tbuckley/cabot-search huggingface dataset:
Authors’ Reply: Calcium-Based Phosphate Binders and Plasma Oxalate Concentration in Dialysis Patients
Authors: Anja Pfau, Felix Knauf
Journal: Journal of the American Society of Nephrology (2022)

We thank Oka and colleagues for their comments on our paper and their suggestion for a possible role for alternative therapeutic interventions to reduce oxalate concentrations and cardiovascular mortality in patients on dialysis. They suggest a low-oxalate diet or calcium-based phosphate binders could decrease oxalate absorption and lead to reduced cardiovascular risk. We agree these measures warrant further evaluation when planning interventional studies examining elevated plasma oxalate concentrations and risk of sudden cardiac death in patients on dialysis. Avoidance of high-oxalate foods makes sense, although the dietary restrictions faced by patients on dialysis are already burdensome.1 Of note, food products high in potassium often contain high amounts of oxalate (nuts, beans, certain vegetables).2 The current Kidney Disease Improving Global Outcomes guidelines3 suggest restricting the dose of calcium-based phosphate binders in adults with CKD stage G3a–G5D receiving phosphate-lowering treatment (2B recommendation), due to a higher mortality risk. For patients on dialysis, this recommendation was made on the basis of a large trial comparing sevelamer to a calcium-containing phosphate binder.4 The eight trials analyzed by Jamal et al.,5 and duly cited by Oka and colleagues, also compared sevelamer with calcium carbonate or acetate. Yet, sevelamer itself may also feature a modest oxalate-lowering effect, as shown in a small trial in patients with enteric hyperoxaluria.6 Future studies could elucidate this issue further. Disclosures F. Knauf reports receiving personal fees from Advicenne, Allena Pharmaceuticals, Alnylam Pharmaceuticals, Fresenius Medical Care, Oxthera Pharmaceuticals, and Sanofi Pharmaceuticals, outside the submitted work; receiving honoraria from Advicenne, ECoR1, Medice, and Sanofi; receiving research funding from Alnylam Pharmaceuticals, Dicerna Pharmaceuticals, Deutsche Forschungsgemeinschaft, and Else Kröner Fresenius Stiftung; having consultancy agreements with Chinook Pharmaceuticals USA, EcoR1 USA, and Zai Pharmaceuticals China; serving on the scientific advisory board of the Oxalosis and Hyperoxaluria Foundation NYC; and having patents or royalties with PocketDoktor Medical Books. F. Knauf and A. Pfau report being employees of the nonprofit institute Charité-Universitätsmedizin Berlin, which has recently filed a patent for oxalate-lowering agents in patients on dialysis, with A. Pfau and F. Knauf listed as inventors. A. Pfau reports receiving personal fees from Alnylam Pharmaceuticals, outside the submitted work. Funding None.
Colonoscopy for Diagnostic Evaluation and Interventions to Prevent Recurrence After Acute Left-Sided Colonic Diverticulitis: A Clinical Guideline From the American College of Physicians
Authors: Amir Qaseem, Itziar Etxeandia-Ikobaltzeta, Jennifer S. Lin, Nick Fitterman, Tatyana Shamliyan, Timothy J. Wilt
Journal: Annals of Internal Medicine (2022)

