tbuckley/cabot-search huggingface dataset:
A phase I dose escalation study of eryaspase in combination with modified FOLFIRINOX in locally advanced and metastatic pancreatic ductal adenocarcinoma.
Authors: Marcus Smith Noel, Philip Agop Philip, Mohamedtaki Abdulaziz Tejani, John Marshall, Aiwu Ruth He, Benjamin Adam Weinberg, Louis M. Weiner, Nigel Biswas-Baldwin, Frank Hoke, Hagop Youssoufian, Iman El-Hariry
Journal: Journal of Clinical Oncology (2021)

TPS453 Background: FOLFIRINOX remains the standard of care for the first line treatment of patients with locally advanced and metastatic pancreatic adenocarcinoma, however the prognosis remains poor, thus novel treatment options are indicated. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. A randomized phase IIb study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180) was previously conducted. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. A second line pivotal randomized phase III trial (Trybeca-1) is currently enrolling (NCT03665441). We design this phase I study to determine the safety of mFOLFIRINOX combined with Eryaspase in the first line of treatment. Methods: Patients with locally or metastatic biopsy proven pancreatic adenocarcinoma will be treated with the combination of mFOLFIRINOX plus Eryaspase. This will be a standard 3+3 design with 4 possible doing levels. mFOLFIRINOX dosing will include 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus Eryaspase 75 Units/kg at dose level 0. Eryaspase will be dose escalated up to 100 Units/kg. The study will enroll at three academic centers. Key eligibility criteria include performance status 0 or 1; locally advanced or metastatic tumor disease; adequate organ function. The primary objective is to determine the maximum tolerated dose and safety of this novel combination. Key secondary objectives include objective response rate, progression-free survival, overall survival, pharmacokinetics, pharmacodynamics, and biomarker research. A data safety monitoring committee will review data every 3 months. Clinical trial information: 04292743.
Anlotinib combined with CAPEOX in first-line treatment of patients with RAS and BRAF wild-type unresectable metastatic colorectal cancer: A single-arm, phase II study (ALTER-C-002 trial).
Authors: Ke-Feng Ding, Yue Liu, Jiaqi Chen, Lifeng Sun, Dong Xu, Xiujun Liao, Qian Xiao, JUN LI, Ying Yuan
Journal: Journal of Clinical Oncology (2021)

75 Background: Anlotinib is an oral small molecule multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR1/2/3, FGFR1-4, PDGFR α/β and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. In a previous trial, Anlotinib had been demonstrated to be safe and efficacious in advanced colorectal cancer after failure of recommended treatment. We aimed to evaluate the efficacy and safety of Anlotinib combined with CAPEOX as first-line treatment for unresectable RAS and BRAF wild-type metastatic colorectal cancer (mCRC). Methods: ALTER-C-002 is a single-arm phase II clinical trial. A total of 30 patients with RAS/BRAF wild-type unresectable mCRC, aged 18-75, without prior systemic treatment and ECOG performance score ≤ 1 will be prospectively included. Patients received Capecitabine (850 mg/m 2 , p.o., on day 1-14 every 3 weeks), Oxaliplatin (130 mg/m 2 , i.v., every 3 weeks) and Anlotinib (12 mg, p.o., 2 weeks on/1 week off). After 6 cycles of inducing therapy, patients will receive Capecitabine and Anlotinib as maintenance therapy until tumor progression. Primary endpoint was objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: As of Sep.15 th , 2020, 19 patients had been enrolled. 12 of 19 patients were evaluable for antitumor activity: 10 patients had partial response, 2 patients had stable disease. The ORR was 83.3% (95% CI: 51.6–97.9%), and DCR was 100% (95% CI: 73.5–108.1%). 9 patients (47.4%) developed grade Ⅲ adverse events with 1 (5.3%) grade Ⅳ AE. The grade Ⅲ AEs included hypertension (n = 8), diarrhea (n = 3), hypertriglyceridemia (n = 2), leukopenia and neutropenia (n = 3), alanine aminotransferase increase (n = 1), intestinal obstruction (n = 1), nausea and vomiting (n = 1), and grade Ⅳ AE was blood bilirubin increase. 1 patient received emergent surgery for relieving intestinal obstruction after 14 days of Anlotinib treatment discontinuation. No extra bleeding or wound healing risk were observed during the perioperative period. No treatment-related deaths occurred. Conclusions: The combination of Anlotinib and CAPEOX displayed promising antitumor activity and manageable toxicity in unresectable RAS and BRAF wild-type mCRC, which should be merited further evaluation in randomized studies. Clinical trial information: NCT04080843.
Inflammasome Activation in Ankylosing Spondylitis Is Associated With Gut Dysbiosis
Authors: Giuliana Guggino, Daniele Mauro, Aroldo Rizzo, Riccardo Alessandro, Stefania Raimondo, Anne‐Sophie Bergot, M. Arifur Rahman, Jonathan J. Ellis, Simon Milling, Rik Lories, Dirk Elewaut, Matthew A. Brown, Ranjeny Thomas, Francesco Ciccia
Journal: Arthritis & Rheumatology (2021)

