tbuckley/cabot-search huggingface dataset:
Safety and Efficacy of Daratumumab in Patients with Proliferative GN with Monoclonal Immunoglobulin Deposits
Authors: Ladan Zand, S. Vincent Rajkumar, Nelson Leung, Sanjeev Sethi, Mireille El Ters, Fernando C. Fervenza
Journal: Journal of the American Society of Nephrology (2021)

Treatment of proliferative GN with monoclonal Ig deposits (PGNMID) is not established. A monoclonal anti-CD38 antibody (daratumumab) is effective in treating multiple myeloma. Abnormal plasma cell clones may play a role in the pathogenesis of PGNMID.We evaluated daratumumab's safety and efficacy in an open-label, phase 2 trial in 11 adults with PGNMID and one with C3 glomerulopathy (C3G) with monoclonal gammopathy. Patients had an eGFR >20 ml/min per 1.73 m2 and proteinuria >1 g/d. They received daratumumab intravenously (16 mg/kg) once weekly for 8 weeks, and then every other week for eight additional doses. Primary outcome was safety, defined as major infections, grade 3 or 4 anemia, leukopenia, or thrombocytopenia. Secondary outcomes were rate of complete remission (proteinuria <500 mg/d with <15% decline in baseline eGFR) or partial remission (>50% reduction in 24-hour proteinuria with <30% decline in eGFR) and proteinuria at 6 and 12 months.One patient with C3G had GN unrelated to the monoclonal gammopathy, and one with PGNMID did not complete the first infusion. Five serious adverse events occurred. During the 12 months of the trial, six of the ten patients with PGNMID who received at least one dose of daratumumab had a partial response, and four had a complete response (an overall response rate of 100%). Three patients experienced relapse, two of whom re-entered partial remission after resuming daratumumab therapy. Proteinuria declined significantly, from a median of 4346 mg/d to 1264 mg/d by 12 months.Daratumumab demonstrated an acceptable safety profile and resulted in significant improvement in proteinuria while stabilizing kidney function in patients with PGNMID, suggesting the drug merits further investigation.Daratumumab in Treatment of PGNMID and C3 GN, NCT03095118.
Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction
Authors: Meri Kaustio, Naemeh Nayebzadeh, Reetta Hinttala, Terhi Tapiainen, Pirjo Åström, Katariina Mamia, Nora Pernaa, Johanna Lehtonen, Virpi Glumoff, Elisa Rahikkala, Minna Honkila, Päivi Olsén, Antti Hassinen, Minttu Polso, Nashat Al Sukaiti, Jalila Al Shekaili, Mahmood Al Kindi, Nadia Al Hashmi, Henrikki Almusa, Daria Bulanova, Emma Haapaniemi, Pu Chen, Maria Suo-Palosaari, Päivi Vieira, Hannu Tuominen, Hannaleena Kokkonen, Nabil Al Macki, Huda Al Habsi, Tuija Löppönen, Heikki Rantala, Vilja Pietiäinen, Shen-Ying Zhang, Marjo Renko, Timo Hautala, Tariq Al Farsi, Johanna Uusimaa, Janna Saarela
Journal: Journal of Allergy and Clinical Immunology (2021)

Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency.We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1.Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used.Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain.Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.
Abstract 19363: Prognostic Ability of VE/VCO2 Slope in Combination With Serum BNP Levels in Patients with Heart Failure
Authors: Tomohiro Sakamoto, Tamiko Kuroki, Naoko Takahashi, Naoko Miyama, Ryuichiro Fukushima, Koichi Nakao, Hisao Ogawa
Journal: Circulation (2010)

Background: Exercise testing with ventilatory expired gas analysis has proven to be a valuable tool for assessing patients with heart failure (HF). Peak oxygen consumption continues to be considere...
Oleic acid restores suppressive defects in tissue-resident FOXP3 regulatory T cells from patients with multiple sclerosis.
Authors: Saige L Pompura, Allon Wagner, Alexandra Kitz, Jacob Laperche, Nir Yosef, Margarita Dominguez-Villar, David Hafler
Journal: Journal of Clinical Investigation (2020)

