tbuckley/cabot-search huggingface dataset:
Auto-CSC: A Transfer Learning Based Automatic Cell Segmentation and Count Framework
Authors: Guangdong Zhan, Wentong Wang, Hongyan Sun, Yaxin Hou, Lin Feng
Journal: Cyborg and Bionic Systems (2022)

Cell segmentation and counting play a very important role in the medical field. The diagnosis of many diseases relies heavily on the kind and number of cells in the blood. convolution neural network achieves encouraging results on image segmentation. However, this data-driven method requires a large number of annotations and can be a time-consuming and expensive process, prone to human error. In this paper, we present a novel frame to segment and count cells without too many manually annotated cell images. Before training, we generated the cell image labels on single-kind cell images using traditional algorithms. These images were then used to form the train set with the label. Different train sets composed of different kinds of cell images are presented to the segmentation model to update its parameters. Finally, the pretrained U-Net model is transferred to segment the mixed cell images using a small dataset of manually labeled mixed cell images. To better evaluate the effectiveness of the proposed method, we design and train a new automatic cell segmentation and count framework. The test results and analyses show that the segmentation and count performance of the framework trained by the proposed method equal the model trained by large amounts of annotated mixed cell images.
Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies
Authors: Minru Liao, Rui Qin, Wei Huang, Hong-Ping Zhu, Fu Peng, Bo Han, Bo Liu
Journal: Journal of Hematology & Oncology (2022)

Abstract Triple-negative breast cancer (TNBC) is a subtype of human breast cancer with one of the worst prognoses, with no targeted therapeutic strategies currently available. Regulated cell death (RCD), also known as programmed cell death (PCD), has been widely reported to have numerous links to the progression and therapy of many types of human cancer. Of note, RCD can be divided into numerous different subroutines, including autophagy-dependent cell death, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis and anoikis. More recently, targeting the subroutines of RCD with small-molecule compounds has been emerging as a promising therapeutic strategy, which has rapidly progressed in the treatment of TNBC. Therefore, in this review, we focus on summarizing the molecular mechanisms of the above-mentioned seven major RCD subroutines related to TNBC and the latest progress of small-molecule compounds targeting different RCD subroutines. Moreover, we further discuss the combined strategies of one drug (e.g., narciclasine) or more drugs (e.g., torin-1 combined with chloroquine) to achieve the therapeutic potential on TNBC by regulating RCD subroutines. More importantly, we demonstrate several small-molecule compounds (e.g., ONC201 and NCT03733119) by targeting the subroutines of RCD in TNBC clinical trials. Taken together, these findings will provide a clue on illuminating more actionable low-hanging-fruit druggable targets and candidate small-molecule drugs for potential RCD-related TNBC therapies. Graphical abstract
Glioblastoma scRNA-seq shows treatment-induced, immune-dependent increase in mesenchymal cancer cells and structural variants in distal neural stem cells
Authors: Charles P Couturier, Javad Nadaf, Zhaorong Li, Salma Baig, Gabriele Riva, Phuong Le, Daan J Kloosterman, Jean Monlong, Andriniaina Nkili Meyong, Redouane Allache, Theresa Degenhard, Mariam Al-Rashid, Marie-Christine Guiot, Guillaume Bourque, Jiannis Ragoussis, Leila Akkari, Francisco J Quintana, Kevin Petrecca
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved. Methods Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ). Results We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo. Conclusion These data reveal the dynamic, immune-dependent nature of glioblastoma’s response to treatments and identify distant NSCs as likely cells of origin.
TCTAP C-058 Reattempt Antegrade CTO PCI Using Turnpike Spiral Catheter Followed by Drug Coated Balloons in De Novo Coronary Lesions Complicated With Iatrogenic Type B Coronary Artery Dissection
Authors: Quah Wy Jin, Chan Ho Thum, Khai Chih Teh, Jayakhanthan Kolanthaivelu
Journal: Journal of the American College of Cardiology (2022)
Pharmacological Treatment for Pedophilic Disorder and Compulsive Sexual Behavior Disorder: A Review
Authors: Valdemar Landgren, Josephine Savard, Cecilia Dhejne, Jussi Jokinen, Stefan Arver, Michael C. Seto, Christoffer Rahm
Journal: Drugs (2022)

