tbuckley/cabot-search huggingface dataset:
D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease
Authors: Irene Sebastianutto, Elise Goyet, Laura Andreoli, Joan Font-Ingles, David Moreno-Delgado, Nathalie Bouquier, Céline Jahannault-Talignani, Enora Moutin, Luisa Di Menna, Natallia Maslava, Jean-Philippe Pin, Laurent Fagni, Ferdinando Nicoletti, Fabrice Ango, M. Angela Cenci, Julie Perroy
Journal: Journal of Clinical Investigation (2020)

Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson's disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated PLC signaling and intracellular calcium release in response to either glutamate or dopamine. In rodent models of Parkinson's disease, D1-mGlu5 nanocomplexes were strongly upregulated in the dopamine-denervated striatum, resulting in a synergistic activation of PLC signaling by D1 and mGlu5 receptor agonists. In turn, D1-mGlu5-dependent PLC signaling was causally linked with excessive activation of extracellular signal-regulated kinases in striatal neurons, leading to dyskinesia in animals treated with L-DOPA or D1 receptor agonists. The discovery of D1-mGlu5 functional heteromers mediating maladaptive molecular and motor responses in the dopamine-denervated striatum may prompt the development of new therapeutic principles for Parkinson's disease.
Interventional Bronchoscopy
Authors: Gerard J. Criner, Ralf Eberhardt, Sebastian Fernandez-Bussy, Daniela Gompelmann, Fabien Maldonado, Neal Patel, Pallav L. Shah, Dirk-Jan Slebos, Arschang Valipour, Momen M. Wahidi, Mark Weir, Felix J. Herth
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

For over 150 years, bronchoscopy, especially flexible bronchoscopy, has been a mainstay for airway inspection, the diagnosis of airway lesions, therapeutic aspiration of airway secretions, and transbronchial biopsy to diagnose parenchymal lung disorders. Its utility for the diagnosis of peripheral pulmonary nodules and therapeutic treatments besides aspiration of airway secretions, however, has been limited. Challenges to the wider use of flexible bronchoscopy have included difficulty in navigating to the lung periphery, the avoidance of vasculature structures when performing diagnostic biopsies, and the ability to biopsy a lesion under direct visualization. The last 10-15 years have seen major advances in thoracic imaging, navigational platforms to direct the bronchoscopist to lung lesions, and the ability to visualize lesions during biopsy. Moreover, multiple new techniques have either become recently available or are currently being investigated to treat a broad range of airway and lung parenchymal diseases, such as asthma, emphysema, and chronic bronchitis, or to alleviate recurrent exacerbations. New bronchoscopic therapies are also being investigated to not only diagnose, but possibly treat, malignant peripheral lung nodules. As a result, flexible bronchoscopy is now able to provide a new and expanding armamentarium of diagnostic and therapeutic tools to treat patients with a variety of lung diseases. This State-of-the-Art review succinctly reviews these techniques and provides clinicians an organized approach to their role in the diagnosis and treatment of a range of lung diseases.
A single-arm, phase II study of intrahepatic chemotherapy in patients with unresectable colorectal liver metastases.
Authors: Kate Elenna Besel, Yoo-Joung Ko, Paul Jack Karanicolas, Christina Yiyoung Kim
Journal: Journal of Clinical Oncology (2020)

162 Background: In Canada, the standard of care for patients with unresectable colorectal liver metastases (uCRLM) is systemic chemotherapy and/or best supportive care. Intrahepatic chemotherapy using floxuridine (FUDR), in addition to systemic chemotherapy, is available in the United States but its adoption outside major centers has been limited. Methods: A single-center, prospective study of intrahepatic chemotherapy for the treatment of patients with uCRLM was initiated at Sunnybrook Health Sciences Centre in 2014. Patients underwent implantation of a hepatic infusion pump with resection of their primary tumor (if in place). Patients were treated with FUDR in addition to systemic chemotherapy (FOLFIRI or FOLFOX). Study objectives include the rate of conversion to complete resection, time to progression (TTP), disease-free survival (DFS), time to progression in liver, overall survival (OS), andresponse rate (RR). Results: From 2014 to present, 46 patients have been enrolled. Median age at the time of HAIP placement was 51 years (30-72 years). Males accounted for 61% (28/46). All patients received at least one cycle of systemic chemotherapy prior to surgery. 44 patients received a minimum of one cycle of FUDR, with the median number of cycles of FUDR received being 7.5 (0-28 cycles). Only one patient was unable to receive any FUDR after surgery. Response rate was 80% (n = 37/46). Three patients are too early for assessment. Eight (17.4%) patients have undergone liver resection. Median number of cycles of FUDR prior to resection was 7 (4-13 cycles). TTP, DFS, time to progression in liver, OS, and safety will be presented. Conclusions: The addition of intrahepatic chemotherapy to best systemic therapy may provide an increase in the rate of conversion to complete hepatic resection in patients with uCRLM. Clinical trial information: ON1233.
Abstract 14222: Cox-Maze IV Procedure is Highly Effective in Restoring Sinus Rhythm in Patients With Hypertrophic Obstructive Cardiomyopathy and Atrial Fibrillation
Authors: Ali J Khiabani, Matthew R Schill, Farah N Musharbash, Joshua L Manghelli, Laurie A Sinn, Richard B Schuessler, Spencer J Melby, Marye J Gleva, Ralph J Damiano
Journal: Circulation (2018)

