tbuckley/cabot-search huggingface dataset:
T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients
Authors: Hye Sun Kuehn, Jingjie Chang, Motoi Yamashita, Julie E. Niemela, Chengcheng Zou, Kazuki Okuyama, Junji Harada, Jennifer L. Stoddard, Cristiane J. Nunes-Santos, Brigette Boast, Ryan M. Baxter, Elena W.Y. Hsieh, Mary Garofalo, Thomas A. Fleisher, Tomohiro Morio, Ichiro Taniuchi, Cullen M. Dutmer, Sergio D. Rosenzweig
Journal: The Journal of Experimental Medicine (2021)

AIOLOS/IKZF3 is a member of the IKAROS family of transcription factors. IKAROS/IKZF1 mutations have been previously associated with different forms of primary immunodeficiency. Here we describe a novel combined immunodeficiency due to an IKZF3 mutation in a family presenting with T and B cell involvement, Pneumocystis jirovecii pneumonia, and/or chronic lymphocytic leukemia. Patients carrying the AIOLOS p.N160S heterozygous variant displayed impaired humoral responses, abnormal B cell development (high percentage of CD21low B cells and negative CD23 expression), and abrogated CD40 responses. Naive T cells were increased, T cell differentiation was abnormal, and CD40L expression was dysregulated. In vitro studies demonstrated that the mutant protein failed DNA binding and pericentromeric targeting. The mutant was fully penetrant and had a dominant-negative effect over WT AIOLOS but not WT IKAROS. The human immunophenotype was recapitulated in a murine model carrying the corresponding human mutation. As demonstrated here, AIOLOS plays a key role in T and B cell development in humans, and the particular gene variant described is strongly associated with immunodeficiency and likely malignancy.
Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment
Authors: Qiwei Yang, Michal Ciebiera, Maria Victoria Bariani, Mohamed Ali, Hoda Elkafas, Thomas G Boyer, Ayman Al-Hendy
Journal: Endocrine Reviews (2021)

Abstract Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.
Recreational Physical Activity and Risk of Incident Knee Osteoarthritis: An International <scp>Meta‐Analysis</scp> of Individual Participant–Level Data
Authors: Lucy S. Gates, Thomas A. Perry, Yvonne M. Golightly, Amanda E. Nelson, Leigh F. Callahan, David Felson, Michael Nevitt, Graeme Jones, Cyrus Cooper, Mark E. Batt, Maria T. Sanchez‐Santos, Nigel K. Arden
Journal: Arthritis & Rheumatology (2021)

The effect of physical activity on the risk of developing knee osteoarthritis (OA) is unclear. We undertook this study to examine the relationship between recreational physical activity and incident knee OA outcomes using comparable physical activity and OA definitions.
Effect of Elective Internal Mammary Node Irradiation on Disease-Free Survival in Women With Node-Positive Breast Cancer
Authors: Yong Bae Kim, Hwa Kyung Byun, Dae Yong Kim, Sung-Ja Ahn, Hyung-Sik Lee, Won Park, Su Ssan Kim, Jin Hee Kim, Kyu Chan Lee, Ik Jae Lee, Won Taek Kim, Hyun Soo Shin, Kyubo Kim, Kyung Hwan Shin, Chung Mo Nam, Chang-Ok Suh
Journal: JAMA Oncology (2021)

