival benefit because &gt;80% of patients with metastatic HNSCC do not respond to PD-1 blockade. Tumor microenvironment mesenchymal stem cells (MSCs) and cancer associated fibroblasts (CAFs) have been reported significantly contribute to chemotherapy and radiation resistance. Moreover, MSCs have been shown to contribute to an immunosuppressive tumor microenvironment by upregulating PD-L1 in breast cancer models. We have previously shown crenolanib improves MSC mediated cisplatin resistance in vitro through modulation of MSC-mediated activation of AKT signaling, therefore we hypothesize that targeting MSCs may be of therapeutic benefit alone and in combination with anti-PD1 immunotherapy. Methods: Oral cancer was induced in the buccal space of C56/BL6 mice with the murine oral cancer cell lines MOC1 or PD-1 resistant cell line, MOC2. When tumors reached approximately 5 × 5 mm, mice were treated with 15 mg/kg (low dose) or 30 mg/kg crenolanib (high dose) for five consecutive days over 3 weeks. Tissue were harvested for immunohistochemistry and immunofluorescence analysis and ex vivo cell cultures prepared for analysis by western immunoblotting and flow cytometry. Results: There was a significant reduction in tumor volume in mice bearing MOC1 and MOC2 tumors (p&lt;0.03) treated with either low or high dose crenolanib compared to vehicle control. Overall survival was also significantly improved in mice bearing MOC1 tumors treated with high dose crenolanib compared to mice treated with vehicle control (p&lt;0.04) and approached significance in MOC2 mice treated with low dose crenolanib. Tumor sections were imaged by immunofluorescence microscopy. There was a decrease in expression of PDGFR-α on MOC1 tumor cells and α-SMA on tumor microenvironment stromal cells in mice treated with crenolanib compared to vehicle control, suggesting crenolanib targets both cell types. There was a significant reduction in tumor volume (p&lt;0.0001) and improved overall survival (p&lt;0.0004) in mice bearing MOC2 tumors treated with combination crenolanib plus pembrolizumab compared to vehicle plus pembrolizumab. Conclusions: Preliminary in vivo data suggests crenolanib may be efficacious when used in combination with anti-PD1 immunotherapy by inhibiting the immunosuppressive effects of tumor microenvironment MSCs. Citation Format: Xiangfeng Shen, Katherine Gonzalez, Rico Castillo, Ashlyn Rickard, Yvonne Mowery, Tammara Watts. Crenolanib improves PD-1 response and overall survival in immune checkpoint inhibitor resistant murine models of oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-093.

Abstract Introduction: The desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) perpetuates therapeutic resistance by impairing drug delivery and effector immune cell infiltration and activation. We have identified tumor cell-derived interleukin-1α (IL1α) as a critical activator of the stroma, comprised of cancer-associated fibroblasts (CAF), towards a pro-inflammatory phenotype via the IL1 receptor, IL1R1, and subsequent activation of p38 MAPK. Our hypothesis is that disruption of the CAF-specific IL1α/p38 MAPK signaling axis can improve chemotherapeutic resistance by remodeling the fibrotic stromal landscape and the overall immune microenvironment in PDAC. Methods: p38 MAPK was pharmacologically inhibited with pexmetinib and genetically with an shRNA lentiviral system. Bulk RNA and ATAC sequencing (RNAseq and ATACseq) were performed on human pancreatic stellate cells (hPSC). Gene set enrichment analyses and motif enrichment analyses were performed on the RNAseq and ATACseq datasets, respectively. Tumor cells (KPC-6694), derived from LSL-KrasG12D/+; LSL-Tp53R172H/+; Pdx1Cre/+ (KPC) murine tumors, were injected orthotopically into Col1a2Cre/+; Mapk14f/f and Col1a2Cre/+; Il1r1f/f mice, and tumors were harvested for downstream analysis. Ptf1aCre/+; LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice were treated with pexmetinib (PEX, 30mg/kg, daily PO), anakinra (AKA, 50mg/kg IP, BID) or vehicle control for 2.5 weeks prior to sacrifice for downstream analyses and single-cell RNA sequencing (scRNA) on tumors. Results: In vitro inhibition of p38 MAPK prevented CAF activation into an inflammatory fibroblast, when stimulated with IL1α, demonstrated through bulk RNAseq and ATACseq. Bulk ATACseq revealed epigenetic regulation of the inflammatory CAF phenotype by IL1-mediated activation of p38 MAPK. Stromal-specific deletion of Il1r1 or Mapk14 resulted in signification reduction of tumor weight and intratumoral myeloid-derived suppressor cells. Additionally, pharmacologic blockade of both IL1R1 (AKA) and p38 MAPK inhibition (PEX) altered intratumoral immune cell and CAF populations, by flow cytometry and scRNA. Lastly, p38 inhibition or IL1R1 blockade combined with chemotherapy significantly reduced tumor burden and favorably altered the immune landscape in a PDAC genetically engineered mouse model. Conclusions: These findings provide important mechanistic data in preclinical PDAC models to explore p38 MAPK inhibition in combination therapy to target the fibrotic stroma and immunosuppressive tumor microenvironment. Citation Format: Samara P. Singh, Austin R. Dosch, Siddharth Mehra, Iago de Castro Silva, Vanessa Tonin Garrido, Anna Bianchi, Haleh Amirian, Edmond W. Box, Jashodeep Datta, Nagaraj S. Nagathihalli, Nipun B. Merchant. Fibroblast-specific IL1R1-p38 MAPK signaling sustains stromal inflammation and contributes to therapeutic resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C025.

