tbuckley/cabot-search huggingface dataset:
Characterising the nationwide burden and predictors of unkept outpatient appointments in the National Health Service in England: A cohort study using a machine learning approach
Authors: Sion Philpott-Morgan, Dixa B. Thakrar, Joshua Symons, Daniel Ray, Hutan Ashrafian, Ara Darzi
Journal: PLoS Medicine (2021)

Background Unkept outpatient hospital appointments cost the National Health Service £1 billion each year. Given the associated costs and morbidity of unkept appointments, this is an issue requiring urgent attention. We aimed to determine rates of unkept outpatient clinic appointments across hospital trusts in the England. In addition, we aimed to examine the predictors of unkept outpatient clinic appointments across specialties at Imperial College Healthcare NHS Trust (ICHT). Our final aim was to train machine learning models to determine the effectiveness of a potential intervention in reducing unkept appointments. Methods and findings UK Hospital Episode Statistics outpatient data from 2016 to 2018 were used for this study. Machine learning models were trained to determine predictors of unkept appointments and their relative importance. These models were gradient boosting machines. In 2017–2018 there were approximately 85 million outpatient appointments, with an unkept appointment rate of 5.7%. Within ICHT, there were almost 1 million appointments, with an unkept appointment rate of 11.2%. Hepatology had the highest rate of unkept appointments (17%), and medical oncology had the lowest (6%). The most important predictors of unkept appointments included the recency (25%) and frequency (13%) of previous unkept appointments and age at appointment (10%). A sensitivity of 0.287 was calculated overall for specialties with at least 10,000 appointments in 2016–2017 (after data cleaning). This suggests that 28.7% of patients who do miss their appointment would be successfully targeted if the top 10% least likely to attend received an intervention. As a result, an intervention targeting the top 10% of likely non-attenders, in the full population of patients, would be able to capture 28.7% of unkept appointments if successful. Study limitations include that some unkept appointments may have been missed from the analysis because recording of unkept appointments is not mandatory in England. Furthermore, results here are based on a single trust in England, hence may not be generalisable to other locations. Conclusions Unkept appointments remain an ongoing concern for healthcare systems internationally. Using machine learning, we can identify those most likely to miss their appointment and implement more targeted interventions to reduce unkept appointment rates.
A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma
Authors: Heng Mei, Chenggong Li, Huiwen Jiang, Xinying Zhao, Zhiping Huang, Dan Jin, Tao Guo, Haiming Kou, Lin Liu, Lu Tang, Ping Yin, Zhihui Wang, Lisha Ai, Sha Ke, Yimeng Xia, Jun Deng, Lei Chen, Li Cai, Chunyan Sun, Linghui Xia, Gaoquan Hua, Yu Hu
Journal: Journal of Hematology & Oncology (2021)

BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations.We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial.BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1-2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10-4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months.Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM.Chictr.org.cn ChiCTR1800018143.
Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome
Authors: Carlo Sorrentino, Stefania Livia Ciummo, Luigi D'Antonio, Cristiano Fieni, Paola Lanuti, Alice Turdo, Matilde Todaro, Emma Di Carlo
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Breast cancer (BC) progression to metastatic disease is the leading cause of death in women worldwide. Metastasis is driven by cancer stem cells (CSCs) and signals from their microenvironment. Interleukin (IL) 30 promotes BC progression, and its expression correlates with disease recurrence and mortality. Whether it acts by regulating BCSCs is unknown and could have significant therapeutic implications. Methods Human (h) and murine (m) BCSCs were tested for their production of and response to IL30 by using flow cytometry, confocal microscopy, proliferation and sphere-formation assays, and PCR array. Immunocompetent mice were used to investigate the role of BCSC-derived IL30 on tumor development and host outcome. TCGA PanCancer and Oncomine databases provided gene expression data from 1084 and 75 hBC samples, respectively, and immunostaining unveiled the BCSC microenvironment. Results hBCSCs constitutively expressed IL30 as a membrane-anchored glycoprotein. Blocking IL30 hindered their proliferation and self-renewal efficiency, which were boosted by IL30 overexpression. IL30 regulation of immunity gene expression in human and murine BCSCs shared a significant induction of IL23 and CXCL10 . Both immunoregulatory mediators stimulated BCSC proliferation and self-renewal, while their selective blockade dramatically hindered IL30-dependent BCSC proliferation and mammosphere formation. Orthotopic implantation of IL30-overexpressing mBCSCs, in syngeneic mice, gave rise to poorly differentiated and highly proliferating MYC + KLF4 + LAG3 + tumors, which expressed CXCL10 and IL23, and were infiltrated by myeloid-derived cells, Foxp3 + T regulatory cells and NKp46 + RORγt + type 3 innate lymphoid cells, resulting in increased metastasis and reduced survival. In tumor tissues from patients with BC, expression of IL30 overlapped with that of CXCL10 and IL23, and ranked beyond the 95th percentile in a Triple-Negative enriched BC collection from the Oncomine Platform. CIBERSORTx highlighted a defective dendritic cell, CD4 + T and γδ T lymphocyte content and a prominent LAG3 expression in IL30 high versus IL30 low human BC samples from the TCGA PanCancer collection. Conclusions Constitutive expression of membrane-bound IL30 regulates BCSC viability by juxtacrine signals and via second-level mediators, mainly CXCL10 and IL23. Their autocrine loops mediate much of the CSC growth factor activity of IL30, while their paracrine effect contributes to IL30 shaping of immune contexture. IL30-related immune subversion, which also emerged from computational analyses, strongly suggests that targeting IL30 can restrain the BCSC compartment and counteract BC progression.
P53.06 A Multi-Phase Quality Initiative to Improve Processes of Care for Non-small Cell Lung Cancer (NSCLC) in US Community Cancer Centers
Authors: M. Smeltzer, D.R. Spigel, M. Shiller, P. Lee, D. Feller-Kopman, A. Spira, H. West, N. Martin, B. Stiles, E. Plotkin, J. Kim, L. Lucas, L. Boehmer
Journal: Journal of Thoracic Oncology (2021)
Perspectives of Stakeholders About an Early Result Acceptance Program to Complement the Residency Match in Obstetrics and Gynecology
Authors: Abigail Ford Winkel, Helen K. Morgan, Oluwabukola Akingbola, Keli Santos-Parker, Erin Nelson, Erika Banks, Nadine T. Katz, Jessica L. Bienstock, David Marzano, Maya M. Hammoud
Journal: JAMA Network Open (2021)

The residency application process is flawed, costly, and distracts from the preparation for residency. Disruptive change is needed to improve the inefficiencies in current selection processes.To determine interest in an early result acceptance program (ERAP) among stakeholders in obstetrics and gynecology (OBGYN), and to estimate its outcome in future application cycles.Surveys of stakeholders in March 2021 queried interest in ERAP across the US. Respondents included OBGYN residency applicants, members of the Association of American Medical Colleges Group on Student Affairs, OBGYN clerkship directors, and residency program directors. Statistical analysis was performed from March to April 2021.Respondents completed surveys sent by email from the Association of American Medical Colleges (to OBGYN applicants and members of the Group on Student Affairs), the Association of Professors of Gynecology and Obstetrics (to clerkship directors), and the Council on Resident Education in Obstetrics and Gynecology (to program directors).Applicants and program directors indicated their interest in participating in ERAP, and clerkship directors and members of the Group on Student Affairs indicated their likelihood of recommending ERAP using a 5-point Likert scale.Respondents included 879 (34.0%) of 2579 applicants to OBGYN, 143 (50.3%) of 284 residency program directors, 94 (41.8%) of 225 clerkship directors, and 51 (32.9%) of 155 student affairs deans. The majority of respondents reported being either somewhat or extremely likely to participate in ERAP, including 622 applicants (70.7%) and 87 program directors (60.8%). Interest in ERAP was independent of an applicant's reported board scores, medical school type, race, number of applications submitted, or number of interviews completed. Among program directors, those at university programs were more likely to participate. Stakeholders supported a limit of 3 applications for ERAP, to fill 25% to 50% of residency positions. Estimating the outcome of ERAP using these data suggests 26 280 to 52 560 fewer applications could be submitted in the regular match cycle.Stakeholders in the OBGYN application process expressed broad support for the concept of ERAP. The majority of applicants and programs indicated that they would participate, with potentially substantial positive impact on the application process. Careful pilot testing and research regarding implementation are essential to avoid worsening an already dysfunctional application process.
A mechanism for inter-areal coherence through communication based on connectivity and oscillatory power
Authors: Marius Schneider, Ana Clara Broggini, Benjamin Dann, Athanasia Tzanou, Cem Uran, Swathi Sheshadri, Hansjörg Scherberger, Martin Vinck
Journal: Neuron (2021)