The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the role of colonoscopy for diagnostic evaluation of colorectal cancer (CRC) after a presumed diagnosis of acute left-sided colonic diverticulitis and on the role of pharmacologic, nonpharmacologic, and elective surgical interventions to prevent recurrence after initial treatment of acute complicated and uncomplicated left-sided colonic diverticulitis. This guideline is based on the current best available evidence about benefits and harms, taken in the context of costs and patient values and preferences.The ACP Clinical Guidelines Committee (CGC) based these recommendations on a systematic review on the role of colonoscopy after acute left-sided colonic diverticulitis and pharmacologic, nonpharmacologic, and elective surgical interventions after initial treatment. The systematic review evaluated outcomes rated by the CGC as critical or important. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method.The target audience is all clinicians, and the target patient population is adults with recent episodes of acute left-sided colonic diverticulitis.ACP suggests that clinicians refer patients for a colonoscopy after an initial episode of complicated left-sided colonic diverticulitis in patients who have not had recent colonoscopy (conditional recommendation; low-certainty evidence).ACP recommends against clinicians using mesalamine to prevent recurrent diverticulitis (strong recommendation; high-certainty evidence).ACP suggests that clinicians discuss elective surgery to prevent recurrent diverticulitis after initial treatment in patients who have either uncomplicated diverticulitis that is persistent or recurs frequently or complicated diverticulitis (conditional recommendation; low-certainty evidence). The informed decision whether or not to undergo surgery should be personalized based on a discussion of potential benefits, harms, costs, and patient's preferences.
Genomic alterations of dermatofibrosarcoma protuberans revealed by whole‐genome sequencing
Authors: Cong Peng, Xingxing Jian, Yang Xie, Lingfeng Li, Jian Ouyang, Ling Tang, Xu Zhang, Juan Su, Shuang Zhao, Hong Liu, Mingzhu Yin, Dan Wu, Miaojian Wan, Lu Xie, Xiang Chen
Journal: British Journal of Dermatology (2022)

Dermatofibrosarcoma protuberans (DFSP) is a rare and marginal cutaneous sarcoma of intermediate-grade malignancy, for which the genomic landscape remains unclear. Understanding the landscape of DFSP will help to further classify the genomic pathway of malignant development in soft tissue.To identify the comprehensive molecular pathogenesis of DFSP.In this study, the comprehensive genomic features, with 53 tumour-normal pairs of DFSP, were revealed by whole-genome sequencing.The mutational signature 1 (C > T mutation at CpG dinucleotides) is featured in DFSP, resulting in higher mutations in DNA replication. Interestingly, the recurrence of DFSP is correlated with low tumour mutation burden. Novel mutation genes in DFSP were identified, including MUC4/6, KMT2C and BRCA1, and subsequently, three molecular subtypes of DFSP were classified on the basis of MUC4 and MUC6 mutations. Various structural aberrations including genomic rearrangements were identified in DSFPs, particularly in 17q and 22q, which cause oncogene amplification (AKT1, SPHK1, COL1A1, PDGFβ) or tumour suppressor deletion (CDKN2A/B). In addition to gene fusion of COL1A1-PDGFβ [t(17;22)], we identified gene fusion of SLC2A5-BTBD7 [t(1;14)] in DFSP through whole-genome sequencing, and verified it experimentally. Enrichment analysis of altered molecules revealed that DNA repair, cell cycle, phosphoinositide 3-kinase and Janus kinase pathways were primarily involved in DFSP.This is the first large-scale whole-genome sequencing for DFSP, and our findings describe the comprehensive genomic landscape, highlighting the molecular complexity and genomic aberrations of DFSP. Our findings also provide novel potential diagnostic and therapeutic targets for this disease. What is already known about this topic? Chromosomal translocation between chromosome 17 and chromosome 22 is the main feature in the pathogenesis of dermatofibrosarcoma protuberans (DFSP). What does this study add? We describe the comprehensive genomic landscape of DFSP, highlighting the molecular complexity and genomic aberrations. Our findings provide novel potential diagnostic and therapeutic targets for this disease. What is the translational message? Our study revealed novel molecular subtypes of DFSP based on genetic mutations, which benefits precision diagnosis. We also found oncogene amplification, including AKT1 and SPHK1, which provides novel potential target molecules for further DFSP treatment. In addition to gene fusion of COL1A1-PDGFβ, we identified a novel gene fusion of SLC2A5-BTBD7 in DFSP, which is a novel potential diagnostic and therapeutic target for this disease.
Cilta-cel OK'd for Multiple Myeloma
Journal: Cancer Discovery (2022)

