tbuckley/cabot-search huggingface dataset:
137P Epidemiology and histological classification of lung cancer patients in Zimbabwe: A five-year retrospective study at Parirenyatwa Radiotherapy Centre, Harare
Authors: T.A. Mazhindu, N. Ndlovu, A. Nyamhunga, S. Chibonda, M. Pepukai, A.M. Nyakabau, W. Kadzatsa
Journal: Annals of Oncology (2022)
Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts
Authors: Jana M. Ellegast, Gabriela Alexe, Amanda Hamze, Shan Lin, Hannah J. Uckelmann, Philipp J. Rauch, Maxim Pimkin, Linda S. Ross, Neekesh V. Dharia, Amanda L. Robichaud, Amy Saur Conway, Delan Khalid, Jennifer A. Perry, Mark Wunderlich, Lina Benajiba, Yana Pikman, Behnam Nabet, Nathanael S. Gray, Stuart H. Orkin, Kimberly Stegmaier
Journal: Cancer Discovery (2022)

Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells implicated in inflammatory pathways. We identified the immune modulator IRF2BP2 as a selective AML dependency. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene-expression studies demonstrated that IRF2BP2 represses IL1β/TNFα signaling via NFκB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival. This study exploits inflammatory programs inherent to AML blasts to identify genetic vulnerabilities in this disease. In doing so, we determined that AML cells are dependent on the transcriptional repressive activity of IRF2BP2 for their survival, revealing cell-intrinsic inflammation as a mechanism priming leukemic blasts for regulated cell death. See related commentary by Puissant and Medyouf, p. 1617. This article is highlighted in the In This Issue feature, p. 1599.
Suppression of Endothelial Cell FAK Expression Reduces Pancreatic Ductal Adenocarcinoma Metastasis after Gemcitabine Treatment
Authors: Marina Roy-Luzarraga, Louise E. Reynolds, Beatriz de Luxán-Delgado, Oscar Maiques, Laura Wisniewski, Emma Newport, Vinothini Rajeeve, Rebecca J.G. Drake, Jesús Gómez-Escudero, Frances M. Richards, Céline Weller, Christof Dormann, Ya-Ming Meng, Peter B. Vermeulen, Dieter Saur, Victoria Sanz-Moreno, Ping-Pui Wong, Cyrill Géraud, Pedro R. Cutillas, Kairbaan Hodivala-Dilke
Journal: Cancer Research (2022)

Abstract Despite substantial advances in the treatment of solid cancers, resistance to therapy remains a major obstacle to prolonged progression-free survival. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with a high level of liver metastasis. Primary PDAC is highly hypoxic, and metastases are resistant to first-line treatment, including gemcitabine. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA-damaging therapy–induced angiocrine factors and chemosensitivity in primary tumor models. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC is not sufficient to affect primary tumor growth but reduces liver and lung metastasis load and improves survival rates in gemcitabine-treated, but not untreated, mice. EC-FAK loss did not affect primary tumor angiogenesis, tumor blood vessel leakage, or early events in metastasis, including the numbers of circulating tumor cells, tumor cell homing, or metastatic seeding. Phosphoproteomics analysis showed a downregulation of the MAPK, RAF, and PAK signaling pathways in gemcitabine-treated FAK-depleted ECs compared with gemcitabine-treated wild-type ECs. Moreover, low levels of EC-FAK correlated with increased survival and reduced relapse in gemcitabine-treated patients with PDAC, supporting the clinical relevance of these findings. Altogether, we have identified a new role of EC-FAK in regulating PDAC metastasis upon gemcitabine treatment that impacts outcome. Significance: These findings establish the potential utility of combinatorial endothelial cell FAK targeting together with gemcitabine in future clinical applications to control metastasis in patients with pancreatic ductal adenocarcinoma.
183P Predictor value of PD-L1 for radiotherapy response in locally advanced non-small cell lung cancer
Authors: V.N. Demircan, E. Acar, E. Senturk, C. Guzel, N. Eroglu Arkoc, N. Akyurek, F. Ozturk, F. Dincbas, M. Akmansu
Journal: Annals of Oncology (2022)
The unforeseen intracellular lifestyle of <i>Enterococcus faecalis</i> in hepatocytes
Authors: Natalia Nunez, Aurélie Derré-Bobillot, Nicolas Trainel, Goran Lakisic, Alexandre Lecomte, Françoise Mercier-Nomé, Anne-Marie Cassard, Hélène Bierne, Pascale Serror, Cristel Archambaud
Journal: Gut Microbes (2022)