Abstract The Bcl-2 inhibitor venetoclax (VEN)/hypomethylation agent (HMA) combination achieves high response rates, has improved outcomes for many patients with AML and is now considered standard of care for patients who are older or unfit to receive intensive chemotherapy. However, the median overall survival is only 14.7 months on this regimen and only 2.5 months post relapse. Molecular analysis demonstrates that mutations in TP53 and oncogenic kinases are key determinants of lower response rates and early relapse. Preclinical studies also show that increased kinase signaling in AML stem/progenitor cells in TP53 mutant AML. The heat shock protein 90 (HSP90) chaperone, a key regulator of proteostasis, is responsible for the correct folding of kinases and transcription factors. HSP90-associated-epichaperomes, formed in malignant cells, are complexes consisting of HSP90, co-chaperones, and associated proteins that support the maturation, activity, and stability of many cancer-associated kinases and transcription factors including mutated TP53. Hence, HSP90 epichaperome inhibition has the potential of targeting TP53 mutant AML. In contrast to other HSP90 ATP inhibitors, PU-H71 (zelavespib) is a competitive inhibitor specific for the ATP binding site of HSP90 epichaperomes. We here investigate the therapeutic potentials of targeting HSP90 epitherachorme with PU-H71 in TP53 mutated AML. Western blot analysis found increased HSP90 and several signaling proteins in TP53 knockout and mutant Molm13 cells generated by CRISPR/cas-9 or by exposing to idasanutlin, compared to the isogeneic wild-type controls. Using a fluorochrome-labelled PU-H71 and flow cytometry, we demonstrate the presence of HSP90 epichaperomes in AML cells and AML stem/progenitor cells with TP53 mutations, but not in normal bone marrow and bone marrow stem/progenitor cells. PU-H71 effectively kills AML cells and AML stem/progenitor cells with various TP53 mutations, and prolongs survival in TP53-mutant AML xenograft mice with minimal effects on normal CD34+ bone marrow cells and hematopoiesis. PU-H71 increased Bim expression and enhanced VEN activity in AML cells and AML stem/progenitor cells with TP53 mutations. Importantly, in a mixture of TP53 wild-type/R248W Molm13 cells (1000:1), nutlin3a selectively killed TP53 wild-type but enriched TP53 mutant Molm13 cells; VEN treatment favored the outgrowth of TP53-mutant cells, while PU-H71 effectively killed TP53 wild-type and mutant cells. Furthermore, PU-H71 exhibited anti-leukemia activity against both TP53 WT and mutant AML cells, which was further enhanced by VEN in vivo in a xenograft model of mixed TP53 WT and mutated Molm13 cells (10:1). Our data support that the HSP90 epichaperome is essential for the growth and survival of AML and AML stem/progenitor cells harboring mutant TP53. Inhibition of HSP90 by PU-H71 targets AML cells/stem/progenitor cells enhances VEN activity and prevents outgrowth of VEN-resistant TP53 mutant AML cells. This concept warrants clinical evaluations. Citation Format: Bing Carter, Po Yee Mak, Wenjing Tao, Lauren B Ostermann, Yuki Nishida, Steffen Boettcher, Michael Andreeff. Targeting HSP90 epichaperome in TP53 mutant AML [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A08.