The FDA has approved ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy targeting BCMA, as a fifth-line option for patients with relapsed/refractory multiple myeloma. Cilta-cel is the second agent in its class to get a regulatory thumbs-up in less than a year.
A novel adoptive synthetic <scp>TCR</scp> and antigen receptor (<scp>STAR</scp>) <scp>T‐Cell</scp> therapy for <scp>B‐Cell</scp> acute lymphoblastic leukemia
Authors: Jiasheng Wang, Xian Zhang, Zhixiao Zhou, Yue Liu, Li Yu, Lemei Jia, Junfang Yang, Jingjing Li, Hanyang Yu, Wenzhong Li, Guangna Liu, Wei Rui, Hongli Zheng, Xueqiang Zhao, Xin Lin, Peihua Lu
Journal: American Journal of Hematology (2022)

Abstract We developed a T‐cell‐receptor (TCR) complex‐based chimeric antigen receptor (CAR) named S ynthetic T CR and A ntigen R eceptor (STAR). Here, we report pre‐clinical and phase I clinical trial data (NCT03953599) of this T‐cell therapy for refractory and relapsed (R/R) B‐cell acute lymphoblastic leukemia (B‐ALL) patients. STAR consists of two protein modules each containing an antibody light or heavy chain variable region and TCR α or β chain constant region fused to the co‐stimulatory domain of OX40. T‐cells were transduced with a STAR‐OX40 lentiviral vector. A leukemia xenograft mouse model was used to assess the STAR/STAR‐OX40 T cell antitumor activity. Eighteen patients with R/R B‐ALL were enrolled into the clinical trial. In a xenograft mouse model, STAR‐T‐cells exhibited superior tumor‐specific cytotoxicity compared with conventional CAR‐T cells. Incorporating OX40 into STAR further improved the proliferation and persistence of tumor‐targeting T‐cells. In our clinical trial, 100% of patients achieved complete remission 4 weeks post‐STAR‐OX40 T‐cell infusion and 16/18 (88.9%) patients pursued consolidative allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Twelve of 16 patients (75%) remained leukemia‐free after a median follow‐up of 545 (433–665) days. The two patients without consolidative allo‐HSCT relapsed on Day 58 and Day 186. Mild cytokine release syndrome occurred in 10/18 (55.6%) patients, and 2 patients experienced grade III neurotoxicity. Our preclinical studies demonstrate super anti‐tumor potency of STAR‐OX40 T‐cells compared with conventional CAR‐T cells. The first‐in‐human clinical trial shows that STAR‐OX40 T‐cells are tolerable and an effective therapeutic platform for treating R/R B‐ALL.
Comparing the levels of CTLA‐4‐dependent biological defects in patients with LRBA deficiency and CTLA‐4 insufficiency
Authors: Mehmet C. Catak, Bengu Akcam, Sevgi Bilgic Eltan, Royala Babayeva, Ibrahim S. Karakus, Gamze Akgun, Dilek Baser, Alper Bulutoglu, Feyza Bayram, Nurhan Kasap, Ayca Kiykim, Gonca Hancioglu, Sefika I. Kokcu Karadag, Yasemin kendir Demirkol, Selime Ozen, Sukru Cekic, Dilek Ozcan, Neslihan Edeer Karaca, Ayse S. Sasihuseyinoglu, Murat Cansever, Esra Ozek Yucel, Zeynep Tamay, Derya U. Altintas, Cigdem Aydogmus, Fatih Celmeli, Haluk Cokugras, Nesrin Gulez, Ferah Genel, Ayse Metin, Sukru N. Guner, Necil Kutukculer, Sevgi Keles, Ismail Reisli, Sara S. Kilic, Alisan Yildiran, Elif Karakoc‐Aydiner, Bernice Lo, Ahmet Ozen, Safa Baris
Journal: Allergy (2022)

Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency.Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (TFH ), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation.LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cTFH cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cTFH frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%).This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway.
Cost-Effectiveness of Long-Acting Injectable HIV Preexposure Prophylaxis in the United States
Authors: Anne M. Neilan, Raphael J. Landovitz, Mylinh H. Le, Beatriz Grinsztejn, Kenneth A. Freedberg, Marybeth McCauley, Nattanicha Wattananimitgul, Myron S. Cohen, Andrea L. Ciaranello, Meredith E. Clement, Krishna P. Reddy, Emily P. Hyle, A. David Paltiel, Rochelle P. Walensky
Journal: Annals of Internal Medicine (2022)

