tbuckley/cabot-search huggingface dataset:
Clinical Significance of <i>PIK3CA</i> and <i>ESR1</i> Mutations in Circulating Tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib plus Fulvestrant
Authors: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Antonio Llombart-Cussac, Hatem Soliman, Hong Wang, Sameera Wijayawardana, Valerie M. Jansen, Lacey M. Litchfield, George W. Sledge
Journal: Clinical Cancer Research (2022)

PIK3CA and ESR1 mutations have been implicated in resistance to endocrine therapy (ET) in HR+, HER2- advanced breast cancer (ABC). Inhibition of CDK4 and 6 has been hypothesized as a therapeutic strategy to overcome endocrine resistance in patients with PIK3CA- or ESR1-mutant breast cancers. The objective of this exploratory analysis was to assess efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2.MONARCH 2 was a global, randomized, double-blind phase III trial of abemaciclib plus fulvestrant in 669 women with HR+, HER2- ABC, which had progressed on ET. Patients were randomized 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Exploratory analyses assessed progression-free survival (PFS) and overall survival (OS), and other endpoints, in patients with or without PIK3CA or ESR1 mutations detectable in baseline ctDNA.From the MONARCH 2 population, 219 and 248 patient samples were successfully analyzed for either PIK3CA or ESR1 mutations, respectively. Abemaciclib plus fulvestrant improved PFS compared with placebo plus fulvestrant in both PIK3CA-wild-type (median 16.9 months vs. 12.3 months; HR, 0.51; 95% CI, 0.33-0.78) and PIK3CA-mutant subgroups (median 17.1 months vs. 5.7 months; HR, 0.53; 95% CI, 0.33-0.84), as well as both ESR1-wild-type (median 15.3 months vs. 11.2 months; HR, 0.44; 95% CI, 0.27-0.71) and ESR1-mutant subgroups (median 20.7 months vs. 13.1 months; HR, 0.54; 95% CI, 0.37-0.79). Additional endpoints, including OS, were also improved following treatment with abemaciclib plus fulvestrant regardless of PIK3CA or ESR1 mutation status.Abemaciclib plus fulvestrant was effective regardless of PIK3CA or ESR1 mutation status, with benefit in both PFS and OS, with a numerically greater improvement in median PFS relative to placebo plus fulvestrant for PIK3CA- or ESR1-mutant tumors compared with the respective wild-type subgroups, in women with HR+, HER2- ABC that had progressed on ET.
A CGA/EGFR/GATA2 positive feedback circuit confers chemoresistance in gastric cancer
Authors: Tianyu Cao, Yuanyuan Lu, Qi Wang, Hongqiang Qin, Hongwei Li, Hao Guo, Minghui Ge, Sarah E. Glass, Bhuminder Singh, Wenyao Zhang, Jiaqiang Dong, Feng Du, Airong Qian, Ye Tian, Xin Wang, Cunxi Li, Kaichun Wu, Daiming Fan, Yongzhan Nie, Robert J. Coffey, Xiaodi Zhao
Journal: Journal of Clinical Investigation (2022)

