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1
Alotaibi, Abdulmajeed, Anna Podlasek, Amjad AlTokhis, Ali Aldhebaib, Rob A. Dineen, and Cris S. Constantinescu. "Investigating Microstructural Changes in White Matter in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging." Brain Sciences 11, no. 9 (August 29, 2021): 1151. http://dx.doi.org/10.3390/brainsci11091151.
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Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.
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Abeykoon, Jithma P., Saurabh Zanwar, Stephen M. Ansell, Shaji Kumar, Carrie A. Thompson, Thomas Matthew Habermann, Thomas E. Witzig, et al. "Outcomes with rituximab plus bendamustine (R-Benda), dexamethasone, rituximab, cyclophosphamide (DRC), and bortezomib, dexamethasone, rituximab (BDR) as primary therapy in patients with Waldenstrom macroglobulinemia (WM)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 7509. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.7509.
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7509 Background: Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Herein, we compare 3 commonly used regimens in WM: R-Benda, DRC, and BDR in frontline setting. Methods: Patients (Pts) with active WM seen at Mayo Clinic between 2000 & 2018 who received R-Benda, DRC or BDR as primary therapy were included in this retrospective study. Response rates were assessed by Consensus Criteria. All time to event analyses were performed from the frontline therapy, using Kaplan-Meier method. Results: The study included 172 pts with active WM (R-Benda, n=67, DRC, n=75, BDR, n=30).The median follow-up for the entire cohort was 3.7 years (y) (95% CI 3.7-3.0). Baseline characteristics, including IPSS, and time to frontline therapy from WM diagnosis were similar across the 3 cohorts. Clinically relevant endpoints are shown in the Table. Hematologic and non-hematologic toxicities were similar across the 3 groups. Grade 3 neuropathy requiring treatment discontinuation was encountered in 13% pts treated with BDR. 56 pts received subsequent salvage therapy [(10% in R-Benda arm, 44% in DRC arm, & 53% in BDR arm]; 29% pts in the R-Benda arm and 30% pts in DRC arm received a PI-based regimen while 69% pts in the BDR arm received alkylator-rituximab based therapy. Conclusions: Outcomes (MRR, TTNT and EFS) with frontline R-Benda are superior in comparison to frontline DRC or BDR in patients with WM. Clinically relevant endpoints are not significantly different with DRC vs. BDR. The toxicity profile across the 3 groups was comparable. [Table: see text]
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Sabah, Katrina, Nachshon Meiran, and Gesine Dreisbach. "Examining the Trainability and Transferability of Working-Memory Gating Policies." Journal of Cognitive Enhancement 5, no. 3 (January 27, 2021): 330–42. http://dx.doi.org/10.1007/s41465-021-00205-8.
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AbstractInternal working memory (WM) gating control policies have been suggested to constitute a critical component of task-sets that can be learned and transferred to very similar task contexts (Bhandari and Badre (Cognition, 172, 33–43, 2018). Here, we attempt to expand these findings, examining whether such control policies can be also trained and transferred to other untrained cognitive control tasks, namely to task switching and AX-CPT. To this end, a context-processing WM task was used for training, allowing to manipulate either input (i.e., top-down selective entry of information into WM) or output (i.e., bottom-up selective retrieval of WM) gating control policies by employing either a context-first (CF) or context-last (CL) task structure, respectively. In this task, two contextual cues were each associated with two different stimuli. In CF condition, each trial began with a contextual cue, determining which of the two subsequent stimuli is target relevant. In contrast, in the CL condition the contextual cue appeared last, preceded by a target and non-target stimulus successively. Participants completed a task switching baseline assessment, followed by one practice and six training blocks with the WM context-processing training task. After completing training, task-switching and AX-CPT transfer blocks were administrated, respectively. As hypothesized, compared to CL training condition, CF training led to improved task-switching performance. However, contrary to our predictions, training type did not influence AX-CPT performance. Taken together, the current results provide further evidence that internal control policies are (1) inherent element of task-sets, also in task switching and (2) independent of S-R mappings. However, these results need to be cautiously interpreted due to baseline differences in task-switching performance between the conditions (overall slower RTs in the CF condition). Importantly though, our results open a new venue for the realm of cognitive enhancement, pointing here for the first time to the potential of control policies training in promoting wider transfer effects.
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Adamia, Sophia, Jennifer Hodges, Patrick M. Pilarski, Steven Treon, Michael J. Mant, Tony Reiman, Andrew R. Belch, and Linda M. Pilarski. "Accumulation of Inherited and Acquired Mutations in Hyaluronan Synthase1 Gene May Contribute Oncogenesis in Multiple Myeloma and Waldenstrom’s Macroglobulinemia." Blood 108, no. 11 (November 16, 2006): 3432. http://dx.doi.org/10.1182/blood.v108.11.3432.3432.
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Abstract In multiple myeloma (MM) and Waldenstrom’s macroglobulinemia (WM), we identified three alternatively and/or aberrantly spliced HAS1 transcripts—HAS1Va, HAS1Vb and HAS1Vc. Statistical analysis of samples taken from 172 untreated MM patients showed that expression of HAS1Vb, an intronic splice variant, strongly correlates with poor survival (P=0.005). We investigated the molecular basis of intron retention during HAS1 splicing in MM and WM patients. We speculated that aberrant HAS1 splicing and the associated reduced survival of MM patients, resulted from an accumulation of mutations in aberrantly spliced regions of HAS1. Exons and introns 3 and 4 of the HAS1 gene were sequenced, because they are hotspots for splicing aberrations. Sequencing of HAS1 was performed for a total 11 patients with WM and MM and 2 healthy donors. HAS1 gene templates for sequencing were isolated from a multiple sorted cell subpopulations, including malignant B and plasma cells (PC), non-malignant T cells and buccal epithelial cells (BECs), as well as hematopoietic progenitor cells (HPCs) from mobilized blood of MM patients. We detected sets of inherited and acquired genetic variations in HAS1 that were recurrent within 5–11 of the MM and WM patients analyzed, but absent from healthy donors. We also identified genetic variations that were unique to individual patients. Those HAS1 mutations found in all cell types tested, including BECs and from the hematopoietic cells (B, PC, T and HPCS) were classified as germline mutations. Those mutations found in hematopoietic cells but absent from BECs were classified as hematopoietic origin which acquired during the lifetime of the individual. Mutations identified only in malignant MM and WM B cells and PCs (absent from T cells, HPCs and BECs) were classified as acquired tumor specific mutations. Recurrent HAS1 mutations were found among both inherited and acquired sets of mutations. Some recurrent HAS1 mutations were common to both MM and WM. The high frequency of inherited HAS1 mutations suggests that they confer predisposition for developing MM or WM. Our sequencing analysis suggests that in MM and WM, sequential accumulation of genetic variations occurs as hematopoietic cells differentiate. Our data also suggest that hematopoietic origin mutations are necessary but by no means sufficient to drive HAS1 gene splicing. Effects of hematopoietic origin mutations on HAS1 splicing are manifested in malignant MM cells in context of additional tumor specific mutations, which are acquired by circulating B cells and passed to their plasma cell progeny. This suggests that mutations which lead to aberrant splicing of HAS1 pre-mRNA undergo mutational selection events, and leave a mutational “trace” throughout the hematopoietic cell lineage, including tumor cells. Existence of same mutational events detected in HAS1 gene from MM and WM supports the speculation that the precursors of both diseases may undergo a series of shared genetic events, diverging only when tumor specific mutations accumulate in distinct subsets of B lineage cells. In silico comparison of splicesomal assembly between wild type and mutated HAS1 gene gave a pattern that precisely predicts partial retention of intron and aberrant splicing of the HAS1 gene.
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Famdan, Famdan, and Arif Hartono. "The Influence of Leadership Style & Environment on Employee Performance With Work Motivation as a Mediation Variable PT. Unilab Perdana." Journal Research of Social Science, Economics, and Management 2, no. 03 (October 25, 2022): 301–10. http://dx.doi.org/10.59141/jrssem.v2i03.270.
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The title of this research is the analysis of the influence of leadership style (LS) and work environment (WE) on employee performance (EP) with work motivation (WM) as a mediating variable at PT. Prime Unilab. This study aims to determine the mediating effect of work motivation in the relationship between leadership style and work environment on employee performance. This research was conducted quantitatively and used a questionnaire as a data collection method. The population is 300 employees. The research sample used was 172 employees. Therefore, sampling is simple and multiple linear regression analysis and path analysis. The results of this study indicate that leadership style and work environment have a positive and significant influence on employee performance, leadership style and work environment have a positive and significant influence on work motivation. Work motivation can mediate the relationship between leadership style and work environment on employee performance.
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Dimopoulos, Meletios A., Marie-Christine Kyrtsonis, Evdoxia Hadjiharissi, Argiris Symeonidis, Eurydiki Michalis, Panayiotis Repoussis, Costas Tsatalas, et al. "Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's Macroglobulinemia (WM) and the Importance of Serum Lactate Dehydrogenase (LDH)." Blood 114, no. 22 (November 20, 2009): 2845. http://dx.doi.org/10.1182/blood.v114.22.2845.2845.
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Abstract Abstract 2845 Poster Board II-821 Recently, the IPSS has been proposed as a staging system for patients with WM who require treatment. This system is based on five adverse covariates: age >65 years, hemoglobin '11.5 g/dL, platelet count '100×109/L, beta2-microglobulin >3 mg/L and serum monoclonal protein concentration >7 g/dL. Low risk is defined by the presence of ' 1 adverse characteristic and age '65 years, intermediate risk by the presence of 2 adverse characteristics or only age >65 years and high risk by the presence of >2 adverse characteristics. The aim of our analysis was to independently validate the significance of IPSS not only for overall survival (OS) but also for cause-specific survival (CSS) (i.e deaths unrelated to WM or to complications of treatment are censored). Furthermore, we wanted to assess whether elevated serum LDH may add to the strength of IPSS. From the data base of the Greek Myeloma Study Group, we identified 335 patients with clearly defined criteria for diagnosis and for initiation of treatment who were treated over the last 20 years. Main primary therapies included alkylating agents (43%), CHOP (3%), nucleoside analogues (3%) and rituximab either alone (3%) or in combination with conventional chemotherapy (44%). Before the initiation of treatment the median age of patients was 68 years (range 28 to 89 years). Fifty-nine percent of patients were >65 years, while 75% of patients had hemoglobin levels of <11.5 g/dL, 57% had beta2-microglobulin of >3 mg/L, 33% had lymphadenopathy, 32% splenomegaly, 23% presence of B-symptoms, 12% platelet count of <100×109/L and 6% had serum monoclonal protein concentration of >7 g/dL. Among 152 patients who had died by the time of this analysis, 33 patients (22%) had died due to causes not related to WM, to disease transformation, to myelodysplasia or to complications of treatment. Most frequent causes were second primary solid tumors, celebrovascular accidents, coronary artery disease and congestive heart failure. For the whole group of patients median OS was 105 months and median CSS was 116 months. Patients were divided into low risk (23%), intermediate risk (38%) and high risk (39%), according to IPSS. Median OS was 161 months, 105 months and 64 months respectively (p<0.01) and median CSS was 172 months, 116 months and 94 months, respectively (p<0.01). Elevated serum LDH >250 IU/L (normal upper limit 225 IU/L) was found in 18% of patients. Serum LDH was elevated in 16%, 12% and 24% of patients with low, intermediate and high risk, respectively. Median OS according to low or elevated LDH was 109 versus 63 months (p<0.01) and median CSS was 116 versus 64 months, respectively (p<0.01). Serum LDH was able to divide high risk patients into two subgroups with different outcome. The median OS was 94 and 35 months, for normal and high LDH group, respectively (p<0.01) and the median CSS was 104 and 36 months, for normal and high LDH group, respectively (p<0.01). We conclude that the recently proposed IPSS for WM is a robust staging system and it is also applicable to patients who received primary treatment with rituximab-based regimens. Elevated serum LDH is an adverse prognostic factor in WM. The combination of high risk according to IPSS and elevated serum LDH identified a subset of patients with very poor outcome. Such patients should be included in trials that evaluate novel agents and new treatment strategies including upfront high dose therapy. Disclosures: No relevant conflicts of interest to declare.
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Chaul Barbosa, Caroline, Lisa Marie DeAngelis, and Christian Grommes. "Ibrutinib associated infections: A retrospective study." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e19020-e19020. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e19020.
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e19020 Background: Ibrutinib (IBRU) is a Bruton tyrosine kinase (BTK) inhibitor that has been FDA approved for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and Waldenstrom's Macroglobulinemia (WM). BTK inhibition may contribute to immunosuppression through B- and T-cell inhibition, resulting in an increase in infections. We therefore characterized IBRU-related infections retrospectively. Methods: The study was an IRB approved retrospective review. Patients (pts) treated with IBRU between 4/2014-11/2016 who developed any infection were identified using ICD10 codes in a clinical database. Study population was defined using descriptive statistics. Results: 200 pts were identified: 78 pts had CLL (39%), 30 diffuse large B-cell lymphoma (15%), 28 MCL (14%), 19 WM (9.5%), 15 (7.5%) marginal zone lymphoma, 14 (7%) follicular lymphoma, 7 (3.5%) multiple myeloma, 7 (3.5%) T-cell lymphoma and 2 (1%) primary central nervous system lymphoma (PCNSL). Median age was 68 (range 28-96), 34% were men and median ECOG was 1. The majority of pts received IBRU as second line treatment (172, 86%) with a median of 2 prior lines of treatment; 23 pts (11.5%) were post transplant. Median IBRU dose was 420mg daily (range 140-840mg), administered a median of 316 days (range 3-1780). Single agent IBRU was used in 162 pts (81%). 105 pts (52%) developed an infection, with pneumonia (30%), upper airway infection (26%); skin infection (18%); and sinusitis (13%) being the most common. 10 (9.5%) had neutropenic fever and 1 (1%) cryptococcal pneumonia. Seven (7%) developed fungal infections, with invasive aspergillosis in 5 (5%). 34 (32%) developed ≥3 infections. 46 pts (44%) were hospitalized, 10 (9.5%) interrupted IBRU and 3 pts (2.9%) died due to infections (2 pneumonia; 1 neutropenic fever). The median time to infection after starting IBRU was 70 days (range 2-1261). The highest infection rate was seen in pts with PCNSL (100%, 2/2), MZL (67%, 10/14), followed by CLL (64%, 50/78). Conclusions: We identified infections in half of the pts treated with IBRU. Pts treated with IBRU should be monitored closely for the development of infections, particularly airway infections.
