tbuckley/cabot-search huggingface dataset:
New evaluation of the tumor immune microenvironment of non-small cell lung cancer and its association with prognosis
Authors: Shuichi Shinohara, Yusuke Takahashi, Hiroyasu Komuro, Takuya Matsui, Yusuke Sugita, Ayako Demachi-Okamura, Daisuke Muraoka, Hirotomo Takahara, Takeo Nakada, Noriaki Sakakura, Katsuhiro Masago, Manami Miyai, Reina Nishida, Shin Shomura, Yoshiki Shigematsu, Shunzo Hatooka, Hajime Sasano, Fumiaki Watanabe, Katsutoshi Adachi, Kazuya Fujinaga, Shinji Kaneda, Motoshi Takao, Takashi Ohtsuka, Rui Yamaguchi, Hiroaki Kuroda, Hirokazu Matsushita
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background A better understanding of the tumor immune microenvironment (TIME) will facilitate the development of prognostic biomarkers and more effective therapeutic strategies in patients with lung cancer. However, little has been reported on the comprehensive evaluation of complex interactions among cancer cells, immune cells, and local immunosuppressive elements in the TIME. Methods Whole-exome sequencing and RNA sequencing were carried out on 113 lung cancers. We performed single sample gene set enrichment analysis on TIME-related gene sets to develop a new scoring system (TIME score), consisting of T-score ( t umor proliferation), I-score (antitumor i mmunity) and S-score (immuno s uppression). Lung cancers were classified according to a combination of high or low T-score, I-score, and S-scores (eight groups; G1-8). Clinical and genomic features, and immune landscape were investigated among eight groups. The external data sets of 990 lung cancers from The Cancer Genome Atlas and 76 melanomas treated with immune checkpoint inhibitors (ICI) were utilized to evaluate TIME scoring and explore prognostic and predictive accuracy. Results The representative histological type including adenocarcinoma and squamous cell carcinoma, and driver mutations such as epidermal growth factor receptor and TP53 mutations were different according to the T-score. The numbers of somatic mutations and predicted neoantigens were higher in T hi (G5-8) than T lo (G1-4) tumors. Immune selection pressure against neoantigen expression occurred only in T hi and was dampened in T hi /I lo (G5-6), possibly due to a reduced number of T cells with a high proportion of tumor specific but exhausted cells. T hi /I lo /S hi (G5) displayed the lowest immune responses by additional immune suppressive mechanisms. The T-score, I-score and S-scores were independent prognostic factors, with survival curves well separated into eight groups with G5 displaying the worst overall survival, while the opposite group T lo /I hi /S lo (G4) had the best prognosis. Several oncogenic signaling pathways influenced on T-score and I-scores but not S-score, and PI3K pathway alteration correlated with poor prognosis in accordance with higher T-score and lower I-score. Moreover, the TIME score predicted the efficacy of ICI in patients with melanoma. Conclusion The TIME score capturing complex interactions among tumor proliferation, antitumor immunity and immunosuppression could be useful for prognostic predictions or selection of treatment strategies in patients with lung cancer.
Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma
Authors: Tom Rosenberg, Kee Kiat Yeo, Audrey Mauguen, Sanda Alexandrescu, Sanjay P Prabhu, Jessica W Tsai, Seth Malinowski, Mrinal Joshirao, Karishma Parikh, Sameer Farouk Sait, Marc K Rosenblum, Jamal K Benhamida, George Michaiel, Hung N Tran, Sonika Dahiya, Kara Kachurak, Gregory K Friedman, Julie I Krystal, Michael A Huang, Ashley S Margol, Karen D Wright, Dolly Aguilera, Tobey J MacDonald, Susan N Chi, Matthias A Karajannis
Journal: Neuro-Oncology (2022)

The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained.
Somatic Mutation: What Shapes the Mutational Landscape of Normal Epithelia?
Authors: Joanna C. Fowler, Philip H. Jones
Journal: Cancer Discovery (2022)