The HIV Prevention Trials Network (HPTN) 083 trial demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with oral emtricitabine-tenofovir disoproxil fumarate (F/TDF) for HIV preexposure prophylaxis (PrEP).To identify the maximum price premium (that is, greatest possible price differential) that society should be willing to accept for the additional benefits of CAB-LA over tenofovir-based PrEP among men who have sex with men and transgender women (MSM/TGW) in the United States.Simulation, cost-effectiveness analysis.Trial and published data, including estimated HIV incidence (5.32, 1.33, and 0.26 per 100 person-years for off PrEP, generic F/TDF and branded emtricitabine-tenofovir alafenamide (F/TAF), and CAB-LA, respectively); 28% 6-year PrEP retention. Annual base-case drug costs: $360 and $16 800 for generic F/TDF and branded F/TAF. Fewer side effects with branded F/TAF versus generic F/TDF were assumed.476 700 MSM/TGW at very high risk for HIV (VHR).10 years.Health care system.CAB-LA versus generic F/TDF or branded F/TAF for HIV PrEP.Primary transmissions, quality-adjusted life-years (QALYs), costs (2020 U.S. dollars), incremental cost-effectiveness ratios (ICERs; U.S. dollars per QALY), maximum price premium for CAB-LA versus tenofovir-based PrEP.Compared with generic F/TDF (or branded F/TAF), CAB-LA increased life expectancy by 28 000 QALYs (26 000 QALYs) among those at VHR. Branded F/TAF cost more per QALY gained than generic F/TDF compared with no PrEP. At 10 years, CAB-LA could achieve an ICER of at most $100 000 per QALY compared with generic F/TDF at a maximum price premium of $3700 per year over generic F/TDF (CAB-LA price <$4100 per year).In a PrEP-eligible population at high risk for HIV, rather than at VHR (n = 1 906 800; off PrEP incidence: 1.54 per 100 person-years), CAB-LA could achieve an ICER of at most $100 000 per QALY versus generic F/TDF at a maximum price premium of $1100 per year over generic F/TDF (CAB-LA price <$1500 per year).Uncertain clinical and economic benefits of averting future transmissions.Effective oral PrEP limits the additional price society should be willing to pay for CAB-LA.FHI 360; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; the Reich HIV Scholar Award; and the Steve and Deborah Gorlin MGH Research Scholars Award.
Bridging the equity gap in patient education: the biliary tract cancer BABEL project
Authors: Raffaella Casolino, Chiara Braconi, MG Prete, F González Romero, RE Castro, JM Banales, V Cardinale, H Morement, J Milne, M Krawczyk, L Krupa, MM Anwar, ES Poles, V Merz, T Perra, A Porcu, V Megdanova, Y Popova, MI Meneses-Medina, AL Reyes Mondragón, A Burguete-Torres, I Brandão Rego, J Magalhães, J Liz Pimenta, J Silva, M João Sousa, S Custódio, T Costa, FD Cojocaru, VL Drug, SU Hassan, NU Ain Azam, J Kupcinskas, E Kreivenaite, E Morkunas, O Nikolaieva, D Calvisi, M Evert, N Terhuja, A Das, KD Hoang, HH Nguyen, V Evseev, N Khuntikeo, O Abdihamid, E Mariamidze, K Tsiklauri, VPB Koyyala, P Medisetty, L Digumarti, RR Digumarti, VLA Konkalla, S Mitra, R Sud, P Parikh, SK Gupta, S Sen, S Chanda, D das, K Domadia, P Goyal, S Goyal, N Dhamne, PV Acharya, P Jain, M Sharma, GA War, SR Singh, C Dodagoudar, RS Patnaik, SS Mashahary, R Paul, T Kannan, V Goel, N Patnaik, A Jajodia, S Pasricha, M Gupta, C Agarwal, DK Mondal, A BP, S Joga, SK Mullapally, P Choudhary, R Saini, T Selvaraju, S Pahwa, G Durga, U Maheshwari, S Dhaka, S Lindsay, A Omar, A La Casta Muñoa
Journal: The Lancet Oncology (2022)
BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study
Authors: Amber Louw, Vasiliki Panou, Weronika Maria Szejniuk, Christos Meristoudis, Siaw Ming Chai, Chris van Vliet, Y. C. Gary Lee, Ian M. Dick, Tina Firth, Louise Andersen Lynggaard, Azadeh Birbaneh Asghari, Mogens Vyberg, Johnni Hansen, Jenette Creaney, Oluf Dimitri Røe
Journal: Journal of Thoracic Oncology (2022)

Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy.PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234).BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01).BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.
Resilience and perseverance under siege: providing cancer care during the invasion of Ukraine
Authors: Darya Kizub, Nelya Melnitchouk, Andriy Beznosenko, Galyna Shabat, Solomiia Semeniv, Leticia Nogueira, Patricia J Watson, Kim Berg, Edward J Trapido, Zelde Espinel, James M Shultz
Journal: The Lancet Oncology (2022)
Enhancer transcription detected in the nascent transcriptomic landscape of bread wheat
Authors: Yilin Xie, Yan Chen, Zijuan Li, Jiafu Zhu, Min Liu, Yijing Zhang, Zhicheng Dong
Journal: Genome biology (2022)

The precise spatiotemporal gene expression is orchestrated by enhancers that lack general sequence features and thus are difficult to be computationally identified. By nascent RNA sequencing combined with epigenome profiling, we detect active transcription of enhancers from the complex bread wheat genome. We find that genes associated with transcriptional enhancers are expressed at significantly higher levels, and enhancer RNA is more precise and robust in predicting enhancer activity compared to chromatin features. We demonstrate that sub-genome-biased enhancer transcription could drive sub-genome-biased gene expression. This study highlights enhancer transcription as a hallmark in regulating gene expression in wheat.
What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 2)
Authors: Amir Qaseem, Jennifer Yost, Itziar Etxeandia-Ikobaltzeta, Mary Ann Forciea, George M. Abraham, Matthew C. Miller, Adam J. Obley, Linda L. Humphrey, Elie A. Akl, Rebecca Andrews, Andrew Dunn, Ray Haeme, Devan L. Kansagara, CDR Mark P. Tschanz, Mary Ann Forciea, Matthew C. Miller, Adam J. Obley, Linda L. Humphrey, Robert M. Centor, Thomas A. Bledsoe, Janet A. Jokela, Maura Marcucci
Journal: Annals of Internal Medicine (2022)

The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these living, rapid practice points to summarize the current best available evidence on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2. This is version 2 of the ACP practice points, which serves to update version 1, published on 16 March 2021. These practice points do not evaluate vaccine-acquired immunity or cellular immunity.The SMPC developed this version of the living, rapid practice points based on an updated living, rapid, systematic review conducted by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality.Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection.Do not use SARS-CoV-2 antibody tests to predict the degree or duration of natural immunity conferred by antibodies against reinfection, including natural immunity against different variants.Although natural immunity remains a topic of scientific interest, this topic is being retired from living status given the availability of effective vaccines for SARS-CoV-2 and widespread recommendations for and prevalence of their use. Currently, vaccination is the best clinical recommendation for preventing infection, reinfection, and serious illness from SARS-CoV-2 and its variants.
Merging bioresponsive release of insulin-like growth factor I with 3D printable thermogelling hydrogels
Authors: Matthias Beudert, Lukas Hahn, Anselm H.C. Horn, Niklas Hauptstein, Heinrich Sticht, Lorenz Meinel, Robert Luxenhofer, Marcus Gutmann, Tessa Lühmann
Journal: Journal of Controlled Release (2022)