De novo and acquired resistance are major impediments to the efficacy of conventional and targeted cancer therapy. In unselected gastric cancer (GC) patients with advanced disease, trials combining chemotherapy and an anti-EGFR monoclonal antibody have been largely unsuccessful. In an effort to identify biomarkers of resistance so as to better select patients for such trials, we screened the secretome of chemotherapy-treated human GC cell lines. We found that levels of CGA, the α-subunit of glycoprotein hormones, were markedly increased in the conditioned media of chemoresistant GC cells, and CGA immunoreactivity was enhanced in GC tissues that progressed on chemotherapy. CGA levels in plasma increased in GC patients who received chemotherapy, and this increase was correlated with reduced responsiveness to chemotherapy and poor survival. Mechanistically, secreted CGA was found to bind to EGFR and activate EGFR signaling, thereby conferring a survival advantage to GC cells. N-glycosylation of CGA at Asn52 and Asn78 is required for its stability, secretion, and interaction with EGFR. GATA2 was found to activate CGA transcription, whose increase, in turn, induced the expression and phosphorylation of GATA2 in an EGFR-dependent manner, forming a positive feedback circuit that was initiated by GATA2 autoregulation upon sublethal exposure to chemotherapy. Based on this circuit, combination strategies involving anti-EGFR therapies or targeting CGA with microRNAs (miR-708-3p and miR-761) restored chemotherapy sensitivity. These findings identify a clinically actionable CGA/EGFR/GATA2 circuit and highlight CGA as a predictive biomarker and therapeutic target in chemoresistant GC.
Abstract P045: Self-reported Anxiety And Patient Activation Among Smartwatch Users Monitored For Atrial Fibrillation Post-stroke: The Pulsewatch Study
Authors: Tenes J Paul, Khanh-van T Tran, Jordy Mehawej, Darleen Lessard, Andreas Filippaios, Eric Ding, Shiksha Joshi, Edith Mensah Otabil, Kamran Noorishirazi, Syed Naeem, Apurv Soni, Jane Saczynski, David D McManus
Journal: Circulation (2022)

Introduction: Wearable devices such as smartwatches are emerging as convenient and accurate means of post-stroke atrial fibrillation (AF) detection, however little is known about how the use of smartwatches for this purpose affects patients’ anxiety or engagement with their medical care. Hypothesis: Use of a smartwatch for atrial fibrillation monitoring will not significantly increase anxiety or affect engagement with medical care in post-stroke patients. Methods: We analyzed data from a randomized controlled trial, the Pulsewatch study, which included patients (&gt;=50 years) who presented to the UMass Memorial Health system with an ischemic stroke in the past decade, and/or had a CHA2DS2-VASc score &gt;2, with no contraindications to anticoagulation. Participants were randomized to either wear a Samsung smartwatch for AF monitoring (intervention) or not wear a smartwatch (control) for 30 days. Participants completed the General Anxiety Disorder-7 (GAD7) and the Consumer Health Activation Index (CHAI), which examined anxiety and patient activation (i.e. personal healthcare knowledge and management ability), prior to and after the 30-day period. Logistic regression was used to examine the association between smartwatch use and changes in anxiety and patient activation before and after the 30-day period. Results: Participants in the control group (N=56) had a mean age of 66, were 43% female, and 88% white, compared to the intervention group (N=54) which had a mean age of 64, were 41% female, and 91% white. There were no significant differences in baseline levels of anxiety (control 15% vs intervention 20%, P=0.3) and patient activation (control 12% vs intervention 10%, P=0.7) between the groups. After 30 days of rhythm monitoring, smartwatch users, as opposed to participants without a smartwatch, did not have a higher odd of having increased anxiety (38.9% vs 29.1%; aOR 1.37; 95% CI 0.45-4.15) or patient activation (20.4% vs 35.7%; aOR 0.62; 95% CI 0.18-2.17), adjusting for baseline anxiety, patient activation, valvular disease, diabetes, beta blocker use, and anticoagulant use. Conclusion: To the best of our knowledge, this is among the first studies to demonstrate a lack of difference in anxiety or patient activation in older stroke survivors who were prescribed a smartwatch for AF monitoring as compared to controls. Further studies are needed to elucidate the benefits and pitfalls related to the use of wearables as an alternative for post-stroke arrhythmia monitoring.
Messenger RNA vaccines for cancer immunotherapy: progress promotes promise
Authors: Amanda L. Huff, Elizabeth M. Jaffee, Neeha Zaidi
Journal: Journal of Clinical Investigation (2022)

