tbuckley/cabot-search huggingface dataset:
Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing
Authors: Yunpeng Yang, Jie Huang, Tao Wang, Jianya Zhou, Jing Zheng, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Huijie Wang, Shundong Cang, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Li Mao, Giovanni Selvaggi, Larry Zhu, Shanshan Xiao, Xiaobin Yuan, Zhilin Shen, Li Zhang
Journal: Journal of Thoracic Oncology (2021)

IntroductionBy implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.MethodsIn a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel.ResultsA total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p < 0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p < 0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation.ConclusionsOur study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.
Abstract PS16-33: Niclosamide reverses cisplatin resistance by inhibiting Bcl-2 and Stat3 in HER2-positive breast cancer
Authors: Junjun Liu
Journal: Cancer Research (2021)

Abstract Background: Breast cancer is the second leading cause of cancer-related deaths. Chemotherapy resistant breast cancer is poorly differentiated and displays aggressive clinical behavior. These tumors become resistant to cytotoxic agents and tumor relapse has been attributed to the presence of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Niclosamide has been shown to have broad clinical applications for the treatment of malignant tumors other than those caused by parasites. However, the specific functions and molecular mechanisms of niclosamide in chemo-resistant HER2 positive breast cancer are still unknown. Methods: HER2 positive breast cancer cell line, BT474, was continuously exposed to increasing concentrations of cisplatin (5-20 μM) to establish stable cell line resistant to cisplatin, BT-CR. Cell viability was determined by alamar blue. Apoptosis was determined by flow cytometry. Mammosphere formation assay was conducted to observe the self-renewal potential. Invasion ability was analyzed by transwell assay. Protein expression was determined by western-blot. Results: BT-CR had EMT and stem-like phenotype with higher invasion ability compared to naive sensitive cells. Alamar Blue assay showed combination of niclosamide with cisplatin could reverse cisplatin resistance. The combination index value of niclosamide combined with cisplatin was less than 1. Niclosamide in combination with cisplatin significantly enhanced apoptosis of BT-CR cells to over 50%. Western-blot showed niclosamide and cisplatin could reverse the EMT phenotype of BT-CR with E-cadherin up-regulated and N-cadherin and vimentin down-regulated. A significant reduction of Bcl-2 and Stat3 phosphorylation (Tyr705) levels was also confirmed. After treatment of niclosamide combined with cisplatin, the inhibition of mammosphere forming efficiency and capability of invasion was also observed in BT-CR. Conclusion: Our results revealed that niclosamide combined with cisplatin inhibited cell growth, invasion, EMT and stem-like phenotype in cisplatin resistant BT474 cells. The inhibitory effect of niclosamide was exerted by increasing apoptosis and down-regulated Bcl-2 expression, whilst inhibiting phosphorylation levels of STAT3. The results suggested that niclosamide combined with cisplatin appears to be a novel therapeutic way in chemo-resistant breast cancer. Citation Format: Junjun Liu. Niclosamide reverses cisplatin resistance by inhibiting Bcl-2 and Stat3 in HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-33.
Multiple Myeloma Presenting as Disseminated Osteoblastic Lesions With Intense 18F-FDG Uptake on PET/CT
Authors: Yueqi Wang, Qiuping Fan, Minggang Su
Journal: Clinical Nuclear Medicine (2021)

A 42-year-old woman presented with numbness and weakness in the lower limbs. The radiograph, MRI, and 99mTc-MDP bone scintigraphy revealed multiple bone lesions. The lesions were sclerotic on radiograph. Subsequent 18F-FDG PET/CT showed the lesions were disseminated and had intense 18F-FDG uptake. Monoclonal lambda plasmacytoma was confirmed after CT-guided biopsy of the third lumbar vertebral lesion. The laboratory data also showed a monoclonal immunoglobulin G lambda protein in serum and urine immunofixation. The patient was diagnosed as multiple myeloma finally. Multiple myeloma should be in the differential diagnosis scope of multiple osteoblastic lesions with intense 18F-FDG uptake on PET/CT.
The role of meta-analysis and preregistration in assessing the evidence for cleansing effects
Authors: Robert M. Ross, Robbie C. M. van Aert, Olmo R. van den Akker, Michiel van Elk
Journal: Behavioral and Brain Sciences (2021)

Abstract Lee and Schwarz interpret meta-analytic research and replication studies as providing evidence for the robustness of cleansing effects. We argue that the currently available evidence is unconvincing because (a) publication bias and the opportunistic use of researcher degrees of freedom appear to have inflated meta-analytic effect size estimates, and (b) preregistered replications failed to find any evidence of cleansing effects.
DDX3X: structure, physiologic functions and cancer
Authors: Jie Mo, Huifang Liang, Chen Su, Pengcheng Li, Jin Chen, Bixiang Zhang
Journal: Molecular Cancer (2021)

