tbuckley/cabot-search huggingface dataset:
Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors
Authors: Aung Naing, Joseph P Eder, Sarina A Piha-Paul, Claude Gimmi, Elizabeth Hussey, Sen Zhang, Vera Hildebrand, Vinayak Hosagrahara, Christina Habermehl, Jacques Moisan, Kyriakos P Papadopoulos
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background M4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors. Methods In preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects. Results In mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%). Conclusions There were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure. Trial registration number NCT03306420 .
Phase II study of capecitabine and oxaliplatin with concurrent radiation therapy (XELOX-XRT) for squamous cell carcinoma of the anal canal
Authors: C. Eng, G. J. Chang, P. Das, M. Rodriguez-Bigas, J. M. Skibber, W. Qiao, G. L. Rosner, L. T. Ukegbu, R. A. Wolff, C. H. Crane
Journal: Journal of Clinical Oncology (2009)

4116 Background: Definitive therapy for squamous cell carcinoma (SCC) of the anal canal consists of external beam radiotherapy with concurrent 5-fluorouracil and mitomycin C or cisplatin. This regimen can be toxic but curative in 80–85% of cases with remaining patients requiring salvage surgical resection. The purpose of this study was to evaluate the tolerability and efficacy of XELOX-XRT as definitive treatment for anal cancer. Primary objectives were time to treatment failure and occurrence of treatment-related toxicity. Methods: Patients with histologically proven SCC of the anal canal, AJCC Stage II-IIIB (T 2–4 or N+M 0 ), ECOG PS 0–1, HIV - , and no prior therapy were eligible for XELOX-based chemoradiotherapy. Chemotherapy initially consisted of capecitabine (825 mg/m 2 ) BID, M-F and weekly oxaliplatin (50 mg/m 2 ) (Group 1) with subsequent modification to omission of chemotherapy during weeks 3 and 6 (Group 2). Radiation therapy was provided in the following manner: T 1 (45 Gy in 25 fractions), T 2 (55 Gy in 30 fractions), and T 3–4 (59 Gy in 32 fractions). Intensity-modulated radiation therapy (IMRT) was allowed. Interim safety analysis was conducted 3 months after the 10 th pt. Patients were followed in a multidisciplinary manner. Response was determined by CT/MRI, digital rectal examination, and proctoscopy. A biopsy was performed for clinical suspicion of residual or progressive disease. Results: Twenty patients were evaluable for toxicity; 17 for response. Five of 11 (45%) patients developed grade 3 treatment-related diarrhea (Group 1). Therefore, the chemotherapy schedule was modified and only 1 of 9 patients in Group 2 developed grade 3 diarrhea. Complete response rates were 90% in Group 1 and 100% in Group 2. One patient in Group 1 developed distant failure. After a median follow-up of 19 months, no patient has developed local recurrence or required salvage resection with colostomy for a colostomy-free rate of 100%. Conclusions: The combination of capecitabine, oxaliplatin, and radiation therapy (XELOX-XRT) is effective for locally advanced squamous cell carcinoma of the anal canal. This trial continues accrual and updated results will be provided. [Table: see text]
Balancing act: when is an elite athlete who has had COVID-19 safe to return to play? When does prudent investigation go offside into overmedicalising?