Objective Caffeine supplementation is a commonly used nutritional practice. Exogenous metabolites from caffeine, such as paraxanthine, theobromine and theophylline, are eventually excreted through urine. Yet, it is less clear whether caffeine would induce endogenous metabolites altered during exercise. Urine metabolomics is non-invasive method, which mainly focus on alterations of endogenous metabolic profiles caused by diseases, drugs, and lifestyle and nutritional interventions as well. Therefore, the purpose of the present study was to examine the effects of supplementation with caffeine in a well-designed high intensity interval training (HITT). We identified significant alterations in urinary metabolite levels and revealed key metabolic pathways involved in caffeine supplementation in HITT. Methods We performed a randomized, double-blind, placebo- controlled crossover study. Twelve women basketball players (age:19.12 ± 2.64 years, mass: 174.73 ± 5.18 cm, height: 62 ± 5.09 kg, with 8.50±2.11 years training period for basketball) were randomized to placebo (PLA) or caffeine (CAF) with dosage of 3mg on the basis of body weight (kg) 45min before a field HITT test. The test was repeated after three days when players were crossed over to the alternate test. The test began with a 30 min warmup, followed by a high intensity intermittent exercise trail with incremental load for about 25min, and a cool-down. Players are familiar with the test program which included 55 sets of dribble shuttle-run, pass, shoot, and rebound with basketball with a distance of 1540m (55 × 28m), the interval between two sets was gradually reduced. Performance (completed time), heart rates immediate (HR0min) and 1 min (HR1min) after test, blood lactate (BLa), proteinuria and ratings of perceived exertion (RPE) were collected during each protocol. Urine samples were obtained before and 1 h after of the test. 1H-NMR spectra (Bruker AVANCE III HD 600MHz) were obtained and then processed by NMR spectra (MestReNova 9.0). The binning values of NMR spectra are imported into MATLAB, and the peaks are aligned with the icoshift algorithm. Then concentrations of the aligned metabolites were calculated by converting the integral area of proton signals with that of the TSP. Pattern recognition was performed to the processed NMR data, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Characteristic metabolites were identified that contribute most to the metabolic pattern between groups according to the OPLS-DA models. Finally, we analyzed the metabolic pathway by importing characteristic metabolites with concentrations into the Enrichment Analysis (MetaboAnalysis 3.0) to determine the metabolic pathways with the greatest disturbance related to caffeine during exercise. Moreover, the main effects of exercise, caffeine and the interaction between exercise and caffeine were determined by Repeated measure GLM analysis (Spss 22.0). Results (1) Compared with PLA, CAF had no significant difference in the completed time (25.9 min vs. 26.8 min). Repeated measured analysis showed that there was significant overall time effect on the routine training monitoring parameters, while no statistically group differences in HR0min, HR1min, BLa (199.02±21.36 vs.189.00±22.38 bpm; 148.02±12.60 vs.148.02±20.34 bpm, and 8.89±2.23 vs. 9.52±2.91 mmol/L, respectively). For the qualitative indexes, the positive rate of urine ketone bodies was increased, while RPE did not changed. (2) We identified 32 metabolites in urine sample. PCA showed distinct differentiation of metabolic patterns between each two groups in the four groups (PLAbefore, PLApost, CAFbefore, CAFafter). By using OPLS-DA, we found that the urine metabolic profiles were differences in between caffeine supplementation group and placebo group during the test. OPLS-DA revealed the identified metabolites of exercise and caffeine respectively, among them, lactate, butyric acid, isobutyric acid, 3-hydroxybutyric acid and pyruvic acid could be used as metabolic biomarkers in the HITT response. Supplementation of caffeine increased the production of fat metabolites in urine compared to the PLA. Enrichment analysis showed that the disturbed metabolic pathways shared by PLA and CAF were purine metabolism, glycolysis, insulin signal transduction, galactose metabolism, gluconeogenesis, glucose-alanine cycle, sphingolipid metabolism, alanine metabolism and citric acid cycle. Yet, when compared to the PLA, CAF enhanced fat metabolism and increased pyruvate metabolism, cysteine metabolism and mitochondrial electron transport. These results suggest that caffeine could promote fatty acid metabolism and amino acid metabolism to improve aerobic metabolism and to reduce oxidative stress, and thus promote exercise capacity. (3) Covariance analysis showed that there were significant individual-specific effects of caffeine supplementation. Conclusions Caffeine supplementation during HITT promoted the fat metabolism, and upregulated the TCA, pyruvate metabolism and mitochondrial electron transfer. It is suggested that caffeine could, to some extent, promote energy supply shift from anaerobic metabolic to an aerobic manner, and the enhancement of fat oxidation would be beneficial to glycogen storage for intensively long-duration exercise. Moreover, there are obvious individual differences in caffeine response on sports.

