tbuckley/cabot-search huggingface dataset:
Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study
Authors: Niannian Ji, Neelam Mukherjee, Ryan M Reyes, Jonathan Gelfond, Martin Javors, Joshua J. Meeks, David J McConkey, Zhen-Ju Shu, Chethan Ramamurthy, Ryan Dennett, Tyler J Curiel, Robert S Svatek
Journal: Journal for ImmunoTherapy of Cancer (2021)

Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG's antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1-2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: -26% (-51% to 24%) for placebo, 9.6% (-59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (-31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02).Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.
CSF3R T618I mutant chronic myelomonocytic leukemia (CMML) defines a proliferative CMML subtype enriched in ASXL1 mutations with adverse outcomes
Authors: Evandro D. Bezerra, Terra L. Lasho, Christy M. Finke, Antoine N. Saliba, Michelle A. Elliott, Animesh D. Pardanani, Naseema Gangat, Abhishek A. Mangaonkar, Rhett P. Ketterling, Ayalew Tefferi, Eric Solary, Mrinal M. Patnaik
Journal: Blood Cancer Journal (2021)
KDIGO made 12 recommendations for managing diabetes with CKD
Authors: Thomas Karagiannis, Apostolos Tsapas, Eleni Bekiari
Journal: Annals of Internal Medicine (2021)

Source Citation Navaneethan SD, Zoungas S, Caramori ML, et al. Diabetes management in chronic kidney disease: synopsis of the 2020 KDIGO Clinical Practice Guideline. Ann Intern Med. 2020. [Epub ahead of print]. 33166222
Sex Differences in Clinical Course and Patient-Reported Outcomes Among Patients Hospitalized for Heart Failure
Authors: Vanessa Blumer, Stephen J. Greene, Angie Wu, Javed Butler, Justin A. Ezekowitz, JoAnn Lindenfeld, Brooke Alhanti, Adrian F. Hernandez, Christopher M. O’Connor, Robert J. Mentz
Journal: JACC Heart Failure (2021)
Neighborhoods with Greater Prevalence of Minority Residents Have Lower Continuous Positive Airway Pressure Adherence
Authors: Priya V. Borker, Emely Carmona, Utibe R. Essien, Gul Jana Saeed, S. Mehdi Nouraie, Jessie P. Bakker, Christy J. Stitt, Mark S. Aloia, Sanjay R. Patel
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Limited data suggest racial disparities in continuous positive airway pressure (CPAP) adherence exist.Objectives: To assess whether CPAP adherence varies by neighborhood racial composition at a national scale.Methods: Telemonitoring data from a CPAP manufacturer database were used to assess adherence in adult patients initiating CPAP therapy between November 2015 and October 2018. Mapping ZIP code to ZIP code tabulation areas, age- and sex-adjusted CPAP adherence data at a neighborhood level was computed as a function of neighborhood racial composition. Secondary analyses adjusted for neighborhood education and poverty.Measurements and Main Results: Among 787,236 patients living in 26,180 ZIP code tabulation areas, the prevalence of CPAP adherence was 1.3% (95% confidence interval [CI], 1.0-1.6%) lower in neighborhoods with high (⩾25%) versus low (<1%) percentages of Black residents and 1.2% (95% CI, 0.9-1.5%) lower in neighborhoods with high versus low percentages of Hispanic residents (P < 0.001 for both), even after adjusting for neighborhood differences in poverty and education. Mean CPAP usage was similar across neighborhoods for the first 2 days, but by 90 days, differences in CPAP usage increased to 22 minutes (95% CI, 18-27 min) between neighborhoods with high versus low percentages of Black residents and 22 minutes (95% CI 17-27 min) between neighborhoods with high versus low percentages of Hispanic residents (P < 0.001 for both).Conclusions: CPAP adherence is lower in neighborhoods with greater proportions of Black and Hispanic residents, independent of education or poverty. These differences lead to a lower likelihood of meeting insurance coverage requirements for CPAP therapy, potentially exacerbating sleep health disparities.
Retrospective cohort analysis of real-world clinical outcomes in nonmetastatic (M0) castration-resistant prostate cancer (CRPC) treated with novel androgen receptor pathway inhibitors (ARPI).
Authors: Richard Gagnon, Nimira S. Alimohamed, Alexander Watson, Eugene Batuyong, Alyssa Chow, Richard M. Lee-Ying
Journal: Journal of Clinical Oncology (2021)