Inter-areal coherence between field potentials is a widespread phenomenon in cortex. Coherence has been hypothesized to reflect phase-synchronization between oscillators and flexibly gate communication according to behavioral and cognitive demands. We reveal an alternative mechanism where coherence is not the cause but the consequence of communication and naturally emerges because spiking activity in a sending area causes post-synaptic potentials both in the same and in other areas. Consequently, coherence depends in a lawful manner on power and phase-locking in the sender and connectivity. Changes in oscillatory power explained prominent changes in fronto-parietal and LGN-V1 coherence across behavioral conditions. Optogenetic experiments and excitatory-inhibitory network simulations identified afferent synaptic inputs rather than spiking entrainment as the principal determinant of coherence. These findings suggest that unique spectral profiles of different brain areas automatically give rise to large-scale coherence patterns that follow anatomical connectivity and continuously reconfigure as a function of behavior and cognition.
The safe and effective intraperitoneal chemotherapy with cathepsin B-specific doxorubicin prodrug nanoparticles in ovarian cancer with peritoneal carcinomatosis
Authors: Jinseong Kim, Man Kyu Shim, Young-Jae Cho, Sangmin Jeon, Yujeong Moon, Jiwoong Choi, Jeongrae Kim, Jaewan Lee, Jeong-Won Lee, Kwangmeyung Kim
Journal: Biomaterials (2021)
MA12.03 A Thoracic Cancers International COVID 19 Collaboration Survey on Patients’ Perceptions of COVID-19 (Teravolt-Paper)
Authors: S. Wong, J. Whisenant, M. Gauthier, M. Garcia, A. Moore, J. King, F. Barlesi, M.C. Garassino, N. Leighl, R. Soo, L. Horn
Journal: Journal of Thoracic Oncology (2021)
Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease
Authors: Melissa D. Docampo, Marina B. da Silva, Amina Lazrak, Katherine B. Nichols, Sophia R. Lieberman, Ann E. Slingerland, Gabriel K. Armijo, Yusuke Shono, Chi Nguyen, Sebastien Monette, Emmanuel Dwomoh, Nicole Lee, Clair D. Geary, Suelen M. Perobelli, Melody Smith, Kate A. Markey, Santosha A. Vardhana, Anastasia I. Kousa, Eli Zamir, Itamar Greenfield, Joseph C. Sun, Justin R. Cross, Jonathan U. Peled, Robert R. Jenq, Christoph K. Stein-Thoeringer, Marcel R. M. van den Brink
Journal: Blood (2021)
Protein profiles of body cavity fluid generated by surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI) is helpful in distinguishing between reactive and neoplastic processes.
Authors: David C. Chhieng, Sreelatha Meleth, Elizabeth Miller, Isam Eltoum, Liu Zhu, William E. Grizzle
Journal: Cancer Research (2004)

3550  Background: SELDI, (Ciphergen, Palo Alto, CA), is a new protein chip technology that profiles mixtures of proteins. Body fluid samples can be applied directly and selected proteins in the mixture bind specifically to a solid phase chromatographic surface and when ionized by a laser pulse are analyzed by time of flight mass spectrometry; the resulting spectra consist of a molecular weight profile of peptides with shared common physiochemical binding characteristics. The objective of this study is to determine if there exist specific proteomic signatures that can differentiate between benign and malignant samples of pleural fluid or ascites. Designs and Results: Body-cavity fluid samples were obtained from 22 patients; 8 had a malignant cytologic diagnosis and 14 a benign diagnosis. Each sample was run in triplicate on WCX2 chips. Spectral analyses were performed using Ciphergen software. The protein content of the cancer group was significantly higher than that of the benign group (Wilcoxon Rank Sum test, p=0.004). Peaks were identified based on the resolution of the instrument, ± 0.2%, and a total of 1074 spectral peaks were resolved per specimen in the molecular weight range up to 10,300 Daltons. The heights of the spectral peaks of each triplicate were normalized to the protein concentration of the specific sample. Selected spectral peaks in the two groups was compared using two different metrics. The first method used the local maximums which were defined as the maximum intensity value within each set of m-z values represented by the m-z variable. A stepwise discriminant analysis was used to identify candidate m-z values, which could help classify the two groups correctly. The 5 most frequently occurring m-z values were then used in the analysis. Cross validation (leaving an individual specimen out, recalibrating the classifier and testing to see if the left over samples are classified correctly) was used to estimate the error rate of the classifier. Principal Components Analysis was used to visualize the separation of the two groups. The second method was similar to the first one except that the area covered by a set of m_z values was calculated using a trapezoidal rule. The sensitivity and specificity of separating benign and malignant fluid specimens were 63% and 100%, respectively by the first method and were both 100% by the second method. Conclusion: SELDI analysis of body cavity fluid samples is capable of generating reproducible protein profiles. The protein signatures appear to differentiate malignant from benign fluid samples.
Efficacy and safety of a novel anti‐HER2 therapeutic antibody RC48 in patients with HER2‐overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single‐arm phase II study
Authors: Zhi Peng, Tianshu Liu, Jia Wei, Airong Wang, Yifu He, Liuzhong Yang, Xizhi Zhang, Nanfeng Fan, Suxia Luo, Zhen Li, Kangsheng Gu, Jianwei Lu, Jianming Xu, Qingxia Fan, Ruihua Xu, Liangming Zhang, Enxiao Li, Yuping Sun, Guohua Yu, Chunmei Bai, Yong Liu, Jiangzheng Zeng, Jieer Ying, Xinjun Liang, Nong Xu, Chao Gao, Yongqian Shu, Dong Ma, Guanghai Dai, Shengmian Li, Ting Deng, Yuehong Cui, Jianmin Fang, Yi Ba, Lin Shen
Journal: Cancer Communications (2021)