Objectives: In patients with hypertrophic obstructive cardiomyopathy (HOCM), atrial fibrillation (AF) is associated with heart failure and increased mortality. However, the role of surgical ablatio...
Phase II study of trifluridine/tipiracil (FTD/TPI) and oxaliplatin as induction chemotherapy (IC) in resectable esophageal and gastroesophageal junction adenocarcinoma (EGAC).
Authors: Sarbajit Mukherjee, Hussein Assi, Christos Fountzilas, Kristopher Attwood, Patrick McKay Boland, Renuka V. Iyer, Daniel V.T. Catenacci, Hassan Hatoum
Journal: Journal of Clinical Oncology (2020)

TPS464 Background: Neoadjuvant chemoradiation (CRT) followed by surgery is a standard approach for localized EGAC. Despite multimodality treatment, 5-year overall survival (OS) is less than 50%, with pathologic complete response (pCR) rates of 20%. Achievement of pCR is associated with an improved OS. We propose to use a novel combination of FTD/TPI and oxaliplatin as IC. We hypothesize that IC before CRT will increase the pCR rate in localized EGAC. Methods: This is an open-label, multicenter phase II trial. Patients (pts) with potentially resectable loco-regional EGAC are eligible. Pts. should have adequate organ function, ECOG performance status of 0 –1, age &lt; 76 years, and endoscopic ultrasound-determined node-positive disease with any T-stage, or T3-T4a with any N stage. Pts. with T4b or M1 disease will be excluded. Pts. will receive three cycles of IC with FTD/TPI and oxaliplatin. Based on the maximum tolerated dose (MTD) observed in a phase I trial, FTD/TPI will be administered 35 mg/m² BID, days 1–5 every 14 days, with a fixed dose of oxaliplatin 85 mg/m² (day 1). Pts will then undergo concurrent CRT (standard radiation dose of 5040 cGY will be utilized) with weekly Carboplatin (AUC 2) and Paclitaxel (50 mg/m2) for 6 weeks followed by surgery. Our primary objective is to evaluate the pCR rate. The secondary objectives include evaluation of 2-year disease-free survival (DFS), 2-year OS, and assessment of toxicities of the IC. As a correlative endpoint, circulating tumor DNA level will be correlated with disease recurrence and metabolic response on PET CT. Assuming a historic pCR rate of 20% with standard CRT, 41 pts (enrollment of up to 45 pts accounting for non-evaluable pts) are needed to show a 15% increase in pCR with IC with 80% power at one-sided significance level of α = 0.1. In stage 1, n 1 = 22 evaluable pts will be enrolled. If there is 5 or more pCRs, an additional n 2 = 19 pts will be enrolled in stage 2. If 12 or more pCRs are observed in the total n = 41 evaluable pts, then the proposed treatment regimen will be considered promising for further study. We anticipate accrual over a 2-year period from 3 sites. Clinical trial information: NCT04097028.
Tumor area and microscopic extent of invasion to determine circulating tumor DNA fraction in plasma and detectability of colorectal cancer (CRC).
Authors: Joerg Bredno, Jafi Lipson, Oliver Venn, Samuel Gross, Alexander P. Fields, John F. Beausang, Qinwen Liu, Jacqueline D. Brooks, Xiaoji Chen, Rita Lopatin, Hai Liu, Nan Zhang, Lori Zhang, Tony Wu, Brian Allen, Anne-Renee Hartman, Earl Hubbell, Arash Jamshidi, Alex Aravanis
Journal: Journal of Clinical Oncology (2020)