is a bacterial species present at a subdominant level in the human gut microbiota. This commensal turns into an opportunistic pathogen under specific conditions involving dysbiosis and host immune deficiency.
A Machine Learning–Based Predictive Model to Identify Patients Who Failed to Attend a Follow-up Visit for Diabetes Care After Recommendations From a National Screening Program
Authors: Akira Okada, Yohei Hashimoto, Tadahiro Goto, Satoko Yamaguchi, Sachiko Ono, Kayo Ikeda Kurakawa, Masaomi Nangaku, Toshimasa Yamauchi, Hideo Yasunaga, Takashi Kadowaki
Journal: Diabetes Care (2022)

OBJECTIVE Reportedly, two-thirds of the patients who were positive for diabetes during screening failed to attend a follow-up visit for diabetes care in Japan. We aimed to develop a machine-learning model for predicting people’s failure to attend a follow-up visit. RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study of adults with newly screened diabetes at a national screening program using a large Japanese insurance claims database (JMDC, Tokyo, Japan). We defined failure to attend a follow-up visit for diabetes care as no physician consultation during the 6 months after the screening. The candidate predictors were patient demographics, comorbidities, and medication history. In the training set (randomly selected 80% of the sample), we developed two models (previously reported logistic regression model and Lasso regression model). In the test set (remaining 20%), prediction performance was examined. RESULTS We identified 10,645 patients, including 5,450 patients who failed to attend follow-up visits for diabetes care. The Lasso regression model using four predictors had a better discrimination ability than the previously reported logistic regression model using 13 predictors (C-statistic: 0.71 [95% CI 0.69–0.73] vs. 0.67 [0.65–0.69]; P &amp;lt; 0.001). The four selected predictors in the Lasso regression model were lower frequency of physician visits in the previous year, lower HbA1c levels, and negative history of antidyslipidemic or antihypertensive treatment. CONCLUSIONS The developed machine-learning model using four predictors had a good predictive ability to identify patients who failed to attend a follow-up visit for diabetes care after a screening program.
Mitochondrial Fragmentation Triggers Ineffective Hematopoiesis in Myelodysplastic Syndromes
Authors: Yasushige Aoyagi, Yoshihiro Hayashi, Yuka Harada, Kwangmin Choi, Natsumi Matsunuma, Daichi Sadato, Yuki Maemoto, Akihiro Ito, Shigeru Yanagi, Daniel T. Starczynowski, Hironori Harada
Journal: Cancer Discovery (2021)

Ineffective hematopoiesis is a fundamental process leading to the pathogenesis of myelodysplastic syndromes (MDS). However, the pathobiological mediators of ineffective hematopoiesis in MDS remain unclear. Here, we demonstrated that overwhelming mitochondrial fragmentation in mutant hematopoietic stem cells and progenitors (HSC/P) triggers ineffective hematopoiesis in MDS. Mouse modeling of CBL exon deletion with RUNX1 mutants, previously unreported comutations in patients with MDS, recapitulated not only clinically relevant MDS phenotypes but also a distinct MDS-related gene signature. Mechanistically, dynamin-related protein 1 (DRP1)-dependent excessive mitochondrial fragmentation in HSC/Ps led to excessive reactive oxygen species production, induced inflammatory signaling activation, and promoted subsequent dysplasia formation and impairment of granulopoiesis. Mitochondrial fragmentation was generally observed in patients with MDS. Pharmacologic inhibition of DRP1 attenuated mitochondrial fragmentation and rescued ineffective hematopoiesis phenotypes in mice with MDS. These findings provide mechanistic insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a therapeutic target for bone marrow failure in MDS. SIGNIFICANCE: We demonstrated that excessive mitochondrial fragmentation is a fundamental pathobiological phenomenon that could trigger dysplasia formation and ineffective hematopoiesis in MDS. Our findings provide mechanistic insights into ineffective hematopoiesis and suggest dysregulated mitochondrial dynamics as a therapeutic target for treating MDS.This article is highlighted in the In This Issue feature, p. 1.
Olaparib With or Without Cediranib Versus Platinum-Based Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer (NRG-GY004): A Randomized, Open-Label, Phase III Trial
Authors: Joyce F. Liu, Mark F. Brady, Ursula A. Matulonis, Austin Miller, Elise C. Kohn, Elizabeth M. Swisher, David Cella, William P. Tew, Noelle G. Cloven, Carolyn Y. Muller, David P. Bender, Richard G. Moore, David P. Michelin, Steven E. Waggoner, Melissa A. Geller, Keiichi Fujiwara, Stacy D. D'Andre, Michael Carney, Angeles Alvarez Secord, Katherine M. Moxley, Michael A. Bookman
Journal: Journal of Clinical Oncology (2022)