Epithelial stem cells accumulate mutations throughout life. Some of these mutants increase competitive fitness and may form clones that colonize the stem cell niche and persist to acquire further genome alterations. After a transient expansion, mutant stem cells must revert to homeostatic behavior so normal tissue architecture is maintained. Some positively selected mutants may promote cancer development, whereas others inhibit carcinogenesis. Factors that shape the mutational landscape include wild-type and mutant stem cell dynamics, competition for the niche, and environmental exposures. Understanding these processes may give new insight into the basis of cancer risk and opportunities for cancer prevention. Recent advances in sequencing have found somatic mutations in all epithelial tissues studied to date. Here we review how the mutational landscape of normal epithelia is shaped by clonal competition within the stem cell niche combined with environmental exposures. Some of the selected mutant genes are oncogenic, whereas others may be inhibitory of transformation. Discoveries in this area leave many open questions, such as the definition of cancer driver genes, the mechanisms by which tissues constrain a high proportion of oncogenic mutant cells, and whether clonal fitness can be modulated to decrease cancer risk.
TCTAP A-068 IVUS Guided Optimal Balloon Artery Ratio for Drug Coated Balloon Strategy of Femoral Popliteal Artery Disease
Authors: Yoshihiro Iwasaki, Shigeru Nakamura, Tomoko Kobayashi, Jumpei Koike, Atsushi Funatsu
Journal: Journal of the American College of Cardiology (2022)
Machine learning for medical imaging: methodological failures and recommendations for the future
Authors: Gaël Varoquaux, Veronika Cheplygina
Journal: npj Digital Medicine (2022)

Research in computer analysis of medical images bears many promises to improve patients' health. However, a number of systematic challenges are slowing down the progress of the field, from limitations of the data, such as biases, to research incentives, such as optimizing for publication. In this paper we review roadblocks to developing and assessing methods. Building our analysis on evidence from the literature and data challenges, we show that at every step, potential biases can creep in. On a positive note, we also discuss on-going efforts to counteract these problems. Finally we provide recommendations on how to further address these problems in the future.
Reply
Authors: Vlad Ratziu
Journal: Hepatology (2022)

We thank Prof. Pattou et al. for providing valuable external validation of our findings on the persistence of advanced fibrosis after bariatric surgery, and for providing evidence that the overall outcome after bariatric surgery is not operator‐dependent. Time is of the essence when studying fibrosis reversal, and it can be argued that, in our series, some of the fibrosis nonresponders had too short a follow‐up (i.e., < 5 years, as suggested by Pattou et al.). Actually, of the 17 fibrosis nonresponders, 6 had the follow‐up biopsy performed more than 4.8 years after the surgery, including four of them more than 5 years later. This is still a substantial fraction of patients with persistent bridging fibrosis after a reasonably long period of time. As shown in our report, these raw data are, to a certain extent, misleading, because of the use of histological scales that are insufficiently sensitive to change. However, even though there was a reduction of fibrosis in most of these fibrosis nonresponders, this reduction was very slow. While the general efficacy of bariatric surgery at improving liver histology is not in dispute here,[1–4] improvement after such a massive weight loss would be expected to occur much faster and in almost all patients. Indeed, previous optimistic reports from dietary and lifestyle open‐label trials reported fibrosis reversal in more than half of patients after only 1 year (the proportion in those with advanced fibrosis was not reported).[5] Pattou et al. claim that histological improvement 5 years or more after bariatric surgery outperforms that of any pharmaceutical intervention. This may or may not be true, but it is impossible to substantiate with the evidence available, as no drugs have been tested in clinical trials over such a long period of time. In fact, the conclusions on the incomplete efficacy of NASH compounds in development are derived from studies 12–18 months long, a duration that, as discussed previously, may be insufficient to reveal the full potential of interventions such as bariatric surgery leading to massive weight loss. Finally, the fact that patients who agreed to have a repeat liver biopsy are more severe than those who did not (i.e., older, with more fibrosis, and higher aminotransferases) is true, but misses the point, which is precisely that there is a category of bariatric surgery candidates whose liver fibrosis is less amenable to improvement, despite an otherwise successful surgical procedure. Clearly, a much longer follow‐up will be needed to understand whether advanced fibrosis regresses after bariatric surgery in most, if not all, patients, although longer‐term studies may be confounded by weight regain after surgery.[6] CONFLICT OF INTEREST Nothing to report.
Molecular, cellular and systemic aspects of epithelial ovarian cancer and its tumor microenvironment
Authors: Esther Schoutrop, Lidia Moyano-Galceran, Stephanie Lheureux, Jonas Mattsson, Kaisa Lehti, Hanna Dahlstrand, Isabelle Magalhaes
Journal: Seminars in Cancer Biology (2022)