Guidelines for the pharmacological treatment of paraphilic disorders have historically been based on data from forensic settings and on risk levels for sexual crime. However, emerging treatment options are being evaluated for individuals experiencing distress because of their sexual urges and preferences, targeting both paraphilic disorders such as pedophilic disorder (PeD) and the new diagnosis of compulsive sexual behavior disorder (CSBD) included in the International Classification of Diseases, 11th Revision (ICD-11). As in other mental disorders, this may enable individualized pharmacological treatment plans, taking into account components of sexuality (e.g. high libido, compulsivity, anxiety-driven/sex as coping), medical and psychiatric comorbidity, adverse effects and patient preferences. In order to expand on previous reviews, we conducted a literature search focusing on randomized controlled trials of pharmacological treatment for persons likely to have PeD or CSBD. Our search was not restricted to studies involving forensic or criminal samples. Twelve studies conducted between 1974 and 2021 were identified regardless of setting (outpatient or inpatient), with only one study conducted during the last decade. Of a total of 213 participants included in these studies, 122 (57%) were likely to have PeD, 34 (16%) were likely to have a CSBD, and the remainder had unspecified paraphilias (40, 21%) or sexual offense (17, 8%) as the treatment indication. The diagnostic procedure for PeD and/or CSBD, as well as comorbid psychiatric symptoms, has been described in seven studies. The studies provide some empirical evidence that testosterone-lowering drugs reduce sexual activity for patients with PeD or CSBD, but the body of evidence is meager. There is a need for studies using larger samples, specific criteria for inclusion, longer follow-up periods, and standardized outcome measures with adherence to international reporting guidelines.
VCP suppresses proteopathic seeding in neurons
Authors: Jiang Zhu, Sara Pittman, Dhruva Dhavale, Rachel French, Jessica N. Patterson, Mohamed Salman Kaleelurrrahuman, Yuanzi Sun, Jaime Vaquer-Alicea, Gianna Maggiore, Christoph S. Clemen, William J. Buscher, Jan Bieschke, Paul Kotzbauer, Yuna Ayala, Marc I. Diamond, Albert A. Davis, Conrad Weihl
Journal: Molecular Neurodegeneration (2022)

Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.
IL-17–induced HIF1α drives resistance to anti–PD-L1 via fibroblast-mediated immune exclusion
Authors: Xing Chen, Junjie Zhao, Tomasz Herjan, Lingzi Hong, Yun Liao, Caini Liu, Kommireddy Vasu, Han Wang, Austin Thompson, Paul L. Fox, Brian R. Gastman, Xiao Li, Xiaoxia Li
Journal: The Journal of Experimental Medicine (2022)

Increasing evidence suggests that intratumoral inflammation has an outsized influence on antitumor immunity. Here, we report that IL-17, a proinflammatory cytokine widely associated with poor prognosis in solid tumors, drives the therapeutic failure of anti-PD-L1. By timing the deletion of IL-17 signaling specifically in cancer-associated fibroblasts (CAFs) in late-stage tumors, we show that IL-17 signaling drives immune exclusion by activating a collagen deposition program in murine models of cutaneous squamous cell carcinoma (cSCC). Ablation of IL-17 signaling in CAFs increased the infiltration of cytotoxic T cells into the tumor mass and sensitized otherwise resistant cSCC to anti-PD-L1 treatment. Mechanistically, the collagen deposition program in CAFs was driven by IL-17-induced translation of HIF1α, which was mediated by direct binding of Act1, the adaptor protein of IL-17 receptor, to a stem-loop structure in the 3' untranslated region (UTR) in Hif1α mRNA. Disruption of Act1's binding to Hif1α mRNA abolished IL-17-induced collagen deposition and enhanced anti-PD-L1-mediated tumor regression.
Journal club
Authors: Carlos Lopes Figueiredo
Journal: Thorax (2022)

TRACHEOSTOMY CAN BE AVOIDED (MOSTLY)For patients with neuromuscular diseases (NMD) and a high level of ventilatory dependence requiring continuous non-invasive ventilatory support (CNVS) and mechanical insufflationexsufflation (MI-E), tracheostomy mechanical ventilation (TMV) is recommended in some guidelines.Improved clinical management and ventilator and chest clearance strategies has led to some patients avoiding tracheostomy even when unable to perform any ventilator-free breathing.Gonçalves et al (Pulmonology 2021;27:509) reported the first multicentre study (19 centres from 16 countries) of CNVS plus MI-E use in 1623 patients with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD) or spinal muscular atrophy type 1 (SMA1).Nearly half (761/1623) progressed to CNVS dependence with no ventilator-free breathing, proceeding to survive a further combined 2218 patient-years without tracheostomy.The most common patient group to procced to tracheostomy were patients with advanced bulbar ALS with stridor, low peak cough flow generated by MI-E and O2 saturation below 95% despite CNVS.In patients with DMD and SMA1 who required intubation for acute respiratory failure the authors reported a ~99% extubation success rate (with CNVS and MI-E protocol) in previously described 'unweanable' patients.The authors comment that a dedicated multidisciplinary team and a well-structured extubation protocol are essential to deliver these results.Therefore, they aim to endorse the CNVS and MI-E protocol as a safe alternative to TMV in NMD patients, even if unable to perform ventilator-free breathing.
Sodium–Glucose Cotransporter-2 Inhibitors in Patients With Heart Failure
Authors: Xinyu Zou, Qingyang Shi, Per Olav Vandvik, Gordon Guyatt, Chim C. Lang, Sameer Parpia, Si Wang, Arnav Agarwal, Yiling Zhou, Ye Zhu, Haoming Tian, Zhiming Zhu, Sheyu Li
Journal: Annals of Internal Medicine (2022)