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Dale, David C., Steven P. Treon, David F. McDermott, Diego Cadavid, Xia Luo, Varun Garg, Weihua Tang, et al. "Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States." Blood 138, Supplement 1 (November 5, 2021): 2186. http://dx.doi.org/10.1182/blood-2021-152990.
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Abstract Introduction: Peripheral leukocyte deficiency is a common feature of multiple diseases and may render affected individuals susceptible to infections, both common and opportunistic. The CXCR4 chemokine receptor regulates the trafficking of leukocytes among the bone marrow, blood, and lymphatic system (Al Ustwani O, et al. Br J Haematol. 2014;164:15-23). Mavorixafor is an orally available investigational, small-molecule, selective antagonist of the CXCR4 receptor with potential to restore physiological trafficking and maturation of white blood cells (WBCs). Mavorixafor was previously shown to increase totals and subsets of WBCs in healthy volunteers and in a phase 2 clinical trial in adults with WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome (Stone N, et al. Antimicrob Agents Chemother. 2007;51(7):2351-2358; Dale D, et al. Blood. 2020;136(26):2994-3003). Here, we report the effect of daily oral administration of mavorixafor on peripheral WBC counts and subsets in patients with clear cell renal cell carcinoma (ccRCC), WHIM syndrome, and Waldenström's macroglobulinemia (WM). Methods: Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations. Results: In the study evaluating combination mavorixafor (400 mg QD) and axitinib in ccRCC, total WBC count, ANC, ALC, and AMC increased to 153%, 158%, 143%, and 182% of baseline after 4 weeks (n=49), and with increases sustained at 159%, 171%, 139% and 166% of baseline after 6 months' treatment (n=20). In the study evaluating mavorixafor in combination with nivolumab in ccRCC, total WBC count, ANC, ALC, and AMC increased to 146%, 143%, 141%, and 179% of baseline after 4 weeks (n=9), and with increases sustained at 147%, 136%, 152%, and 191% of baseline after 6 months (n=2). In an interim analysis of the phase 1b trial in WM, compared to screening values, total WBC count, ANC, ALC, and AMC increased to 192%, 170%, 219%, and 186% of baseline after 4 weeks (n=8), and with increases sustained at 163%, 192%, 106%, 172% of baseline after 6 months' (n=5) treatment. In the WHIM syndrome phase 2 extension, total WBC count, ANC, ALC, and AMC increased to 339%, 652%, 239%, and 486% of baseline after 6 months' (n=5) treatment, with annualized infection rate decreasing from 5.6 (SD ± 3.13) events at baseline to 2.2 (SD ± 0.93) events after 40 months. Mavorixafor was generally well tolerated, with manageable safety profile across all indications either alone or in combination with other drugs. Conclusions: Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome. Assessment of the beneficial effects of mavorixafor on total and WBC subsets is ongoing in a phase 3 trial of WHIM syndrome and a phase 1 trial of severe chronic neutropenia (SCN) that will assess the potential to correct cytopenias by elevating total WBC counts. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Treon: AbbVie: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; X4: Research Funding. McDermott: Johnson and Johnson: Consultancy, Honoraria; Genentech: Research Funding; Eisia Inc.: Consultancy, Honoraria; Werewolf Therapeutics: Consultancy, Honoraria; Calithera Biosciences: Consultancy, Honoraria; X4 Pharmaceuticals: Research Funding; Iovance: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Exelixis: Research Funding; Alkermes, Inc.: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luo: X4 Pharmaceuticals: Consultancy. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bhandari: X4 Pharmaceuticals: Current Employment.
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Lu, Jiadong, Songli Zhang, Leizhi Zhang, Chenxi Wang, and Chunying Min. "Preparation and Properties of Hollow Glass Microspheres/Dicyclopentadiene Phenol Epoxy Resin Composite Materials." Materials 16, no. 10 (May 16, 2023): 3768. http://dx.doi.org/10.3390/ma16103768.
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With the development of the integrated circuit and chip industry, electronic products and their components are becoming increasingly miniaturized, high-frequency, and low-loss. These demand higher requirements for the dielectric properties and other aspects of epoxy resins to develop a novel epoxy resin system that meets the needs of current development. This paper employs ethyl phenylacetate cured dicyclopentadiene phenol (DCPD) epoxy resin as the matrix and incorporates KH550 coupling-agent-treated SiO2 hollow glass microspheres to produce composite materials with low dielectric, high heat resistance, and high modulus. These materials are applied as insulation films for high density interconnect (HDI) and substrate-like printed circuit board (SLP) boards. The Fourier transform infrared spectroscopy (FTIR) technique was used to characterize the reaction between the coupling agent and HGM, as well as the curing reaction between the epoxy resin and ethyl phenylacetate. The curing process of the DCPD epoxy resin system was determined using differential scanning calorimetry (DSC). The various properties of the composite material with different HGM contents were tested, and the mechanism of the impact of HGM on the properties of the composite material was discussed. The results indicate that the prepared epoxy resin composite material exhibits good comprehensive performance when the HGM content is 10 wt.%. The dielectric constant at 10 MHz is 2.39, with a dielectric loss of 0.018. The thermal conductivity is 0.1872 Wm−1 k−1, the coefficient of thermal expansion is 64.31 ppm/K, the glass transition temperature is 172 °C, and the elastic modulus is 1221.13 MPa.
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Kriangkum, Jitra, Andrew R. Belch, and Linda M. Pilarski. "Clinically Significant Aberrant HAS1Vb Splicing of the Hyaluronan Synthase 1 Gene (HAS1) Requires a Combination of Mutations and Deletions in Introns 3 and 4 of HAS1 Minigene,." Blood 118, no. 21 (November 18, 2011): 3931. http://dx.doi.org/10.1182/blood.v118.21.3931.3931.
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Abstract Abstract 3931 Clinically important aberrant splicing of the hyaluronan synthase 1 gene (HAS1) occurs in malignant B cells from multiple myeloma (MM) and Waldenstrom macroglobulimenia (WM) patients but is undetectable in B cells from healthy donors (HD)1. HAS1 splice variants are generated by aberrant alternative splicing (AS) within exons 3, 4 and 5, involving exon 4 skipping (Va), partial intron 4 retention (Vc, Vd) or a combination of both (Vb). Aberrant splicing of HAS1Vb has previously shown to correlate with reduced survival in a cohort of MM patients1. In patients, frequent mutations have been identified in introns 3 and 4, suggesting their roles in AS1. To identify genetic regions involved in splice site selection leading to HAS1Vb expression, we performed in vitro sequence manipulation of introns 3 and 4. We established a mammalian expression system to analyse HAS1 splicing by fusing a minigene extending from exon 3 to exon 5 with the upstream cDNA sequence. In an unaltered sequence of the HAS1 minigene, splicing of HAS1 full length predominated, with trace amount of variants, including the novel HAS1Vd, identified for the first time in transfectants. HAS1Vd shared an alternative acceptor site with HAS1Vb (retained 59 bp of downstream intron 4) but unlike HAS1Vb, retained exon 4. Analysis of peripheral blood mononuclear cells (PBMC) revealed that 9% of healthy donors (n=102) and MM patients (n=93) expressed HAS1Vd. About 2% coexpressed HAS1Vb and Vd. In this cohort of patients, HAS1Vb was found in 20% of unfractionated MM PBMC compared to 5% in HD PBMC, supporting our previous finding that HAS1Vb was restricted to sorted MM B cells1and suggesting that in HD PBMC, non-B cells are responsible for this splicing. While MM PBMCs expressed HAS1Vb>Vd, HD PBMCs and transfectants expressed HAS1Vd>Vb, indicating that splicing directed by the minigene construct was substantively different from that occurring in MM patients. In transfectants, partial deletion of HAS1 intron 4 increased HAS1Vd expression but did not affect HAS1Vb despite the fact that both variants use the same 3' splice site in intron 4. Proper joining of exons 3, 4 and 5 required a minimum of 172 bp of downstream intron 4 and acceptor site selection may be regulated by sequence between 172 and 84 bp upstream of exon 5. Thus, changes in intron 4 alone were insufficient to promote the splicing pattern observed in patients (i.e., elevated HAS1Vb). We then employed site directed mutagenesis to alter multiple G-rich regions in downstream intron 3, a strategy which enhanced exon 4 skipping as shown by increased HAS1Va expression, but did not lead to HAS1Vb splicing. Minimal manipulation to promote exon 4 skipping included base changes within the 2 tandem G-repeats (8 bp) located 73 bp upstream of exon 4, where splicing enhancer/silencer sequences were also identified. Thus, changes in intron 3 also affected the HAS1 splicing profile but like deletions in intron 4, were insufficient on their own to promote HAS1Vb expression. We next developed expression constructs that combined deletion in intron 4 with mutations in intron 3. We are able to demonstrate that when both introns were co-modified, the splicing pattern shifted towards increased HAS1Vb expression, similar to that observed in malignant cells from MM patients. Our previous work showed that deletions or mutations in the 3' end of intron 4 are frequent in MM; in silico analysis predicts splicing to form HAS1Vb2. To determine whether intron 3 genetic changes occur in patients, we sequenced intron 3 from genomic DNA of 50 MM PBMC. In 22/50 patients, 18 recurrent mutations unique to MM were identified in intron 3; many were also recurrent in our previous study2. Individual mutations recurred in 2–7 patients. Among these, 17/18 recurrent mutations increased the G-C content of intron 3 and 6/18 created or disrupted G runs in intron 3. This supports the idea that in MM patients, cumulative variations in introns 3 and 4 alter splice site selection, operationally resulting in loss of HAS1Vd and enhanced expression of the clinically relevant HAS1Vb variant. We speculate that individuals who accumulate genetic variations in introns 3 and 4 of HAS1 are predisposed to aberrant splicing of HAS1 which may contribute to development of malignancy in MM and WM. Disclosures: Belch: Celgene: Research Funding; Onyx: Research Funding.
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Kobuszewski, Bartosz, Piotr Winciunas, Jacek Pruszyński, and Wojciech Stefan Zgliczyński. "Sickness absence in 2019-2020 and the activities of the Social Insurance Institution (ZUS) to prevent incapacity for work." Wiedza Medyczna 4, no. 1 (June 28, 2022): 33–38. http://dx.doi.org/10.36553/wm.112.
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Sickness absence is an important measure of the current situation on the labor market and a source of information on the health condition of the working part of the society. It is also a phenomenon that directly affects the economy. Monitoring the size and causes of sickness absence enables the adjustment of the social and health policy in the country. In Poland, sickness absence is most often analyzed in the context of people receiving sickness allowance - a benefit from the social security system granted to insured persons in the event of incapacity to work due to illness. In 2020, there were noticed over 256 million days of sickness absence, of which the largest part (45 million days) were due to conditions related to pregnancy, childbirth and puerperium. In turn, COVID-19 was responsible for almost 5 million days of sickness absence, of which 179 thousand days is the period of hospitalizations.
In order to prevent permanent incapacity to work, the Social Insurance Institution (ZUS) runs a program of comprehensive therapeutic rehabilitation for insured persons with: diseases of motor organs (also after accidents), cardiovascular and respiratory diseases, psychosomatic diseases, oncological diseases after treatment of breast cancer and voice organ' cancer.
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Ostrowski, Janusz, Wojciech Stefan Zgliczyński, Jarosław Pinkas, and Ryszard Gellert. "History of the School of Public Health at the Centre of Postgraduate Medical Education (1971 to 2021)." Wiedza Medyczna 4, no. 1 (June 28, 2022): 1–7. http://dx.doi.org/10.36553/wm.132.
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The 50th anniversary of the Centre of Postgraduate Medical Education (CMKP) was celebrated in 2021. Since the beginning, the School of Public Health (SZP) has been inseparable linked with the CMKP. Throughout this period, the position of the SZP director has been held by eight persons i.e. Bogusław Kożusznik (1971 to 1977), Marek Sanecki (1978 to 1991), Andrzej Wojtczak (1991 to 1996), Jerzy Leowski (1996 to 2003), Janusz Opolski (2003 to 2004 and 2005 to 2011), Maria Miller (2005 to 2005), Dorota Cianciara (2011 to 2018) and Jarosław Pinkas (since 2018). In the paper, the consecutive directors and the SZP modifications during the period of the recent 50 years is presented.
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Grudziąż-Sękowska, Justyna, Jacek Pruszyński, Paweł Goryński, Agnieszka Jasik, Piotr Gumowski, Urszula Religioni, Janusz Ostrowski, and Bartosz Kobuszewski. "The situation of people suffering from diabetes in Poland. Needs of changes in the health care system." Wiedza Medyczna 4, no. 1 (June 28, 2022): 53–57. http://dx.doi.org/10.36553/wm.122.
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Diabetes mellitus affects about 3 million Poles, which is almost 8% of the population. It belongs to the national health priorities defined in the regulation of the Minister of Health. If poorly controlled, it leads to the development of many serious complications, both acute and chronic. It excludes people who are often of productive age from an effective, satisfactory life, and therefore causes an increase in public costs due to health and social insurance, and a decrease in state budget revenues from production and consumption. Measures taken in the areas of: population prevention addressed to the entire population, with particular emphasis on vulnerable groups, early diagnosis of diabetes and its effective treatment, and support for patients preventing disability and exclusion, should help reduce these costs.
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Dalal, Nicole H., Graca Dores, Rochelle E. Curtis, Martha S. Linet, and Lindsay M. Morton. "Cause-specific mortality in survivors of lymphoplasmacytic lymphoma (LPL) and waldenstrom macroglobulinemia (WM)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e19056-e19056. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e19056.