FOXP3+ regulatory T cells (Tregs) rely on fatty acid -oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for differentiation and function. Recent data demonstrate a role for Tregs in the maintenance of tissue homeostasis with tissue-resident Tregs possessing tissue-specific transcriptomes. However, specific signals that establish tissue-resident Treg programs remain largely unknown. Tregs metabolically rely on FAO, and considering the lipid-rich environments of tissues, we hypothesized that environmental lipids drive Treg homeostasis. First, using human adipose tissue to model tissue residency, we identified oleic acid as the most prevalent free fatty acid. Mechanistically, oleic acid amplified Treg FAO-driven OXPHOS metabolism, creating a positive feedback mechanism that increased the expression of FOXP3 and phosphorylation of STAT5, which enhanced Treg suppressive function. Comparing the transcriptomic program induced by oleic acid to the pro-inflammatory arachidonic acid, we found that Tregs sorted from peripheral blood and adipose of healthy donors transcriptomically resembled the oleic acid in vitro treated Tregs, whereas Tregs from the adipose of MS patients more closely resembled an arachidonic acid transcriptomic profile. Finally, we found oleic acid concentrations were reduced in the adipose of MS patients, and exposure of MS Tregs to oleic acid restored defects in their suppressive function. These data demonstrate the importance of fatty acids in regulating tissue inflammatory signals.
PET-2-guided escalated BEACOPP for advanced nodular lymphocyte-predominant Hodgkin lymphoma: a subgroup analysis of the randomized German Hodgkin Study Group HD18 study
Authors: D.A. Eichenauer, S. Kreissl, I. Bühnen, C. Baues, C. Kobe, L. van Heek, H. Goergen, M. Fuchs, S. Hartmann, B. von Tresckow, A. Engert, P. Borchmann
Journal: Annals of Oncology (2021)
Need for clarifying remote physiologic monitoring reimbursement during the COVID-19 pandemic: a respiratory disease case study
Authors: Robert Jarrin, Meredith A. Barrett, Leanne Kaye, Sibel Sayiner, Amanda von Leer, Jennifer Johns, Larissa D’Andrea, Carlos Nunez, Andrey Ostrovsky
Journal: npj Digital Medicine (2021)

The use of remote monitoring and virtual visits has accelerated to support socially-distanced patient care during the COVID-19 pandemic. Despite the necessity of this expansion, ambiguity in coding is hindering adoption and patient access, most notably for remote physiologic monitoring due to a lack of definition of the term "physiologic". In this analysis, we describe the history of remote monitoring code development, present several examples in respiratory disease and other chronic conditions in which gaps and confusion remain and suggest ways to clarify and broaden coverage to ensure equitable access to remote monitoring.
Impact of concomitant prostate cancer therapy on efficacy and safety of relugolix versus leuprolide in men with advanced prostate cancer: Subgroup analysis from the phase III HERO study.
Authors: Daniel J. George, Neal D. Shore, Fred Saad, Michael Cookson, Daniel Saltzstein, Ronald F. Tutrone, Hideyuki Akaza, Alberto Bossi, Elaine K. Wong, Bryan Selby, Xiaolin Fan, Jackie Walling, Bertrand Tombal
Journal: Journal of Clinical Oncology (2021)

106 Background: In the phase 3 HERO study, the oral GnRH receptor antagonist, relugolix, demonstrated suppression of testosterone to castrate levels in 96.7% of patients, which was superior to leuprolide, and a 54% lower risk of major adverse cardiovascular events relative to leuprolide. To characterize the impact of concomitant prostate cancer treatments with the use of relugolix in advanced prostate cancer from the HERO study, a subgroup analysis for patients receiving various therapies was undertaken. Methods: The HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide (ENZ) or docetaxel (DOC) 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (&lt;50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant ENZ, DOC, and any radiation therapy (RT). A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Results: Overall, 125 patients (13.4%) took at least one concomitant therapy that could impact testosterone levels. RT was received by 15.9% and 18.8% of patients in the relugolix and leuprolide groups, respectively. ENZ was the most frequently used therapy in the relugolix group (2.7%), with similar use in the leuprolide group (1.9%). DOC was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in &lt;1% of population. The sensitivity analysis results indicated that use of these concomitant therapy that could affect testosterone levels did not impact the primary endpoint. Castration rates were similar with and without concomitant use of ENZ and DOC, or RT (table). No clinically relevant differences in adverse events were observed between patients with or without concomitant use of ENZ, DOC, or RT in either treatment group. Conclusions: While the numbers are small, treatment with relugolix was associated with a similar efficacy and safety profiles in patients who received concomitant administration of ENZ, DOC, or RT to that observed in patients not receiving those concomitant treatments. Clinical trial information: NCT03085095. [Table: see text]
Mucin degrader <i>Akkermansia muciniphila</i> accelerates intestinal stem cell-mediated epithelial development
Authors: Seungil Kim, Yun-Chan Shin, Tae-Young Kim, Yeji Kim, Yong-Soo Lee, Su-Hyun Lee, Mi-Na Kim, Eunju O, Kwang Soon Kim, Mi-Na Kweon
Journal: Gut Microbes (2021)