243 Background: Circulating Cell-free Genome Atlas (CCGA; NCT02889978) is a multi-center, case-control, observational study with longitudinal follow-up to develop a cfDNA assay in which classifiers were trained on whole-genome bisulfite sequencing (WGBS) and targeted methylation (TM) sequencing data for detection of multiple cancer types. Previously, we showed that the fraction of ctDNA fragments (TF) was a stronger predictor of cancer detection than clinical stage and an equivalent predictor for survival. Given that CRC tumors can be described via surface area (TSA) and microscopic tumor extent (microinvasion), CRC was used as a model to examine the biophysical determinants of TF. Methods: Detection of multiple cancers with WGBS at 98% and TM at &gt; 99% specificity, and methods for determining TF, were previously reported. A model to predict the presence of detectable cfDNA fragments for CRC adenocarcinomas of stages I, II, and III included TSA and microinvasion beyond the subserosa. Predictors were combined assuming a linear increase of cfDNA shedding with tumor size, with scaling factors depending on microinvasion. Model parameters were determined for 27 participants (7, 11, 9 for stages I, II, III, resp.) with WGBS and applied to 40 participants (12, 15, 13 for I, II, III, resp.) with TM assay and information on tumor size and microinvasion. Results: CRC detection at stages I/II/III was 33/46, 61/73, 57/74% for WGBS/TM. TF predicted detection with AUC = 97.6. The model predicted TF as TSA multiplied by 3.81*10 −6 / mm 2 for tumors that invaded beyond the subserosa (p &lt; 0.001). This was 4.4x higher than estimates for tumors below the subserosa. The model trained on the WGBS assay predicted CRC detection in the TM assay with an AUC of 0.844. Conclusions: This model used TSA (number of tumor cells) and microinvasion (bloodstream access) to predict the fraction of CRC ctDNA fragments in blood without needing to account for stage. Tumors not penetrating the subserosa had low ctDNA shedding that likely limited detection. These findings may generalize to other cancer types, providing principles to predict ctDNA shedding and thus cancer detectability based on microinvasion and surface area. Clinical trial information: NCT02889978.
Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors
Authors: Michael W. Ronellenfitsch, Patrick N. Harter, Martina Kirchner, Christoph Heining, Barbara Hutter, Laura Gieldon, Jens Schittenhelm, Martin U. Schuhmann, Marcos Tatagiba, Gerhard Marquardt, Marlies Wagner, Volker Endris, Christian H. Brandts, Victor-Felix Mautner, Evelin Schröck, Wilko Weichert, Benedikt Brors, Andreas von Deimling, Michel Mittelbronn, Joachim P. Steinbach, David E. Reuss, Hanno Glimm, Albrecht Stenzinger, Stefan Fröhling
Journal: Journal of Clinical Investigation (2020)

BACKGROUNDNeurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking.METHODSWe used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs.RESULTSWhole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns.CONCLUSIONThese findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications.FUNDINGThis work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.
The Transcriptome of Hepatic Fibrosis Revealed by Single‐Cell RNA Sequencing
Authors: Loretta L. Jophlin, Sheng Cao, Vijay H. Shah
Journal: Hepatology (2020)

Jophlin, Loretta L. M.D., Ph.D.; Cao, Sheng M.D.; Shah, Vijay H. M.D.Editor(s): Corey, Kathleen E.2; Malhi, Harmeet3 Author Information
Impact of antibiotic exposure on the efficacy of immune checkpoint blockade in MSI-H metastatic CRC.
Authors: Victoria Serpas, Jane Elizabeth Rogers, Lianchun Xiao, Kerri Mola-Rudd, Arvind Dasari, Bryan K. Kee, Michael J. Overman, Benny Johnson
Journal: Journal of Clinical Oncology (2020)