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e19056 Background: LPL and WM are rare, indolent mature B-cell lymphomas. While recent studies reveal improving survival after LPL/WM, cause-specific mortality has not been comprehensively studied. Methods: We identified 6659 adults with first primary LPL (n = 2866) or WM (n = 3793) within 17 US population-based cancer registries from 2000 to 2015. Patients were followed for vital status (mean follow-up = 5.07 years), and causes of death were determined from death certificates. Standardized mortality ratios (SMRs) estimated relative risk of death compared to the general population. We estimated cumulative mortality and absolute excess risk (AER) per 10,000 person-years. Results: We observed 2826 deaths overall, of which 43%, 13%, and 42% were due to lymphoma, cancers excluding lymphoma, and non-malignant causes, respectively. There was a 20% higher risk of death due to non-malignant causes compared to the general population (n = 1194, SMR = 1.2, 95% confidence interval [CI] = 1.1 to 1.2). The most common non-malignant causes included infectious (n = 162, SMR = 1.8, 95% CI = 1.5 to 2.1, AER = 21.0), respiratory (n = 131, SMR = 1.2, 95% CI = 1.0 to 1.5, AER = 7.4), and digestive (n = 76, SMR = 1.9, 95% CI = 1.5 to 2.4, AER = 10.7) diseases. Cause-specific mortality varied by time since and age at LPL/WM diagnosis. Risks were highest in the first year after LPL/WM for non-malignant causes (SMR = 1.4, AER = 34.3), particularly infections (SMR = 2.4, AER = 34.4) and non-neoplastic hematologic diseases (SMR = 17.3, AER = 20.7). In contrast, risk of death due to cancers excluding lymphoma increased with time since diagnosis (SMR< 1y = 1.2, SMR≥5y = 1.7; AER< 1y = 15.1, AER≥5y = 60.0). Analyses by age, focused on AERs, showed generally similar risks across age groups (cancers excluding lymphoma: AER< 65= 26, AER65-75= 28, AER≥75= 31; non-malignant causes: AER< 65= 52, AER65-75= 66, AER≥75= 23). Cumulative mortality from non-malignant causes (23.7%) exceeded that from lymphoma (22.9%) beginning 9 years after LPL/WM diagnosis. Conclusions: Using population data, we identified areas to improve survivorship care of LPL/WM patients, particularly for non-malignant causes of death.
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Nguyen-Khac, Florence, Julie Lejeune, Elise Chapiro, Aurore Grelier, Sarah Mould, Carole Barin, Agnes Daudignon, et al. "Cytogenetic Abnormalities In a Cohort of 171 Patients with Waldenström Macroglobulinemia Before Treatment: Clinical and Biological Correlations." Blood 116, no. 21 (November 19, 2010): 801. http://dx.doi.org/10.1182/blood.v116.21.801.801.
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Abstract Abstract 801 The genetic bases of Waldenström Macroglobulinemia (WM) are poorly understood. Because of the difficulty in obtaining tumor metaphases for karyotype studies, few recurrent chromosomal abnormalities have been reported in WM. We have studied a cohort of 171 untreated WM patients, enrolled in a prospective randomized trial from the French Cooperative Group on Chronic Lymphocytic Leukemia and Waldenstrom Macroglobulinemia (FCG-CLL/WM) comparing the efficacy of fludarabine to that of chlorambucil, by conventional cytogenetic (CC) and Fluorescence in situ hybridization (FISH). CC was systematically performed on bone marrow or peripheral blood, and FISH analysis carried out using 8 probes CEP4, CEP12, 13q14, 11q22 (ATM), 17p13 (TP53), IGH, BCL2 Abbott, 6q21 Q-Biogene, on metaphases and interphase nuclei. The sex ratio was 2.1M/1F, the average age at inclusion was 66.9 years [40-89]. The mean percentage of lymphoplasmacytic cells was 53% [8-97]. Out of 140/171 successful CC, 65 (46.4%) showed clonal abnormalities. Out of 65 abnormal CC, 19 (29.2%) were complex, with at least 3 chromosomal changes, and 22 (33.8%) showed translocations (balanced and unbalanced). Using CC and FISH, we observed 29/132 (22%) 6q deletion, 18/141 (12.8%) 13q14 deletion, 9/80 (11.2%) trisomy 18, 11/135 (8.1%) TP53 deletion, 10/133 (7.5%) trisomy 4, 10/132 (7.6%) ATM deletion, 4/118(3.4%) IGH rearrangement, and 4/136 (2,9%)trisomy 12. Chromosomal abnormalities were compared to adverse characteristics described by Morel et al (ISSWM, Blood 2009,113(8),4163-70): advanced age (> 65 years), hemoglobin < 11.5g/dl, platelet count < 100×109/l, b2-microglobulin > 3 mg/l, and serum monoclonal protein concentration > 7g/dl. Patients with 6q deletion had significantly more frequently albumin < 3.5g/dl (15/29 (51.7%) vs 24/103 (23.3%), p=0.005), b2microglobuline > 3 mg/l (20/29 (68.9%) vs 48/103 (46.6%), p=0.04). Similarly, patients with trisomy 4 had significantly more frequently b2microglobuline > 3 mg/l (9/10 (90%) vs 59/123 (47.9%), p=0.02). Of note, all patients with trisomy 4 had M-protein concentration > 2 g/dl (10/10 (100%) vs 73/123 (59.3%), p=0.02). Finally, there were significantly more patients with age > 65 years, when ATM deletion was observed (9/10 (90%) vs 65/122 (53.2%), p=0.04). Cytogenetic abnormalities did not influence the response rate but in multivariate analysis, TP53 deletion was associated with a shorter time to progression (15months (m) versus 35m, p=0.0007) and 6q deletion with a longer time to progression (55m versus 24m, p=0.04) in responding patients. Cytogenetic abnormalities in WM differ from those commonly reported in other B-cell neoplasms and confirm the originality of this disease. The 6q deletion is frequent compared to chronic lymphocytic leukaemia (CLL) or marginal zone lymphoma (MZL) and 13q14 deletion is rare compared to CLL. In our series trisomy 12 is rare compared to atypical-CLL and MZL. Involvement of the IGH locus, which is frequent in multiple myeloma or lymphoplasmocytic lymphoma, is rare in WM. Finally trisomy 4 is present in WM but not reported in other B-cell malignancies. The 6q deletion is the most frequent reported cytogenetic abnormality in WM. We found 22% cases with deletions of 6q21, a lower percentage compared with the literature [38-54%].Conversely to previous publications, 6q deletion was associated with a longer response duration to treatment and did not influence the overall survival. These discrepancies could be explained by the heterogeneity of the previous published series, mixing untreated patients and treated patients in various ways. In our trial, all patients were analyzed before randomization. As in CLL patients, TP53 deletion seems to be associated with a shorter response duration. However, regarding the small numbers of patients with cytogenetic abnormalities, these results must be confirmed in larger series. Disclosures: Leblond: ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Landgren, Ola, Sigurdur Y. Kristinsson, Lynn R. Goldin, Neil E. Caporaso, Cecilie Blimark, Ulf-Henrik Mellqvist, Anders Wahlin, Magnus Bjorkholm, and Ingemar Turesson. "Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden." Blood 114, no. 4 (July 23, 2009): 791–95. http://dx.doi.org/10.1182/blood-2008-12-191676.
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Abstract Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.
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Wang, Q., C. Cheung, W. Deng, M. Li, C. Huang, X. Ma, Y. Wang, et al. "Fronto-parietal white matter microstructural deficits are linked to performance IQ in a first-episode schizophrenia Han Chinese sample." Psychological Medicine 43, no. 10 (December 14, 2012): 2047–56. http://dx.doi.org/10.1017/s0033291712002905.
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BackgroundEvidence shows that cognitive deficits and white matter (WM) dysconnectivity can independently be associated with clinical manifestations in schizophrenia. It is important to explore this triadic relationship in order to investigate whether the triplet could serve as potential extended endophenotypes of schizophrenia.MethodDiffusion tensor images and clinical performances were evaluated in 122 individuals with first-episode schizophrenia and 122 age- and gender-matched controls. In addition, 65 of 122 of the patient group and 40 of 122 controls were measured using intelligence quotient (IQ) testing.ResultsThe schizophrenia group showed lower fractional anisotropy (FA) values than controls in the right cerebral frontal lobar sub-gyral (RFSG) WM. The schizophrenia group also showed a significant positive correlation between FA in the RFSG and performance IQ (PIQ); in turn, their PIQ score showed a significant negative correlation with negative syndromes.ConclusionsOverall, these findings support the hypothesis that WM deficits may be a core deficit that contributes to cognitive deficits as well as to negative symptoms.
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Ikeda, Yoshifumi, Yosuke Kita, Yuhei Oi, Hideyuki Okuzumi, Silvia Lanfranchi, Francesca Pulina, Irene Cristina Mammarella, Katie Allen, and David Giofrè. "The Structure of Working Memory and Its Relationship with Intelligence in Japanese Children." Journal of Intelligence 11, no. 8 (August 18, 2023): 167. http://dx.doi.org/10.3390/jintelligence11080167.
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There is a host of research on the structure of working memory (WM) and its relationship with intelligence in adults, but only a few studies have involved children. In this paper, several different WM models were tested on 170 Japanese school children (from 7 years and 5 months to 11 years and 6 months). Results showed that a model distinguishing between modalities (i.e., verbal and spatial WM) fitted the data well and was therefore selected. Notably, a bi-factor model distinguishing between modalities, but also including a common WM factor, presented with a very good fit, but was less parsimonious. Subsequently, we tested the predictive power of the verbal and spatial WM factors on fluid and crystallized intelligence. Results indicated that the shared contribution of WM explained the largest portion of variance of fluid intelligence, with verbal and spatial WM independently explaining a residual portion of the variance. Concerning crystallized intelligence, however, verbal WM explained the largest portion of the variance, with the joint contribution of verbal and spatial WM explaining the residual part. The distinction between verbal and spatial WM could be important in clinical settings (e.g., children with atypical development might struggle selectively on some WM components) and in school settings (e.g., verbal and spatial WM might be differently implicated in mathematical achievement).
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Treon, Steven, Zachary Hunter, Bryan Ciccarelli, Yangsheng Zhou, Christina Hanzis, Robert Manning, Leukothea Ioakimidis, Lian Xu, Christopher Patterson, and Massimo Morra. "IgA and IgG Hypogammaglobulinemia Is a Constitutive Feature in Most Waldenstrom’s Macroglobulinemia Patients and May Be Related to Mutations Associated with Common Variable Immunodeficiency Disorder (CVID)." Blood 112, no. 11 (November 16, 2008): 3749. http://dx.doi.org/10.1182/blood.v112.11.3749.3749.
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Abstract Background: Hypogammaglobulinemia of the “uninvolved” immunoglobulins is commonly observed in Waldenstrom’s macroglobulinemia (WM), and has often been attributed to disease-related suppression. However, there is a paucity of information related to the pathogenesis of hypogammaglobulinemia in these disorders. Methods: We evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 patients with WM, and addressed the impact of therapy and response on IgA and IgG levels for 93 of these patients who required subsequent treatment. We also performed extensive sequence analysis of the promoter, all exonic, and flanking intronic regions from peripheral blood of 19 untreated WM patients who demonstrated IgA and/or IgG hypogammaglobulinemia for 8 genes often observed in common variable immunodeficiency disorders (CVID) and B cell deficiency i.e. AICDA, BTK, CD40, CD154, NEMO(IkBkG), TACI, SH2D1A, UNG. Results: At baseline, 120/207 (58.0%), 131/207 (63.3%), and 102/196 (49.3%) patients had abnormally low levels of serum IgG (<700 mg/dL), IgA (<70 mg/dL), or both, respectively. No correlation between baseline bone marrow disease involvement and immunoglobulin levels was observed. With a median follow-up of 12 months following completion of therapy, IgA and/or IgG levels remained abnormally low for 92.1% and 87.3% of responding patients, respectively, including those who achieved a complete remission. Sequence analysis of the NEMO and CVID gene panel demonstrated intronic variation at position c.1056-6T>C (n=2) and a hemizygous missense mutation at codon 113 for NEMO (n=1), and a heterozygous missense mutation at codon 142 in UNG (n=1). Conclusions: The results of these studies demonstrate that IgA and IgG hypogammaglobulinemia is a constitutive feature of patients with WM, which neither correlates with, nor is impacted by disease burden, despite therapeutic intervention and response. The results also suggest that patients with WM may harbor sequence mutations, which may be a contributor to the pathogenesis and/or morbidity of WM.
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Xu, Lian, Zachary Hunter, Nicholas Tsakmaklis, Yang Cao, Guang Yang, Jie Chen, Xia Liu, et al. "The Clonal Architecture of CXCR4mutations in Waldenstrom's Macroglobulinemia Shows Highly Variable Subclonal Distribution, and Multiple Mutations within Individual Patients Indicative of Targeted Genomic Instability." Blood 126, no. 23 (December 3, 2015): 1486. http://dx.doi.org/10.1182/blood.v126.23.1486.1486.
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Abstract Background: Whole genome sequencing (WGS) identified activating CXCR4WHIM somatic mutations in nearly 30% of patients with Waldenstrom's Macroglobulinemia (WM) (Blood 123(11):1637-46). Both nonsense and frameshift CXCR4WHIM mutations occur in WM, with over 30 different types of mutations described within the regulatory carboxyl-terminal domain of CXCR4. CXCR4WHIM mutations almost always occur with activating MYD88 mutations, and impact both disease presentation and treatment outcome (Blood 123(18):2791-6; NEJM 372(15):1430-40.). The clonal architecture of CXCR4WHIM mutations relative to MYD88 mutations and their role in disease evolution remains to be clarified. Methods: We used Sanger sequencing and highly sensitive AS-PCR assays that we developed for the most common CXCR4WHIM mutations (S338X C>A and C>G) to evaluate for CXCR4WHIM mutations. In conjunction with an AS-PCR MYD88L265P assay that we previously developed (Leukemia 28(8):1698-707), we also profiled tumor samples for MYD88L265P and CXCR4S338X mutations in 164 WM, 12 IgM MGUS, 20 MZL, 32 CLL, 14 MM, 7 non-IGM MGUS patients, and 32 healthy donors. Next generation transcriptome sequencing data was also performed for validation in select cases. Results: AS-PCR detected CXCR4S338X mutations in WM and IgM MGUS patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%), and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and MZL patients, respectively, but not in CLL, MM, non-IGM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution (median 35.1%, range 1.2%-97.5%; Figure 1). Sanger sequencing identified 3 patients with multiple CXCR4 mutations, which were shown to be compound heterozygous by TA cloning and sequencing of at least 40 clones. The addition of AS-PCR to the Sanger sequencing results also revealed multiple CXCR4WHIM mutations in many individual patients that included homozygous and compound heterozygous mutations that were validated by next generation sequencing that offered a median of 5,819 (range 5,217-12,235) reads that overlapped the mutated loci. Conclusions: Taken together, these findings show that CXCR4WHIM mutations are more common in WM patients than previously revealed by WGS or Sanger sequencing. Moreover, CXCR4 mutations are primarily subclonal supporting their acquisition after MYD88L265P in WM oncogenesis. The exclusive finding of frameshift and nonsense but not missense variants within the carboxyl-terminal domain of CXCR4 suggests that significant selection pressures exist for activating mutations within the WM clone. Lastly, multiple CXCR4WHIM mutations are common in WM patients indicative of targeted genomic instability within the carboxyl-terminal domain of CXCR4. Disclosures No relevant conflicts of interest to declare.