<h3>Importance</h3> The benefit of internal mammary node irradiation (IMNI) for treatment outcomes in node-positive breast cancer is unknown. <h3>Objective</h3> To investigate whether the inclusion of IMNI in regional nodal irradiation improves disease-free survival (DFS) in women with node-positive breast cancer. <h3>Design, Setting, and Participants</h3> This multicenter, phase 3 randomized clinical trial was conducted from June 1, 2008, to February 29, 2020, at 13 hospitals in South Korea. Women with pathologically confirmed, node-positive breast cancer after breast-conservation surgery or mastectomy with axillary lymph node dissection were eligible and enrolled between November 19, 2008, and January 14, 2013. Patients with distant metastasis and those who had received neoadjuvant treatment were excluded. Data analyses were performed according to the intention-to-treat principle. <h3>Interventions</h3> All patients underwent regional nodal irradiation along with breast or chest wall irradiation. They were randomized 1:1 to receive radiotherapy either with IMNI or without IMNI. <h3>Main Outcomes and Measures</h3> The primary end point was the 7-year DFS. Secondary end points included the rates of overall survival, breast cancer–specific survival, and toxic effects. <h3>Results</h3> A total of 735 women (mean [SD] age, 49.0 [9.1] years) were included in the analyses, of whom 373 received regional nodal irradiation without IMNI and 362 received regional nodal irradiation with IMNI. Nearly all patients underwent taxane-based adjuvant systemic treatment. The median (IQR) follow-up was 100.4 (89.7-112.1) months. The 7-year DFS rates did not significantly differ between the groups treated without IMNI and with IMNI (81.9% vs 85.3%; hazard ratio [HR], 0.80; 95% CI, 0.57-1.14; log-rank<i>P</i> = .22). However, an ad hoc subgroup analysis showed significantly higher DFS rates with IMNI among patients with mediocentrally located tumors. In this subgroup, the 7-year DFS rates were 81.6% without IMNI vs 91.8% with IMNI (HR, 0.42; 95% CI, 0.22-0.82; log-rank<i>P</i> = .008), and the 7-year breast cancer mortality rates were 10.2% without IMNI vs 4.9% with IMNI (HR, 0.41; 95% CI, 0.17-0.99; log-rank<i>P</i> = .04). No differences were found between the 2 groups in the incidence of adverse effects, including cardiac toxic effects and radiation pneumonitis. <h3>Conclusions and Relevance</h3> This randomized clinical trial found that including IMNI in regional nodal irradiation did not significantly improve the DFS in patients with node-positive breast cancer. However, patients with medially or centrally located tumors may benefit from the use of IMNI. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT04803266
Phase II, single-arm trial of preoperative short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer
Authors: Zhenyu Lin, Ming Cai, Peng Zhang, Gang Li, Tao Liu, Xin Li, Kailin Cai, Xiu Nie, Jing Wang, Junli Liu, Hongli Liu, Weikang Zhang, Jingbo Gao, Chuanqing Wu, Linfang Wang, Jun Fan, Lan Zhang, Zheng Wang, Zhiguo Hou, Chi Ma, Kunyu Yang, Gang Wu, Kaixiong Tao, Tao Zhang
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background In locally advanced rectal cancer (LARC), preoperative short-course radiotherapy (SCRT) with delayed surgery has been shown to be as effective as long-course chemoradiotherapy, with only modest benefits. This study aimed to evaluate the efficacy and safety of preoperative SCRT combined with subsequent CAPOX (capecitabine and oxaliplatin) and the anti-PD-1 antibody camrelizumab in patients with LARC. Methods This was a prospective, single-arm, phase II trial. Treatment-naïve patients with histologically confirmed T3-4N0M0 or T1-4N+M0 rectal adenocarcinoma received 5×5 Gy SCRT with two subsequent 21-day cycles of CAPOX plus camrelizumab after 1 week, followed by radical surgery after 1 week. The primary endpoint was pathological complete response (pCR) rate. Biomarker analysis was performed to identify a potential predictor of pCR to treatment. Results From November 7, 2019 to September 14, 2020, 30 patients were enrolled, and 27 patients received at least one dose of CAPOX plus camrelizumab. Surgery was performed in 27 (100%) patients. The pCR (ypT0N0) rate was 48.1% (13/27), including 46.2% (12/26) for proficient mismatch repair (MMR) tumors and 100% (1/1) for deficient MMR tumors. Immune-related adverse events were all grade 1–2, with the most common being reactive cutaneous capillary endothelial proliferation (81.5%). No grade 4/5 adverse events occurred. Biomarker analysis showed patients without FGFR1–3 deletions had a better tendency for pCR. Conclusions SCRT combined with subsequent CAPOX plus camrelizumab followed by delayed surgery showed a favorable pCR rate with good tolerance in patients with LARC, especially in the proficient MMR setting. A randomized controlled trial is ongoing to confirm these results. Trial registration number ClinicalTrials.gov identifier: NCT04231552 .
Prediagnostic Progression of Lymphocytosis in Chronic Lymphocytic Leukemia Is Predictive of Progression Free Survival As Early As Five Years Prior to Diagnosis
Authors: Michael Asger Andersen, Mia Klinten Grand, Volkert Siersma, Niels Olivarius, Christen Lykkegaard Andersen, Carsten Utoft Niemann
Journal: Blood (2017)
Primary Analysis of ZUMA-7: A Phase 3 Randomized Trial of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma
Authors: Frederick L. Locke, David B. Miklos, Caron Jacobson, Miguel-Angel Perales, Marie José Kersten, Olalekan O. Oluwole, Armin Ghobadi, Aaron P. Rapoport, Joseph P. McGuirk, John M. Pagel, Javier Muñoz, Umar Farooq, Tom Van Meerten, Patrick M. Reagan, Anna Sureda, Ian W. Flinn, Peter Vandenberghe, Kevin Song, Michael Dickinson, Monique C. Minnema, Peter A. Riedell, Lori A. Leslie, Sridhar Chaganti, Yin Yang, Simone Filosto, Marco Schupp, Christina To, Paul Cheng, Leo I. Gordon, Jason R. Westin
Journal: Blood (2021)
A neuroscientific perspective on the computational theory of social groups
Authors: Marco K. Wittmann, Nadira S. Faber, Claus Lamm
Journal: Behavioral and Brain Sciences (2022)