161 Background: Immunotherapy has improved outcomes for many patients (pts) with advanced cancers found to be microsatellite instability high (MSI-H). However, not all MSI-H pts exhibit the same efficacy from immunotherapy. Previous studies have suggested that concomitant antibiotic use while receiving immunotherapy may result in poorer outcomes. We aimed to evaluate what factors impacted immune checkpoint blockade (ICB) response in pts with MSI-H metastatic colorectal cancer (mCRC) treated at a large academic referral center. Methods: We completed a single-site, retrospective review of 45 pts with MSI-H mCRC that received ICB. Data was collected including patient demographics, tumor and mutational data, ICB agent, length of treatment, and antibiotic use. Both single and multi-course antibiotic use was included from 2 weeks prior until 6 weeks following ICB treatment. Fisher’s exact test was used to evaluate the association of response and covariables. Log rank test was used to compare progression free survival (PFS) between subgroups. Results: A majority of pts were male (n = 25, 56%) and Caucasian (n = 30, 66%) with right sided tumors (n = 26, 62%). Combination Nivolumab and Ipilimumab was used in 7 (16%) with single agent Nivolumab in 10 (22%) and single agent pembrolizumab in 28 (62%). Of the pts in this cohort, 28 (62%) received antibiotics with 11 (39%) receiving a single round of antibiotics and 17 (61%) receiving multiple courses. Those that did not receive antibiotics had a greater response (partial or complete) at first scan while on ICB therapy (75% vs 32%, p = 0.01). No significant difference was noted between class of antibiotic, age, sex, or tumor sidedness. The median 12 month PFS (12-PFS) was also higher in the group that did not require antibiotics but was not statistically significant (82% vs 72%, p = 0.298). Conclusions: This study shows that MSI-H mCRC pts that received antibiotics while on ICB had impaired response rate and a trend towards lower PFS. This suggests alteration of the gut microbiome may impact ICB response warranting a larger, prospective study.
A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)
Authors: Ying-Hui Jin, Lin Cai, Zhen-Shun Cheng, Hong Cheng, Tong Deng, Yi-Pin Fan, Cheng Fang, Di Huang, Lu-Qi Huang, Qiao Huang, Yong Han, Bo Hu, Fen Hu, Bing-Hui Li, Yi-Rong Li, Ke Liang, Li-Kai Lin, Li-Sha Luo, Jing Ma, Lin-Lu Ma, Zhi-Yong Peng, Yun-Bao Pan, Zhen-Yu Pan, Xue-Qun Ren, Hui-Min Sun, Ying Wang, Yun-Yun Wang, Hong Weng, Chao-Jie Wei, Dong-Fang Wu, Jian Xia, Yong Xiong, Hai-Bo Xu, Xiao-Mei Yao, Yu-Feng Yuan, Tai-Sheng Ye, Xiao-Chun Zhang, Ying-Wen Zhang, Yin-Gao Zhang, Hua-Min Zhang, Yan Zhao, Ming-Juan Zhao, Hao Zi, Xian-Tao Zeng, Yong-Yan Wang, Xing-Huan Wang
Journal: Military Medical Research (2020)

In December 2019, a new type viral pneumonia cases occurred in Wuhan, Hubei Province; and then named "2019 novel coronavirus (2019-nCoV)" by the World Health Organization (WHO) on 12 January 2020. For it is a never been experienced respiratory disease before and with infection ability widely and quickly, it attracted the world's attention but without treatment and control manual. For the request from frontline clinicians and public health professionals of 2019-nCoV infected pneumonia management, an evidence-based guideline urgently needs to be developed. Therefore, we drafted this guideline according to the rapid advice guidelines methodology and general rules of WHO guideline development; we also added the first-hand management data of Zhongnan Hospital of Wuhan University. This guideline includes the guideline methodology, epidemiological characteristics, disease screening and population prevention, diagnosis, treatment and control (including traditional Chinese Medicine), nosocomial infection prevention and control, and disease nursing of the 2019-nCoV. Moreover, we also provide a whole process of a successful treatment case of the severe 2019-nCoV infected pneumonia and experience and lessons of hospital rescue for 2019-nCoV infections. This rapid advice guideline is suitable for the first frontline doctors and nurses, managers of hospitals and healthcare sections, community residents, public health persons, relevant researchers, and all person who are interested in the 2019-nCoV.
The impact of body mass index (BMI) on the safety and outcomes of small molecule inhibitors (SMI) in gastrointestinal cancer.
Authors: Colleen McCabe, Urvi Patel, Tyler Beardslee, Sarah Caulfield, Christin Lee, Rosie Pruitt, Zhengjia Chen, Subir Goyal, Amber Draper, Walid Labib Shaib
Journal: Journal of Clinical Oncology (2020)