Authors: Harald T Jorstad, Joost G van den Aardweg
Journal: British Journal of Sports Medicine (2020)

σ-Receptors are strongly overexpressed in most rodent and human tumors and are proliferation markers. To evaluate the potential of a radiolabeled σ<sub>1</sub>-ligand for therapy monitoring, we compared early changes of <sup>11</sup>C-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (<sup>11</sup>C-SA4503) binding and <sup>18</sup>F-FDG uptake in gliomas after in vivo chemotherapy. <b>Methods:</b> C6 cells (2.5 × 10<sup>6</sup>) were subcutaneously injected into the right shoulder of male Wistar rats. After 7 d, the tumor volume was 0.60 ± 0.08 cm<sup>3</sup>. Animals then received either saline or doxorubicin (8 mg/kg, intraperitoneally). One control and 1 treated rat were imaged simultaneously, 24 or 48 h after treatment, under pentobarbital anesthesia. Rodents (<i>n</i> = 20) were scanned first with <sup>11</sup>C-SA4503 (25 MBq, intravenously) followed more than 100 min afterward by <sup>18</sup>F-FDG (20 MBq, intravenously), using a dedicated small-animal PET camera (60-min protocol, tumors in the field of view). Tumor homogenates were prepared and subjected to σ-receptor assays. The biodistribution of <sup>18</sup>F-FDG was assessed. <b>Results:</b> Tumors appeared 4–5 d after inoculation and grew exponentially. No significant reduction of tumor growth was visible within 48 h after doxorubicin treatment. Both PET tracers visualized the tumors and showed reduced uptake after chemotherapy (<sup>11</sup>C-SA4503: 26.5% ± 6.5% at 24 h, 26.5% ± 7.5% at 48 h; <sup>18</sup>F-FDG: 22.6% ± 3.2% at 24 h, 27.4% ± 3.2% at 48 h; ex vivo <sup>18</sup>F-FDG: 22.4% ± 5.4% at 24 h, 31.7% ± 12.7% at 48 h). σ<sub>1</sub>-Receptor density in treated tumors was also reduced (from 172 ± 35 to 125 ± 28 fmol/mg of protein). <b>Conclusion:</b> Both <sup>11</sup>C-SA4503 binding and <sup>18</sup>F-FDG uptake declined in gliomas after chemotherapy. Decreased binding of <sup>11</sup>C-SA4503 corresponded to a loss of σ<sub>1</sub>-receptors from the tumors. Changes in tracer uptake preceded the morphologic changes by at least 48 h.
Determinants and Clinical Significance of Musculoskeletal Symptoms in Patients With Chronic Graft-Versus-Host Disease
Authors: Ana Zelic Kerep, Filip Pirsl, Seth Steinberg, Sandra Mitchell, Lauren Curtis, Noa Holtzman, Sencer Goklemez, Ervina Bilic, Edward Cowen, Dominique Pichard, Galen Joe, Leora Comis, Annie Im, Ann Berger, Laura Parsons-Wandell, Drazen Pulanic, Kristin Baird, Ronald Gress, Steven Pavletic
Journal: HemaSphere (2022)

Musculoskeletal symptoms in chronic graft-versus-host disease (cGVHD) are rare manifestations contributing to disease burden. This study assesses the frequency of muscle cramps, joint and muscle aches, and muscle weakness in a cohort of patients severely affected by cGVHD. Three hundred thirty-four patients participated in the NCI natural history study of cGVHD (NCT00092235) from October 2004 to March 2017. Five-point Lee cGVHD Symptom Scale was dichotomized (less symptom bother-0, 1, 2; severe symptom bother-3, 4) and tested for associations with: Short Form 36 (SF36), 2-minute walk test, grip strength, joint range of motion, and human activity profile, clinical and laboratory data. Seventy-five point four percent of patients reported joint and muscle aches (36.8% severe, Lee Symptom Scale score 3-4), 74.3% muscle cramps (33.5% severe), and 82.34% muscle weakness (45.51% severe), which were associated with reduced functional capacity (SF36 Physical Component Scale, P < 0.0001). Muscle cramps were associated with limited joint movement (P < 0.0001) and skin manifestations (skin thickening, P = 0.0008; itchy skin, P = 0.0003). Muscle cramps did not show association with potential causative agents, such as concomitant calcineurin inhibitors therapy, statins, or use of antidiabetic drugs. Joint and muscle aches showed associations with multiple variables (including strong associations with mood symptoms and fatigue, P < 0.0001). Muscle weakness was not associated with steroid dose, but was significantly associated with depression (P < 0.0001) and anxiety (P = 0.0009). This study documents a high frequency of musculoskeletal symptoms in a cohort of adult patients with cGVHD. The multivariable logistic regression models showed that a joint set of factors were moderately well associated with musculoskeletal symptoms in this study.
SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function
Authors: Emma S. Winkler, Adam L. Bailey, Natasha M. Kafai, Sharmila Nair, Broc T. McCune, Jinsheng Yu, Julie M. Fox, Rita E. Chen, James T. Earnest, Shamus P. Keeler, Jon H. Ritter, Liang-I Kang, Sarah Dort, Annette Robichaud, Richard Head, Michael J. Holtzman, Michael S. Diamond
Journal: Nature Immunology (2020)
Abstract 6393: Targeting the increased endocytosis of Na/K ATPase α1 subunit as a new therapeutic approach to prostate cancer
Authors: Moumita Banerjee, Zhichuan Li, Yingnyu Gao, Minqi Huang, Liquan Cai, Tianyan Gao, Xie Zijian
Journal: Cancer Research (2020)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in males and there is no effective therapeutics to treat aggressive metastatic PCa (~70% mortality rate). We previously reported that the α1 Na/K-ATPase (α1 NKA), the product of ATP1A1 gene, is a tumor suppressor protein whose expression was significantly reduced in primary tumor and further reduced in the bone metastatic lesions (≤10% of normal tissue). Here we show that loss of cell surface expression of ATP1A1 induces Epithelial Mesenchymal Transition (EMT), and promotes metastatic potential and tumor growth of PCa by decreasing E-cadherin expression and upregulating c-Myc expression via Src-dependent signaling. The progressive loss of α1 NKA in PCa is because of increased endocytosis by activating the α1 NKA/Src receptor complex. Using a unique α1 NKA screening platform, we have discovered MB5, an inverse agonist of receptor α1 NKA that can block ouabain, an agonist-induced signaling and endocytosis of α1 NKA. Functionally, MB5 treatment increased the expression of α1 NKA and E cadherin-which reversed EMT and decreased the invasion and growth of tumor xenografts. Thus, we have revealed a hitherto unrecognized mechanism that regulates the EMT and invasiveness, and identified α1 NKA inverse agonists such as MB5 as a potential drug candidate for the treatment of aggressive PCa. Citation Format: Moumita Banerjee, Zhichuan Li, Yingnyu Gao, Minqi Huang, Liquan Cai, Tianyan Gao, Xie Zijian. Targeting the increased endocytosis of Na/K ATPase α1 subunit as a new therapeutic approach to prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6393.
Weight Management and Healthy Lifestyles
Authors: Theodore K. Kyle, Joseph F. Nadglowski, Fatima Cody Stanford
Journal: JAMA Internal Medicine (2020)

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Patients’ experiences and reported barriers to screening colonoscopy: A systematic review
Authors: S. McLachlan, A. Clements, J. Austoker
Journal: Journal of Clinical Oncology (2009)

1537 Background: Colonoscopy is a component of most colorectal screening programs, as a primary test or as follow-up to an abnormal FOB test. Little is known about why some patients do not comply with colonoscopy after being referred. Methods: A search strategy using three themes of screening, colonoscopy, and patient acceptance was developed and used in MEDLINE, EMBASE and PSYCHinfo (1996–2008). Retrieved citations were assessed for eligibility by two reviewers using prespecified criteria. A qualitative synthesis was conducted. Results: From an initial 3,174 studies, 264 were identified as potentially eligible for review. After full text assessment, 64 studies met eligibility criteria and were included in the final analysis. Six studies examined the experience of a primary colonoscopy by eliciting patients’ views soon after they had the test. Fifty-six studies addressed patient-reported concerns and barriers to an anticipated primary colonoscopy. Most patients perceived the laxative bowel preparation to be the most burdensome part and the greatest barrier to colonoscopy. Other reported difficulties included anxiety and anticipation of pain. Feelings of embarrassment and vulnerability occurred, particularly in women, and also acted as barriers to adherence. Inadequate knowledge about screening was common and was identified as an obstacle to the uptake of screening colonoscopy as was fear of finding cancer. Physician endorsement, having a family history, knowing someone with cancer, and perceived accuracy of the test were incentives to having a colonoscopy. The most common reported practical barriers were inconvenience, transportation, scheduling, and cost. Only two studies focused on colonoscopy as a secondary procedure in the screening context. Similar procedural, personal, and practical concerns were reported by patients in this setting. Conclusions: Bowel preparation, lack of awareness of the importance of screening, and feelings of vulnerability in women are all significant barriers to colonoscopy in the screening context. These obstacles need to be addressed, and further research undertaken on barriers to second line colonoscopy. No significant financial relationships to disclose.
Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses
Authors: Brigid S. Boland, Zhaoren He, Matthew S. Tsai, Jocelyn G. Olvera, Kyla D. Omilusik, Han G. Duong, Eleanor S. Kim, Abigail E. Limary, Wenhao Jin, J. Justin Milner, Bingfei Yu, Shefali A. Patel, Tiani L. Louis, Tiffani Tysl, Nadia S. Kurd, Alexandra Bortnick, Lauren K. Quezada, Jad N. Kanbar, Ara Miralles, Danny Huylebroeck, Mark A. Valasek, Parambir S. Dulai, Siddharth Singh, Li-Fan Lu, Jack D. Bui, Cornelis Murre, William J. Sandborn, Ananda W. Goldrath, Gene W. Yeo, John T. Chang
Journal: Science Immunology (2020)

Single-cell sequencing analyses reveal changes in B and T cell transcriptional states in the context of ulcerative colitis.
Plasma C3d levels as a diagnostic marker for complete complement factor I deficiency
Authors: Leslie Naesens, Julie Smet, Simon J. Tavernier, Petra Schelstraete, Levi Hoste, Stijn Lambrecht, Helene Verhelst, Jutte van der Werff ten Bosch, Alina Ferster, Sophie Blumental, Pascale Hilbert, Tessa Kerre, Johan Vande Walle, Christoph Licht, Lubka T. Roumenina, Patrick Stordeur, Filomeen Haerynck
Journal: Journal of Allergy and Clinical Immunology (2020)
SAT0166 Alendronate reduces the risk of clinical vertebral fracture in osteopenic women: data from fit
Authors: S Quandt, D Thompson, D Schneider, M Nevitt, T Musliner
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine the effectiveness of alendronate in reducing the risk of clinical vertebral fractures (CVFX) in women with osteopenia who do not meet the BMD criterion for osteoporosis. <h3>Methods</h3> We studied 3737 women, age 55 to 80, from the Fracture Intervention Trial who had BMD T-score &gt; -2.5 at the femoral neck: 940 with an existing morphometric vertebral fracture (MVFX) and 2797 without. 1859 were treated with PBO and 1878 were treated with ALN 5 mg per day for the first two years and 10 mg for the remaining period for up to 2.5 years. All CVFX were confirmed by a physician. <h3>Results</h3> The absolute risk of CFVX was about 4 to 5 fold greater in women with existing MVFX than in those without. Alendronate significantly (p = 0.005) reduced the overall risk of CFVX by 60% (RR = 0.40 (0.19, 0.76)). The reductions were consistent among those with and without MVFX: 0.34 (0.12, 0.84) and 0.46 (0.16, 1.17) respectively. The effect was observed very early. There were no CFVX in the first year among the alendronate patients. <h3>Conclusion</h3> Alendronate was equally effective in reducing the relative risk of painful clinical vertebral fractures in women with and without existing MVFX. The effect of alendronate was seen early.
Solving the Puzzle to Lasting Impact of the National Diabetes Prevention Program
Authors: Natalie D. Ritchie
Journal: Diabetes Care (2020)

To address the burden of type 2 diabetes, the Centers for Disease Control and Prevention (CDC) launched the National Diabetes Prevention Program (National DPP) in 2010 (1). The program promotes weight loss through lifestyle change, based on remarkable findings of 58% reduced cumulative incidence over 3 years in an efficacy trial (2). Major successes include reaching hundreds of thousands of at-risk individuals nationwide, robust outcomes, and widespread insurance coverage (1,3), but more work is needed to ensure lasting impact, and retention plays a critical part. This Commentary briefly reviews the new retention study by Cannon et al. (4), linkage to other critical pieces, and future directions. In considering solutions to a complex national problem, I seek to contribute my uniquely broad experience with the National DPP working as a lifestyle coach, securing funding, overseeing delivery, reaching disadvantaged populations, serving on state workgroups, rate setting, becoming a Medicare supplier, advocating to payers and legislators, and authoring over 20 peer-reviewed articles on the program. Beginning with doctoral training on a preceding translational study (5), I now lead a large pragmatic trial a decade later to improve retention with presessions to the National DPP (6). I am also ashamedly familiar with diabetes risks and lost over 50 pounds in my own personal journey with lifestyle change.

With rigorous analysis of 41,203 participants across 581 organizations, Cannon et al. show incremental attrition that leaves only a third (32%) remaining by month 10 of the yearlong intervention (data not presented for months 11–12) (4). Racial/ethnic minority and younger individuals, and those lacking successful lifestyle change, drop out disproportionately more. The findings help replicate my early studies on retention gaps for these groups (7–9 …
Normal Karyotype-Acute Myeloid Leukemia With The CD4- CD7+ CD15+ CD34+ Immunophenotype Is a Clinically Distinct Entity With a Favorable Outcome
Authors: Noriyoshi Iriyama, Norio Asou, Toru Sakura, Tomoya Maeda, Hiroshi Handa, Masatomo Takahashi, Shigeki Ohtake, Yoshihiro Hatta, Hisashi Sakamaki, Sumihisa Honda, Yasushi Miyazaki, Shuichi Miyawaki, Masafumi Taniwaki, Tomohiko Taki, Shunichiro Yamaguchi, Shinya Satou, Tomoki Naoe
Journal: Blood (2013)
SP0068 Pregnancy and rheumatoid arthritis
Authors: M Hazes
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Women will hardly ever get their first signs of rheumatoid arthritis (RA) during pregnancy, whereas the onset of RA seems to cluster in the postpartum period. This clinical and epidemiological observation may be explained by a postponement of the onset of symptomatic RA by pregnancy, which is in line with the observed amelioration of disease activity in women with established RA. Up to 75% of women with RA improve during pregnancy, starting in the first or second trimester with maximum improvement during the third trimester of pregnancy. More than 90% of these patients will experience a flare of their disease within two to six months after delivery. Women who have ever been pregnant have a lower risk of developing RA, particularly when they had their first pregnancy at an early age. Several biological mechanisms have been put forward to explain the favourable effect of pregnancy on the onset and course of RA, but there is still no fully satisfactory explanation. The profound hormonal shifts (e.g. increased estrogens, progesterone and corticosteroids) have been implicated in the favourable effect of pregnancy through their effect on the immune system. Pregnancy is an immunological challenge requiring immunological protection or tolerance for the partly non-self fetus. Cellular immunity is decreased during pregnancy, which may play a role in the positive effect of pregnancy in RA. Pregnancy is associated with decreased production of TH1 associated cytokines (IL2, interferon gamma), increased production of TH2 associated cytokines (IL-4, IL-10), and decreased production of proinflammatory cytokines (TNF alpha, IL-12). Alterations in the glycosylation of IgG have also been put forward as a possible explanation. The question why not all women improve during pregnancy is still not answered by the above mechanisms. There is some evidence that HLA disparity between mother and fetus will play a role in the suppression of autoimmunity, which will differ between different pregnancies. A better understanding in how pregnancy exerts its effect on the onset and course of RA will help to unravel possible immunological mechanisms in RA and may lead to more effective treatments.