Objective We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis. Methods An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase–polymerase chain reaction (qRT‐PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn’s disease. Bacteria was visualized using silver stain in human samples, and antibiotics were administered to HLA–B27–transgenic rats. The NLRP3 inhibitor MCC950 was administered to SKG mice, and ileal and joint tissues were assessed by IHC analysis and real‐time qRT‐PCR. The role of inflammasome in modulating the interleukin‐23 (IL‐23)/IL‐17 axis was studied ex vivo. Results Expression levels of Nlrp3 , Nlrc4 , and Aim2 were increased in the gut of HLA–B27–transgenic rats and reduced by antibiotic treatment ( P &lt; 0.05). In curdlan‐treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset ( P &lt; 0.05). Compared to healthy controls, AS patients demonstrated overexpression of NLRP3 (fold induction 2.33 versus 22.2; P &lt; 0.001), NLRC4 (fold induction 1.90 versus 6.47; P &lt; 0.001), AIM2 (fold induction 2.40 versus 20.8; P &lt; 0.001), CASP1 (fold induction 2.53 versus 24.8; P &lt; 0.001), IL1B (fold induction 1.07 versus 10.93; P &lt; 0.001), and IL18 (fold induction 2.56 versus 15.67; P &lt; 0.001) in the ileum, and caspase 1 activity was increased ( P &lt; 0.01). The score of adherent and invasive mucosa‐associated bacteria was higher in AS ( P &lt; 0.01) and correlated with the expression of inflammasome components in peripheral blood mononuclear cells ( P &lt; 0.001). NLRP3 expression was associated with disease activity (the Ankylosing Spondylitis Disease Activity Score using the C‐reactive protein level) (r 2 = 0.28, P &lt; 0.01) and with IL23A expression (r 2 = 0.34, P &lt; 0.001) . In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL‐1β and IL‐18. Induction of IL23A , IL17A, and IL22 was IL‐1β–dependent. Conclusion Inflammasome activation occurs in rodent models of AS and in AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasomes drive type III cytokine production with an IL‐1β–dependent mechanism in AS patients.
Continuing besifovir dipivoxil maleate versus switching from tenofovir disoproxil fumarate for treatment of chronic hepatitis B: Results of 192-week phase 3 trial
Authors: Do Seon Song, Won Kim, Sang Hoon Ahn, Hyung Joon Yim, Jae Young Jang, Young Oh Kweon, Yong Kyun Cho, Yoon Jun Kim, Gun Young Hong, Dong Joon Kim, Young Kul Jung, Joo Hyun Sohn, Jin-Woo Lee, Sung Jae Park, Byung Seok Lee, Ju Hyun Kim, Hong Soo Kim, Seung Kew Yoon, Moon Young Kim, Kwan Sik Lee, Young Suk Lim, Wan Sik Lee, Jin Mo Yang, Kyun-Hwan Kim, Kwang-Hyub Han, Soon Ho Um
Journal: Clinical and Molecular Hepatology (2021)

Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, shows potent antiviral activity against hepatitis B virus. Our previous 48-week trial revealed that BSV has comparable antiviral efficacy to tenofovir disoproxil fumarate (TDF) and better safety profiles in terms of improved renal and bone safety. This extension study evaluated the prolonged efficacy and safety of BSV in treatment-naive chronic hepatitis B patients.Patients continued to participate in an open-label BSV study after an initial 48-week double-blind comparison of BSV and TDF treatment. The antiviral efficacy and drug safety was evaluated up to 192 weeks in two groups: patients continuing BSV treatment (BSV-BSV) and patients switching from TDF to BSV after 48 weeks (TDF-BSV).Among 197 patients receiving randomized treatments, 170 (86%) entered the open-label phase and 152 (77%) entered the 192-week extension study. Virological response rates over 192 weeks were 92.50% and 93.06% in the BSV-BSV and TDF-BSV groups, respectively (P=0.90). Hepatitis B envelop antigen seroconversion and alanine aminotransferase normalization rates were similar between the groups (P=0.75 and P=0.36, respectively). There were no drug-resistant mutations to BSV. Bone mineral density and renal function were well preserved in the BSV-BSV group, whereas these initially worsened then recovered after switching therapy in the TDF-BSV group.BSV maintained potent antiviral efficacy after 192 weeks and showed no evidence of drug resistance. BSV was safe, well tolerated, and effective in patients who switched from TDF to BSV. Trial Registration Number: NCT01937806 (date: 10 Sep 2013).
Global BRAF testing practices in metastatic colorectal cancer.
Authors: Scott Kopetz, Axel Grothey, Fortunato Ciardiello, Jayesh Desai, Tae Won Kim, Tim Maughan, Eric Van Cutsem, Harpreet Singh Wasan, Rona Yaeger, Takayuki Yoshino, Ashwin Gollerkeri, Michelle Edwards, Montessa Rodriguez Lizaso, Josep Tabernero
Journal: Journal of Clinical Oncology (2021)

128 Background:The BRAF V600E mutation is a marker of poor prognosis in patients with metastatic colorectal cancer (mCRC). Targeted therapy, such as encorafenib plus cetuximab, is approved in the US/Europe for the treatment (tx) of BRAF V600E-mutated mCRC and demonstrated improved survival vs historical standard of care (SOC). Determining BRAF mutation status in mCRC is recommended by NCCN and ESMO guidelines although adherence to guidelines may not be uniform. This report’s objective is to communicate global survey results of mCRC BRAF testing practices. Identifying regions where BRAF testing is not SOC may help identify where education efforts are needed improve effective tx decision making. Methods: Oncology tx centers were identified from a registry and public information. Centers were selected for research experience, historic data quality, and estimated mCRC patients. A BRAF testing practices survey using an online platform of verified centers was conducted March-August 2020; 395 centers/38 countries have responded thus far. Results: Respondents indicated BRAF-mutation testing is performed as SOC for patients with mCRC in most regions; Eastern Europe and South America are exceptions: only 47% (45/95) and 45% (9/20) of centers, respectively routinely performed mutation testing. Most test tumor tissue, few test both tumor tissue or blood, and none conduct blood mutation testing only. Most regions perform BRAF testing at initial diagnosis or confirmation of advanced disease. Individual country statistics will be presented. Conclusions: BRAF testing has global variability, impacting tx decisions. Increased awareness and routine testing may lead to informed decisions regarding targeted therapies, such as encorafenib plus cetuximab where approved, in patients with BRAF V600E-mutant mCRC. [Table: see text]
Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes
Authors: Jonas Peper, Daniel Kownatzki-Danger, Gunnar Weninger, Fitzwilliam Seibertz, Julius Ryan D. Pronto, Henry Sutanto, David Pacheu-Grau, Robin Hindmarsh, Sören Brandenburg, Tobias Kohl, Gerd Hasenfuss, Michael Gotthardt, Eva A. Rog-Zielinska, Bernd Wollnik, Peter Rehling, Henning Urlaub, Jörg Wegener, Jordi Heijman, Niels Voigt, Lukas Cyganek, Christof Lenz, Stephan E. Lehnart
Journal: Circulation Research (2021)

[Figure: see text].
MicroRNA-372 promotes metastasis in non-small cell lung cancer.
Authors: Ay-Huey Huang, Tei-Jen Su, Ai-Me Lin, Pan-Chyr Yang, Jeremy J.W. Chen, Sung-Liang Yu
Journal: Cancer Research (2008)