Abstract We welcome a computational theory on social groups, yet we argue it would benefit from a broader scope. A neuroscientific perspective offers the possibility to disentangle which computations employed in a group context are genuinely social in nature. Concurrently, we emphasize that a unifying theory of social groups needs to additionally consider higher-level processes like motivations and emotions.
Abstract 3617: Secretory Leucocyte Protease Inhibitor and Matricellular Protein Modulation of Post Reperfused Myocardial Infarction Healing, Fibrosis and Remodeling in Rat Model: Effect of Candesartan and Omapatrilat
Authors: Arivazhagan Palaniyappan, Halliday Idikio, Bodh I Jugdutt
Journal: Circulation (2009)

Mice deficient in secretory-leucocyte-protease-inhibitor (SLPI) have impaired healing of skin wounds and SLPI may improve post infarct healing and remodeling. Studies in mice suggest matricellular ...
TCT-312 Computational Modeling of Coronary Obstruction (CO) in Valve-in-Valve (ViV) Transcatheter Aortic Valve Replacement (TAVR): Comparison With Computed Tomography (CT)-Based Risk Assessment
Authors: Sri Krishna Sivakumar, Breandan Yeats, Venkateshwar Polsani, Pradeep Yadav, Vinod Thourani, Lakshmi Dasi
Journal: Journal of the American College of Cardiology (2021)
Reply to Hertenstein et al.'s commentary on Brupbacher et al.: The effects of exercise on sleep in unipolar depression: A systematic review and network meta-analysis
Authors: Gavin Brupbacher, Heike Gerger, Thea Zander-Schellenberg, Doris Straus, Hildburg Porschke, Markus Gerber, Roland von Känel, Arno Schmidt-Trucksäss
Journal: Sleep Medicine Reviews (2021)
Comprehensive Immunophenotyping Panel in Japan Enables to Detect Rare Subtypes in Childhood Leukemia
Authors: Takao Deguchi, Nobutaka Kiyokawa, Kentaro Ohki, Yoshiko Hashii, Atsushi Manabe, Souichi Adachi, Akiko Moriya Saito, Keizo Horibe
Journal: Blood (2017)
Tuberculosis Pathways to Care and Transmission of Multidrug Resistance in India
Authors: Sachin R. Atre, Jayshri D. Jagtap, Mujtaba I. Faqih, Yogita K. Dumbare, Trupti U. Sawant, Sunil L. Ambike, Jitendra S. Bhawalkar, Sandeep K. Bharaswadkar, Padmaja K. Jogewar, Ramji S. Adkekar, Balasaheb P. Hodgar, Vaishali Jadhav, Nitin D. Mokashi, Jonathan E. Golub, Avika Dixit, Maha R. Farhat
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: India is experiencing a regional increase in cases of multidrug-resistant tuberculosis (MDR-TB). Objectives: Given the complexity of MDR-TB diagnosis and care, we sought to address key knowledge gaps in MDR risk factors, care delays, and drivers of delay to help guide disease control. Methods: From January 2018 to September 2019, we conducted interviews with adults registered with the National TB Elimination Program for MDR (n = 128) and non–MDR-TB (n = 269) treatment to quantitatively and qualitatively study care pathways. We collected treatment records and GeneXpert-TB/RIF diagnostic reports. Measurements and Main Results: MDR-TB was associated with young age and crowded residence. GeneXpert rifampicin resistance diversity was measured at 72.5% Probe E. Median time from symptom onset to diagnosis of MDR was 90 days versus 60 days for non-MDR, Wilcoxon P < 0.01. Delay decreased by a median of 30 days among non-MDR patients with wider access to GeneXpert, Wilcoxon P = 0.02. Pathways to care were complex, with a median (interquartile range) of 4 (3–5) and 3 (2–4) encounters for MDR and non-MDR, respectively. Of patients with MDR-TB, 68% had their first encounter in the private sector, and this was associated with a larger number of subsequent healthcare encounters and catastrophic expenditure. Conclusions: The association of MDR with young age, crowding, and low genotypic diversity raises concerns of ongoing MDR transmission fueled by long delays in care. Delays are decreasing with GeneXpert use, suggesting the need for routine use in presumptive TB. Qualitatively, we identify the need to improve patient retention in the National TB Elimination Program and highlight patients' trust relationship with private providers.
When and how to deintensify type 2 diabetes care
Authors: Carole E Aubert, Iliana C Lega, Olivier Bourron, Alice J Train, Jeffrey T Kullgren
Journal: BMJ (2021)

