tbuckley/cabot-search huggingface dataset:
Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors
Authors: Jayesh Desai, Hui Gan, Catherine Barrow, Michael Jameson, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael Brown, Ben Markman, William Patterson, Andrew Hill, Lisa Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedlander, Phillip Parente, Ben Tran, Lai Wang, Yunxin Chen, Zhiyu Tang, Wendy Huang, John Wu, Dewan Zeng, Lusong Luo, Benjamin Solomon
Journal: Journal of Clinical Oncology (2020)

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAF V600E , wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAF V600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAF V600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAF V600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF V600 –mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.
CAROTID ARTERY AS AN ALTERNATE ACCESS SITE FOR TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Sharan Sharma, Arjun Raval, Angela Ghuneim, Kelsey Patel, William Harder, Crystal Marsh, Keith Frank, Pravalika Rudraraju, Elias Kassab, Ashok Kondur
Journal: Journal of the American College of Cardiology (2020)
SUPPRESSION OF TUMORIGENICITY 2 (ST2) TURBIDIMETRIC IMMUNOASSAY AND ENZYME-LINKED IMMUNOSORBENT ASSAY: PREDICTING RISK IN HEART FAILURE
Authors: Lindsey Aurora, James Snider, Edward Peterson, Tim Bryson, Hongsheng Gui, James McCord, David E. Lanfear
Journal: Journal of the American College of Cardiology (2020)
TEN YEAR EXPERIENCE OF AXILLARY INTRA AORTIC BALLOON PUMP SUPPORT FOR HEART FAILURE PATIENTS
Authors: Hidefumi Nishida, Takeyoshi Ota, Yojiro Koda, David Onsager, Ann Nguyen, Bow Chung, Bryan Smith, Sara Kalantari, Nitasha Sarswat, Gene Kim, Valluvan Jeevanandam, Tae Song
Journal: Journal of the American College of Cardiology (2020)
Effects of PKC beta inhibitor enzastaurin on parental and chemoresistant ovarian cancer cell lines
Authors: I. Meinhold-Heerlein, D. O. Bauerschlag, K. Bräutigam, N. Maass, C. Mundhenke, F. Hilpert, C. Kaisenberg von, W. Jonat, T. Bauknecht, N. Arnold
Journal: Journal of Clinical Oncology (2006)

20037 Background: Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase C beta (PKCβ), inhibits induction of angiogenesis and apoptosis. Activation of PKCβ has been correlated with tumor cell proliferation and invasiveness. The impact of Enzastaurin was investigated in an ovarian cancer tissue culture model utilizing the parental cell line HEY and resistant subclones against different cytostatic drugs. Methods: The ovarian cancer cell line HEY was used to develop subclones with selective resistance against Cisplatin, Etoposide, Docetaxel and Paclitaxel, respectively. The ovarian cell line IGROV-1 with high expression of PKC beta served as control. All cell lines were stimulated with 5 μM Enzastaurin for up to four hours. Immunoblotting analyses determined the expression of GSK3β, a target of PKCβ. Proliferation and apoptosis induction after Enzastaurin treatment was analysed by a proliferation assay and DAPI staining. Results: All cell lines showed phosphorylation of GSK3β, the highest expression level was found in parental and Cisplatin-resistant HEY cells as well as in IGROV-1 cells. Phosphorylation decreased after stimulation with 5 μM Enzastaurin for 30 minutes, most obvious detectable in parental and Cisplatin-resistent HEY cells and also IGROV-1 cells. Proliferation and apoptosis assays demonstrated the Paclitaxel- and Docetaxel-resistant HEY cells as the most sensitive cell lines for Enzastaurin treatment. In contrast, Cisplatin-resistant HEY cells and IGROV-1 cells exhibited the highest resistance against Enzastaurin. Conclusion: The results indicate that ovarian cell lines with a high expression level of active PKCβ like Cisplatin-resistant HEY cells and IGROV-1 cells display also strong phosphorylation of GSK3β. Though in these cell lines the inhibitory effect of Enzastaurin is most prominent, the cell proliferation is hardly affected, nor apoptosis is accelerated when Enzastaurin concentrations up to 10–15 μM were used. Compared to the Cisplatin-resistant variants the normal HEY cells are more sensitive to the inhibitor. Taxane-resistant cells seem to respond to low concentrations of Enzastaurin. Therefore, Enzastaurin may become an effectful drug to treat ovarian carcinomas with resistance to Taxane-based chemotherapies. [Table: see text]
Partha Kar: Covid-19—we must keep faith in our experts
Authors: Partha Kar
Journal: BMJ (2020)