5061  microRNAs (miRs) inhibited translational process through imperfectly binding 3’ untranslated region (3’ UTR) of target mRNAs. Recent studies provided the evidences that miRNAs have the critical effects on the gene regulation of cancer progression. A lot of miRNAs have been proven their expressional level correlated with the malignant characters of lung cancers in vitro and in vivo. Moreover, our previous study identified 5 miRs (let-7a, miR-182*, miR-372, miR-137 and miR-221) whose expression could predict the outcome of non-small cell lung cancer (NSCLC) patients independent from stage effects. Among them, miR-137, miR-182 and miR-372 act as risky miRs; in contrast, let-7a and miR-221 are potential protective miRs. However, how miRNAs are involved in the mechanisms by which they govern the tumor initiation and progression of lung cancers remains unclear. To address these issues, first, 2D-DIGE (two-dimensional difference gel electrophoresis) and public computational prediction algorithms were applied to identify the potential targets of miR-372 in miR-372 constitutively expressed lung cancer cells in which the expression of miR-372 is nearly absent. The ectogenic expression of miR-372 significantly promoted the invasion ability, but did not interfere with the tumorigenecity in vitro and in vivo. Several potential targets were selected to further validate the regulatory relationship between miR-372 and its targets by Luciferase reporter assay, Western blot and site-directed mutagenesis. The anti-miR-372 could attenuate the metastatic effects induced by miR-372. In this study, the results indicated that miR-372 might be mainly involved in metastasis, not tumorigenesis in lung cancers. Taken together, the results showed that miR-372 might be a potential target for promoting tumor metastasis in lung cancer.
Disparities in Cancer Survival Among Adolescents and Young Adults: A Population-Based Study of 88 000 Patients
Authors: Caitlin C Murphy, Philip J Lupo, Michael E Roth, Naomi J Winick, Sandi L Pruitt
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Adolescents and young adults (AYA, aged 15-39 years) diagnosed with cancer comprise a growing, yet understudied, population. Few studies have examined disparities in cancer survival in underserved and diverse populations of AYA. Methods Using population-based data from the Texas Cancer Registry, we estimated 5-year relative survival of common AYA cancers and examined disparities in survival by race and ethnicity, neighborhood poverty, urban or rural residence, and insurance type. We also used multivariable Cox proportional hazards regression models to examine associations of race or ethnicity, neighborhood poverty, urban or rural residence, and insurance type with all-cause mortality. Results We identified 55 316 women and 32 740 men diagnosed with invasive cancer at age 15-39 years between January 1, 1995, and December 31, 2016. There were disparities in relative survival by race and ethnicity, poverty, and insurance for many cancer types. Racial and ethnic disparities in survival for men with non-Hodgkin lymphoma (74.5% [95% confidence interval (CI) = 72.1% to 76.7%] White vs 57.0% [95% CI = 51.9% to 61.8%] Black) and acute lymphocytic leukemia (66.5% [95% CI = 61.4% to 71.0%] White vs 44.4% [95% CI = 39.9% to 48.8%] Hispanic) were striking, and disparities remained even for cancers with excellent prognosis, such as testicular cancer (96.6% [95% CI = 95.9% to 97.2%] White vs 88.7% [95% CI = 82.4% to 92.8%] Black). In adjusted analysis, being Black or Hispanic, living in high-poverty neighborhoods, and having Medicaid, other government insurance, or no insurance at diagnosis were associated with all-cause mortality in both women and men (all 2-sided P &amp;lt; .01). Conclusions Our study adds urgency to well-documented disparities in cancer survival in older adults by demonstrating persistent differences in relative survival and all-cause mortality in AYAs. Findings point to several areas of future research to address disparities in this unique population of cancer patients.
Phase III study of NUC-1031 + cisplatin vs gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).
Authors: Jennifer J. Knox, Mairead Geraldine McNamara, Lipika Goyal, David Cosgrove, Christoph Springfeld, Katrin Marie Sjoquist, Joon Oh Park, Helena Verdaguer, Chiara Braconi, Paul J. Ross, Aimery De Gramont, Rachna T. Shroff, John Raymond Zalcberg, Daniel H. Palmer, Juan W. Valle
Journal: Journal of Clinical Oncology (2021)