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Ciccarelli, Bryan, Christopher J. Patterson, Zachary Hunter, Christina Hanzis, Thea Ioakimidis, Robert Manning, Guang Yang, et al. "Patients with Waldenstrom's Macroglobulinemia Are Often Hypoferremic That Is Refractory to Oral Iron Repletion and Responsive to Parental Iron Infusions, and Demonstrate Elevated Levels of Hepcidin." Blood 114, no. 22 (November 20, 2009): 2952. http://dx.doi.org/10.1182/blood.v114.22.2952.2952.
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Abstract Abstract 2952 Poster Board II-928 Background: Patients with Waldenstrom's macroglobulinemia (WM) often present with anemia, that can occur independent of bone marrow disease involvement, serum IgM levels, and in the absence of any hemolysis (Treon, Blood 2009). Iron deficiency is commonly observed in WM patients, and is often oral iron refractory. Parenteral administration of iron (Ferrlicit) in such patients can lead to improvements in hematocrit in patients who are oral iron refractory as shown below in Table 1: As such, we investigated mechanisms by which oral iron uptake could be impaired in patients with WM. Hepcidin is a peptide which acts as a master regulator of iron homeostasis by binding to and disabling the only known iron-export protein, ferroportin, resulting in the inhibition of iron transfer from enterocytes and macrophages into the circulation. We therefore sought to delineate the role of Hepcidin in WM patients presenting with and without anemia, and in those patients who did not respond to oral iron intake. Patients and Methods: Serum levels of Hepcidin were determined in 53 previously untreated patients with WM [Median Age: 63; BM Involvement 40%; Beta 2 Microglobulin (B2M) 2.6 g/L; Hematocrit 34.2%; Iron 67 ug/dL; TIBC 321 ug/dL] along with 20 healthy donors [Median Age: 63.5, Female N=8, Male N=12] using the Hepcidin-P competitive ELISA for hepcidin-25, the biologically-active form of the hormone [Intrinsic LifeSciences, La Jolla, CA USA]. Of the patients examined, 45 were anemic, 12 were hypoferremic [<37-170 mg/dL]. All but 5 individuals had normal TIBC levels [210-480 mg/dL]. Results: Serum Hepcidin levels were elevated among all WM patients [107.5 ng/mL, range 11.3-689 ng/mL] versus healthy donors [91.8 ng/mL, range 12.2-211.6 ng/mL; p=.04]. Levels of Hepcidin positively correlated with BM disease involvement (p=0.004; Spearmans rho=0.4), and inversely with hematocrit (p=0.08; Spearman's rho=-.24) [Figure 1,2]. Among the 45 WM patients who demonstrated anemia, the median level of Hepcidin was higher at 118.5 ng/mL [Range 11.3-689 ng/mL; p=0.025 versus healthy donors]. Among 5 WM patients who failed to respond to oral iron repletion and who subsequently responded to parenteral iron (Table 1), the median Hepcidin level was 189.1 (range 40.6-444.1 ng/mL). Among non-anemic WM patients, hepcidin levels were lower [66.5 ng/mL; range 31.7-401.8 ng/mL; p=0.35 versus anemic WM patients), though these patients demonstrated a lower bone marrow disease burden (30% vs. 50%; p=0.03). Conclusions: Hepcidin levels are elevated in patients with WM, and show a positive correlation with bone marrow disease burden, and an inverse relationship with hematocrit. Importantly, higher levels of Hepcidin may be associated with refractoriness to oral iron intake. Further studies addressing the role of Hepcidin in the management of WM related anemia are warranted. Disclosures: No relevant conflicts of interest to declare.
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Ntim, Stephen K. "Working Memory Failures and Comprehension Monitoring Impairments in Primary Readers." Psychology and Cognitive Sciences – Open Journal 9, no. 1 (December 27, 2023): 17–26. http://dx.doi.org/10.17140/pcsoj-9-170.
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Background This paper investigates the relationship between working memory (WM) failures and comprehension impairments in text comprehension among L2 primary readers in primary four through primary six in selected schools in Ghana. Method Five measures—decoding, vocabulary, working memory, comprehension monitoring, and reading comprehension—were used to test three research questions on the L2 primary reader’s ability to notice inconsistencies in paragraphs, stronger academic language, re-reading times for mismatched words in sentences, and self-reporting and comprehension. Results Major findings were that the primary readers’ ability to notice inconsistencies between paragraphs showed a significant average change between primary 4 and 5 in non-linear terms, with a correlation of r=-0.51 and a significant inverse correlation between the inability to see inconsistencies and the ability to recognize them. Vocabulary had a stronger positive relationship with comprehension monitoring (β=0.07, p<0.001) for primary five and six and primary four and five (β=0.04, p<0.001), respectively. Conclusion Decoding, vocabulary, and WM were found to be predominant factors for reading (β=0.46, p<0.00010), (β=0.37, p<0.0001), and (β=0.45, p<0.0001), while vocabulary and WM combination accounted for 25% of the additional reading variance in primary six, suggesting the significance of WM on self-reporting as a comprehension measure. The recommended classroom practice was for teachers to be mindful of working memory capacities, imposing mental demands on struggling L2 pupils.
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Croucher, Danielle C., Victor H. Jimenez-Zepeda, Zhi Hua Li, Ellen Wei, Brent DG Page, James Turkson, Patrick T. Gunning, and Suzanne Trudel. "The Potent STAT3/5 Inhibitor, BP-1-102 Demonstrates Significant Anti-Tumor Activity Against Waldenström Macroglobulinemia." Blood 118, no. 21 (November 18, 2011): 5101. http://dx.doi.org/10.1182/blood.v118.21.5101.5101.
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Abstract Abstract 5101 STAT3 is a cytoplasmic transcription factor, transiently activated in response to external stimuli such as growth factors and cytokines. As a transcription factor, STAT3 induces the expression of genes known to be involved in tumorigenesis, implicating STAT3 dysregulation in a number of hallmark oncogenic processes including tumor cell survival, proliferation, angiogenesis, metastasis, and drug resistance. Aberrant STAT3 signaling is prevalent in hematologic malignancies including Waldenstrom Macroglobulinemia (WM), a rare form of B cell non-Hodgkin lymphoma that is characterized by hyper-monoclonal IgM secretion in the peripheral blood. Despite the development of novel therapies and combinatorial treatment regimes, WM remains uniformly fatal, and as the limits of current chemotherapies have been reached, new approaches to treatment are urgently needed to improve patient outcome. Analysis of the gene and protein expression profiles of WM patients suggests that activation of STAT3 signaling plays a critical role in WM, providing rationale for the therapeutic use of STAT3 inhibitors. We have demonstrated pre-clinical efficacy of a novel, highly specific and potent small molecule STAT3/5 inhibitor, BP-1-102, in both hyper-IgM secreting B cell lymphoma cell lines (Mec-1 and RL) as well as two WM cell lines (MWCL-1 and BCWM-1). BP-1-102 directly targets STAT proteins by specifically blocking the SH2 domain that is a required for the phosphorylation, dimerization and nuclear localization of STAT3, ultimately resulting in inhibition of STAT3 transcriptional activation of target genes. We have shown that BP-1-102 directly interacts with STAT3's SH2 domain and is one of the most effective disruptors of STAT3 activity described to date. Treatment of cell lines with low μM doses of BP-1-102 induced dose-dependent decreases in constitutive and IL10-induced STAT3 phosphorylation (pSTAT3) as well as pSTAT3 nuclear localization. We further evaluated the potency of BP-1-102 against STAT1 and 5 compared to STAT3 using phosphor-flow cytometry to measure STAT phosphorylation status. BP-1-102 effectively inhibited GM-CSF induced STAT5 phosphorylation in AML2 cells at low dose concentrations (< 12.5uM) but only weakly inhibited IFNγ induced STAT1 phosphorylation in U937 leukemic cells at similar dose concentrations confirming the selectivity of BP-1-102 for STAT 3 and 5. Using a STAT3 dependent luciferase reporter construct, we confirmed repression of STAT3 transcriptional activity which correlated with a dose-dependent decrease in expression of STAT3 target genes (Mcl-1, Bcl-XL, Survivin and c-Myc). Inhibition of pSTAT3 resulted in decreased cell viability as assessed by MTT assay after 72 hours of in vitro exposure, with IC50 values ranging from 6uM to 10uM. In addition, treatment of cells with BP-1-102 resulted in caspase-dependent apoptosis which correlated with the activation of caspase-3 and PARP cleavage. Interestingly, co-culture of Mec-1 and RL with bone marrow stroma cells reduced the cytotoxicity of BP-1-102 suggesting stroma-conferred resistance, while MWCL-1 were equally sensitive to the cytotoxic effects of BP-1-102 regardless of either culture condition. Preliminary investigation suggests that the efflux system, used by cells to extrude toxic substances and linked to drug resistance in cancer, may be responsible for conferring stroma-mediate resistance to BP-1-102 in Mec-1 and RL cells. Finally, xenograft experiments to determine in vivo efficacy and safety are planned and will be presented. Collectively, these findings demonstrate a critical role for STAT3 signaling in WM pathology and provide the rationale for further development of STAT3 inhibitors for the treatment of WM. Disclosures: No relevant conflicts of interest to declare.
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Hunter, Z. R., K. O'Connor, J. Soumerai, A. Branagan, X. Leleu, E. Hatjiharissi, and S. Treon. "IgG and IgA hypogammaglobulinemia is pervasive in Waldenstrom's macroglobulinemia (WM) and persists regardless of response or type of therapeutic intervention." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 8042. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.8042.
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8042 Background: IgG and IgA hypogammaglobulinemia (HG) is a commonly observed in patients with WM and has often been attributed to the extensive infiltration of lymphoplasmacytic cells in the bone marrow (BM). Methods: In this retrospective study we analyzed immunoglobulin and BM infiltration levels from 196 previously untreated patients at their first visit to our clinic who met the clinical and pathological criteria for WM. In addition, we also serially evaluated 65 WM patients who received various therapies for changes in IgA and IgG. All lab values and biopsies used were conducted at our clinic at the Dana-Farber Cancer Institute to insure consistency. Pre-therapy, end of therapy, and best Ig response post therapy were evaluated and patients were followed up to the point of their next treatment regimen. Results: Of the 197 previously untreated patients, 117 (59.7%) demonstrated abnormally low levels of IgG (<700 mg/dl), whereas 131 (66.8%) had abnormally low levels of IgA (<70 mg/dl), and 102 (52.0%) had abnormally low levels of both IgG and IgA. Median value for IgM was 2820 mg/dl (Range 179 - 12400), for IgG 623 mg/dl (Range 127–2770), for IgA 48.5 mg.dl (range 7 - 509), and for the 94 patients for whom BM biopsies were available, the median intratrabecular space involvement was 37.5% (range 5 - 95). No correlation was found between BM involvement and any Ig level. Results from each of the trials is summarized in the table below. Median follow up was 455 days. No correlation between degree of response and Ig recovery was observed. No Ig level that started abnormally low was ever restored to normal levels in this study despite the fact that some recovery is noted in the non-rituximab based trials. Conclusions: These studies indicate that there is no relationship between BM involvement HG in WM. Moreover, therapeutic intervention does not restore IgG or IgA levels indicating a possible constitutive Ig dysregulation problem in patients with WM. No significant financial relationships to disclose. [Table: see text]
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Gardi, Romain. "Les premiers débats tactiques de l’équipe de France. La Coupe du monde de football de 1934 et la difficile diffusion du WM en France." Football(s). Histoire, culture, économie, société, no. 1 (November 17, 2022): 53–61. http://dx.doi.org/10.58335/football-s.112.
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Le WM est la principale innovation tactique de l’entre-deux-guerres. Adaptation à la modification de la règle du hors-jeu de 1925, ce schéma tactique est diffusé par les matchs de l’équipe d’Arsenal et des entraîneurs britanniques comme William Aitken ou Gabriel Sibley Kimpton. Ce dernier l’introduit dans le jeu de l’équipe de France participant à la Coupe du monde 1934, mais le WM ne fait pas l’unanimité parmi les joueurs et les clubs français et cette défiance contribue au manque d’identité et style du jeu hexagonal. Il n’en est pas moins utilisé par des équipes amateures notamment dans le Vaucluse.
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Paludo, Jonas, Shayna R. Sarosiek, Gottfried R. von Keudell, Monika Salkar, Summera Zhou, Sonia Kim, Ning Cheng, Michelle Pacia, Sudeep Karve, and Jorge J. Castillo. "Real-World Treatment Patterns and Healthcare Resource Utilization in Patients with Waldenström Macroglobulinemia Initiating First-Line Treatment with Ibrutinib or Zanubrutinib." Blood 142, Supplement 1 (November 28, 2023): 7385. http://dx.doi.org/10.1182/blood-2023-181053.
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Background: A pivotal clinical trial comparing the efficacy and safety of ibrutinib with zanubrutinib in patients with Waldenström macroglobulinemia (WM) did not achieve its primary endpoint of complete response or very good partial response. In addition, median progression-free survival was not reached in either treatment arm. In the absence of treatment effectiveness differentiation based on clinical trial evidence, we conducted a real-world study to assess patient characteristics, treatment patterns, and all-cause healthcare resource utilization (HRU) in patients with WM who received ibrutinib or zanubrutinib as first-line (1L) therapy. Methods: In this retrospective cohort study, we used the ConcertAI Database to collect claims data of patients with WM aged ≥18 years who initiated single-agent ibrutinib (420 mg/day) or zanubrutinib (320 mg/day) as 1L therapy on or after 9/1/2021 (index date). A 6-month washout period of guideline-recommended WM antineoplastic agents was required to confirm 1L status. Patients were excluded if they were receiving ibrutinib and zanubrutinib concurrently, died within 30 days of the index date, had a record of hematopoietic stem cell transplant, had a record of other ibrutinib indications in the 6 months before index, or were participating in a clinical trial. Baseline demographics and clinical characteristics, therapy duration (number of days between the first and last day of the medication supply), and HRU (all-cause and WM-specific) per-patient-per-month (PPPM) were assessed. Results: The study included 51 patients (ibrutinib, n=30; zanubrutinib, n=21). In both cohorts, most participants were male (ibrutinib, n=20 [67%]; zanubrutinib, n=16 [76%]), and the mean age at baseline was 73 years and 75 years, respectively. At baseline, the median Charlson Comorbidity Index was 0, and the WM-related and ibrutinib/zanubrutinib-related clinical events were similar between the two cohorts. While the zanubrutinib cohort had a higher prevalence of infections (33% vs 3%) and musculoskeletal pain (24% vs 7%) at baseline, the ibrutinib cohort had a higher prevalence of hypertension (20% vs 14%). The baseline prevalence of anemia was similar in both cohorts (ibrutinib, 27%; zanubrutinib, 29%). Mean follow-up was 6.9 months (ibrutinib) and 6.3 months (zanubrutinib). The mean ± SD duration of therapy was 152 ± 112 days (ibrutinib) and 113 ± 99 days (zanubrutinib; p=0.195). The ibrutinib cohort had a significantly lower all-cause HRU PPPM (4.53 ± 3.96 vs 8.53 ± 6.66, p=0.020) and lower WM-specific HRU PPPM (0.11 ± 0.26 vs 0.54 ± 1.14, p=0.104). Conclusions: In this real-world analysis, patients with WM treated with 1L ibrutinib had a numerically longer duration of therapy and lower all-cause and WM-specific HRU PPPM, compared to those treated with 1L zanubrutinib. Due to a small sample size and short follow-up, these findings should be interpreted cautiously.