Portsmouth Hospitals NHS TrustWe live in the age of information overload.Once you factor the unregulated world of social media and self-appointed experts, as well as the urge for people to jump in with their two pennies' worth and a disregard for real experts, it becomes quite difficult to find sources you can trust.Then covid-19 appears, and the information world looks like a maze full of pitfalls for anyone trying to ascertain the correct information.
Plasma microRNA signatures to predict EGFR-TKI resistance in EGFR-mutant advanced NSCLC patients.
Authors: Shuhang Wang, Jie Wang, Hua Bai, Tongtong An, Jun Zhao, Zhijie Wang, Jianchun Duan, Minglei Zhuo, Yuyan Wang, Meina Wu
Journal: Journal of Clinical Oncology (2013)

e19136 Background: EGFR mutation is a strong predictor of EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitor) therapy in advanced NSCLC. However, 20-30% of patients with EGFR mutation are resistant to EGFR-TKIs, suggesting that other determinants of outcome beyond EGFR mutation might exist. We hypothesized that plasma microRNA (miRNA) might play a role. Methods: Training group: 20 advanced NSCLC patients treated with EGFR-TKIs as first-line therapy with EGFR 19 deletion mutation were enrolled, 10 of whom responded dramatically while other 10 are resistant. Matched plasma were collected for miRNA profile detection using TaqMan Low-Density (TLDA). Testing group: Real-time PCR were employed to identify the level of miRNAs found significant differently expressed in training step; bioinformatics was applied to find related miRNAs possibly account for resistance. Validation group: Another cohort with EGFR 19 deletion mutation present dramatically different response to EGFR-TKI was used to analyze the difference of miRNAs expression between responding and resistant group. Results: Training group: 153 miRNAs were found differently expressed between responding and resistant group. Testing group: 3 miRNAs (miR-21, AmiR-27a, and miR-218) were verified significantly higher (P=0.004, A0.009, A0.041, respectively) in resistant group than responding group. Validation group: expression level of these 3 miRNAs was validated to be significantly different (P=0.011, A0.011, A0.026, respectively) between 17 couples advanced NSCLC patients with different response to EGFR-TKI. Conclusions: Higher expression level of miR-21, AmiR-27a, and miR-218 might play the role in the resistance to EGFR-TKI for advanced NSCLC patients who had an EGFR exon 19 deletion mutation treated with EGFR-TKI, which needs further validation.
Frequency of BRCA1 5382insC mutations in Russian non-selected pancreatic cancer patients.
Authors: Alexey Kashintsev
Journal: Journal of Clinical Oncology (2013)