The COVID-19 pandemic has elevated mRNA vaccines to global recognition due to their unprecedented success rate in protecting against a deadly virus. This international success is underscored by the remarkable versatility, favorable immunogenicity, and overall safety of the mRNA platform in diverse populations. Although mRNA vaccines have been studied in preclinical models and patients with cancer for almost three decades, development has been slow. The recent technological advances responsible for the COVID-19 vaccines have potential implications for successfully adapting this vaccine platform for cancer therapeutics. Here we discuss the lessons learned along with the chemical, biologic, and immunologic adaptations needed to optimize mRNA technology to successfully treat cancers.
Persistence of ctDNA in Patients with Breast Cancer During Neoadjuvant Treatment Is a Significant Predictor of Poor Tumor Response
Authors: Qing Zhou, Simon P. Gampenrieder, Sophie Frantal, Gabriel Rinnerthaler, Christian F. Singer, Daniel Egle, Georg Pfeiler, Rupert Bartsch, Viktor Wette, Angelika Pichler, Edgar Petru, Peter C. Dubsky, Zsuzsanna Bago-Horvath, Christian Fesl, Margaretha Rudas, Anders Ståhlberg, Ricarda Graf, Sabrina Weber, Nadia Dandachi, Martin Filipits, Michael Gnant, Marija Balic, Ellen Heitzer
Journal: Clinical Cancer Research (2021)

Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions.
Double Trouble: Whole-Genome Doubling Distinguishes Early from Late Ovarian Cancer
Authors: Shih Yu Cindy Yang, Trevor J. Pugh, Amit M. Oza
Journal: Clinical Cancer Research (2022)

Dramatic differences in outcome between early- and late-stage high-grade serous ovarian cancer (HGSC) suggest perhaps distinct genetic origins due to differences in exposures to mutational processes. Evidence to support this hypothesis was recently reported by comparative analysis of copy-number signatures between early- and late-stage HGSCs. See related article by Cheng et al., p. 2911.
Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE
Authors: Akito Hata, Isamu Okamoto, Naoki Inui, Morihito Okada, Masahiro Morise, Kohei Akiyoshi, Masayuki Takeda, Yasutaka Watanabe, Shunichi Sugawara, Naofumi Shinagawa, Kaoru Kubota, Toshiaki Saeki, Tomohide Tamura
Journal: Journal of Clinical Oncology (2021)

We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone.
Abstract 001: Association Between Acculturation Level And Cardiovascular Risk Factor Prevalence Among Asian American Subgroups
Authors: Yuemeng Li, Alicia Zhu, Austin Le, Jaiveer Singh, Shozen Dan, Latha Palaniappan, Malathi Srinivasan, Tali Elfassy, Javier Valero Elizondo, Eugene Yang
Journal: Circulation (2022)

Introduction: Limited disaggregated Asian subgroup data exist on the association between cardiovascular (CV) risk factors and acculturation level. Hypothesis: The association between acculturation levels and CV risk factors will differ by Asian subgroups. Methods: We used the National Health Interview Survey, a nationally representative US survey, years 2014-18. Acculturation was defined using the sum of: (a) years in the US (b) citizenship (c) English proficiency. An acculturation index was created and categorized as low, moderate, or high (scores of 0-1, 2 and ≥ 3, respectively). Self-reported risk factors included high cholesterol, obesity, tobacco use, physical activity level, diabetes and hypertension. Age-adjusted, weighted proportions were used to compare the prevalence of CV risk factors between Asian subgroups using Rao-Scott Chi Square. Results: Study sample consisted of 10,891 adults, representing 7.5 million US adults ≥ 18 years (46 % male; mean age 48.3 [SD 15.7]). The distribution by race/ethnicity was Asian Indian 15.1%, Chinese 12.9%, Filipino 10.2%, other Asian 18.2%, and NHW 43.7%. We found a positive association between prevalence of high cholesterol and acculturation level among all Asian subgroups, with increases of 50 to 90% when comparing low vs high acculturation ( Table ). Filipinos had a higher prevalence of obesity and tobacco use associated with higher acculturation level (p&lt; 0.05), but this was not observed among other Asian subgroups. In contrast, physical activity levels were higher among Asian subgroups with higher acculturation levels. No differences were seen for prevalence of hypertension or diabetes based on acculturation level. Conclusion: This study demonstrates that acculturation level was associated with higher prevalence of CV risk factors with significant variability among Asian subgroups. It highlights the need for more studies to better understand these differences based on acculturation level and can help inform targeted, culturally specific interventions.
Calm before the Storm
Authors: Manuel B. Braga Neto, Andrew D. Badley, Sameer A. Parikh, Rondell P. Graham, Patrick S. Kamath
Journal: New England Journal of Medicine (2022)