51 Background: The landscape of M0 CRPC has changed with the recent demonstration of metastasis-free survival (MFS) and overall survival (OS) improvements with the use of ARPIs in clinical trial settings. However, the extrapolation of this data to clinical practice is limited by strict exclusion criteria in these trials, including prior or concurrent malignancy, cardiovascular disease, or hypertension. The purpose of this study was to assess real-world outcomes in patients with M0 CRPC treated with ARPIs compared to historical controls. Methods: We designed a retrospective cohort study with the inclusion of patients in Alberta, Canada diagnosed with M0 CRPC between 2001-2020. Via chart review, we identified baseline characteristics, potential confounders, treatment details, and clinical outcomes. The primary outcome of interest was MFS. Secondary outcomes included: second progression-free survival (PFS2) and OS. Median survival times were measured using the Kaplan-Meier method and the log-rank test was used for comparison of outcomes based on ARPI exposure. Cox proportional hazard regression models were used to calculate hazard ratios (HR) accounting for impact of PSA doubling time (PSADT), use of osteoclast inhibiting agents, and presence of pelvic lymphadenopathy. Results: We identified 211 patients across multiple centres in Alberta with M0 CRPC, with 54 having received apalutamide (40/54), enzalutamide (7/54), or darolutamide (7/54). Median age at M0 CRPC diagnosis was 74 years; median PSADT was 4.4 months; and 19% of patients (40/211) had pelvic lymphadenopathy at diagnosis. Median MFS in patients treated with ARPIs was 47.5 months compared to 20.6 months in those not treated with ARPIs (HR, 0.23; 95% confidence interval [CI], 0.11-0.49; p &lt; 0.001). Median PFS2 in ARPI treated patients was 66.3 months compared with 35.6 months (HR, 0.40; 95% CI, 0.18-0.87; p = 0.022). Median OS for patients treated with ARPI was not reached. Conclusions: Given the older age of men with advanced prostate cancer, real-world outcomes that include patients with comorbidities are important adjuncts to the interpretation of clinical trials exploring the benefit of novel therapeutics. Here, we demonstrate that in a real-world, unselected population of men with M0 CRPC, apalutamide, enzalutamide, and darolutamide seem to confer similar MFS and PFS2 benefits to those demonstrated in the SPARTAN, PROSPER, and ARAMIS studies. Real-world OS data remain immature and will be an important addition to these findings.
Phase II study of the efficacy of abirateron acetate with dutasteride for castration-resistant prostate cancer.
Authors: Hideyasu Matsuyama, Masaki Shiota, Kojiro Tashiro, Hiromi Kanji, Shizuyo Horiyama, Masatoshi Eto, Shin Egawa, Jun Haginaka, Ryo Inoue
Journal: Journal of Clinical Oncology (2021)

112 Background: Abiraterone (Abi) has been becoming a pivotal drug not only for metastatic castration resistant prostate cancer (mCRPC), but also for metastatic hormone sensitive prostate cancer (mHSPC). Abi is metabolized to delta-4 Abi (D4A), the strongest antitumor metabolite, by 3βHSD, and D4A is metabolized to 3-keto-5-α Abi, which acts as agonist to AR, by 5 α reductase. Reduction of 3-keto-5-α Abi by 5 α reductase inhibitor may increase the antitumor activity of Abi. Purpose of this study is to evaluate the efficacy and safety of the combination therapy of Abi and dutasteride (Duta), a 5 α reductase inhibitor, for the patients with CRPC. Methods: This is a non-randomized single-arm prospective phase II study. Patients with CRPC without any prior AR-targeting agent or docetaxel were recruited in this study with estimated enrollment of 20. Patients were treated with Abi (1,000 mg daily) and prednisone (5 mg daily) for 4 weeks, followed by the add-on of Duta (0.5 mg daily) for 12weeks. If PSA decline continued, combination treatment was allowed until progression. Abi and its metabolites including D4A and 3-keto-5-α Abi were measured by ESI-TOF-MS at baseline, 4, 6, 8, 12, 16, and 20 weeks, and the sample was collected at 2-4 hours after Abi administration. Primary endpoint was PSA decline &gt;50%, and secondary endpoints were Time-to-treatment failure (TTF), and safety. Results: Totally 17 cases with CRPC (mean age: 78.4, initial PSA:92.6ng/ml, median Gleason score: 9) were recruited, and 14 were eligible for starting the combination therapy. Efficacy could be evaluated in 11 cases except 3 on-protocol treatment. Mean PSA decline of Abi/Duta combination therapy was significantly higher than that of monotherapy (p = 0.0143, 73 vs. 35 %). PSA decline&gt;50% was noted in 36.4% for monotherapy, and 72.7% for combination therapy, respectively. Surprisingly, PSA decline&gt;50% was significantly associated with lower Abi, D4A, and 3-keto 5 α Abi at 2 and 4 weeks after combination. Median TTF and progression (radiographic and/or PSA) was noted in 10.4 months (0.9-32), and 5 (45,4%), respectively with a median follow-up of 13.8 months. Progression was significantly associated with lower D4A, and 3-keto 5 a Abi at 4 and 8 weeks after combination therapy. Concerning safety, Grade 2 vertigo occurred in a case during Abi monotherapy period, while no adverse effect was found in combination therapy. Conclusions: Abi/Duta combination therapy seems to be theoretical to decrease AR-agonistic metabolite (3-keto 5 α Abi), and feasible for patients with first-line treatment of CRPC with lesser toxicity. Clinical trial information: UMIN000027795.
Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity
Authors: Tu-Xiong Huang, Xiang-Yu Tan, Hui-Si Huang, Yu-Ting Li, Bei-Lei Liu, Kai-Sheng Liu, Xinchun Chen, Zhe Chen, Xin-Yuan Guan, Chang Zou, Li Fu
Journal: Gut (2021)

Solid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).Anti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.A negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.CAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.
Regulation of immune cells in lung fibrosis: the reign of regnase-1?
Authors: Antoine Froidure, Bruno Crestani
Journal: European Respiratory Journal (2021)

Since the failure of the PANTHER trial in 2012 [1] and the demonstration that immunosuppressants could be harmful for idiopathic pulmonary fibrosis (IPF) patients, the role of immunity in lung fibrosis has been somehow neglected. Later, the negative results of clinical trials that evaluated the effect of a targeted inhibition of tumour necrosis factor-α [2], CCL2 [3], or interleukin (IL)-13 and/or IL-4 [4, 5], have reinforced the opinion that immune-related cytokines were not a target of choice in IPF. However, recent data have emerged suggesting that immune cells present within fibrotic areas of the lung might either accelerate or slow down the fibrotic process, through their interplay with alveolar epithelial cells and fibroblasts [6]. Ever since, the potential role of lymphoid cells in IPF is under serious consideration, supported by the identification of lymphoid populations essential for the reparative process after organ injury [7]. Regnase-1, a natural regulator of ILC2 function, regulates the production of pro-Th2 cytokines (IL-25, IL-33, TSLP) within the fibrotic lung <https://bit.ly/32eVRiJ>
Repurposing carrimycin as an antiviral agent against human coronaviruses, including the currently pandemic SARS-CoV-2
Authors: Haiyan Yan, Jing Sun, Kun Wang, Huiqiang Wang, Shuo Wu, Linlin Bao, Weiqing He, Dong Wang, Airu Zhu, Tian Zhang, Rongmei Gao, Biao Dong, Jianrui Li, Lu Yang, Ming Zhong, Qi Lv, Feifei Qin, Zhen Zhuang, Xiaofang Huang, Xinyi Yang, Yuhuan Li, Yongsheng Che, Jiandong Jiang
Journal: Acta Pharmaceutica Sinica B (2021)

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.
It’s All About Trust!
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2021)

It's All About Trust!I n February, national news media highlighted the struggle that some hospitals are facing in getting staff vaccinated for COVID-19.One hospital featured was Roseland Community Hospital in Chicago, a facility that serves local Black residents and has a high proportion of Black providers and staff.In this case, the problem was not access to vaccine, but vaccine hesitancy.I was somewhat shocked by this.After all, Blacks have been hit so much harder than other Americans by this virus.And these care workers, like so many others across the country, have been battling in a fierce war that has taken many friends and family.Wouldn't the staff be eager to get some protection for themselves and, indirectly, their loved ones?I listened carefully to an interview with a care worker.She said she wasn't sure.The vaccine came along too fast.She was concerned about safety.This hesitancy was not about lack of education; it was about trust.Black Americans have many reasons to be wary.The classic example of a root cause for this, of course, is the infamous Tuskegee Syphilis Study, which began in 1932 and ended in 1972. 1 During this time, Public Health Service officials decided not to treat a cohort of Black men with syphilis so they could study the natural history of the disease.It seems barbaric today, but it was real.Clearly, to those public health officials, Black lives did NOT matter.It took until 1997 for the United States to issue a public apology, articulated by then-President Bill Clinton.But how can words alone erase such a heinous act?In some weird way, the news about vaccine hesitancy among Black Americans also helped me understand why we have so much difficulty enrolling Black patients on clinical trials.If it is difficult for them to accept a proven remedy for a disease that is killing people in front of them, how much harder might it be to trust the potential benefit of an experimental cancer drug?Or to enroll in a trial where they might receive a placebo?A recent study of registration trials for new cancer drugs showed that only 1.9% of trial participants are Black, while US cancer statistics indicate that 10.8% of patients with cancer are Black. 2Something is wrong with this picture.We in healthcare are embracing a number of strategies to change this.Obviously, there is an emphasis on bringing more healthcare workers of color onto every team.We have worked at the community level, especially in faith-based organizations, to encourage trust.And we have tried to emphasize diversity in messaging, including in educational materials.But I think the basic lesion is a fundamental one.I don't think trust will be achieved until it is clear, in every sector of our society, by our words and by our actions, that Black lives DO matter.
Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion
Authors: Chris J. Frangieh, Johannes C. Melms, Pratiksha I. Thakore, Kathryn R. Geiger-Schuller, Patricia Ho, Adrienne M. Luoma, Brian Cleary, Livnat Jerby-Arnon, Shruti Malu, Michael S. Cuoco, Maryann Zhao, Casey R. Ager, Meri Rogava, Lila Hovey, Asaf Rotem, Chantale Bernatchez, Kai W. Wucherpfennig, Bruce E. Johnson, Orit Rozenblatt-Rosen, Dirk Schadendorf, Aviv Regev, Benjamin Izar
Journal: Nature Genetics (2021)
Tracking SARS-CoV-2 lineage B.1.1.7 dissemination: insights from nationwide spike gene target failure (SGTF) and spike gene late detection (SGTL) data, Portugal, week 49 2020 to week 3 2021
Authors: Vítor Borges, Carlos Sousa, Luís Menezes, António Maia Gonçalves, Miguel Picão, José Pedro Almeida, Margarida Vieita, Rafael Santos, Ana Rita Silva, Mariana Costa, Luís Carneiro, Pedro Casaca, Pedro Pinto-Leite, André Peralta-Santos, Joana Isidro, Sílvia Duarte, Luís Vieira, Raquel Guiomar, Susana Silva, Baltazar Nunes, João P Gomes
Journal: Eurosurveillance (2021)