Abstract Objectives The objective of our study is to evaluate the effect of storage temperature and time to analysis on arterial blood gas parameters in order to extend the CLSI recommendations. Methods Stability of 12 parameters (pH, pCO₂, pO₂, Na+, K+, Ca2+, glucose, lactate, hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin) measured by GEM PREMIER™ 5000 blood gas analyzer was studied at room temperature and at +4 °C (52 patients). The storage times were 30, 45, 60, 90 and 120 min. Stability was evaluated on the difference from baseline, the difference from the analyte-specific measurement uncertainty applied to the baseline value, and the impact of the variation on the clinical interpretation. Results At room temperature, all parameters except the lactate remained stable for at least 60 min. A statistically significant difference was observed for pH at T45 and T60 and for pCO2 at T60 without modification of clinical interpretation. For lactate, clinical interpretation was modified from T45 and values were outside the range of acceptability defined by the measurement uncertainty. All parameters except pO2 remained stable for at least 120 min at +4 °C. Conclusions A one-hour transport at room temperature is compatible with the performance of all the analyses studied except lactate. If the delay exceeds 30 min, the sample should be placed at +4 °C for lactate measurement. If the samples are stored in ice, it is important to note that the pO2 cannot be interpreted.

Abstract Electrochemical water oxidation reaction (WOR) lies among the most forthcoming approaches toward eco-conscious manufacturing of green hydrogen owing to its environmental favors and high energy density values. Its vast commoditization is restricted by high-efficiency and inexpensive catalysts that are extensively under constant research. Herein, calcium, magnesium, and yttrium doped lithium nickel phosphate olivines (LiNi1−x M x PO, LNMP; x = 0.1–0.9; M = Ca2+, Mg2+, and Y3+) were synthesized via non-aqueous sol-gel method and explored for catalytic WOR. Lithium nickel phosphates (LNP) and compositions were characterized via Fourier transform infrared, scanning electron microscopy, X-ray diffraction, and energy dispersive X-ray diffraction techniques for the structural and morphological analyses. Glassy carbon electrode altered with the LNMPs when studied in a standard redox system of 5 mM KMnO4, displayed that yttrium doped LNP, i.e. LNYP-3 exhibits the highest active surface area (0.0050 cm2) displaying the lowest average crystallite size (D avg) i.e. ∼7 nm. Electrocatalytic behavior monitored in KOH showed that LNMP-2 offers the highest rate constant “k o,” value, i.e. 3.9 10−2 cm s−1 and the largest diffusion coefficient “D o,” i.e. 5.2 × 10−5 cm2 s−1. Kinetic and thermodynamic parameters demonstrated the facilitated electron transfer and electrocatalytic properties of proposed nanomaterials. Water oxidation peak current density values were indicative of the robust catalysis and facilitated water oxidation process besides lowering the Faradic onset potential signifying the transformation of less LNP into more conducive LNMP toward water oxidation.

Introdução: O maior foco das pesquisas odontológicas nos últimos 60 anos tem sido a adesão e suas técnicas. Mais de 7000 artigos já foram publicados a este respeito. O desenvolvimento dos materiais odontológicos adesivos e as técnicas a eles relacionadas possuem uma história interessante, onde descobertas do passado ainda são usadas de alguma forma no presente. Objetivo: expor, através de uma revisão de literatura, um breve histórico sobre materiais e técnicas restauradoras, bem como o estágio atual da odontologia adesiva, com ênfase na tradução de evidências baseadas em pesquisas laboratoriais para a prática clínica. Materiais e Métodos: Foram selecionados livros de preferência do autor para a introdução de conceitos clássicos e artigos de revisão publicados nos últimos 10 anos, utilizando as cinco palavras-chave: “Dental Bonding” AND “Dental Cements” AND “Resin Cements” AND “Adhesives” AND “Ceramics”, sorteados pela melhor combinação na plataforma Pub/Med/MEDLINE. Resultados: Duzentos e um artigos, foram encontrados, sendo utilizados para análise qualitativa e quantitativa aqueles pertinentes ao direcionamento do autor, de acordo com o tema. Conclusão: Considerando as limitações do estudo, concluiu-se que a odontologia adesiva é uma área que segue em constante desenvolvimento, fundamental para a realização de restaurações minimamente invasivas e estéticas. Onde para que seja possível consequentemente longevidade clínica, os materiais utilizados e substrato dentário requerem conhecimento do profissional e fidelidade na execução de um correto pré-tratamento das superfícies, respeitando suas naturezas e composições.Descritores: Colagem Dentária; Cimentos Dentários; Cimentos de Resina; Adesivos; Cerâmica.ReferênciasVan Meerbeek B, De Munck J, Yoshida Y, Inoue S, Vargas M, Vijay P, et al. Buonocore memorial lecture. Adhesion to enamel and dentin: current status and future challenges. Oper Dent. 2003;28:215-35.Miyashita E, Fonseca AS. 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