### What you need to know Antidiabetic treatment can delay long term complications of type 2 diabetes. However, in some patients—in particular older patients with multimorbidity or those who are frail—the benefits of tight glycaemic control decline and the risks and burdens of antidiabetic treatment increase.123 Observational studies of people with type 2 diabetes who are older or have high clinical complexity have found an association between tight blood glucose control (haemoglobin A1c (HbA1c) of <7% (53 mmol/mol)) and higher risk of falls, severe hypoglycaemia, emergency department visits, hospitalisations, and death.123 Although these risks are well known, there is little advice for clinicians on how and when to discuss deintensifying diabetes care, in contrast to the wealth of guidance on escalating treatment. In this article, we offer an approach to identifying patients who may benefit from deintensification (that is, loosening blood glucose control targets and other measures that may reduce the burden of diabetes monitoring and care for the patient) and how to reach an individualised and shared management plan with the patient (see fig 1 and box 1). These discussions may also include the patient's informal care givers and relatives, depending on the patient's wishes and mental capacity. Fig 1 Approach to care individualisation and deintensification Box 1 ### Clinical vignette A 77 year old woman diagnosed with type 2 diabetes for 15 years, for which she takes metformin and gliclazide. She also takes regular medication (15 tablets each day) for hypertension, atrial fibrillation, heart failure, osteoporosis, and chronic kidney … RETURN TO TEXT
COVID-19 mRNA Vaccine-Associated Autoimmunity Presenting as Minimal Change Disease and Membranous Nephropathy
Authors: Kenar D. Jhaveri, Vanesa Bijol, Rimda Wanchoo, Keith H. Keller, Mariam P. Alexander, Astrid Weins
Journal: Journal of the American Society of Nephrology (2021)