Mucin-degrading bacteria are densely populated in the intestinal epithelium; however, their interaction with intestinal stem cells (ISCs) and their progeny have not been elucidated. To determine whether mucin-degrading bacteria play a role in gut homeostasis, mice were treated with Akkermansia muciniphila, a specialized species that degrades mucin. Administration of A. muciniphila for 4 weeks accelerated the proliferation of Lgr5+ ISCs and promoted the differentiation of Paneth cells and goblet cells in the small intestine (SI). We found similar effects of A. muciniphila in the colon. The levels of acetic and propionic acids were higher in the cecal contents of A. muciniphila-treated mice than in PBS-treated mice. SI organoids treated with cecal contents obtained from A. muciniphila-treated mice were larger and could be diminished by treatment with G protein-coupled receptor (Gpr) 41/43 antagonists. Pre-treatment of mice with A. muciniphila reduced gut damage caused by radiation and methotrexate. Further, a novel isotype of the A. muciniphila strain was isolated from heathy human feces that showed enhanced function in intestinal epithelial regeneration. These findings suggest that mucin-degrading bacteria (e.g., A. muciniphila) may play a crucial role in promoting ISC-mediated epithelial development and contribute to intestinal homeostasis maintenance.
Interferent Effect of Hydroxyurea on Continuous Glucose Monitoring
Authors: Emily D. Szmuilowicz, Grazia Aleppo
Journal: Diabetes Care (2021)

While currently available continuous glucose monitoring (CGM) systems have continually improving accuracy that has revolutionized modern diabetes care, potential medication interferences are recognized for all available CGM systems (1). For Dexcom CGM systems, hydroxyurea was recently recognized as an interfering substance that can falsely elevate sensor glucose (SG) readings (2), but the data demonstrating this interference have not been previously published.

We report a patient with type 1 diabetes taking hydroxyurea who experienced falsely elevated SG values using the Dexcom G5 and G6 CGM systems, which led to the recognition of the interferent effect of hydroxyurea.

A 69-year-old woman with type 1 diabetes using an insulin pump (Medtronic Paradigm Revel 723) and real-time CGM (initially Dexcom G5, then G6) took hydroxyurea (1,000 mg daily) for treatment of essential thrombocytosis. She noted that, for approximately 6 h after taking hydroxyurea, SG measurements predictably and markedly increased, even while fasting and when the time of hydroxyurea ingestion varied. In addition, the glucose management indicator (7.6%) based on 14-day average SG (170 mg/dL) was significantly higher than concomitant glycated hemoglobin (6.3%, 45 mmol/mol), suggestive of artifactual discordance.

Subsequently, the patient simultaneously wore the Dexcom G6 …
Cancer Mortality After Nonmelanoma Skin Cancer—Reply
Authors: Henry S. Kahn, Michael J. Thun
Journal: JAMA (1999)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Gestational Diabetes — On Broadening the Diagnosis
Authors: Brian Casey
Journal: New England Journal of Medicine (2021)

Gestational diabetes mellitus, which is defined as the onset or first recognition of carbohydrate intolerance during pregnancy, is estimated to affect between 6 and 9% of pregnant women in the United States.1,2 Associated perinatal outcomes include excessive fetal growth that can lead to maternal or fetal birth trauma, hypertensive disorders of pregnancy, and neonatal hypoglycemia.3 Trials have shown that the treatment of women with gestational diabetes can reduce many of these immediate outcomes,4,5 and these trials led the U.S. Preventive Services Task Force to conclude that there is a net benefit to routinely screening for and treating gestational diabetes.6 Despite . . .
Modular immune-homeostatic microparticles promote immune tolerance in mouse autoimmune models
Authors: Xin Chen, Xiaoshan Yang, Pingyun Yuan, Ronghua Jin, Lili Bao, Xinyu Qiu, Siying Liu, Tao Liu, John Justin Gooding, WanJun Chen, Guozhen Liu, Yongkang Bai, Shiyu Liu, Yan Jin
Journal: Science Translational Medicine (2021)

Modular microparticles induce antigen-specific immune tolerance by inducing apoptosis and promoting T reg differentiation.
Abstract PO005: Hepatic stellate cells suppress NK cell sustained breast cancer dormancy
Authors: Ana Luisa Correia
Journal: Cancer Research (2021)