The DEAD-box helicase family member DDX3X (DBX, DDX3) functions in nearly all stages of RNA metabolism and participates in the progression of many diseases, including virus infection, inflammation, intellectual disabilities and cancer. Over two decades, many studies have gradually unveiled the role of DDX3X in tumorigenesis and tumour progression. In fact, DDX3X possesses numerous functions in cancer biology and is closely related to many well-known molecules. In this review, we describe the function of DDX3X in RNA metabolism, cellular stress response, innate immune response, metabolic stress response in pancreatic β cells and embryo development. Then, we focused on the role of DDX3X in cancer biology and systematically demonstrated its functions in various aspects of tumorigenesis and development. To provide a more intuitive understanding of the role of DDX3X in cancer, we summarized its functions and specific mechanisms in various types of cancer and presented its involvement in cancer-related signalling pathways.
Abstract SP012: Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine signaling inhibitors
Authors: JI Griffiths, J Chen, PA Cosgrove, A O'Dea, P Sharma, CX Ma, M Trivedi, K Kalinsky, KB Wisinski, R O'Reagan, I Makhoul, LM Spring, A Bardia, FR Adler, AL Cohen, JT Chang, QJ Khan, AH Bild
Journal: Cancer Research (2021)

Abstract Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionary trajectories of early stage breast cancer tumors using serial tumor biopsies from a clinical trial of preoperative endocrine therapy alone (letrozole) or in combination with the cell cycle inhibitor ribociclib. Applying hierarchical regression and Gaussian process mathematical modelling, we classified each tumor by whether it shrinks or persists with therapy and determined cancer phenotypes related to evolution of resistance and cell cycle transcriptional rewiring. We found that all patients’ tumors undergo subclonal evolution during therapy, irrespective of the clinical response. However, tumors subjected to endocrine therapy alone showed reduced diversity over time, those facing combination therapy exhibited increased diversity. Despite different diversity, single nuclei RNA sequencing uncovered common phenotypic changes in tumor cells that persist following treatment. In these tumors, accelerated loss of estrogen signaling is convergent with up-regulation of the JNK pathway, while persistent tumors that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. Cell cycle reconstruction identified that these tumors can rebound during combination therapy treatment, indicating stronger selection and promotion of a proliferative state. These results indicate that combination therapy in early stage ER+ breast cancers with ER and CDK inhibition drives rapid evolution of resistance via a shift from estrogen signaling to alternative growth factor receptor mediated proliferation and JNK signaling activation, concordant with a bypass in the G1 checkpoint. Citation Format: JI Griffiths, J Chen, PA Cosgrove, A O'Dea, P Sharma, CX Ma, M Trivedi, K Kalinsky, KB Wisinski, R O'Reagan, I Makhoul, LM Spring, A Bardia, FR Adler, AL Cohen, JT Chang, QJ Khan, AH Bild. Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine signaling inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP012.
COVID-19 mental health impact and responses in low-income and middle-income countries: reimagining global mental health
Authors: Lola Kola, Brandon A Kohrt, Charlotte Hanlon, John A Naslund, Siham Sikander, Madhumitha Balaji, Corina Benjet, Eliza Yee Lai Cheung, Julian Eaton, Pattie Gonsalves, Maji Hailemariam, Nagendra P Luitel, Daiane B Machado, Eleni Misganaw, Olayinka Omigbodun, Tessa Roberts, Tatiana Taylor Salisbury, Rahul Shidhaye, Charlene Sunkel, Victor Ugo, André Janse van Rensburg, Oye Gureje, Soumitra Pathare, Shekhar Saxena, Graham Thornicroft, Vikram Patel
Journal: The Lancet Psychiatry (2021)
A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial
Authors: Sumanta K Pal, Catherine Tangen, Ian M Thompson, Naomi Balzer-Haas, Daniel J George, Daniel Y C Heng, Brian Shuch, Mark Stein, Maria Tretiakova, Peter Humphrey, Adebowale Adeniran, Vivek Narayan, Georg A Bjarnason, Ulka Vaishampayan, Ajjai Alva, Tian Zhang, Scott Cole, Melissa Plets, John Wright, Primo N Lara
Journal: The Lancet (2021)
Assessing the Outcomes of Procedural Innovation
Authors: Peter W. Groeneveld
Journal: JAMA Network Open (2021)