Background: Vaccine-triggered complications, including autoimmune diseases and minimal change disease (MCD), were reported during recent COVID-19 vaccine rollout. Anti-nephrin autoantibodies were described in nephrotic syndrome (NS) with kidney biopsy (Kbx)-proven MCD. Therefore, we examined patients with COVID-19 vaccineassociated NS for anti-nephrin autoantibodies. Methods: 5 patients presenting with nephrotic-range proteinuria 1-3 weeks after COVID-19 vaccine and a KBx were identified (3 Pfizer/BioNTech, 2 Moderna). Past medical history and lab tests including serum creatinine (sCr), urine protein-to-creatinine ratio (UPCR), and serological workup were recorded. KBx were routinely evaluated by light microscopy (LM), immunofluorescence microscopy (IF), and electron microscopy (EM), followed by confocal examination of relative IgG and nephrin localization in all patients;serological studies for anti-nephrin antibodies using human glomerular extract and recombinant nephrin extracellular domain were performed using plasma available on 2 patients. Results: In all patients, sCr was 0.5-1.2 mg/dl and UPCR 4.5-7.6 g/g. 1 patient had MCD in remission diagnosed 6 months prior;others had no relevant PMH. All workup was negative, except low positive ANA in 2 patients. On KBx, diagnosis of MCD was made in 4 and stage I membranous nephropathy (MN) in 1 patient(s) (serum albumin 2.0-2.4g/dl in MCD and 3.6g/dl in MN patient(s));all had mild chronic changes. All 4 MCD patients had fine granular punctate podocyte staining for polyclonal IgG colocalizing with nephrin by IF and diffuse FPE by EM;in 1 patient plasma was saved during NS and was serologically positive for anti-nephrin. The MN patient had 3+ fine granular IF staining for polyclonal IgG and PLA2r along GBMs with sparse superficial subepithelial electron-dense deposits on EM, and was serologically negative for antinephrin. All MCD patients were successfully treated with oral glucocorticoids, while the MN patient was monitored closely under RAAS blockage. Conclusions: COVID-19 mRNA vaccines can trigger de-novo or relapsing anti-nephrin-and PLA2r-mediated NS, thus adding both autoimmune-mediated podocytopathies to vaccine-induced complications. Temporal association is essential for diagnosis;prompt accurate diagnosis benefits treatment and response.
Safety, Efficacy, and Biomarker Analysis of Toripalimab in Patients with Previously Treated Advanced Urothelial Carcinoma: Results from a Multicenter Phase II Trial POLARIS-03
Authors: Xinan Sheng, Haige Chen, Bin Hu, Xudong Yao, Ziling Liu, Xin Yao, Hongqian Guo, Yi Hu, Zhigang Ji, Hong Luo, Benkang Shi, Jiyan Liu, Jin Wu, FangJian Zhou, Zhisong He, Jinhai Fan, Weifeng Wang, Hui Feng, Sheng Yao, Patricia Keegan, Yiran Huang, Jun Guo
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Immunotherapy offers a second-line option for patients with metastatic urothelial carcinoma (mUC) who failed standard therapy, but the biomarkers for predicting response remain to be explored. This study aims to evaluate the safety, efficacy, and correlative biomarker of toripalimab in patients with previously treated mUC. Patients and Methods: Patients with mUC received toripalimab 3 mg/kg Q2W. Clinical response was assessed every 8 weeks by an independent review committee per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated. Results: Among the intention-to-treat population (n = 151), 85% of the patients experienced treatment-related adverse event (TRAE) and 20% experienced grade 3 and above TRAE. The objective response rate (ORR) was 26% with a disease control rate (DCR) of 45%. The median duration of response, progression-free survival (PFS), and overall survival (OS) were 19.7 months [95% confidence interval (CI): 13.9–not estimable], 2.3 months (95% CI, 1.8–3.6), and 14.4 months (95% CI, 9.3–23.1), respectively. Both PD-L1+ and TMB-high (10 mutations/Mb as the cutoff) patients had better ORR than PD-L1− patients (42% vs. 17%, P = 0.002) and TMB-low patients (48% vs. 22%, P = 0.014), respectively. The TMB-high group also showed better PFS (12.9 vs. 1.8 months, P &amp;lt; 0.001) and OS (not reached versus 10.0 months, P = 0.018) than the TMB-low group. Conclusions: Toripalimab has demonstrated encouraging clinical activity in the second-line treatment of mUC with a manageable safety profile. PD-L1 expression and TMB were two independent biomarkers in the study.
Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development
Authors: Jennifer A. Kricker, Clive P. Page, Fridrik Runar Gardarsson, Olafur Baldursson, Thorarinn Gudjonsson, Michael J. Parnham
Journal: Pharmacological Reviews (2021)

Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance. An additional crucial aspect of chronic airway inflammation, such as chronic obstructive pulmonary disease, as well as other inflammatory disorders, is the loss of epithelial barrier protection against pathogens and pollutants. In recent years, azithromycin has been shown with time to enhance the barrier properties of airway epithelial cells, an action that makes an important contribution to its therapeutic efficacy. In this article, we review the background and evidence for various immunomodulatory and time-dependent actions of macrolides on inflammatory processes and on the epithelium and highlight novel nonantibacterial macrolides that are being studied for immunomodulatory and barrier-strengthening properties to circumvent the risk of bacterial resistance that occurs with macrolide antibacterials. We also briefly review the clinical effects of macrolides in respiratory and other inflammatory diseases associated with epithelial injury and propose that the beneficial epithelial effects of nonantibacterial azithromycin derivatives in chronic inflammation, even given prophylactically, are likely to gain increasing attention in the future. <h3>Significance Statement</h3> Based on its immunomodulatory properties and ability to enhance the protective role of the lung epithelium against pathogens, azithromycin has proven superior to other macrolides in treating chronic respiratory inflammation. A nonantibiotic azithromycin derivative is likely to offer prophylactic benefits against inflammation and epithelial damage of differing causes while preserving the use of macrolides as antibiotics.
Practices for monitoring and responding to incoming data on self-injurious thoughts and behaviors in intensive longitudinal studies: A systematic review
Authors: Kate H. Bentley, Joseph S. Maimone, Erin N. Kilbury, Marshall S. Tate, Hannah Wisniewski, M. Taylor Levine, Regina Roberg, John B. Torous, Matthew K. Nock, Evan M. Kleiman
Journal: Clinical Psychology Review (2021)