e15165 Background: Pancreatic cancer (PC) is known to be associated with BRCA2 mutations, while the role of BRCA1 in the increase of PC risk is less evident. BRCA1/2-driven tumors, including pancreatic cancer, are sensitive to platinating agents and PARP inhibitors. Epidemiology of BRCA1 mutations in Russia is characterized by a pronounced founder effect, with the allele BRCA1 5382insC being detected in 70-90% of all BRCA1 mutation carriers. Methods: 237 patients with consecutive patients with pancreatic cancer were by questionnaires, and 149 have provided their normal DNA to the study and underwent genotyping for BRCA 1 5382insC mutations. Results: Among all the patients in 105/237 (44.3%) patients reported first-degree relatives with various types of cancer, including 11/237 (4.6%) cases of pancreatic cancer. 2/149 genotyped patients carried BRCA1 5382insC allele. Both mutation carriers had first-degree family history of breast cancer. Conclusions: Given the simplicity of founder mutation detection, BRCA1 5382insC allele deserves to be tested in Slavic pancreatic cancer, especially in those reporting family history of BRCA1-associated tumors.
A phase I dose-escalation trial of SRS boost treatment of human papilloma virus (HPV)-unassociated oropharyngeal squamous cell carcinoma (OPSCC).
Authors: David L. Schwartz, Sara Parise, Jordan Denitz, Vinh Nguyen, John Fantasia, Bhoomi Mehrotra, Benjamin Saltman, Douglas Frank
Journal: Journal of Clinical Oncology (2012)

e16026 Background: HPV-negative status and/or significant smoking history predict for poor radiation response in patients with OPSCC. To improve disease control outcomes in this population, we are conducting a phase I dose-escalation trial of stereotactic radiotherapy boost delivery to primary disease. Methods: Thirteen consecutive patients with newly diagnosed HPV-unassociated OPSCC were enrolled onto this IRB-approved clinical trial between 5/2010 and 10/2011. Eligible patients had HPV-negative disease and/or tobacco exposure history of &gt;10 pack-years. The cohort consisted of 12 males/1 female with a median age of 58.5 yrs (range: 46-64). There were 9 tonsil/2 tongue base/1 soft palate/1 GP sulcus cases, with 5 T2/5 T3/3 T4 primaries and 2 AJCC stage III/11 stage IV disease. Primary disease received 60 Gy, gross nodal disease 66 Gy, and prophylactic nodal target volumes 54-60 Gy with routine IMRT technique in 30 daily fractions. All patients received concurrent chemotherapy (12 cisplatinum-based, 1 cetuximab). Within one week of IMRT completion, SRS boost treatment was delivered to the primary disease target volume. Initial SRS dose level was set at 8 Gy, and has been delivered to 11 enrolled patients, with 1 patient pending and 1 patient self-removed from protocol. Median follow up for completed patients is 11 (range: 5-17) months. Results: Twelve cases are evaluable. Post-SRS boost adverse events have remained limited mostly to Gr 2-3 xerostomia, pain, and dysphagia. Five patients have required PEG placement. No acute or chronic Gr 4-5 toxicity has been observed. One patient with bulky T4 disease died of persistent disease. One patient with residual adenopathy had consolidative neck dissection and remains free of disease, as do the remaining 10 patients who responded completely. Conclusions: 8 Gy SRS boost treatment to high-risk primary OPSCC disease is feasible and safe, and step-wise dose escalation is ongoing.
HYPERTENSION MANAGEMENT IN ALL CAUSE SUDDEN DEATH
Authors: Albert Chang, Suhani Gupta, Chelsea Deitelzweig, Elham Masoudi, Mojtaba Mirzaei, Sanjana Thota, Serafim Pistiolis, Caroline Tybout, Susan Keen, Feng-Chang Lin, Ross Simpson
Journal: Journal of the American College of Cardiology (2020)
Electronic medical record (EMR) order sets, counseling, and complementary therapy for chemotherapy induced nausea/vomiting (CINV) control.
Authors: Richard E. Nora, Roger Greenlaw, Lori Macy
Journal: Journal of Clinical Oncology (2013)