Ovarian cancer encompasses a heterogeneous group of malignancies that involve the ovaries, fallopian tubes and the peritoneal cavity. Despite major advances made within the field of cancer, the majority of patients with ovarian cancer are still being diagnosed at an advanced stage of the disease due to lack of effective screening tools. The overall survival of these patients has, therefore, not substantially improved over the past decades. Most patients undergo debulking surgery and treatment with chemotherapy, but often micrometastases remain and acquire resistance to the therapy, eventually leading to disease recurrence. Here, we summarize the current knowledge in epithelial ovarian cancer development and metastatic progression. For the most common subtypes, we focus further on the properties and functions of the immunosuppressive tumor microenvironment, including the extracellular matrix. Current and future treatment modalities are discussed and finally we provide an overview of the different experimental models used to develop novel therapies.
Emerging role of RNA sensors in tumor microenvironment and immunotherapy
Authors: Rui Yang, Sihui Yu, Tianhan Xu, Jiawen Zhang, Sufang Wu
Journal: Journal of Hematology & Oncology (2022)

Abstract RNA sensors detect foreign and endogenous RNAs to protect the host by initiating innate and adaptive immune response. In tumor microenvironment (TME), activation of RNA sensors induces tumor-inhibitory cytotoxic T lymphocyte responses and inhibits the activity of immunosuppressive cells though stimulating type I IFN signaling pathway. These characteristics allow RNA sensors to be prospective targets in tumor immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine.
A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer
Authors: Yara Rodríguez, Kenji Unno, Mihai I. Truica, Zachary R. Chalmers, Young A. Yoo, Rajita Vatapalli, Vinay Sagar, Jindan Yu, Barbara Lysy, Maha Hussain, Huiying Han, Sarki A. Abdulkadir
Journal: Cancer Research (2022)

Abstract Androgen receptor (AR) pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance to therapy is common. Here, we used a CRISPR activation screen in metastatic castration-sensitive prostate cancer cells to identify genes that promote resistance to AR inhibitors. Activation of the TGFβ target gene paired-related homeobox2 (PRRX2) promoted enzalutamide resistance. PRRX2 expression was the highest in double-negative prostate cancer (DNPC), which lack AR signaling and neuroendocrine differentiation, and a PRRX2-related gene signature identified a subset of patients with DNPC with reduced overall survival. PRRX2-expressing cells showed alterations in the CDK4/6/Rb/E2F and BCL2 pathways. Accordingly, treatment with CDK4/6 and BCL2 inhibitors sensitized PRRX2-expressing, castration-resistant tumors to enzalutamide. Overall, PRRX2 was identified as a driver of enzalutamide resistance. The PRRX2 signature merits investigation as a biomarker of enzalutamide resistance in prostate cancer that could be reversed with CDK4/6 and BCL2 inhibitors. Significance: PRRX2 mediates enzalutamide resistance via activation of the E2F and BCL2 pathways, which can be targeted with CDK4/6 and BCL2 inhibitors to reverse resistance.
Development of the Cold Urticaria Activity Score
Authors: Dalia Melina Ahsan, Sabine Altrichter, Annika Gutsche, Jonathan A. Bernstein, Tatjana Altunergil, Maxi Brockstaedt, Marcus Maurer, Karsten Weller, Dorothea Terhorst‐Molawi
Journal: Allergy (2022)