Jesse A. Columbo, MD, MS; Pablo Martinez-Camblor, PhD; A. James O’Malley, PhD; David H. Stone, MD; Vikram S. Kashyap, MD; Richard J. Powell, MD; Marc L. Schermerhorn, MD; Mahmoud Malas, MD, MHS; Brian W. Nolan, MD, MS; Philip P. Goodney, MD, MS
ELEVATED INTERLEUKIN-6 LEVELS IN COVID-19-INFECTED PATIENTS ARE ASSOCIATED WITH MAJOR ADVERSE CARDIAC EVENTS AND/OR MORTALITY
Authors: Nicholas Nguyen, Chijioke Ukoha, Farukh Ikram, Chirag Patel, Hao Nguyen, Lawrence Hoang, Priyanka Acharya, Anmol Dhillon, Manavjot Sidhu
Journal: Journal of the American College of Cardiology (2021)
Adaptive Natural Killer Cells Facilitate Effector Functions of Daratumumab in Multiple Myeloma
Authors: Hyunsoo Cho, Kyung Hwan Kim, Hoyoung Lee, Chang Gon Kim, Haerim Chung, Yoon Seok Choi, Su-Hyung Park, June-Won Cheong, Yoo Hong Min, Eui-Cheol Shin, Jin Seok Kim
Journal: Clinical Cancer Research (2021)

To investigate the different roles of heterogeneous natural killer (NK)-cell subpopulations in multiple myeloma and to identify NK-cell subsets that support the robust anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC).We performed single-cell RNA sequencing of NK cells from patients with newly diagnosed multiple myeloma (NDMM) and delineated adaptive NK cells in their bone marrow (BM). We further characterized the distinct immunophenotypic features and functions of adaptive NK cells by multicolor flow cytometry in 157 patients with NDMM.Adaptive NK cells exhibit a significantly lower level of CD38 expression compared with conventional NK cells, suggesting that they may evade daratumumab-induced fratricide. Moreover, adaptive NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared with conventional NK cells. The composition of adaptive NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in patients with NDMM. Unlike conventional NK cells, sorted adaptive NK cells from the BM of patients with NDMM exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab.Our findings indicate that adaptive NK cells are an important mediator of ADCC in multiple myeloma and support direct future efforts to better predict and improve the treatment outcome of daratumumab by selectively employing adaptive NK cells.
The potential effect of COVID-19-related disruptions on HIV incidence and HIV-related mortality among men who have sex with men in the USA: a modelling study
Authors: Kate M Mitchell, Dobromir Dimitrov, Romain Silhol, Lily Geidelberg, Mia Moore, Albert Liu, Chris Beyrer, Kenneth H Mayer, Stefan Baral, Marie-Claude Boily
Journal: The Lancet HIV (2021)

During the COVID-19 pandemic, men who have sex with men (MSM) in the USA have reported similar or fewer sexual partners and reduced HIV testing and care access compared with before the pandemic. Pre-exposure prophylaxis (PrEP) use has also declined. We aimed to quantify the potential effect of COVID-19 on HIV incidence and HIV-related mortality among US MSM.
Bone loss in patients with SAPHO syndrome: a preliminary study
Authors: Xiao Chen, Miaomiao Wang, Wenjing Cui, Zhongqiu Wang
Journal: Annals of the Rheumatic Diseases (2021)

Synovitis, acne, palmoplantar pustulosis, hyperostosis and osteitis (SAPHO) syndrome is a rare entity that involves the skin, bones and joints. The estimated prevalence of SAPHO syndrome is lower than 1/10 000.1 The real prevalence may be underestimated because of lack of typical symptoms.2 Bone is one of the critical affected organs for SAPHO. The most common site is the anterior chest wall (65%–90%), followed by the thoracic spine.1 However, the effects of SAPHO syndrome on bone loss or osteoporosis have not been clarified. We performed a case–control study to show bone loss in patients with SAPHO syndrome in a Chinese population.

From June 2014 to August 2019, a total of 27 new-onset SAPHO patients were included in the study after excluding patients who had been diagnosed for more than 6 months and who were younger than 25 years old. The diagnosis of SAPHO syndrome was based on clinical symptoms and radiological examinations.2 The diagnosis is based on the presence of at least one of four features: (1) osteoarticular manifestations with severe acne; (2) osteoarticular manifestations with palmoplantar pustulosis; (3) hyperostosis with or without skin lesions; (4) recurrent multifocal chronic osteomyelitis involving the axial or peripheral skeleton, with or without skin lesions. Two or three age-matched and gender-matched control subjects who underwent chest CT scan for physical examinations …
Abstract PS8-21: The impact of exogenous estrogen exposure on the characteristics of estrogen receptor (ER) positive, early-stage breast cancer (EBC)
Authors: Orly Yariv, Rinat Yerushalmi, Assaf Moore, Tzippy Shohat, Ofer Rotem, Yasmin Korzets Ceder, Hadar Goldvaser
Journal: Cancer Research (2021)

Abstract Background: Oral contraceptives (OC) and hormone replacement therapy (HRT) are well-established risk factors for ER positive breast cancer. Infertility is associated with an increased breast cancer risk and there is conflicting data on the influence of fertility treatments on breast cancer risk. The impact of exogenous estrogen exposure on breast cancer characteristics is not well described. Methods: A single center retrospective cohort study comprising all women with ER positive, human epidermal growth factor receptor 2 (HER2) negative, EBC whose tumors were sent to OncotypeDX analysis and were treated in our institute between 2005 and 2012. Data on exogenous estrogen exposure were collected including: OC and HRT use and prior fertility treatments. The impact of these exposures was assessed on pre-specified histopathological features including: tumor size, nodal status, ER and progesterone receptor (PR) staining, grade, Oncotype recurrence score (RS), ki67, lymphovascular and perineural invasion. Results: A total of 620 women were included, 79% (Num) were postmenopausal. Prior exposure to OC, HRT and fertility treatments was documented in 19% (103), 30% (136) and 11% (62), respectively. OC use was associated with smaller (≤1cm) tumors (30% vs. 20%, p=0.023) and were less likely to have grade 3 disease (10% vs. 19%, p=0.049). No other associations were found between exogenous estrogen exposures and tumor characteristics (Table). Conclusions: Use of OC may be associated with breast cancer with a distinct features compared to women with luminal breast cancer without history of OC use. Large scale studies are needed to better characterize these findings. Fertility treatmentHRT ≥ 2 yearsHRTOCPNo (%)Yes(%)PNo(%)Yes (%)PNo (%)Yes (%)PNo(%)Yes(%)0.1722254252165150.7002355222057240.7002255232456200.023205723304426T≤1 cm 1&amp;lt;T≤2 T&amp;gt;2 cm0.85917180.09815200.09815210.6671815Node positive0.06479138891100.29982126761590.29982135771590.207791488795IDC ILC Other0.1671864181473130.5001667181664190.5001667171762210.049186319187310Grade 1 230.18922078329680.70811781122770.70811781221780.7392227732275ER intensity≤1 1&amp;lt;ER⇐2 ER&amp;gt;20.1121470.67116150.67116140.103148PR Negative1.000530.455520.455530.28252PNI present0.772670.351780.351570.056105LVI present0.18620290.36222190.36223180.5282218Ki67 &amp;gt;20%0.85917180.78718160.78717180.5701816Oncotype RS&amp;gt;25 Citation Format: Orly Yariv, Rinat Yerushalmi, Assaf Moore, Tzippy Shohat, Ofer Rotem, Yasmin Korzets Ceder, Hadar Goldvaser. The impact of exogenous estrogen exposure on the characteristics of estrogen receptor (ER) positive, early-stage breast cancer (EBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-21.
Creating Composite Indices From Continuous Variables for Research: The Geometric Mean
Authors: Hertzel C. Gerstein, Chinthanie Ramasundarahettige, Shrikant I. Bangdiwala
Journal: Diabetes Care (2021)

Clinical research focuses on the relationship between one or more independent variables and some dependent variable or outcome chosen to reflect some underlying process. For categorical variables, the research may either be focused on a specific end point such as myocardial infarction (MI) or on an underlying construct such as vascular disease (with MI as just one exemplar). In the latter instance, a composite index such as major adverse cardiovascular event (MACE), defined as either a nonfatal stroke, nonfatal MI, or cardiovascular death, may be used.

Composite categorical outcomes such as MACE optimize power by ensuring a high event rate, and the results they yield are generalizable to diseases that are consistent with the underlying construct. It is therefore surprising that there is no widely used method to combine continuous variables into composite continuous outcomes. Nevertheless, there is a clear need for such a methodology when the underlying construct cannot be easily captured by one measurement. Glucose control is an example of a construct that can be assessed in many ways, including fasting or postprandial plasma glucose, HbA1c, fructosamine, or “time in target.” A composite of two or more of these could provide a better reflection of glucose control than any one alone. Whereas sophisticated statistical techniques such as structural equation modeling (1) can be used to model some underlying construct or latent variable from two or more measurements, a simpler way of combining them into an index that reflects the underlying construct could provide a powerful tool for both researchers and clinicians. Such an approach is described below.

When the same measurements are made using the …
Trends in Cardiovascular Medicine Use in 65 Middle- and High-Income Countries
Authors: Vincent K.C. Yan, Joseph E. Blais, Xue Li, Celine S.L. Chui, Li Wei, Bryan P. Yan, Martin R.J. Knapp, Chung Wah Siu, Ian C.K. Wong, Esther W. Chan
Journal: Journal of the American College of Cardiology (2021)
Arrhythmia Risk Prediction in Patients With Preserved Left Ventricular Function: The Final Frontier?⁎⁎Editorials appearing in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Thomas Klingenheben
Journal: Journal of the American College of Cardiology (2006)