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Chalmers, Kerry A., and Emily E. Freeman. "Working Memory Power Test for Children." Journal of Psychoeducational Assessment 37, no. 1 (September 15, 2017): 105–11. http://dx.doi.org/10.1177/0734282917731458.
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Low working memory (WM) capacity has been linked to poor academic performance and problem behavior. Availability of easy-to-administer screening tests would facilitate early detection of WM deficits. This study investigated the psychometric properties of the Working Memory Power Test for Children (WMPT) in 170 Australian schoolchildren (8½-11 years). Reliability (internal consistency) and validity of WMPT accuracy scores were examined. WMPT accuracy predicted achievement in reading, numeracy, and spelling. The results provide preliminary evidence of reliability and validity that supports interpretation of the WMPT accuracy score. With additional research, the WMPT could be valuable as an easy-to-administer screener for WM deficits.
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Pergola, G., P. Di Carlo, I. Andriola, B. Gelao, S. Torretta, M. T. Attrotto, L. Fazio, et al. "Combined effect of genetic variants in the GluN2B coding gene(GRIN2B)on prefrontal function during working memory performance." Psychological Medicine 46, no. 6 (December 22, 2015): 1135–50. http://dx.doi.org/10.1017/s0033291715002639.
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BackgroundThe GluN2B subunit ofN-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear howGRIN2Bgenetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect ofGRIN2Bvariants on prefrontal activity during WM performance in healthy subjects.MethodWe computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontalGRIN2BmRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n= 46), in a WM behavioural study (n= 116) and in a WM functional magnetic resonance imaging study (n= 122).ResultsFive polymorphisms were associated withGRIN2Bexpression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all correctedp< 0.05). The score computed to account for their combined effect reliably indexed gene expression.GRIN2Bcomposite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association betweenGRIN2Bgenetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex.ConclusionsMultiple genetic variants inGRIN2Bare jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role ofGRIN2Bgenetic variants in WM prefrontal activity in human adults.
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Kyriakou, Charalampia, C. Canals, A. Sureda, G. Taghipour, C. Gisselbrecht, P. Mazza, E. Montserrat, et al. "The Role of Autologous Stem Cell Transplantation (ASCT) in Patients with Advanced Waldenström’s Macroglobulinemia." Blood 110, no. 11 (November 16, 2007): 941. http://dx.doi.org/10.1182/blood.v110.11.941.941.
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Abstract Waldenström’s macroglobulinaemia (WM) is a relatively rare disorder that primarily affects elderly patients. Conventional therapies for symptomatic WM result in response rates of up to 70%. However, complete responses are rare and the disease remains incurable. Due to the indolent nature of the disease and the older age of patients the role of autologous stem cell transplantation (ASCT) in the treatment of patients with WM has not been analyzed in large series. In this retrospective multicenter study we report the outcome of 201 WM patients (132 male, 69 female), who underwent ASCT between 1992 and 2005. The median age at transplant was 53 years (22–73) and the median time from diagnosis to transplant was 18 months (3–239). Forty patients (20%) were in 1st maximum response (MR1), 24 (12%) in ≥MR2, 83 (41%) in PR1, 27 (13%) in ≥PR2 and 27(14%) were primary refractory to treatment. Conditioning regimens were BEAM (44%), TBI/Cyclophosphamide or Melphalan (28%), Melphalan (14%), BuCy (2%) and others (12%). The source of stem cells was PB in 188, BM in 10, and both in 3 patients. All patients but 3 had successful engraftment. With a median follow-up of 26 months (5–163), 112 (56%) patients are alive and free of disease, 73 (36%) patients have relapsed after a median of 14 months (1–110) post ASCT. Fifty-two patients died, 36(18%) from disease progression and 16(8%) from treatment toxicity. Non- relapse mortality was 6% at 1 year. The actuarial OS was 86% at 1 year, 75% at 3 years, and 61% at 5 years. The probability of relapse was 20% at 1 year, 38% at 3 years and 55% at 5 years with an estimated PFS of 74%, 54% and 33% at 1, 3, and 5 years respectively. Multivariate analysis revealed that, chemosensitive disease at the time of ASCT was the most important factor for NRM (p<0.001), relapse rate (p<0.01), PFS (p<0.001) and OS (p<0.001). In conclusion, this study suggests that ASCT is a safe procedure in patients with WM and that a significant proportion of heavily pre-treated patients with this disorder can respond to the procedure and achieve prolonged PFS.
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Kristinsson, Sigurdur Y., Magnus Bjorkholm, Jill Koshiol, Lynn R. Goldin, Mary L. McMaster, Ingemar Turesson, and Ola Landgren. "Immune-Related and Inflammatory Conditions Likely Play a Role in the Development of Lymphoplasmacytic Lymphoma/Waldenström’s Macroglobulinemia." Blood 112, no. 11 (November 16, 2008): 3758. http://dx.doi.org/10.1182/blood.v112.11.3758.3758.
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Abstract Introduction: Certain autoimmune and infectious conditions are associated with increased risks of subtypes of non-Hodgkin lymphomas (NHL). A few prior studies suggest that chronic immune stimulation may particularly elevate risk for the NHL subtype lymphoplasmacytic lymphoma (LPL)/Waldenström’s macroglobulinemia (WM). To improve our understanding on the role of immune-related and inflammatory conditions in LPL/WM pathogenesis, we conducted a large population-based study including close to 2,500 LPL/WM patients diagnosed in Sweden and almost 10,000 matched controls. Methods: Using both the central Cancer registry and local hospital-based registries, we identified all LPL/WM patients diagnosed in Swedish hospitals 1958–2005. From the Swedish Population Registry we identified four matched controls per LPL/WM patient. Through data linkage with the central Inpatient registry, we gathered information on hospital inpatient discharges that listed autoimmune-, infectious-, and other inflammatory/allergic diseases present at least 1 year prior to LPL/WM. Using Poisson regression, we calculated rate ratios (RR) and 95% confidence intervals (CI) adjusted for categorical year of birth, date of diagnosis, gender, and county. Results: A total of 2,470 LPL/WM patients (647 LPL and 1,823 WM), and 9,698 population-based matched controls were included in the study. We found an increased risk of developing LPL/WM among individuals with a prior history of systemic sclerosis (RR=4.7; 1.4–15.3), Sjögren’s syndrome (RR=12.1; 3.3–45.0), autoimmune hemolytic anemia (AIHA) (RR=24.2; 5.4–108.2), polymyalgia rheumatica (RR=2.9; 1.6–5.2), and temporalis arteritis (RR=8.3; 2.1–33.1). We also found excess risk of LPL/WM among persons with a history of pneumonia (RR=1.4; 1.1–1.7), septicaemia (RR=2.4; 1.2–4.3), pyelonephritis (RR=1.7; 1.1–2.5), sinusitis (RR=2.7; 1.4–4.9), herpes zoster (RR=3.4; 2.0–5.6), and influenza (RR=2.9; 1.7–5.0). Importantly, when we assessed the associations by latency (time between immune-related or inflammatory conditions and LPL/WM), for most autoimmune- and infectious diseases the excess LPL/WM risk remained significant at >5 years latency. We found no significant increased risk for LPL/WM among individuals with prior chronic inflammatory or allergic conditions. Conclusions: In the largest investigation of risk factors for LPL/WM to date, we found a personal history of certain autoimmune and infectious diseases to be associated with excess LPL/WM risk. Immune-related conditions might act as potential LPL/WM triggers or they could represent premalignant immune disruptions preceding LPL/WM. Our results provide novel insights into the as yet unclear pathogenesis of LPL/WM.
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Berner, Lise-Prune, Tae-Hee Cho, Julie Haesebaert, Julien Bouvier, Marlène Wiart, Niels Hjort, Irene Klærke Mikkelsen, et al. "MRI Assessment of Ischemic Lesion Evolution within White and Gray Matter." Cerebrovascular Diseases 41, no. 5-6 (2016): 291–97. http://dx.doi.org/10.1159/000444131.
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Background: In acute ischemic stroke (AIS), gray matter (GM) and white matter (WM) have different vulnerabilities to ischemia. Thus, we compared the evolution of ischemic lesions within WM and GM using MRI. Methods: From a European multicenter prospective database (I-KNOW), available T1-weighted images were identified for 50 patients presenting with an anterior AIS and a perfusion weighted imaging (PWI)/diffusion weighted imaging (DWI) mismatch ratio of 1.2 or more. Six lesion compartments were outlined: initial DWI (b = 1,000 s/mm2) lesion, initial PWI-DWI mismatch (Tmax >4 s and DWI-negative), final infarct mapped on 1-month fluid-attenuated inversion recovery (FLAIR) imaging, lesion growth between acute DWI and 1-month FLAIR, DWI lesion reversal at 1 month and salvaged mismatch. The WM and GM were segmented on T1-weighted images, and all images were co-registered within subjects to the baseline MRI. WM and GM proportions were calculated for each compartment. Results: Fifty patients were eligible for the study. Median delay between symptom onset and baseline MRI was 140 min. The percentage of WM was significantly greater in the following compartments: initial mismatch (52.5 vs. 47.5%, p = 0.003), final infarct (56.7 vs. 43.3%, p < 0.001) and lesion growth (58.9 vs. 41.2%, p < 0.001). No significant difference was found between GM and WM percentages within the initial DWI lesion, DWI reversal and salvaged mismatch compartments. Conclusions: Ischemic lesions may extend preferentially within the WM. Specific therapeutic strategies targeting WM ischemic processes may deserve further investigation.
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Wang, Jun, Yuting Yan, Wenjie Xiong, Ge Song, Yi Wang, Zhen Yu, Ying Yu, et al. "The Landscape of Immunoglobulin Heavy Chain Gene Repertoire in Lymphoplasmacytic Lymphoma / Waldenström Macroglobulinemia." Blood 138, Supplement 1 (November 5, 2021): 1346. http://dx.doi.org/10.1182/blood-2021-149397.
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Abstract Introduction Immunoglobulin heavy-chain variable genes (IGHV) is critical for the defining epitope binding affinityand B cell differentiation. Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous diseasewhose role of IGHV usage remains unknown. Besides, the clinical relevance of IGHV repertoire for LPL/WM remain largely unexplored. The aim of our study is to explore the IGH repertoire of LPL/WM in by far the largest series, and to evaluate the correlation between IGH rearrangements and genetic aberrations and clinical characteristics of LPL/WM patients. Methods A total of 162 patients with a diagnosis of LPL/WM were included in this study. Polymerase chain reaction (PCR)amplification of IGHV-IGHD-IGHJ was performed on genomic DNA or cDNA samples using the IGH Somatic Hypermutation Assay v2.0 (Invivoscribe, Technologies, San Diego, US). Sequences were aligned to IMGT (http://www.imgt.org/IMGT_vquest/vquest) and IGBLAST (https://www.ncbi.nlm.nih.gov/igblast/) databases. IGH gene repertoires, mutation status, IGHV CDR3 characteristics, genetic aberrations, MYD88 mutation status and clinical characteristics were collected to evaluate the relevance. Results Productive IGHV-D-J rearrangements were obtained in 136 out of 162 patients (84.0%). The IGHV gene repertoire was remarkably biased in LPL/WM. IGHV3-23 (15.4%), IGHV4-34 (10.3%), IGHV3-7 (8.1%), IGHV3-30 (7.4%) and IGHV3-74 (7.4%) were significantly overrepresented in LPL/WM(Figure 1). Among the 134 IGHD data, the most frequent segment was IGHD3-10 (21/134, 15.7%), followed by IGHD6-13 (18/134, 13.4%) (Figure 2). Among the 134 IGHJ data, IGHJ4 segment was selected in more than half of these rearrangements (70/136; 51.5%), followed by IGHJ6 (23/136; 16.9%) and IGHJ5 (21/136; 15.4%) (Figure 3). Most of the cases were mutated (97.0%) using a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating the specific antigen selection in LPL/WM. Patients with IGHV3-7 were significantly more likely to harbor 6q deletion (p<0.001)(Figure 4) and abnormal karyotype (p=0.004)(Figure 5).The IGHV hypermutation rate in patients with MYD88 L265P mutation was significantly higher than in wild-type patients (7.3% vs5.6%, p=0.009). IGHV3-23 and IGHV3-74 segments were more frequently detected in MYD88 mutated LPL/WM patients (25.7% vs. 4.3%, p=0.025). IGHV3-7 and IGHV4-59 were represented more in MYD88 wildtype patients (30.4% vs. 8.9%，p=0.005). Moreover, Patients with IGHV4 especially IGHV4-34 had higher level of LDH. IGHV4 was a prognostic marker of shorter progression-free-survival (Figure 6). Conclusion LPL/WM appears to be composed ofdifferent subgroups based on the IGHV repertoire. The mutational status and the IGHV CDR3 length indicated the role for antigenselection in LPL/WM development. The presence of IGHV4 genes proved to be a potential risk factor associated with outcome which deserved further study.These results showed for the first time that IGHV repertoire had clinical relevance in LPL/WM. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.
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SUGAWARA, Takeru, Hiroaki HASEGAWA, and Takumi OKADA. "112 Low Speed Wm Tunnel Tests Using Magnetic Suspension and Balance System." Proceedings of Conference of Tohoku Branch 2004.39 (2004): 24–25. http://dx.doi.org/10.1299/jsmeth.2004.39.24.
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Pavlakis, K. G., D. Hatzidimitriou, C. Matsoukas, E. Drakakis, N. Hatzianastassiou, and I. Vardavas. "Ten-year global distribution of downwelling longwave radiation." Atmospheric Chemistry and Physics 4, no. 1 (January 30, 2004): 127–42. http://dx.doi.org/10.5194/acp-4-127-2004.