Background: Randomized controlled trials established the cardiac protection of sodium–glucose cotransporter-2 (SGLT2) inhibitors among adults with type 2 diabetes. New evidence suggests that these results could extend to people without diabetes. Purpose: To evaluate the effect of SGLT2 inhibitors in patients with heart failure, regardless of the presence of type 2 diabetes. Data Sources: PubMed, Web of Science, Cochrane Library, and Embase (OVID interface). Study Selection: Eligible trials randomly assigned adults with heart failure to SGLT2 inhibitors or control. Data Extraction: Time-to-event individual patient data were reconstructed from published Kaplan–Meier plots; time-varying risk ratios (RRs) were calculated in half-, 1-, and 2-year time frames; and anticipated absolute benefits were calculated using simple models applying relative effects to baseline risks. Data Synthesis: Sodium–glucose cotransporter-2 inhibitors reduce hospitalization for heart failure by 37% (95% CI, 25% to 47%) at 6 months, 32% (CI, 20% to 42%) at 1 year, and 26% (CI, 10% to 40%) at 2 years (all high certainty) and reduce cardiovascular death by 14% (CI, 1% to 25%) at 1 year (high certainty). Nevertheless, low-certainty evidence did not indicate protection against all-cause death, kidney disease progression, or kidney failure. Anticipated absolute benefits are greater for patients treated in the first year and for those with poorer prognoses, such as those newly diagnosed with heart failure in the hospital. In addition, SGLT2 inhibitors doubled the risk for genital infections (RR, 2.69 [CI, 1.61 to 4.52]; high certainty). Limitation: Covariates were unavailable in meta-analyses with reconstructed individual patient data. Conclusion: Among people with heart failure, SGLT2 inhibitors reduce hospitalizations for heart failure regardless of the presence of diabetes; absolute benefits are most pronounced in first-year treatment and vary with prognostic factors. Clinicians should note the increased risk for genital infection in patients receiving SGLT2 inhibitors. Primary Funding Source: 1.3.5 Project for Disciplines of Excellence, West China Hospital of Sichuan University. (PROSPERO: CRD42021255544)
Development and Validation of a Decision Analytical Model for Posttreatment Surveillance for Patients With Oropharyngeal Carcinoma
Authors: Vivek Nair, Samuel Auger, Sara Kochanny, Frederick M. Howard, Daniel Ginat, Olga Pasternak-Wise, Aditya Juloori, Matthew Koshy, Evgeny Izumchenko, Nishant Agrawal, Ari Rosenberg, Everett E. Vokes, M. Reza Skandari, Alexander T. Pearson
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Clinical practice regarding posttreatment radiologic surveillance for patients with oropharyngeal carcinoma (OPC) is neither adapted to individual patient risk nor fully evidence based. <h3>Objectives</h3> To construct a microsimulation model for posttreatment OPC progression and use it to optimize surveillance strategies while accounting for both tumor stage and human papillomavirus (HPV) status. <h3>Design, Setting, and Participants</h3> In this decision analytical modeling study, a Markov model of 3-year posttreatment patient trajectories was created. The training data source was the American College of Surgeon's National Cancer Database from 2010 to 2015. The external validation data set was the 2016 International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S) study. Training data comprised 2159 patients with OPC treated with primary radiotherapy who had known HPV status and disease staging information. Patients with American Joint Committee on Cancer, 7th edition stage III to IVB disease and those with clinical metastases during the time of primary treatment were included. Data were analyzed from August 1 to October 31, 2020. <h3>Main Outcomes and Measures</h3> Main outcomes included disease stage and HPV status, specific disease transition probabilities, and latency of surveillance regimens, defined as time between recurrence incidence and disease discovery. <h3>Results</h3> Training data consisted of 2159 total patients (1708 men [79.1%]; median age, 59.6 years [range, 40-90 years]; 401 with stage III disease, 1415 with stage IVA disease, and 343 with stage IVB disease). Cohorts predominantly had HPV-negative disease (1606 [74.4%]). With model-optimized regimens, recurrent disease was discovered a mean of 0.6 months (95% CI, 0.5-0.8 months) earlier than with a standard surveillance regimen based on current clinical guidelines. Recurrent disease was discovered using the optimized regimens without significant reduction in sensitivity. Compared with strategies based on reimbursement guidelines, the model-optimized regimens found disease a mean of 1.8 months (95% CI, 1.3-2.3 months) earlier. <h3>Conclusions and Relevance</h3> Optimized, risk-stratified surveillance regimens consistently outperformed nonoptimized strategies. These gains were obtained without requiring any additional imaging studies. This approach to risk-stratified surveillance optimization is generalizable to a broad range of tumor types and risk factors.
Breaking the DLG shackles in glioblastoma
Authors: Sourav Ghosh
Journal: Neuro-Oncology (2022)