e20698 Background: EMR order sets entry can standardize CINV therapy and reduce errors. EMR CINV control, impact of counseling and use of complementary therapies for nutrition and control of CINV are rarely reported. Methods: Patient interview regarding CINV, nutrition education, weight change, and use of other therapies for nutrition and nausea control. Patients initially medicated with parenteral short T1/2 5HT3 antagonist and dexamethasone and oral prochlorperazine. Antiemetics changed at physician discretion. Medical records review for chemotherapy, antiemetics, and weights. Interviews conducted by a research coordinator who did not counsel, prescribe, or treat the patients. Results: 79 patients participated after minimum 2 and maximum 6 cycles of chemotherapy, 24 males and 55 females, age range 38-87 years. 76/79 received moderately or highly emetogenic chemotherapy. 78/79 reported good control of CINV at the time of interview. 38/79 reported decrease in appetite or dysgeusia associated with chemotherapy. 7 patients had change short to long T1/2 5HT3 antagonist. 9 patients had oral aprepitant added. All patients were prescribed oral prochlorperazine and ondansetron, but home use was not assessed as part of the study. 77/79 recalled dietary counsel, but recollection of source and content was not consistent with curriculum or medical record. 8 patients had weight loss &gt;10 pounds, 4 patients had weight gain &gt;10 pounds during chemotherapy. 18 patients reported weight change at least 10 pounds different from measured change. 28/79 patients used calorie and/or protein supplements. 24/79 used ginger related products. 7/79 reported improvement in dysgeusia or appetite with use of plastic utensils. Conclusions: CINV control can be achieved for most patients with combination antiemetics prescribed by EMR order set. Some patients require additional or alterative therapy. A substantial number of patients access nutritive or complementary therapy for CINV control. Patients’ recall of dietary counseling was poor, possibly related to timing of education. Patient reports and possibly perception of chemotherapy associated weight changes are frequently inaccurate.
ELECTROANATOMICAL MAPPING OF LEFT VENTRICULAR SCAR IS INSENSITIVE TO SUBENDOCARDIAL SCAR ON THICK WALL
Authors: Selcuk Kucukseymen, Hagai Yavin, Ayelet Shapira-Daniels, David Shim, Michael Barkagan, Jihye Jang, Patrick Pierce, Warren J. Manning, Elad Anter, Reza Nezafat
Journal: Journal of the American College of Cardiology (2020)
Genomic Signature of Shifts in Selection in a Subalpine Ant and Its Physiological Adaptations
Authors: Francesco Cicconardi, Patrick Krapf, Ilda D’Annessa, Alexander Gamisch, Herbert C Wagner, Andrew D Nguyen, Evan P Economo, Alexander S Mikheyev, Benoit Guénard, Reingard Grabherr, Philipp Andesner, Arthofer Wolfgang, Daniele Di Marino, Florian M Steiner, Birgit C Schlick-Steiner
Journal: Molecular Biology and Evolution (2020)

Understanding how organisms adapt to extreme environments is fundamental and can provide insightful case studies for both evolutionary biology and climate-change biology. Here, we take advantage of the vast diversity of lifestyles in ants to identify genomic signatures of adaptation to extreme habitats such as high altitude. We hypothesized two parallel patterns would occur in a genome adapting to an extreme habitat: 1) strong positive selection on genes related to adaptation and 2) a relaxation of previous purifying selection. We tested this hypothesis by sequencing the high-elevation specialist Tetramorium alpestre and four other phylogenetically related species. In support of our hypothesis, we recorded a strong shift of selective forces in T. alpestre, in particular a stronger magnitude of diversifying and relaxed selection when compared with all other ants. We further disentangled candidate molecular adaptations in both gene expression and protein-coding sequence that were identified by our genome-wide analyses. In particular, we demonstrate that T. alpestre has 1) a higher level of expression for stv and other heat-shock proteins in chill-shock tests and 2) enzymatic enhancement of Hex-T1, a rate-limiting regulatory enzyme that controls the entry of glucose into the glycolytic pathway. Together, our analyses highlight the adaptive molecular changes that support colonization of high-altitude environments.
Dose-efficacy relationship for molecularly targeted agents: A literature review of monotherapy phase I cancer clinical trials.
Authors: Jennifer Arrondeau, Xavier Paoletti, Marie-Paule Sablin, Simona Pop, Christophe Le Tourneau
Journal: Journal of Clinical Oncology (2013)