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Abstract. Downwelling longwave fluxes, DLFs, have been derived for each month over a ten year period (1984-1993), on a global scale with a spatial resolution of 2.5x2.5 degrees and a monthly temporal resolution. The fluxes were computed using a deterministic model for atmospheric radiation transfer, along with satellite and reanalysis data for the key atmospheric input parameters, i.e. cloud properties, and specific humidity and temperature profiles. The cloud climatologies were taken from the latest released and improved International Satellite Climatology Project D2 series. Specific humidity and temperature vertical profiles were taken from three different reanalysis datasets; NCEP/NCAR, GEOS, and ECMWF (acronyms explained in main text). DLFs were computed for each reanalysis dataset, with differences reaching values as high as 30 Wm-2 in specific regions, particularly over high altitude areas and deserts. However, globally, the agreement is good, with the rms of the difference between the DLFs derived from the different reanalysis datasets ranging from 5 to 7 Wm-2. The results are presented as geographical distributions and as time series of hemispheric and global averages. The DLF time series based on the different reanalysis datasets show similar seasonal and inter-annual variations, and similar anomalies related to the 86/87 El Niño and 89/90 La Niña events. The global ten-year average of the DLF was found to be between 342.2 Wm-2 and 344.3 Wm-2, depending on the dataset. We also conducted a detailed sensitivity analysis of the calculated DLFs to the key input data. Plots are given that can be used to obtain a quick assessment of the sensitivity of the DLF to each of the three key climatic quantities, for specific climatic conditions corresponding to different regions of the globe. Our model downwelling fluxes are validated against available data from ground-based stations distributed over the globe, as given by the Baseline Surface Radiation Network. There is a negative bias of the model fluxes when compared against BSRN fluxes, ranging from -7 to -9 Wm-2, mostly caused by low cloud amount differences between the station and satellite measurements, particularly in cold climates. Finally, we compare our model results with those of other deterministic models and general circulation models.
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Park, Soon O., Dermot P. Coyne, James R. Steadman, Paul W. Skroch, and Geunhwa Jung. "550 Mapping of QTL for Partial Physiological Resistance and Field Reaction to White Mold, Plant Architecture, and Plant Height in Common Bean." HortScience 35, no. 3 (June 2000): 490D—490. http://dx.doi.org/10.21273/hortsci.35.3.490d.
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The objective was to detect molecular markers associated with QTL for partial physiological resistance (PPR) to two white mold (WM) isolates, partial field resistance (PFR), plant architecture (PA), and plant height (PH) in a genetic linkage map constructed using recombinant inbred lines (RILs) from the cross `PC-50' (resistant to WM) × XAN-159 (susceptible to WM). Significant correlations (+0.39 and +0.47) were noted between the WM reactions in the greenhouse and field. A significant but negative correlation (–0.33) was observed between the WM reaction and PH in the field. Six QTL affecting PPR to isolate 152 were found on LGs 4, 5, 7, and 8. Six QTL affecting PPR to isolate 279 were found on LGs 2, 3, 4, 7, and 8. Five QTL for PFR were observed on LGs 2, 5, 7, 8, and 11. Two QTL affecting PA were detected on LGs 7 and 8. Two QTL affecting PH were identified on LGs 7 and 8. On one end of LG 8 marker H19.1250 was significant for PPR to both isolates. On the other end of LG 8 the region closely linked to the C locus was significantly associated with PPR to both isolates, PFR, PA and PH. Marker J09.950 on LG 7 was significantly associated with PPR to both isolates, PFR, PH and seed weight. Marker J01.2000 on LG 2 was the most significant locus for both PPR to the isolate 279 and PFR. QTL on LG 5 were found for PPR to the isolate 152 and PFR. Overall, four of the five QTL affecting PFR were also found for PPR to one or both isolates.
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Kicińska, Urszula. "„Co moment wyglądałam łaski Pańskiej WM Pani i Dobrodziki" – korespondencja Elżbiety z Lubomirskich Sieniawskiej, kasztelanowej krakowskiej z Joanną Gołyńską, ksienią jarosławskich benedyktynek jako przykład relacji klientalnych w czasach saskich." Archiwa, Biblioteki i Muzea Kościelne 120 (June 30, 2023): 241–60. http://dx.doi.org/10.31743/abmk.13233.
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W dawnej Polsce kobiety mocno angażowały się w działalność publiczną, a jednym z jej przejawów był sprawowany przez nie patronat religijny, który stanowił bardzo ważny element budowania więzi klientalnych. Znakomitym materiałem służącym do prześledzenia relacji pomiędzy daną patronką a jej duchowną klientelą są listy proszalne, w których pod pokładami rozbudowanej ceremonialności pojawiały się rzeczywiste cele i oczekiwania obu negocjujących ze sobą stron. W gronie owych zacnych kolatorek znalazła się również Elżbieta z Lubomirskich Sieniawska (zm. 1729), która wraz ze swym mężem Adamem Mikołajem (zm. 1726) dokonała wielu fundacji kościelnych. Pod opieką patronacką kasztelanowej krakowskiej znalazł się także konwent jarosławskich benedyktynek, w którym funkcję ksieni w tym okresie pełniła Joanna Gołyńska (zm. 1725). W przeanalizowanych listach, które wspomniana przełożona słała do swej dobrodziejki, przewija się kwestia relacji patronackich pomiędzy kolatorką a jej duchowną klientką oraz pojawiają się sprawy dotyczące codziennego funkcjonowania jarosławskiego konwentu. J. Gołyńska bezustannie narzekała na to, że nie ma za co utrzymać klasztoru, gdyż czasy, w których przyszło jej żyć, coraz bardziej pogrążają klasztor w długach i w ruinie. Warto zauważyć, że kierowane przez benedyktynkę proklamacje niejednokrotnie nie spotykały się z aprobatą, a nawet jakąkolwiek reakcją E. Sieniawskiej, co rzuca się cieniem na działalność kolatorską kasztelanowej krakowskiej. Mamy bowiem dowód na to, że nie każdemu proszącemu, a w tym wypadku klientowi duchownemu, Sieniawska, pomimo obowiązków wynikających z bycia patronką, mogła lub chciała w pełni pomóc.
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Castillo, Jorge J., Adam J. Olszewski, Sandra Kanan, Kirsten Meid, Zachary Hunter, and Steven P. Treon. "Incidence and Survival Outcomes of Secondary Malignancies Among Survivors of Waldenström Macroglobulinemia." Blood 124, no. 21 (December 6, 2014): 855. http://dx.doi.org/10.1182/blood.v124.21.855.855.
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Abstract Background: Waldenstrom macroglobulinemia (WM) is an indolent malignancy characterized by extended survival, and affects predominantly older individuals, who are at risk for secondary malignancies (SM). The objectives of our study were to characterize incidence and outcomes of SM after WM diagnosis using the Surveillance, Epidemiology and End Results (SEER) database. Methods: Using the SEER-13 data from 1992-2011, we calculated standardized incidence ratios (SIR) with 95% confidence intervals (CI) for rates of solid and hematologic SM in WM patients compared with matched general population, excluding synchronous tumors. We compared SIR in groups defined by attained age, calendar year, sex and race. SIRs from SM with less than 10 cases are not reported. Also, overall survival (OS) after a malignancy diagnosis was compared between patients with or without antecedent WM in Cox proportional-hazard regression models adjusting for attained age, sex, race and tumor stage using SEER-18 data from 2000-2011. The outcome of interest for survival was hazard ratio (HR) with 95% CI. Results: Among the 4,676 WM patients in the SEER-13 database, 681 SM were recorded (Table). The overall SIR was 1.49 (95% CI 1.38-1.61) and the median time to SM was 3.7 years (95% CI 3.2-4.2 years). The cumulative incidence of SM was 9.5% (95% CI 8.6-10.5%) at 5 years, and 16.1% (95% CI 14.8-17.3%) at 10 years. The cumulative incidence at 10 years was 12.2% (95% CI 11.1-13.3%) for solid tumors and 4.2% (95% CI 3.5-4.9%) for hematologic SM. The excess risk of solid tumors peaked between 5-10 years from WM diagnosis (SIR 1.1, 1.4 and 1.1 for latency of 0-5, 5-10 and more than 10 years, respectively), while for hematologic malignancies it grew continuously with time (SIR 3.8, 4.4 and 6.7, respectively). The risk of solid tumors was significantly increased for cancers of the lung, urinary tract, thyroid gland and melanoma, but not for breast, prostate or colorectal cancer. Among lymphomas, diffuse large B-cell (DLBCL) was the most frequent subtype. Patients younger than 65 had a significantly higher SIR for any SM (SIR 2.2, 95% CI 1.9-2.6) than those 65 years or older (SIR 1.4, 95% CI 1.3-1.5). The SIR for SM was similar in the 1990s (SIR 1.3, 95% CI 1.1-1.6) and 2000s (SIR 1.5, 95% CI 1.4-1.7). The SIR for solid tumors was the same (SIR 1.2) among men and women, but for hematologic malignancies the excess risk was significantly higher in women (SIR 5.8, 95% CI 4.6-7.2) than men (SIR 3.4, 95% CI 2.8-4.2). There was no difference for white and non-white patients, either for aggregate SM or for the solid/hematologic categories. Compared with age- and sex-matched population and adjusting for race and stage, OS was worse with antecedent WM for colon cancer (HR, 2.0, 95% CI 1.4-2.7), melanoma (HR, 2.6, 95% CI 1.8-4.0) and DLBCL (HR, 1.9, 95% CI 1.2-3.0). It was not significantly different for acute leukemia (HR 0.9, 95% CI 0.5-1.4), prostate (HR 1.2, 95% CI 0.9-1.6), breast (HR 1.1, 95% CI 0.7-1.9), bladder (HR 1.2, 95% CI 0.8-1.7), thyroid (HR 0.9, 95% CI 0.1-6.0) or lung cancer (HR 1.2, 95% CI 1.0-1.4). Conclusions: Patients with WM have a 49% higher risk of a SM than the general population. Further research is needed to elucidate the increased incidence of leukemia and DLBCL possibly resulting from therapy and transformation, respectively, and melanoma, lung, bladder and thyroid cancers, possibly associated with defective immune surveillance. Comparatively poor survival in WM patients with colon cancer underscores the need for guideline-adherent screening and therapy. Table Incidencea SIR 95% CI Excess casesa All malignancies 681 1.5 1.4-1.6 95 Solid tumors 484 1.2 1.1-1.3 35 Lung 101 1.5 1.2-1.8 14 Prostate 95 1.0 0.8-1.3 1 Urinary tract 62 1.4 1.1-1.8 8 Colorectal 48 0.9 0.7-1.2 -2 Other gastrointestinal 43 1.0 0.7-1.4 0 Breast 43 1.0 0.8-1.4 1 Melanoma 35 1.9 1.3-2.7 7 Other gynecologic 21 1.3 0.8-2.0 2 Head and neck 13 0.9 0.5-1.6 0 Thyroid 10 2.7 1.3-4.9 3 Hematologic malignancies 174 4.2 3.6-4.9 56 All lymphomas 120 4.4 3.6-5.2 39 Diffuse large B-cell 31 4.3 2.9-6.1 10 Extranodal marginal zone 16 14.8 8.5-24.1 6 Other indolent B-cell 19 3.7 2.2-5.8 6 Myeloma 31 4.7 3.2-6.6 10 Acute leukemia 15 3.2 1.8-5.3 4 a per 10,000 person-years Disclosures No relevant conflicts of interest to declare.
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Sanford, Nicole, and Todd S. Woodward. "Functional Delineation of Prefrontal Networks Underlying Working Memory in Schizophrenia: A Cross-data-set Examination." Journal of Cognitive Neuroscience 33, no. 9 (August 1, 2021): 1880–908. http://dx.doi.org/10.1162/jocn_a_01726.
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Abstract Background: Working memory (WM) impairment in schizophrenia substantially impacts functional outcome. Although the dorsolateral pFC has been implicated in such impairment, a more comprehensive examination of brain networks comprising pFC is warranted. The present research used a whole-brain, multi-experiment analysis to delineate task-related networks comprising pFC. Activity was examined in schizophrenia patients across a variety of cognitive demands. Methods: One hundred schizophrenia patients and 102 healthy controls completed one of four fMRI tasks: a Sternberg verbal WM task, a visuospatial WM task, a Stroop set-switching task, and a thought generation task (TGT). Task-related networks were identified using multi-experiment constrained PCA for fMRI. Effects of task conditions and group differences were examined using mixed-model ANOVA on the task-related time series. Correlations between task performance and network engagement were also performed. Results: Four spatially and temporally distinct networks with pFC activation emerged and were postulated to subserve (1) internal attention, (2) auditory–motor attention, (3) motor responses, and (4) task energizing. The “energizing” network—engaged during WM encoding and diminished in patients—exhibited consistent trend relationships with WM capacity across different data sets. The dorsolateral-prefrontal-cortex-dominated “internal attention” network exhibited some evidence of hypoactivity in patients, but was not correlated with WM performance. Conclusions: Multi-experiment analysis allowed delineation of task-related, pFC-anchored networks across different cognitive constructs. Given the results with respect to the early-responding “energizing” network, WM deficits in schizophrenia may arise from disruption in the “energization” process described by Donald Stuss' model of pFC functions.
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Berlanga, Oscar, Jane Birtwistle, Syreeta Allen, Gemma Malin, Cristina Simion, Habib El-Khoury, Julia Colchie, et al. "Multi-Center Clinical Validation of a Mass Spectrometry Immunoassay for the Diagnosis and Monitoring of Multiple Myeloma and Associated Disorders." Blood 142, Supplement 1 (November 28, 2023): 3667. http://dx.doi.org/10.1182/blood-2023-189050.