PURPOSE Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy. PATIENTS AND METHODS NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs). RESULTS Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, –2.0 to –0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed. CONCLUSION Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.
Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome
Authors: Paolo Zanoni, Grigorios Panteloglou, Alaa Othman, Joel T. Haas, Roger Meier, Antoine Rimbert, Marta Futema, Yara Abou Khalil, Simon F. Norrelykke, Andrzej J. Rzepiela, Szymon Stoma, Michael Stebler, Freerk van Dijk, Melinde Wijers, Justina C. Wolters, Nawar Dalila, Nicolette C. A. Huijkman, Marieke Smit, Antonio Gallo, Valérie Carreau, Anne Philippi, Jean-Pierre Rabès, Catherine Boileau, Michele Visentin, Luisa Vonghia, Jonas Weyler, Sven Francque, An Verrijken, Ann Verhaegen, Luc Van Gaal, Adriaan van der Graaf, Belle V. van Rosmalen, Jerome Robert, Srividya Velagapudi, Mustafa Yalcinkaya, Michaela Keel, Silvija Radosavljevic, Andreas Geier, Anne Tybjaerg-Hansen, Mathilde Varret, Lucia Rohrer, Steve E. Humphries, Bart Staels, Bart van de Sluis, Jan Albert Kuivenhoven, Arnold von Eckardstein
Journal: Circulation Research (2021)

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25 , are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25 , overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. Conclusions: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.
FDG PET/CT Demonstrated Epstein-Barr Virus–Associated Leiomyosarcoma in a Pediatric Patient With Wiskott-Aldrich Syndrome
Authors: Cuicui Li, Xu Yang, Xia Lu, Wei Wang, Jigang Yang
Journal: Clinical Nuclear Medicine (2022)

A 7-year-old boy with Wiskott-Aldrich syndrome underwent FDG PET/CT to evaluate hepatic lesions revealed by an ultrasound. The images demonstrated multiple hypermetabolic lesions in the liver, lung, and lymph nodes. Biopsy of liver and lymph nodes demonstrated Epstein-Barr virus-associated leiomyosarcoma.
Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types
Authors: Hanneke van der Wijngaart, Louisa R. Hoes, J. Maxime van Berge Henegouwen, Daphne L. van der Velden, Laurien J. Zeverijn, Paul Roepman, Erik van Werkhoven, Wendy W.J. de Leng, Anne M.L. Jansen, Niven Mehra, Debbie G.J. Robbrecht, Mariette Labots, Derk Jan A. de Groot, Ann Hoeben, Paul Hamberg, Hans Gelderblom, Emile E. Voest, Henk M.W. Verheul
Journal: Clinical Cancer Research (2021)

Abstract Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non–BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay.
Abstract P142: Number Of Children Three Or More And Having First Child Before Age 22 Are Linked To Increased Risk Of All-cause Dementia
Authors: Dongshan Zhu, Chunying Fu, Wenting Hao
Journal: Circulation (2022)