Cold urticaria (ColdU) is a form of inducible urticaria where cold induces wheals and/or angioedema. The burden of disease is high and linked to trigger thresholds, exposure, and avoidance. There are presently no validated patient-reported outcome measures (PROMs) to assess and monitor disease activity. Our objective was to develop a disease-specific activity score for ColdU that is easy to administer and evaluate.A Cold Urticaria Activity Score (ColdUAS) questionnaire was developed, directed by PROM developing guidelines. After the generation of a conceptional framework, the item generation phase included the literature research on ColdU signs and symptoms and on comparable tools for similar diseases and 47 ColdU patient interviews. Subsequently, an impact analysis for content validity was performed. The final selection of items underwent expert review for face validity and cognitive debriefing.The ColdUAS, a self-administered questionnaire for the prospective assessment of disease activity in patients with ColdU, consists of 4 items: 1. the frequency and severity of the signs (wheals and/or angioedema), 2. the frequency and severity of the symptoms (e.g., itch and burn), 3. the exposure to specific triggers, and 4. the avoidance of these triggers. The recall period for each item is the last 24 h.The ColdUAS is the first disease-specific PROM to assess ColdU disease activity. It may help to better assess patients' disease status in routine clinical practice as well as in clinical trials. Anchor-based approaches are currently used to validate the ColdUAS.
Clinical Outcomes of Patients With Suspicious (LI-RADS 4) Liver Observations
Authors: Kristeen Onyirioha, Sagar Joshi, Daniel Burkholder, Sruthi Yekkaluri, Neehar D. Parikh, Amit G. Singal, Erin Wolf, Takeshi Yokoo, Travis Browning, Mishal Mendiratta-Lala, Nicole E. Rich, Purva Gopal
Journal: Clinical Gastroenterology and Hepatology (2022)
TCTAP C-074 High-Risk Coronary Intervention to the ‘Last Standing’ Left Circumflex Artery
Authors: Huzairi Sani, Khairul Shafiq Ibrahim, Muhammad Hanis Muhmad Hamidi, Ahmad Bakhtiar Md Radzi, Raja Ezman Raja Shariff, Johan Rizwal Ismail, Abdul Wahab Undok, Hafisyatul Aiza Zainal Abidin, Sazzli Kasim
Journal: Journal of the American College of Cardiology (2022)
JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia
Authors: Kimberly Bodaar, Natsuko Yamagata, Anais Barthe, Jack Landrigan, Triona Ni Chonghaile, Melissa Burns, Kristen E. Stevenson, Meenakshi Devidas, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Lewis B. Silverman, David T. Teachey, Jules P. Meijerink, Anthony Letai, Alejandro Gutierrez
Journal: Leukemia (2022)
Population-level implications of the Israeli booster campaign to curtail COVID-19 resurgence
Authors: Nir Gavish, Rami Yaari, Amit Huppert, Guy Katriel
Journal: Science Translational Medicine (2022)

Israel was one of the first countries to administer mass vaccination against severe acute respiratory syndrome coronavirus 2. Consequently, it was among the first countries to experience substantial breakthrough infections due to the waning of vaccine-induced immunity, which led to a resurgence of the epidemic. In response, Israel launched a booster campaign to mitigate the outbreak and was the first country to do so. Israel's success in curtailing the Delta resurgence while imposing only mild nonpharmaceutical interventions influenced the decision of many countries to initiate a booster campaign. By constructing a detailed mathematical model and calibrating it to the Israeli data, we extend the understanding of the impact of the booster campaign from the individual to the population level. We used the calibrated model to explore counterfactual scenarios in which the booster vaccination campaign is altered by changing the eligibility criteria or the start time of the campaign and to assess the direct and indirect effects in the different scenarios. The results point to the vast benefits of vaccinating younger age groups that are not at a high risk of developing severe disease but play an important role in transmission. We further show that, when the epidemic is exponentially growing, the success of the booster campaign is highly sensitive to the timing of its initiation. Hence, a rapid response is an important factor in reducing disease burden using booster vaccination.
Difficult-to-treat inflammatory bowel disease: results from a global IOIBD survey
Authors: Tommaso Lorenzo Parigi, Ferdinando D'Amico, Maria T Abreu, David T Rubin, Axel Dignass, Iris Dotan, Vipul Jairath, Fernando Magro, Laurent Peyrin-Biroulet, Subrata Ghosh, Silvio Danese
Journal: The Lancet. Gastroenterology & hepatology (2022)
School Outcomes Among Children Following Death of a Parent
Authors: Can Liu, Alessandra Grotta, Ayako Hiyoshi, Lisa Berg, Mikael Rostila
Journal: JAMA Network Open (2022)