Abstract The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a singular therapeutic window to prevent metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of dormant DTC reservoirs is imperative. Here we reveal tissue-specific microenvironments that restrain or concede progression of breast cancer in the liver, a frequent site of metastasis and most times associated with patients’ cause of death. Using mouse models, we show that the dormant milieu features a selective accumulation of natural killer (NK) cells. Preserving the NK cell pool with adjuvant interleukin-15-based immunotherapy prevents hepatic metastases and prolongs survival. Exit from dormancy follows a dramatic contraction of the NK cell compartment, and concurrent accumulation of activated stellate cells. Our data identify the interplay between NK cells and activated stellate cells as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing DTC outgrowth and metastasis. Citation Format: Ana Luisa Correia. Hepatic stellate cells suppress NK cell sustained breast cancer dormancy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO005.
Germline alterations in cancer susceptibility genes in women with high-risk bladder cancer: Implications for germline testing and clinical management.
Authors: Hong Truong, Rania Sheikh, Aliya Khurram, Yelena Kemel, Andrew Thomas Lenis, Peter Reisz, Vijai Joseph, Alvin Goh, Eugene K. Cha, Timothy F. Donahue, Jonathan Coleman, Eugene J. Pietzak, Bernard H. Bochner, Kenneth Offit, Maria Isabel Carlo
Journal: Journal of Clinical Oncology (2021)

418 Background: Gender differences exist in bladder cancer incidence, stage at diagnosis, and outcomes. Women have lower incidence of bladder cancer but are diagnosed with more advanced disease at presentation. They also have less favorable outcomes even after adjusting for tumor stage and treatment modality. The biologic mechanisms underlying gender disparities in bladder cancer remain unknown. Methods: We leveraged a prospective matched tumor-normal genomic profiling initiative to determine the prevalence and spectrum of pathogenic/likely pathogenic (P/LP) germline variants in women with bladder cancer. Germline DNA was tested for mutations in ≥77 cancer susceptibility genes using next-generation sequencing in 686 patients with bladder cancer. Mutation frequency and clinical characteristics were assessed by gender. Results: A total of 184 (27%) women and 502 (73%) men with bladder cancer underwent germline testing; median age of diagnosis was 66 ± 11.3 and 65 ± 11.3 years, respectively. Twenty-two women (12%) had bladder cancer diagnosis at age ≤ 50 years. Both groups had similar rate of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.5), and disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 54% vs 54%, MIBC 38% vs 39%, and metastatic disease 8% vs 6%, p = 0.7). Women had more non-urothelial carcinoma histology than men (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001). More P/LP germline variants were found in women than men (38 [21%] vs. 70 [14%], p = 0.04). Twenty-eight women (15%) had P/LP variants in DNA-damage repair (DDR) genes; 23 (13%) carried moderate/high penetrance germline mutations, the most common were BRCA1/ 2, CHEK2, NBN, ATM, and MITF. Current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. Nine women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers ( BRCA1/ 2 [5], ATM [2], MLH1 [1], TP53 [1]). Conclusions: Deleterious germline alterations are commonly present in women with high-risk bladder cancer. The presence of germline variants in some genes, such as BRCA1/2, can guide cancer screening and risk-reducing surgeries for patients and their families. Women with high-risk bladder cancer should be evaluated for suitability of germline testing, especially those who desire preservation of uterus and ovaries at the time of radical cystectomy, to rule out the presence of P/LP variants that increase risk of future gynecologic malignancies.
Abstract IA-19: Machine learning and AI in molecular pathology diagnostics and clinical management of cancer
Authors: Matija Snuderl
Journal: Clinical Cancer Research (2021)

Abstract Molecular diagnostics of cancer has undergone a revolution driven by development of high throughput molecular techniques. It is increasingly recognized that malignant tumors previously considered a single entity are in fact composed of multiple different entities that vary in their molecular genetics, underlying biology and most importantly clinical outcome. Integration of omic- and clinical data into practical classification schemes requires novel machine learning approaches to manage big data in a clinically reasonable turnaround time. Accurate molecular classification will make future clinical trials more informative and lead to development of novel therapeutic strategies. While highly informative, advanced molecular testing is expensive and not widely available. We have developed novel methods to predict mutations directly from histopathological slides using artificial intelligence (AI) and image analysis. Mutations in various genes including EGFR, STK11, and BRAF can be predicted with high accuracy by the analysis of the H&amp;E slide image, which is a standard stain in pathology laboratories across the world. Mutational prediction by AI provides a rapid low-cost method to screen patients for potentially targetable mutations in cancer. Cloud based AI mutational predictors could also bring molecular diagnostics to remote or medically underserved areas. Citation Format: Matija Snuderl. Machine learning and AI in molecular pathology diagnostics and clinical management of cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-19.