TPS351 Background: Biliary tract cancer (BTC) carries a poor prognosis and no first-line treatments are approved. The accepted global standard of care is gemcitabine + cisplatin (GemCis). NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome key cancer resistance mechanisms that are associated with gemcitabine. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 14 patients enrolled in 2 cohorts (NUC-1031 625 mg/m 2 or 725 mg/m 2 + cisplatin 25 mg/m 2 on Days 1 and 8 of 21-day cycle), 1 had a CR and 6 had PRs, resulting in an unconfirmed ORR of 50%. This represents an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected AEs or DLTs. The RP2D of NUC-1031 with cisplatin was 725 mg/m 2 . The tolerability profile, together with encouraging efficacy, suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global registrational study. Methods: NuTide:121 is a Phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m 2 NUC-1031 or 1000 mg/m 2 gemcitabine, both with 25 mg/m 2 cisplatin, administered on days 1 and 8 of 21-day cycles. Primary objectives are OS and ORR. Secondary objectives include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses, including two designed to support accelerated approval, are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.
Trends in hospitalizations among patients with colorectal cancer: Results from the National Inpatient Sample (2007 through 2017).
Authors: Udhayvir Singh Grewal, Harsh Patel, Shiva Jashwanth Gaddam, Aakash R Sheth, Kirtenkumar Patel, Glenn Morris Mills
Journal: Journal of Clinical Oncology (2021)

135 Background: Colorectal cancer is the second leading cause of cancer-related deaths in the United States with a rising incidence, especially in young adults. Care for patients with colorectal cancer is associated with significant health care costs and expenditures. We analyzed trends in admissions and outcomes related to hospitalizations in patients with colorectal cancer. Methods: We retrospectively interrogated the National Inpatient Sample for admissions in patients with colorectal cancer from 2007 – 2017. Records were stratified based upon the anatomical site and were analyzed for various inpatient outcomes. SAS version 9.4 (SAS Institute Inc.) was used for statistical analysis. Results: A total of 1,962,705 admissions were identified. About 50.2% patients were males, 64.4% were white and median age was 67.7 (53.8-81.6). Majority (47.8%) of the admissions that were coded for anatomical location of malignancy were for ascending colon cancer. 60.7% of the admissions were non-elective and Medicare was the primary payer for 58.6% of admissions. Most patients admitted for colon cancer belonged to the lower income quartile (28.3%) and were concentrated in large (58.9%), urban teaching hospitals (53.4%) in Southern US (38.8%). Hypertension (53.6%) and diabetes mellitus (18.6%) were the most common co-morbidities (p &lt; 0.0001). Average in-hospital mortality was 4.9% and was lower in patients with ascending colon cancer (2.9, p &lt; 0.001). Median length of stay was 5 days, but was higher in patients with transverse colon cancer (9 days, p &lt; 0.0001). Median cost of hospitalization was found to be $12,295 and was significantly higher for patients with descending colon malignancy ($16,369, p &lt; 0.0001). The number of annual hospitalizations stayed steady overall; the number of annual hospitalizations increased by 98.6% for rectosigmoid cancer. Conclusions: Despite highest number of hospitalizations, patients with ascending colon cancer had lowest in-hospital mortality. Cost of hospitalization and median length of stay were highest for patients with descending colon and transverse colon respectively. Number of annual hospitalizations has significantly increased for rectosigmoid cancer. Our findings may help inform physicians and healthcare administrators to devise appropriate strategies to efficiently channelize healthcare resources in order to decrease the overall economic burden associated with hospitalizations in patients with colorectal cancer.
Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities
Authors: Laiying Zhang, Jun He, Lang Bai, Shihua Ruan, Tao Yang, Youfu Luo
Journal: Medicinal Research Reviews (2021)

Abstract Ribosomes, which synthesize proteins, are critical organelles for the survival and growth of bacteria. About 60% of approved antibiotics discovered so far combat pathogenic bacteria by targeting ribosomes. However, several issues, such as drug resistance and toxicity, have impeded the clinical use of ribosome‐targeting antibiotics. Moreover, the complexity of the bacteria ribosome structure has retarded the discovery of new ribosome‐targeting agents that are considered as the key to the drug‐resistance and toxicity. To deal with these challenges, efforts such as medicinal chemistry optimization, combination treatment, and new drug delivery system have been developed. But not enough, the development of structural biology and new screening methods bring powerful tools, such as cryo‐electron microscopy technology, advanced computer‐aided drug design, and cell‐free in vitro transcription/translation systems, for the discovery of novel ribosome‐targeting antibiotics. Thus, in this paper, we overview the research on different aspects of bacterial ribosomes, especially focus on discussing the challenges in the discovery of ribosome‐targeting antibacterial drugs and advances made to address issues such as drug‐resistance and selectivity, which, we believe, provide perspectives for the discovery of novel antibiotics.