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Introduction: Mass spectrometry (MS) technology holds great promise for the investigation of monoclonal proteins (M proteins) in peripheral blood. We present results from a multi-center clinical validation study using quantitative immunoprecipitation MS (QIP-MS). QIP-MS combines isotype-specific immunopurification with matrix-assisted laser-desorption ionization MS, and offers automated, sensitive detection, isotyping and quantification of M proteins. It reports the mass/charge ratio (m/z) of the involved light chain, which serves as molecular fingerprint for monitoring the M protein. Methods: The study included 460 diagnosed monoclonal gammopathy (MG) patients (160 multiple myeloma (MM), 112 smoldering MM (SMM), 120 monoclonal gammopathy of undetermined significance (MGUS), 47 Waldenström's Macroglobulinemia (WM), and 21 AL amyloidosis), and 170 disease controls for assessing diagnostic sensitivity and specificity. Sixty-four MM patients with 439 follow-up samples and 10 WM patients with 91 follow-up samples were included to evaluate the ability of QIP-MS to detect M protein changes related to treatment. Median follow up was 19 and 15 months, respectively. Serum samples were retrospectively analyzed at three sites. QIP-MS was carried out using the automated EXENT® solution (in development, The Binding Site, part of Thermo Fisher Scientific). The assay's diagnostic sensitivity and specificity were calculated based on categorizing results as positive or negative. A positive result was defined in baseline samples as the presence of an M protein which was either an intact immunoglobulin ≥0.200 g/L or a light chain only. Results by QIP-MS were also compared to serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE). QIP-MS response categories were defined based on M protein changes per international guidelines criteria, and compared to response categories assigned by the treating physician. Complete response (CR) was defined as absence of the M-peak that was observed at baseline, using isotype and m/z value of ±4 as criterion for identity. Results: The overall diagnostic sensitivity of QIP-MS in this study was 95.0%: 93.3% for MGUS; 100.0% for SMM; 94.4% for MM; 100.0% for WM; and 71.4% for AL amyloidosis. The diagnostic specificity of the assay was 68.2%. QIP-MS identified an M protein in more MG patients compared to SPE: 437 (95.0%) vs 398 (86.5%). The positivity rate by QIP-MS vs SPE was 93.3% vs 84.2% in MGUS; 100% vs 92.9% in SMM; 94.3% vs 85.0% in MM; 100% vs 100% in WM and 71.4% vs 47.6% in AL amyloidosis. Method comparison demonstrated a Passing-Bablok slope of 0.8 to 1.2 between QIP-MS and SPE for the quantification of M proteins for each disease group and for each isotype, except for monoclonal IgM and in WM (slope of 1.58). In SPE-positive MG patients, the overall concordance between QIP-MS and IFE for M protein isotype was 97%. The overall concordance rate between QIP-MS response categories and standard response assignment was 55% for MM and 56% for WM: 48% for progressive disease (PD); 63% for stable disease (SD); 46% for minimal response (MR); 71% for partial response (PR); 66% for very good partial response (VGPR); and 25% for CR in MM patients. Among 73 responses categorized as CR, QIP-MS produced a positive result for the original clone in 55 (75.3%) cases. Concordance rates in WM patients were 71% for PD%; 30% for SD; 38% for MR; and 74% for PR; no VGPR or CR were reported by either method. Conclusions: In this study, QIP-MS demonstrated the potential for same or superior diagnostic sensitivity compared to SPE, high concordance with IFE for the M protein isotype and good quantitative agreement with SPE measurements of the M proteins. It reported higher IgM values compared to SPE, likely due to reliance on turbidimetric immunoglobulin measurement for quantitations. Diagnostic specificity was impacted by the identification of minor M proteins, not detectable by SPE, and whose clinical significance requires further investigation. QIP-MS demonstrated “moderate” to “fair” agreement for response assignment in MM and WM, respectively, mostly due to the detection of residual M proteins in a significant proportion of patients in CR, in line with its enhanced analytical sensitivity. These data support the use of QIP-MS as an aid in the diagnosis and monitoring of MGs.
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Aoki, H., M. Takishita, M. Kosaka, and S. Saito. "Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenstrom's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL." Blood 85, no. 7 (April 1, 1995): 1913–19. http://dx.doi.org/10.1182/blood.v85.7.1913.bloodjournal8571913.
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V(D)J recombination and somatic hypermutations are developmentally regulated during B-cell differentiation; therefore, DNA analysis of the Ig gene delineates the cellular origin of B-cell neoplasms. We analyzed the third complementarity-determining region and adjacent regions of the Ig heavy-chain gene of tumor cells from 7 patients with Waldenstrom's macroglobulinemia (WM) and from 10 patients with B-cell chronic lymphocytic leukemia (CLL), 2 of whom progressed to high-grade non-Hodgkin's lymphoma (NHL), ie, Richter's syndrome (RS). There were no intraclonal variations resulting from VH replacements or ongoing somatic mutations in both WM and CLL. We found replacement mutations in the D and/or JH segments in all patients with WM and in 4 of the 10 patients with CLL, including the 2 RS patients. Replacement mutations were clustered in codon 102 of the JH segment. Preferential utilization of the JH4 gene was found in WM (5 of 7 [71.4%]) and in CLL (7 of 10 [70.0%]), and DXP family genes in CLL (5 of 10 [50.0%]). In conclusion, WM and CLL with RS are generated under the influence of antigenic stimulation and selection. However, the majority of CLL may arise from a distinct subpopulation that has the restricted repertoire of nonmutated Ig genes.
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Vincenzi, Margherita, Erika Borella, Enrico Sella, César F. Lima, Rossana De Beni, and E. Glenn Schellenberg. "Music Listening, Emotion, and Cognition in Older Adults." Brain Sciences 12, no. 11 (November 17, 2022): 1567. http://dx.doi.org/10.3390/brainsci12111567.
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Using the arousal and mood hypothesis as a theoretical framework, we examined whether community-dwelling older adults (N = 132) exhibited cognitive benefits after listening to music. Participants listened to shorter (≈2.5 min) or longer (≈8 min) excerpts from recordings of happy- or sad-sounding music or from a spoken-word recording. Before and after listening, they completed tasks measuring visuospatial working memory (WM), cognitive flexibility and speed, verbal fluency, and mathematical ability, as well as measures of arousal and mood. In general, older adults improved from pre- to post-test on the cognitive tasks. For the test of WM, the increase was greater for participants who heard happy-sounding music compared to those in the other two groups. The happy-sounding group also exhibited larger increases in arousal and mood, although improvements in mood were evident only for the long-duration condition. At the individual level, however, improvements in WM were unrelated to changes in arousal or mood. In short, the results were partially consistent with the arousal and mood hypothesis. For older adults, listening to happy-sounding music may optimize arousal levels and mood, and improve performance on some cognitive tasks (i.e., WM), even though there is no direct link between changes in arousal/mood and changes in WM.
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Song, Yan, Mengyu Chai, Junnan Lv, Zelin Han, Pan Liu, Haoqi Yan, and Zhendong Sha. "Creep rupture behavior of 2.25Cr1Mo0.25V steel and weld for hydrogenation reactors under different stress levels." REVIEWS ON ADVANCED MATERIALS SCIENCE 61, no. 1 (January 1, 2022): 334–49. http://dx.doi.org/10.1515/rams-2022-0037.
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Abstract In the present research work, the 2.25Cr1Mo0.25V steel plates with a thickness of 112 mm were welded using the multi-pass submerged automatic arc welding process. The creep specimens were prepared from the base metal (BM) and weld metal (WM) in the welded joint after heat treatment process. The uniaxial creep tests were performed to investigate the creep deformation and rupture behaviors at 550°C under different applied stress levels. The microstructure and fracture surface morphology of crept BM and WM samples were also characterized using the scanning electron microscope with energy-dispersive X-ray spectroscopy. The results showed that typical three-stage creep deformation curves are observed in both BM and WM specimens, and the BM exhibits a faster deformation rate than the WM. Both the creep rupture time and uniaxial creep ductility are found to be increased with a decrease in applied stress. Furthermore, the relationship between the minimum creep rate and time to rupture of both BM and WM samples was obtained, and it can be described using a unified Monkman–Grant equation. In addition, it is found that the creep fractures of the BM and WM are a transgranular ductile failure. The creep damages of both materials are mainly associated with the microstructural degradations, that is, the initiation and coalescence of creep cavities at second phase particles such as carbide and inclusion particles along the loading direction.
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Yang, Guang, Xia Liu, Jie Chen, Lian Xu, Nicholas Tsakmaklis, Jiaji Chen, Christopher J. Patterson, et al. "Targeting IRAK1/IRAK4 Signaling in Waldenstrom's Macroglobulinemia." Blood 126, no. 23 (December 3, 2015): 4004. http://dx.doi.org/10.1182/blood.v126.23.4004.4004.
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Abstract Background: MYD88 L265P somatic mutations are highly prevalent in Waldenström's macroglobulinemia (WM) (NEJM 367(9):826-33). MYD88 L265P activates multiple downstream signaling pathways including BTK and IRAK1/IRAK4 that support malignant cell growth and survival (Nature 470(7332):115-9; Blood 122(7):1222-32). Ibrutinib targets BTK, and shows high overall and major clinical response rates, though no complete responses are observed indicating alternative survival signaling. Methodology: Phospho-flow analysis of IRAK1, IRAK4, and BTK was performed in primary WM cells taken from untreated WM patients, and those on ibrutinib therapy. IRAK1 or IRAK4 knockdown experiments were performed using lentiviral shRNA transduction. Immunoprecipitation, western blot and phospho-flow studies were used to detect protein expression and phosphorylation in WM cells. Cell survival following IRAK4 or IRAK1 knockdown, ibrutinib and/or IRAK4/IRAK1 inhibitor (EMD Millipore) treatment was assessed by Annexin V staining, AlamarBlue® Cell Viability Assay or CellTiter-Glo® Luminescent Cell Viability Assays. Results: Phospho-flow analysis of bone marrow lymphoplasmacytic cells taken from WM patients following > 6 months of continued ibrutinib treatment demonstrated highly active IRAK1 and IRAK4, but not BTK. These findings prompted us to dissect the relative impact of IRAK1 and IRAK4 in supporting WM cell survival. Using lentiviral transduction, we identified shRNAs that produced similar levels of protein reduction by western blot analysis for both IRAK1 and IRAK4. Compared to scrambled control vector, knockdown of IRAK1 or IRAK4 both produced decreased tumor cell survival in MYD88 mutated BCWM.1 and MWCL-1 cells. More pronounced apoptosis, as well as sustained reduction in tumor cell growth occurred following knockdown of IRAK1 versus IRAK4. Treatment of primary WM cells taken from untreated patients, patients on ibrutinib therapy, as well as MYD88 mutated WM cells lines with ibrutinib and a toolbox IRAK4/IRAK1 inhibitor resulted in more robust reductions in NFkB signaling, and at least additive tumor cell killing versus either agent alone. Conclusions: MYD88 L265P mutated WM cells show greater dependence on IRAK1 versus IRAK4 directed signaling. IRAK1/IRAK4 signaling may contribute to persistent WM cell survival following ibrutinib treatment. Combined BTK and IRAK inhibition leads to augmented blockade of NFKB signaling and enhanced WM cell killing. The studies provide a framework for the development and investigation of IRAK inhibitors, alone and in combination with ibrutinib in WM patients. Disclosures No relevant conflicts of interest to declare.
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Hanzis, Christina, Zachary Hunter, Robert Manning, Megan Lewicki, Philip Brodsky, Leukothea Ioakimidis, Christina Tripsas, Christopher Patterson, Patricia Sheehy, and Steven P. Treon. "Associated Malignancies Among Patients and Kin with Waldenstrom's Macroglobulinemia." Blood 116, no. 21 (November 19, 2010): 4159. http://dx.doi.org/10.1182/blood.v116.21.4159.4159.
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Abstract Abstract 4159 Waldenstrom's macroglobulinemia (WM) is a B-cell malignancy characterized as an IgM secreting lymphoplasmacytic lymphoma. Familial predisposition is common in WM. Studies to date by us and others have revealed three identifiable clinical subtypes for WM predisposition: * Sporadic; proband has WM, but there is an absence of WM or other B-cell disorders in other family members; * Familial, Mixed B-cell Disorders Subtype; proband has WM, and various B-cell disorders are manifested by other family members. * Familial, WM Only Subtype; proband has WM, and only WM is present in other family members; While these studies suggest a separate genetic predisposition for WM, the correlation of additional cancer risk among all patients with WM and their kin, and well as those sub typed by familial WM predisposition may herald important information for common genetic risks to cancer. We therefore examined the incidence of additional malignancies in 923 consecutive WM patients seen at our Institution, and characterized the frequencies of additional malignancies based on familial subtype and against SEER data. In addition, we also characterized the incidence of solid cancers in kin of WM patients, and sub typed these cancers based on familial WM presentation. Of the 923 patients, 221 (23.9%) patients had at least one additional malignancy to WM. Among these patients, 32 had 2, and 4 (0.43%) had 3 additional malignancies. For 167/221 (75.5%), the associated cancers were diagnosed before WM. The associated malignancies for all patients were as follows: Prostate (n=53; 9.2% of all males); Breast (n=27; 7.7% of all females); Skin (Basal and Squamous; n=61; 6.6%); Skin (Melanoma; n=16; 1.7%); Lung (n=12; 1.3%); Thyroid (n=10; 1.1%); Colorectal (n=7; 0.8%); Bladder (n=8; 0.9%) Other B-cell Malignancies (n=18; 2.0%); Renal (n=6; 0.7%); MDS (n=6; 0.65%); Other (n=11; 1.2%). The incidence of Lung (p=0.002) and Prostate (p=0.07) were higher among WM patients with Familial, Mixed B-cell Disorders Subtype. To avoid potential treatment related impact on additional cancer development, we next adjusted the observed versus expected frequencies based on SEER-17 data. The age adjusted incidence for development of any malignancy among WM patients was 7.6 fold higher when the development of another cancer antedated the diagnosis of WM. Among all WM patients, the incidence of solid cancers among first degree kin were as follows: Prostate (n=98; 10.6%); Breast (n=133; 14.4%); Skin (Basal and Squamous; n=21; 2.3%); Skin (Melanoma; n=21; 2.3%); Lung (n=116; 12.5%); Thyroid (n=9; 1.0%), Colorectal (n=79; 8.6%); Renal (n=8; 0.9%); and Gastric (n=20; 2.2%). The incidence of Breast (p=0.0098), and Skin (Melanoma) (p=0.037) cancers were higher among first degree kin of patients with the Sporadic versus Familial, Mixed B-cell Disorders Subtype. In summary, the above data suggest an increased risk for additional cancers among all WM patients, as well as specific risks for lung and prostate cancer among patients with Familial, Mixed B-cell Disorders Subtype. Moreover, these data also show the association of specific types of solid cancers in first degree kin of WM patients, particularly for WM patients with the Sporadic Subtype. n= Age (Yrs) Gender % Treated Additional Cancers Sporadic 666 60 (29–91) 64% M; 36% F 515 (77%) 163 (24.4%) Familial, Mixed B–cell Disorders 212 58 (36–85) 57% M; 43% F 156 (73%) 50 (23.5%) Familial, WM Only 45 61 (35–89) 56% M; 44% F 35 (77%) 8 (17.7%) Total 923 59 (29–91) 62% M; 38% F 706 (76.4%) 221 (23.9%) Disclosures: No relevant conflicts of interest to declare.
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Paba-Prada, Claudia E., Ranjit Banwait, Steven Treon, and Irene M. Ghobrial. "Incidence of Peripheral Neuropathy in Waldenström Macroglobulinemia Patients At Diagnosis,." Blood 118, no. 21 (November 18, 2011): 3692. http://dx.doi.org/10.1182/blood.v118.21.3692.3692.
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Abstract Abstract 3692 INTRODUCTION: Waldenström Macroglobulinemia (WM) is a rare indolent B-cell lymphoma characterized by lymphoplasmacytic infiltration of the bone marrow and a monoclonal immunoglobulin M (IgM). One common complication of WM is peripheral neuropathy (PN). However, the incidence of PN in WM has not been established. The most frequent neurologic abnormality is distal, symmetric, and slowly progressive sensorimotor polyneuropathy characterized by paresthesias and weakness. Although the exact pathogenesis remains unclear, neurological complications of WM can occur as a result of hyperviscosity, deposition of the monoclonal protein, direct infiltration of nerves by neoplastic lymphoplasmacytic cells, and IgM antibodies binding to myelin-associated glycoprotein in nerves such as anti-MAG and anti-GM1. Cryoglobulinemia and amyloidosis deposits are also associated with nerve damage. We aimed to describe the incidence of PN in a large population of WM patients and the possible associated clinical and laboratory features that may contribute to the development of PN. METHODS: A retrospective analysis was performed on 182 WM patients seen at Dana-Farber Cancer Institute between November 2000 to October 2009. Patient medical records were studied to gather information on demographics, initial diagnosis, disease staging by ISS-WM (age, beta-2 microglobulin, hemoglobin, platelet count and IgM level at the time of initial therapy), bone marrow involvement, neuropathic symptoms, anti-GM1 and anti-MAG antibodies, B12 and folate levels, and presence of cryoglobulins, and amyloid deposits. RESULTS: Of the 182 patients, 112 (62%) were female, and the median age was 63 years (range, 42–86). Based on the Morel ISS-WM study (ISS-WM), 51 (28%) patients were high risk, 56 (31%) were intermediate risk, and 75 (41%) were low risk. Forty-seven (25%) patients were identified with neuropathic symptoms at the time of initial presentation. The most common neurologic symptoms included paresthesias and distal extremity weakness. Among the 47 patients with neuropathic symptoms, 9 (19%) were high risk, 12 (26%) were intermediate risk and 26 (55%) were low risk by ISS-WM staging. The median hemoglobin level in the patients with PN was 11.1 g/dL (range, 6.8–15.6 g/dL) and the median platelet count was 222 K/uL (range, 30–560 K/uL), while in patients without PN had a median hemoglobin of 10.2 g/dl (range, 4.9–15.1 g/dL) and median platelet count of 217 K/uL (range, 29–675 K/uL). Additionally, patients with PN had a median IgM level of 3095 mg/dL (251–12,700 mg/dL) and median beta-2 microglobulin level of 2.5 mg/L (1.0–8.8 mg/L). In the patients without PN, the median IgM level was found to be 4002 mg/dL (range, 222–9550 mg/dL) and beta-2 microglobulin was 3.5 mg/L (range, 1.2–14.4 mg/L). Furthermore, we identified 2 patients with positive anti-MAG (4%) and 1 patient with anti-GM1 antibodies (2%). Three patients (6%) had evidence of concurrent amyloidosis and 2 patients (4%) had positive cryoglobulins. Among the patient with PN, the median bone marrow involvement by lymphoplasmacytic cells was 50% (range, 5–90%). We also identified 3 patients (6%) with concomitant B12 deficiency (B12 levels <300 pg/mL), which could have contributed to the etiology of their neuropathy. CONCLUSION: Peripheral neuropathy is a common finding among WM patients with 25% of the cases presenting at diagnosis. The findings suggest that at the time of initial assessment, most WM patients with PN present with a low ISS-WM staging, and interestingly a lower beta-2 microglobulin level than the patients without PN. No association with IgM levels or bone marrow percent involvement with the incidence of neuropathy was found in this patient population. Few of these patients have positive anti-MAG and anti-GM1 antibodies, or other concurrent cause for neuropathy such as amyloidosis. Identifying these patients for specific clinical trials that are tailored to overcome IgM mediate neuropathy is warranted. Disclosures: Treon: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Regmi, Santosh, and Sunil Adhikary. "Solar Energy Potential in Kathmandu Valley, Nepal." Journal of Hydrology and Meteorology 8, no. 1 (August 30, 2016): 77–82. http://dx.doi.org/10.3126/jhm.v8i1.15576.
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Meteorological data such as solar radiation (1975-1984, and 2002-2010) and sunshine duration (1968-2004) were analyzed to study temporal characteristics of solar energy and investigate solar energy potential in Kathmandu valley. Pre-monsoon and post monsoon seasons have higher mean monthly sunshine duration (about 8 hours/day) than summer (about 5 hours/day) and winter (about 7 hours/day) seasons over Kathmandu. Pre-monsoon and monsoon seasons receive solar energy of about 190 Wm-2 and 170 Wm-2 respectively. The winter season receives the least amount of solar radiation (135 Wm-2). Approximately 220 MW of solar electricity can be produced in Kathmandu that will substantially fulfill current energy demand and reduce environmental pollution in the valley by replacing fossil fuels with clean solar electricity.Journal of Hydrology and Meteorology, Vol. 8(1) 2012, p.77-82
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Ricca, Irene, Giacomo Tamponi, Celeste Arnò, Angelo Bosio, Flavio Cerrato, Marisa Coggiola, Giuseppe Epifani, et al. "Epidemiology of Plasma Cell Disorders in a General Hospital: A Retrospective Study of 102 Patients." Blood 110, no. 11 (November 16, 2007): 4754. http://dx.doi.org/10.1182/blood.v110.11.4754.4754.
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Abstract INTRODUCTION Plasma cell disorders are a group of diseases characterized by the proliferation of a plasma cell clone which produces a monoclonal protein (M protein). The most common type is Monoclonal Gammopathies of Undetermined Significance (MGUS), followed by multiple myeloma (MM) and Waldenstrom’s Macroglobulinemia (WM). In particular, the frequency of MGUS increases with age and its rate of progression is approximately 1% per year. Because of the high prevalence and the different fields of clinical practice in which these patients are followed, it could be of great interest to know the epidemiology of these diseases out of the Hematology Units. AIM OF THE STUDY to describe the frequency and the progression risk of plasma cell disorders in a General Hospital during more than a twenty-year period. METHODS We retrospectively reviewed the medical records of patients with diagnosis of MGUS, MM or WM seen at our center from 1984 through 2006. Statistical analysis were performed using GraphPad Prism 4 (GraphPad Software, Inc.). RESULTS The study included 102 patients: 78 affected by MGUS (76%), 14 by MM (14%) and 10 by WM (10%). Patients’ clinical features are summarized in the Table. Median follow-up was 48 months (range:12–280). Among the 89 patients with a first diagnosis of MGUS, malignant transformation occurred in 11 patients (7 MM and 4 WM). The median time from diagnosis of MGUS to diagnosis of a lymphoplasma cell proliferative disorder was 60 months (range 12–196). Median time to progression (TTP) was 167 months, as shown in Figure. The cumulative probability of progression was 13.5% at 5 years and 29.2% at 10 years. The amount of serum M protein at diagnosis was a significant predictor of progression. CONCLUSIONS MGUS are very common in clinical practice, accounting in our study for more than 75% of plasma cell disorders. The premalignant nature of this condition is comfirmed by the rate of transformation in lymphoplasma cell proliferative disorders (50% of MM and 40% of WM, in this study). Even if our results may be biased by the short follow-up period, the only significant predictor of progression was the size of serum M protein at presentation. Table: Patients’ characteristics Characteristics MGUS MM WM Gender male/female 41/37 4/10 7/3 Age at diagnosis median (range) 69 yrs (30–91) 72 yrs (51–90) 75 yrs (67–85) Serum M protein median (range) 1.26 g/dl (0.17–2.92) 3.85 g/dl (0.62–8.10) 3.20 g/dl (2.22–4.9) Isotype IgG 46 8 - IgA 14 6 - IgM 15 - 10 biclonal 3 - - Immunoparesis yes/no 20/58 14/0 10/0 BJ proteinuria pos/neg 11/67 11/3 1/9 Figure Figure
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Gao, Xia, Qiuying Li, Yanwen Qu, Jinzhi Zhang, Yougang Xing, and Shichun Li. "Effect of Combination of Traditional Chinese Medicine with Western Medicine on Endometrial Carcinoma and Its Influence on Ultrasound, MRI, Tumor Markers HE4 and CA125." Evidence-Based Complementary and Alternative Medicine 2021 (December 2, 2021): 1–8. http://dx.doi.org/10.1155/2021/6053406.
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Objective. To study the clinical efficacy of integrated traditional Chinese medicine (TCM) and Western medicine (WM) in treating endometrial cancer and the influence on ultrasound, magnetic resonance imaging (MRI), tumor markers, human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125). Method. A total of 152 cases of patients with endometrial carcinoma were randomly divided into two groups: the TCM + WM group and the WM group. The WM group was treated with megestrol acetate tablets, and the TCM + WM group was treated with Radix Astragali injection on the basis of the control group. The levels of inflammatory factors, HE4 and CA125 in serum, were detected using enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. The characteristics of ultrasound images and MRI images were observed and recorded. Toxicity, side effects, and the 3-year cumulative survival rate after treatment were assessed. Results. After treatment, the levels of interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) in both groups decreased, and the decrease in the TCM + WM group was more obvious than that in the WM group. There were statistically significant differences between the two groups in lesion shape, boundary, blood flow signal, lesion diameter, resistance index (RI), echo, intima thickness, and muscle layer infiltration from transvaginal ultrasound images after treatment. The diameter, echo, boundary, shape, composition, and enhancement degree of lesions between the two groups have a significant difference. Moreover, the levels of serum HE4 and CA125 in both groups decreased after treatment, and the decrease in the TCM + WM group was more obvious than that in the WM group. There were statistically significant differences between the two groups in the occurrence of myelosuppression, abnormal liver function, decreased platelet number, gastrointestinal reactions, leukopenia, and cardiotoxicity. After three years of follow-up, the cumulative survival rate of the TCM + WM group was 76.32%, and the cumulative survival rate of the WM group was 57.89%. Conclusion. Radix Astragali injection combined with megestrol acetate tablets has obvious therapeutic effects against endometrial cancer. Through vaginal ultrasonography and MRI, it can significantly improve the size, shape, and blood flow signals of patients’ lesions, reduce the level of serum inflammatory factors and tumor markers HE4 and CA125, reduce the incidence of toxic and side reactions, improve the patient’s immunity, improve the patient’s condition significantly, and prolong the survival time of patients.
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Derks, Marloes, Jacobus van der Velden, Minke M. Frijstein, Willemijn M. Vermeer, Anne M. Stiggelbout, Jan Paul W. R. Roovers, Cornelis D. de Kroon, Moniek M. ter Kuile, and Gemma G. Kenter. "Long-term Pelvic Floor Function and Quality of Life After Radical Surgery for Cervical Cancer: A Multicenter Comparison Between Different Techniques for Radical Hysterectomy With Pelvic Lymphadenectomy." International Journal of Gynecologic Cancer 26, no. 8 (October 2016): 1538–43. http://dx.doi.org/10.1097/igc.0000000000000776.
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ObjectiveThis study aimed to compare urinary and bowel symptoms and quality of life (QoL) among women treated with a Wertheim–Meigs (WM, type III) or Wertheim–Okabayashi (WO, type IV) radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer.MethodsIn this cross-sectional observational study, patients treated with a WO or a (nerve sparing) WM radical hysterectomy (with or without adjuvant radiotherapy) between January 2000 and December 2010 in the Center for Gynaecological Oncology Amsterdam or Leiden University Medical Center were included. To assess QoL, urinary and bowel symptoms we used the EORTC QLQ-C30, EORTC QLQ-CX24, and Leiden Questionnaire. We performed a multivariate analysis to identify factors associated with urinary symptoms.ResultsTwo hundred sixty-eight women were included (152 WO and 116 WM). Quality of life was not significantly different in patients treated by WO or WM. Urinary symptoms were more often reported by patients in the WO group compared to the WM group: “feeling of urine retention” (53% vs 32%), “feeling less/no urge to void” (59% vs 14%), and “timed voiding” (49% vs 10%). With regard to bowel symptoms, there was no difference between both. Multivariate analysis showed that surgical technique was an independent factor for differences in urinary symptoms.ConclusionsPatients undergoing more radical surgery for early-stage cervical cancer report significantly more urinary dysfunction, whereas bowel function and health-related QoL are not decreased.
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Bergé, Daniel, Anna Mané, Tyler A. Lesh, Miquel Bioque, Fe Barcones, Ana Maria Gonzalez-Pinto, Mara Parellada, et al. "Elevated Extracellular Free-Water in a Multicentric First-Episode Psychosis Sample, Decrease During the First 2 Years of Illness." Schizophrenia Bulletin 46, no. 4 (January 9, 2020): 846–56. http://dx.doi.org/10.1093/schbul/sbz132.
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Abstract Recent diffusion imaging studies using free-water (FW) elimination have shown increased FW in gray matter (GM) and white matter (WM) in first-episode psychosis (FEP) and lower corrected fractional anisotropy (FAt) in WM in chronic schizophrenia. However, little is known about the longitudinal stability and clinical significance of these findings. To determine tissue-specific FW and FAt abnormalities in FEP, as part of a multicenter Spanish study, 132 FEP and 108 healthy controls (HC) were clinically characterized and underwent structural and diffusion-weighted MRI scanning. FEP subjects were classified as schizophrenia spectrum disorder (SSD) or non-SSD. Of these subjects, 45 FEP and 41 HC were longitudinally assessed and rescanned after 2 years. FA and FW tissue-specific measurements were cross-sectional and longitudinally compared between groups using voxel-wise analyses in the skeletonized WM and vertex-wise analyses in the GM surface. SSD and non-SSD subjects showed (a) higher baseline FW in temporal regions and in whole GM average (P.adj(SSD vs HC) = .003, P.adj(Non-SSD vs HC) = .040) and (b) lower baseline FAt in several WM tracts. SSD, but not non-SSD, showed (a) higher FW in several WM tracts and in whole WM (P.adj(SSD vs HC)= .049) and (b) a significant FW decrease over time in temporal cortical regions and in whole GM average (P.adj = .011). Increased extracellular FW in the brain is a reliable finding in FEP, and in SSD appears to decrease over the early course of the illness. FAt abnormalities are stable during the first years of psychosis.