e13553 Background: Data regarding the dose-efficacy relationship for molecularly targeted agents (MTAs) are conflicting and all based on institution data. We report the largest study evaluating this relationship based on an extensive literature review of phase I trials of MTAs administered as single agents over the last decade. Methods: Efficacy defined by the occurrence of partial or complete responses was recorded and related to the dose administered expressed as a percentage of the maximum tolerated dose (MTD) or the maximum administered dose (MAD) when the MTD was not reached. Association was estimated using logit model with random intercept to adjust for the study. Results: Hundred and sixty eight phase I trials evaluating 116 MTAs involving 5,668 patients were reviewed. Efficacy was present in 39% of trials, but in only 134 patients (2.3%). Among these 134 patients, the dose at which signs of efficacy occurred was known for 113 patients. Overall, the crude response rate slightly increased from 4% at doses &lt;40% of the MTD/MAD to 6%, 7% and 7% at doses 40-80%, 80-120% and &gt;120%, respectively. However, statistical significance was not reached (p=0.28), whether or not the MTD had been reached. Conclusions: Antitumor activity infrequently occurs in phase I trials of MTAs administered as single agents. Although efficacy seemed to increase with dose, statistical significance was not reached, possibly due to the low response rate and sample size.
Measuring vs Estimating LDL-C Levels in a Clinical Trial of Bempedoic Acid
Authors: Hua-Guo Xu, Shiyang Pan
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Phase I study of cisplatin (cDDP)/hyperthermia (HT)/lapatinib (Lap) in patients (pts) with recurrent carcinoma of the uterine cervix (rCC) in previously irradiated area (PIA).
Authors: Esther Van Meerten, A.M. Westermann, H. C. van Doorn, Martine Franckena, Jaco Kraan, Erik A.C. Wiemer, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2013)

e16504 Background: Pts with rCC in PIA might benefit from cDDP plus HT. Lap inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and HER2. Overexpression of EGFR and HER2 is often seen in pts with CC and might be involved in chemotherapy resistance. Besides, preclinical data suggest a synergistic effect of combining cDDP and Lap. Therefore, this phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of Lap added to fixed doses of cDDP and HT. Methods: Pts with rCC in PIA, adequate organ function and ECOG performance status 0-1 were scheduled for 6 weekly administrations of 70 mg/m 2 cDDP plus locoregional HT. Daily Lap was added on days 1-56, starting at a dose-level of 1000 mg. The MTD was defined as the highest dose where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety, pharmacodynamics (PhD) and response were assessed. Results: Eight pts were treated. The first 4 pts (2 each at dose 1000 mg and 750 mg) experienced DLT. Of the 4 pts treated at dose level -2 (500 mg), only 1 pt was able to complete the treatment as planned, 2 pts experienced a DLT and 1 pt was not evaluable (NE), because of early progressive disease (PD) (see Table). In the evaluable pts 1 PD, 4 stable diseases and 2 partial responses (PR) were observed. One patient with PR had a resection of the local recurrence. Analysis of the resected specimen showed a pathological complete response (pCR). Enumeration of circulating endothelial cells measured at baseline and during therapy did not show consistent results. The same applied for the PhD on Ki-67, p27 Kip1 and EGFR in pretreatment and on-therapy skin biopsies. Conclusions: It is not feasible to combine Lap with fixed doses of cDDP and HT in pts with rCC in PIA mainly due to increased cDDP-related toxicity. The observed pCR is intriguing and warrants further investigation of combining HER2-blockade and cDDP/HT. Clinical trial information: NL24464.078.08. [Table: see text]
Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity
Authors: John W. McGinty, Hung-An Ting, Tyler E. Billipp, Marija S. Nadjsombati, Danish M. Khan, Nora A. Barrett, Hong-Erh Liang, Ichiro Matsumoto, Jakob von Moltke
Journal: Immunity (2020)