Glioblastoma stem-like cells (GSCs) depend on a multitude of neurodevelopmental signaling pathways for their stemness and ability to seed glioblastoma tumors. The stemness of GSCs and re-seeding of tumors can account for treatment resistance and recurrence of glioblastoma. Therefore, identifying and targeting developmental pathways hold promise as therapeutic strategies in this aggressive disease. The developmental signaling pathways Notch, BMP, WNT, and Sonic Hedgehog (SHH) have all been implicated in glioblastoma growth. In this issue of Neuro-Oncology, Kundu et al.1 describe their findings on a mechanism of aberrant SHH pathway activation in glioblastoma (Figure 1). SHH binds to and inactivates the transmembrane protein Patched (PTCH1). PTCH1, in the absence of SHH, inhibits the activity of the G-protein-coupled receptor Smoothened (SMO). Thus, SHH relieves the inhibition of SMO. SMO activation results in translocation of GLI transcription factors to the nucleus, where they drive gene expression including that of PTCH1 as negative feedback and of GLI1 as positive feedback.2 Incidentally, GLI1 was originally identified as an amplified oncogene in glioblastoma.3 Kundu et al. discovered that a scaffold protein Disc-Large Homolog 5 (DLG5) has a critical functional role in sustaining SHH pathway signaling in GSCs.1 The authors demonstrated that DLG5 was highly upregulated in glioblastoma compared to other solid tumors, and was the only DLG paralog that was highly expressed in all molecular subtypes of glioblastoma. DLG5 supported GSC viability and self-renewal. Additionally, DLG5 function contributed to GSC invasion in vitro and ex vivo. In vivo, DLG5 knockdown resulted in impaired tumor cell proliferation, reduced tumor volume, and modestly increased overall survival in an orthotopic immunodeficient mouse model. DLG5-deficient tumors had reduced expression of GLI1, as well as of stemness (such as OLIG2) and mesenchymal markers (such as CD44). DLG5 overexpression upregulated components of the SHH pathway such as PTCH1, SMO, and GLI1.
Correction to: Sunitinib-suppressed miR-452-5p facilitates renal cancer cell invasion and metastasis through modulating SMAD4/SMAD7 signals
Authors: Wei Zhai, Saiyang Li, Jin Zhang, Yonghui Chen, Junjie Ma, Wen Kong, Dongkui Gong, Junhua Zheng, Wei Xue, Yunfei Xu
Journal: Molecular Cancer (2022)
Association of Selective Serotonin Reuptake Inhibitor Use With Abnormal Physical Movement Patterns as Detected Using a Piezoelectric Accelerometer and Deep Learning in a Nationally Representative Sample of Noninstitutionalized Persons in the US
Authors: Michael V. Heinz, George D. Price, Franklin Ruan, Robert J. Klein, Matthew Nemesure, Aliza Lopez, Nicholas C. Jacobson
Journal: JAMA Network Open (2022)

Selective serotonin reuptake inhibitors (SSRIs) are a common first-line treatment for some psychiatric disorders, including depression and anxiety; although they are generally well tolerated, SSRIs have known adverse effects, including movement problems, sleep disruption, and gastrointestinal problems (eg, nausea and upset stomach). No large-scale studies using naturalistic, longitudinal, objective data have validated physical activity findings, and actigraphy data are well suited to address this task.
Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept
Authors: Lee S Nguyen, Marie Bretagne, Jennifer Arrondeau, Noel Zahr, Stephane Ederhy, Baptiste Abbar, Bruno Pinna, Yves Allenbach, Jean-Paul Mira, Javid Moslehi, Michelle Rosenzwajg, Joe-Elie Salem
Journal: Journal for ImmunoTherapy of Cancer (2022)

Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.