Introduction: Evidence on the association between number of children and risk of all-cause dementia has been discordant, and whether timing of birth and span of birth are related to the risk of dementia is unclear. Hypothesis: Estrogen level maintains high during pregnancy and declines dramatically after giving birth. More times of giving birth means more times of drastic fluctuations of endogenous estrogen. We hypothesized that the times of dramatic estrogen fluctuations in a woman’s life course (indicated by number of children) might be associated with risk of dementia. Methods: We used cohort data from UK Biobank, a large population-based prospective cohort study that recruited 502 649 individuals ages 40– 69, between 2006 and 2010. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the associations between number of children (categorized as zero, one, two, three or more) and incident all-cause dementia. We also examined the role of timing of birth and span of birth in the association with dementia. Timing of birth included age of first birth (categorized as &lt;22, 22-25, 26-29, and ≥30 years) and age of last birth (categorized as &lt;26, 26-29, 30-33, ≥34 yeas). Span of birth (the span between age of first birth and age of last birth) was categorized as ≤2, 3-4, 5-6, and &gt;6 years). All HRs were adjusted for race/ethnicity, education level, income, body mass index, smoking status, physical activities, number of leisure activities, hypertension status, diabetes status and baseline age. Results: Overall, 253 169 women were included, and we identified 2426 women with dementia. The median follow-up was 11.9 years. Compared to women with no child, the HRs (95% CI) with incident dementia in women with one, two, three or more children were 0.97 (0.83, 1.13), 0.95 (0.84, 1.07) and 1.17 (1.03, 1.33) respectively. Compared to women who had their first child after age 30 years, those first birth before age 22 years had elevated risk of dementia (HR: 1.25, 95%CI: 1.09-1.44), even after parity was further adjusted (1.19, 1.03-1.37). No association was observed between age of last child, span of birth and incident dementia. Nevertheless, subgroup analysis found that the elevated risk between number of three or more children and dementia was only observed in women with age of last birth less than 30 years (1.31, 1.12-1.53), or span of birth less than seven years (1.24, 1.07-1.44). Conclusions: Women with three or more children was linked to 17% higher risk of dementia compared to those with no child, and women who had their first child before age 22 years had around 20% higher risk of dementia compared to those with first child after age 30. Age of last child and span of birth may moderate the relationship between number of children and risk of dementia.
HEPATIC T1-TIMES ON CARDIOVASCULAR MAGNETIC RESONANCE IMAGING REFLECT LIVER FIBROSIS AND PREDICT OUTCOME IN AN ALL-COMER COHORT
Authors: Katharina Mascherbauer, Carolina Dona, Matthias Koschutnik, Christian Nitsche, Varius Dannenberg, Constanze Bardach, Dietrich Beitzke, Chrisitan Loewe, Julia Mascherbauer, Christian Hengstenberg, Andreas Kammerlander
Journal: Journal of the American College of Cardiology (2022)
Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Susana Banerjee, Kathleen N Moore, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander, Alla Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S Sonke, Charlie Gourley, Amit Oza, Antonio González-Martín, Carol Aghajanian, William H Bradley, Eileen Holmes, Elizabeth S Lowe, Paul DiSilvestro
Journal: The Lancet Oncology (2021)
Tumor Microenvironment–Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy
Authors: Yuting Tang, Qian Xu, Liang Hu, Xiaomei Yan, Xiaomin Feng, Asumi Yokota, Weinan Wang, Di Zhan, Durga Krishnamurthy, David E. Ochayon, Lijun Wen, Li Huo, Huimin Zeng, Yingwan Luo, L. Frank Huang, Mark Wunderlich, Jiwang Zhang, Eric Vivier, Jianfeng Zhou, Stephen N. Waggoner, Gang Huang
Journal: Cancer Discovery (2021)

Abstract Natural killer (NK) cells and T cells are key effectors of antitumor immune responses and major targets of checkpoint inhibitors. In multiple cancer types, we find that the expression of Wnt signaling potentiator R-spondin genes (e.g., RSPO3) is associated with favorable prognosis and positively correlates with gene signatures of both NK cells and T cells. Although endothelial cells and cancer-associated fibroblasts comprise the R-spondin 3–producing cells, NK cells and T cells correspondingly express the R-spondin 3 receptor LGR6 within the tumor microenvironment (TME). Exogenous expression or intratumor injection of R-spondin 3 in tumors enhanced the infiltration and function of cytotoxic effector cells, which led to tumor regression. NK cells and CD8+ T cells independently and cooperatively contributed to R-spondin 3–induced control of distinct tumor types. The effect of R-spondin 3 was mediated in part through upregulation of MYC and ribosomal biogenesis. Importantly, R-spondin 3 expression enhanced tumor sensitivity to anti–PD-1 therapy, thereby highlighting new therapeutic avenues. Significance: Our study identifies novel targets in enhancing antitumor immunity and sensitizing immune checkpoint inhibition, which provides a rationale for developing new immunotherapies against cancers. It also offers mechanistic insights on Wnt signaling–mediated modulation of anticancer immunity in the TME and implications for a putative R-spondin–LGR6 axis in regulating NK-cell biology. This article is highlighted in the In This Issue feature, p. 2945
63P Immune-related adverse events (irAEs) in advanced non-small cell lung cancer (aNSCLC) patients (pts): Neutrophil to lymphocyte ratio (NLR) and the risk for toxicity recurrence
Authors: G. Pretelli, A. Pavan, A. Dal Maso, M.V. Resi, C. Mulargiu, A. Ferro, B. Benetti, M. Lorenzi, G.M. Marinato, S. Frega, G. Pasello, P.F. Conte, V. Guarneri, L. Bonanno
Journal: Annals of Oncology (2022)