We show that the SARS-CoV-2 B.1.1.7 lineage is highly disseminated in Portugal, with the odds of B.1.1.7 proportion increasing at an estimated 89% (95% confidence interval: 83–95%) per week until week 3 2021. RT-PCR spike gene target late detection (SGTL) can constitute a useful surrogate to track B.1.1.7 spread, besides the spike gene target failure (SGTF) proxy. SGTL/SGTF samples were associated with statistically significant higher viral loads, but not with substantial shift in age distribution compared to non-SGTF/SGTL cases.
Abstract 16567: Validity and Reliability of a Novel Slow Cuff-Deflation System for Non-Invasive Blood Pressure Monitoring in Patients with Continuous-Flow Left Ventricular Assist Device (CF-LVAD)
Authors: Gregg Lanier, Khristine Orlanes, Ryan T Demmer, Yacki Hayashi, Jennifer Murphy, Margaret Flannery, Rosie Te-Frey, Nir Uriel, Donna M Mancini, Yoshifumi Naka, Hiroo Takayama, Ulrich P Jorde, Paolo C Colombo
Journal: Circulation (2012)

Background Non-invasive BP measurements are difficult to obtain in CF-LVAD pts due to diminished pulse pressure. We tested Terumo’s Elemano BP Monitor (which has a unique slow cuff-deflation settin...
Abstract IA-24: Towards robust image based models for cancer risk assessment
Authors: Regina Barzilay, Adam Yala
Journal: Clinical Cancer Research (2021)

Abstract To enable targeted personalized screening, we need to advance cancer risk models. Despite significant research on this topic, statistical models used today in clinical practice routinely undeperform. In this talk, I explore the potential of AI-based models for breast cancer prediction based on mammographic images. These models have already shown significantt performance gains over their counterparts. However, to bring deep learning models to clinical practice, we need to further refine their accuracy, validate them across diverse populations, and demonstrate their potential to improve clinical workflows. To this end, we propose Mirai, a new risk algorithm designed to predict risk at multiple time points, leverage potentially missing risk-factor information, and produce predictions that are consistent across mammography machines. The architectture of the new model will be covered in detail in the talk. Mirai was trained on a large dataset from Massachusetts General Hospital (MGH) in the US and was tested on held-out test sets from MGH, Karolinska in Sweden and Chang Gung Memorial Hospital in Taiwan, obtaining C-indices of 0.76 (95% CI 0.74, 0.80), 0.81 (0.79, 0.82), 0.79 (0.79, 0.83), respectively. Mirai obtained significantly higher five-year ROC AUCs than the Tyrer-Cuzick model (p&amp;lt;0.001) and prior deep learning models, Hybrid DL (p&amp;lt;0.001) and ImageOnly DL (p&amp;lt;0.001), trained on the same MGH dataset. Citation Format: Regina Barzilay, Adam Yala. Towards robust image based models for cancer risk assessment [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-24.