144 Background: A number of studies have demonstrated that overweight and early obese states are associated with improved survival in renal and melanoma cancer patients. The purpose of this study was to investigate the impact of BMI on outcomes of GI cancers treated with SMIs. Methods: A retrospective chart review was conducted to compare outcomes between patients with BMIs ≥ 25 and &lt; 25 who received treatment at Winship between 1/2010-8/2019. The primary objective was to determine the PFS, OS, and ADR rates of patients with BMI ≥ 25 treated with SMIs compared to patients with BMIs &lt; 25. PFS and OS rates were estimated with the Kaplan-Meier method and compared between the groups using the log-rank test. The incidence of adverse events was estimated as frequency and percentage and logistic regression was used to estimate the impact of BMI on adverse effects. Results: 269 patients were included in analysis for PFS, 61 for OS and 281 for ADR rate analysis. Diagnoses included HCC (n = 123, 44%) and CRC (n = 158, 56%). There was no significant difference seen in PFS and OS between the BMI &lt; 25 and BMI ≥ 25 groups (HR 1.17 (0.87-1.56), p = 0.291, HR 1.10 (0.66-1.84), p = 0.713, respectively). A significant difference was demonstrated in the rates of adverse reactions between the two groups (OR 0.31 (0.19-0.52), p&lt;.001) with BMI &lt; 25 having a lower rate of ADRs. After adjusting for covariates, HCC vs CRC diagnosis (p = 0.002) and not requiring dose reduction or delay due to toxicity (p&lt;0.001) were significantly associated with better PFS. Conclusions: Based on the multiple regression analysis, patients with a BMI ≥ 25 do not have improved outcomes over those with a BMI &lt; 25 when taking SMIs for their GI malignancies. Patients with BMI &lt; 25 experienced less drug toxicity that required dose reduction, discontinuation, or treatment delays. [Table: see text]
APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid
Authors: Na Zhao, Olivia N. Attrebi, Yingxue Ren, Wenhui Qiao, Berkiye Sonustun, Yuka A. Martens, Axel D. Meneses, Fuyao Li, Francis Shue, Jiaying Zheng, Alexandra J. Van Ingelgom, Mary D. Davis, Aishe Kurti, Joshua A. Knight, Cynthia Linares, Yixing Chen, Marion Delenclos, Chia-Chen Liu, John D. Fryer, Yan W. Asmann, Pamela J. McLean, Dennis W. Dickson, Owen A. Ross, Guojun Bu
Journal: Science Translational Medicine (2020)

The apolipoprotein E (
Attenuated regimen of biweekly gemcitabine/nab-paclitaxel in patients aged &gt; 65 years with advanced pancreatic cancer (APC).
Authors: Hasan Rehman, Jeffrey Chi, Nausheen Hakim, Shreya Prasad Goyal, Coral Olazagasti, Jyothi Jose, Linda Moriarty, Wasif M. Saif
Journal: Journal of Clinical Oncology (2020)

705 Background: Treatment with gemcitabine/nab-paclitaxel confers a survival benefit over gemcitabine monotherapy in APC. However, such treatment can be associated with significant toxicities especially in older patients and carries practical disadvantages related to a weekly schedule along with financial cost. We retrospectively analyzed patients &gt; 65 years of age with APC who received a modified biweekly regimen of gemcitabine/nab-paclitaxel to evaluate efficacy and toxicity. Methods: Patients aged &gt; 65 years with chemo-naive APC and ECOG PS &lt; 2 were studied. Patients were treated with a modified regimen of gemcitabine 1000 mg/m 2 and nab-paclitaxel 125 mg/m 2 every 2 weeks on days 1 and 15 of a 28-day cycle. Patients were evaluated for progression-free survival (PFS) and overall survival (OS) with analyses performed using Kaplan-Meier method. Adverse events were recorded on the day of chemotherapy. CA19-9 was measured every cycle and restaging scans were performed every two cycles. Results: Seventy-three patients (median age: 73; range: 66 - 93) were treated with biweekly gemcitabine/nab-paclitaxel as first-line treatment. The median OS and PFS were 9.1 months and 4.8 months respectively. 66% of patients received growth factor support based on ASCO guidelines and no patients developed neutropenic fever. The incidence of grade &gt; 3 toxicity for neutropenia, anemia, thrombocytopenia, and neurotoxicity were 2%, 7%, 3%, and 5% respectively. Dose reductions of gemcitabine/nab-paclitaxel were required in 10% and 4% patients respectively. Conclusions: In patients &gt; 65 years of age with APC, a modified regimen of biweekly gemcitabine/nab-paclitaxel was found to be effective when compared with historical control from the MPACT study. This regimen allowed for less dose reductions, reduced healthcare costs from additional appointments, travel-related cost, as well as favorable side effect profile while maintaining efficacy. Though retrospective in nature, this study underlines the need for further investigation, particularly in elderly patients with APC and poor performance status. Better tolerability may allow for combination with a third agent, such as a targeted or immunotherapy.