<h3>Importance</h3> To better support children with the experience of parental death, it is crucial to understand whether parental death increases the risk of adverse school outcomes. <h3>Objectives</h3> To examine whether parental death is associated with poorer school outcomes independent of factors unique to the family, and whether children of certain ages are particularly vulnerable to parental death. <h3>Design, Setting, and Participants</h3> This population-based sibling cohort study used Swedish national register-based longitudinal data with linkage between family members. Register data were collected from January 1, 1990, to December 31, 2016. Data analyses were performed on July 14, 2021. The participants were all children born between 1991 and 2000 who lived in Sweden before turning age 17 years (N = 908 064). <h3>Exposure</h3> Parental death before finishing compulsory school. <h3>Main Outcomes and Measures</h3> Mean school grades (year-specific<i>z</i>scores) and ineligibility for upper secondary education on finishing compulsory school at age 15 to 16 years. Population-based cohort analyses were conducted to examine the association between parental death and school outcomes using conventional linear and Poisson regression models, after adjustment for demographic and parental socioeconomic and health indicators measured before childbirth. Second, using fixed-effect linear and Poisson regression models, children who experienced parental death before finishing compulsory school were compared with their siblings who experienced the death after. Third, the study explored the age-specific associations between parental death and school outcomes. <h3>Results</h3> In the conventional population-based analyses, bereaved children (N = 22 634; 11 553 boys [51.0%]; 11 081 girls [49.0%]; mean [SD] age, 21.0 [2.8] years) had lower mean school grade<i>z</i>scores (adjusted β coefficient, −0.19; 95% CI, −0.21 to −0.18;<i>P</i> &lt; .001) and a higher risk of ineligibility for upper secondary education than the nonbereaved children (adjusted risk ratio, 1.36; 95% CI, 1.32-1.41;<i>P</i> &lt; .001). Within-sibling comparisons using fixed-effects models showed that experiencing parental death before finishing compulsory school was associated with lower mean school grade<i>z</i>scores (−0.06; 95% CI, −0.10 to −0.01;<i>P</i> = .02) but not with ineligibility for upper secondary education (adjusted risk ratio, 1.07; 95% CI, 0.93-1.23;<i>P</i> = .34). Independent of birth order, losing a parent at a younger age was associated with lower grades within a family. <h3>Conclusions and Relevance</h3> In this cohort study, childhood parental death was associated with lower school grades after adjustment for familial confounders shared between siblings. Children who lost a parent may benefit from additional educational support that could reduce the risk of adverse socioeconomic trajectories later in life.
TCTAP A-067 Elevated C-Reactive Protein/Albumin Ratio Is Associated With Lesion Complexity, Multilevel Involvement, and Adverse Outcomes in Patients With Peripheral Artery Disease
Authors: Byung Gyu Kim, Jongkwon Seo, Gwang Sil Kim, Moo-Nyun Jin, Hye Young Lee, Young Sup Byun, Byung Ok Kim
Journal: Journal of the American College of Cardiology (2022)
Multifunctional Double‐Layer Composite Hydrogel Conduit Based on Chitosan for Peripheral Nerve Repairing
Authors: Pengpeng Deng, Feixiang Chen, Haodong Zhang, Yun Chen, Jinping Zhou
Journal: Advanced Healthcare Materials (2022)

Abstract Peripheral nerve regeneration and functional recovery is a major challenge in clinical practice. Nerve conduit is an effective treatment for peripheral nerve repair, but the traditional hollow nerve conduit is not satisfactory in peripheral nerve repair due to the limitation of cell migration and nutrient transport. Herein, the double cross‐linked hydrogels with injectable, self‐healing, and conductive properties are synthesized by the Schiff base reaction between polyaniline‐modified carboxymethyl chitosan and aldehyde‐modified Pluronic F‐127 (F127‐CHO), and the hydrophobic interaction of F127‐CHO. The conductive hydrogel is injected into the cavity of chitosan conduit prepared by electrodeposition. The inner conductive hydrogel and the outer chitosan conduit are formed into a whole through the Schiff base reaction to obtain a double‐layer composite hydrogel nerve conduit. The double‐layer composite hydrogel neural conduit loaded with 7,8‐dihydroxyflavone (DHF) has excellent degradability, biocompatibility, antioxidant activity, and Schwann cell proliferation activity. In the rat sciatic nerve defect model, the double‐layer composite hydrogel nerve conduit significantly promotes sciatic nerve regeneration compared with the chitosan hollow conduit. Surprisingly, the repair ability of double‐layered hydrogel nerve conduit loaded with DHF is comparable to that of autologous transplantation. Therefore, this multifunctional double‐layer composite hydrogel conduit has great potential for peripheral nerve repairing.
BRD2 compartmentalizes the accessible genome
Authors: Liangqi Xie, Peng Dong, Yifeng Qi, Tsung-Han S. Hsieh, Brian P. English, SeolKyoung Jung, Xingqi Chen, Margherita De Marzio, Rafael Casellas, Howard Y. Chang, Bin Zhang, Robert Tjian, Zhe Liu
Journal: Nature Genetics (2022)