A 61-year-old man was evaluated in West Africa for a 1-week history of jaundice, light-colored stools, dark urine, pruritus, fatigue, and fever, with temperatures up to 38.5°C, without chills.He had dull pain in the right upper quadrant of the abdomen and had nausea but no vomiting.Jaundice results from overproduction of bilirubin, impairment of bilirubin uptake or conjugation in the liver, hepatocellular inflammation, or biliary obstruction.History taking that obtains information about transfusions, travel, and the use of alcohol, medication, herbal supplements, and illicit drugs may provide clues to the cause of jaundice.In West Africa, viral hepatitis A, B, and E and the use of herbal drugs are common causes of jaundice.Drug-induced liver injury is always a consideration in patients with elevated liver-enzyme levels, and it is important to know whether this patient is taking medications, but other causes of liver injury must be ruled out.The presence of dark urine, light-colored stools, and pruritus suggests cholestasis, which can be intrahepatic (owing to impaired canalicular excretion of bilirubin) or extrahepatic (owing to obstruction of the extrahepatic bile ducts).Choledocholithiasis, the most common cause of extrahepatic cholestasis with fever, is unlikely to be the cause in the absence of biliary colic but cannot be ruled out.Pancreatic cancer or other malignant conditions that cause biliary obstruction can manifest with abdominal pain or painless jaundice and should be considered, particularly in older persons.Intrahepatic cholestasis with fever is usually attributed to viral or alcohol-related hepatitis or to sepsis.Drug-induced liver injury is a common cause of cholestasis.Less common causes include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, lymphoma, and granulomatous infiltration of the liver by sarcoidosis or tuberculosis.Fever may also suggest a malignant cause.
Abstract 040: Sleep Regularity And Subclinical Markers Of Cardiovascular Disease: The Multi Ethnic Study Of Atherosclerosis (MESA)
Authors: Kelsie M Full, Tianyi Huang, Neomi Shah, Matthew A Allison, Erin D Michos, Daniel Duprez, Susan Redline, Pamela L Lutsey
Journal: Circulation (2022)

Background: Sleep irregularity has been linked to incident cardiovascular disease (CVD). Less is known about sleep regularity and associations with atherosclerosis. Our objective was to examine associations of sleep regularity with measures of atherosclerosis in the diverse MESA cohort. Methods: Participants from the MESA Sleep Study (2010-2013; N=2,032, Mean age: 68.6 ± 9.2 years; 53% Female, 38% White, 28% Black or African American, 23% Hispanic, 11% Chinese) completed 7-days of actigraphy. At the same exam, coronary artery calcium (CAC) was derived from computed tomography, carotid plaque presence and carotid intima-media thickness (cIMT) were derived from ultrasonography, and the ankle brachial index (ABI) was calculated from extremity measured systolic blood pressure. Sleep regularity was quantified by standard deviations in sleep durations and sleep onset time across wear days and categorized in 30 minute (mins) increments. Adjusted relative risk regression models were used to calculate prevalence ratios (PRs) and 95% confidence intervals (CI) for associations of measures of sleep regularity with each subclinical marker of CVD. Models adjusted for demographics, CVD risk factors, and objectively-assessed obstructive sleep apnea. Results: After multivariable adjustment, and compared to those with regular sleep durations (SD≤60 mins), participants with greater sleep duration irregularity (SD&gt;120 mins) were more likely to have high CAC burden [CAC &gt;300; PR (95% CI): 1.36 (1.03-1.78)], carotid plaque [1.10 (1.00-1.22)] and an abnormal ABI [ABI &lt;0.9; 1.74 (1.00-3.02)]. Compared to participants with regular sleep timing (SD≤30 mins), those with irregular sleep timing (SD&gt;90 mins) were 1.38 (1.04-1.83) times more likely to have high CAC burden. Associations did not vary by age or sex. Conclusion: Sleep regularity, particularly sleep duration regularity, was associated with measures of subclinical CVD in this diverse cohort. Sleep regularity is a modifiable sleep dimension worthy of further investigation.
SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling
Authors: Chuan Xu, Guoxiang Jin, Hong Wu, Wei Cui, Yu-Hui Wang, Rajesh Kumar Manne, Guihua Wang, Weina Zhang, Xian Zhang, Fei Han, Zhen Cai, Bo-Syong Pan, Che-Chia Hsu, Yiqiang Liu, Anmei Zhang, Jie Long, Hongbo Zou, Shuang Wang, Xiaodan Ma, Jinling Duan, Bin Wang, Weihui Liu, Haitao Lan, Qing Xiong, Gang Xue, Zhongzhu Chen, Zhigang Xu, Mark E. Furth, Sarah Haigh Molina, Yong Lu, Dan Xie, Xiu-Wu Bian, Hui-Kuan Lin
Journal: Journal of Clinical Investigation (2022)

Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.
Small Extracellular Vesicles From Brown Adipose Tissue Mediate Exercise Cardioprotection
Authors: Hang Zhao, Xiyao Chen, Guangyu Hu, Congye Li, Lanyan Guo, Ling Zhang, Fangfang Sun, Yunlong Xia, Wenjun Yan, Ze Cui, Yongzhen Guo, Xiong Guo, Chong Huang, Miaomiao Fan, Shan Wang, Fuyang Zhang, Ling Tao
Journal: Circulation Research (2022)

Rationale: Long-term exercise provides reliable cardioprotection via mechanisms still incompletely understood. Although traditionally considered a thermogenic tissue, brown adipose tissue (BAT) communicates with remote organs (eg, the heart) through its endocrine function. BAT expands in response to exercise, but its involvement in exercise cardioprotection remains undefined. Objective: This study investigated whether small extracellular vesicles (sEVs) secreted by BAT and their contained microRNAs (miRNAs) regulate cardiomyocyte survival and participate in exercise cardioprotection in the context of myocardial ischemia/reperfusion (MI/R) injury. Methods and Results: Four weeks of exercise resulted in a significant BAT expansion in mice. Surgical BAT ablation before MI/R weakened the salutary effects of exercise. Adeno-associated virus 9 vectors carrying short hairpin RNA targeting Rab27a (a GTPase required for sEV secretion) or control viruses were injected in situ into the interscapular BAT. Exercise-mediated protection against MI/R injury was greatly attenuated in mice whose BAT sEV secretion was suppressed by Rab27a silencing. Intramyocardial injection of the BAT sEVs ameliorated MI/R injury, revealing the cardioprotective potential of BAT sEVs. Discovery-driven experiments identified miR-125b-5p, miR-128-3p, and miR-30d-5p (referred to as the BAT miRNAs) as essential BAT sEV components for mediating cardioprotection. BAT-specific inhibition of the BAT miRNAs prevented their upregulation in plasma sEVs and hearts of exercised mice and attenuated exercise cardioprotection. Mechanistically, the BAT miRNAs cooperatively suppressed the proapoptotic MAPK (mitogen-associated protein kinase) pathway by targeting a series of molecules (eg, Map3k5 , Map2k7 , and Map2k4 ) in the signaling cascade. Delivery of BAT sEVs into hearts or cardiomyocytes suppressed MI/R-related MAPK pathway activation, an effect that disappeared with the combined use of the BAT miRNA inhibitors. Conclusions: The sEVs secreted by BAT participate in exercise cardioprotection via delivering the cardioprotective miRNAs into the heart. These results provide novel insights into the mechanisms underlying the BAT-cardiomyocyte interaction and highlight BAT sEVs and their contained miRNAs as alternative candidates for exercise cardioprotection.