Abstract Background Current treatment options for human epidermal growth factor receptor 2 (HER2)‐overexpressing gastric cancer at third‐line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in‐situ hybridization‐negative patients. Here, we report the efficacy and safety of a novel anti‐HER2 antibody RC48 for patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer. Methods Patients with HER2‐overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second‐line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. Results Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%‐33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7‐4.9 months) and 7.9 months (95% CI: 6.7‐9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48‐related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48‐related. Conclusions RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.
Association of Cannabis Use–Related Predictor Variables and Self-Reported Psychotic Disorders: U.S. Adults, 2001–2002 and 2012–2013
Authors: Ofir Livne, Dvora Shmulewitz, Aaron L. Sarvet, Melanie M. Wall, Deborah S. Hasin
Journal: American Journal of Psychiatry (2021)

Objective: The authors sought to determine the association of cannabis indicators with self-reported psychotic disorders in the U.S. general population. Methods: Participants were from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; 2001–2002; N=43,093) and NESARC-III (2012–2013; N=36,309). Logistic regression was used to estimate standardized prevalences of past-year self-reported psychotic disorders within each survey and to evaluate the association of past-year self-reported psychotic disorders with indicators of nonmedical cannabis use (any use; frequent use [at least three times/week], daily/near-daily use, and DSM-IV cannabis use disorder) compared with those with no past-year nonmedical cannabis use. Whether the strength of associations differed between surveys was indicated by difference-in-difference tests (between-survey contrasts) and ratios of odds ratios between surveys. Results: Self-reported psychotic disorders were significantly more prevalent among participants with any nonmedical cannabis use than those without (2001–2002: 1.65% compared with 0.27%; 2012–2013: 1.89% compared with 0.68%). In 2001–2002, self-reported psychotic disorders were unrelated to either frequent use or daily/near-daily use. However, in 2012 − 2013, compared with nonusers, self-reported psychotic disorders were more common among participants with frequent use and those with daily/near-daily nonmedical cannabis use (2012–2013: 2.79% and 2.52%, respectively, compared with 0.68% among nonusers). Self-reported psychotic disorders were significantly more prevalent among participants with cannabis use disorder than nonusers in both surveys (2001–2002: 2.55% compared with 0.27%; 2012 − 2013: 3.38% compared with 0.68%). The strength of these associations did not change over time. Conclusions: Data from the U.S. general population, especially more recent data, suggest associations between self-reported psychotic disorder and frequent nonmedical cannabis use and cannabis use disorder. Clinicians and policy makers should consider these relationships when monitoring patients and formulating programs.
Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors
Authors: Anita C. Bellail, Hong Ri Jin, Ho-Yin Lo, Sung Han Jung, Chafiq Hamdouchi, Daeho Kim, Ryan K. Higgins, Maximilian Blanck, Carlos le Sage, Benedict C.S. Cross, Jing Li, Amber L. Mosley, Aruna B. Wijeratne, Wen Jiang, Manali Ghosh, Yin Quan Zhao, Paula M. Hauck, Anantha Shekhar, Chunhai Hao
Journal: Science Translational Medicine (2021)

Discovery of small-molecule degraders that activate ubiquitin ligase–mediated ubiquitination and degradation of targeted oncoproteins in cancer cells has been an elusive therapeutic strategy. Here, we report a cancer cell–based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007’s binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007’s binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin ligase complex, where SUMO1 was ubiquitinated in several of human cancer cells. HB007 selectively degraded SUMO1 in patient tumor–derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the animals. This cancer cell–based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins.