tbuckley/cabot-search huggingface dataset:
Abstract #3391: S9, a novel anticancer agent, exerts its anti-proliferative activity by interfering with both PI3K-Akt-mTOR signaling and microtubule cytoskeleton
Authors: Chao Zhang, Na Yang, Chun-Hao Yang, Hua-Sheng Ding, Cheng Luo, Yu Zhang, Mao-Jiang Wu, Xiong-Wen Zhang, Xu Shen, Hua-Liang Jiang, Ling-Hua Meng, Jian Ding
Journal: Cancer Research (2009)

Deregulation of the phosphatidylinositol 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays a central role in tumor formation and progression, providing validated targets for cancer therapy. S9, a hybrid of \#945;-methylene-\#947;-lactone and 2-phenyl indole compound, was found to abrogate EGF-activated PI3K-Akt-mTOR signaling cascade and Akt translocation to cellular membrane. S9 possesses inhibitory activity against both PI3K and mTOR with little effect on other tested 30 kinases. S9 also completely impedes hyper-phosphorylation of Akt as a negative feedback of inhibition of mTOR by rapamycin. S9 unexpectedly arrested cells in M phase other than G1 phase, which was distinct in compounds targeting PI3K-Akt-mTOR pathway. Further study revealed that S9 inhibited tubulin polymerization via binding to colchicines-binding site of tubulin and resulted in microtubule disturbance. Molecular modeling indicated that S9 could potentially bind to the kinase domains of PI3K p110\#945; subunit and mTOR, and shared similar hydrophobic interactions with colchicines in the complex with tubulin. Moreover, S9 induced rapid apoptosis in tumor cell, which might reflect a synergistic cooperation between blockade of both PI3-Akt-mTOR signaling and tubulin cytoskeleton. Finally, S9 displayed potent antiproliferative activity in a panel of tumor cells originated from different tissue types including drug-resistant cells and in nude mice bearing human tumor xenografts. Taken together, we herein show for the first time that S9 functions as a multi-inhibitor simultaneously targeting both PI3K-mTOR axis and microtubule cytoskeleton. The converged outcome of both cytostatic and cytotoxic effects of S9  in   vitro  and  in vivo , together with its appreciable anti-MDR profile, help prove to be a promising alternative template for rational designing of anticancer drugs.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3391.
Abstract 167: Epinephrine Plus Chest Compressions May Be Superior to Epinephrine Alone in a Hypoxia-Induced Porcine Model of Lifeless Shock
Authors: Felipe Teran, Claire Centeno, Alex L Lindqwister, William J Hunckler, William Landis, Karen L Moodie, Benjamin S Abella, Norman A Paradis
Journal: Circulation (2019)

Background: Lifeless shock (LS) (previously called EMD and pseudo-PEA) is a global hypotensive ischemic state with retained coordinated myocardial contractile activity and an organized ECG. We have previously described our hypoxic LS model. The role of standard external chest compressions remains unclear in the setting of LS and its associated intrinsic hemodynamics. Although it is known the patients with LS have better prognosis compared to PEA, it is unclear what is the best treatment strategy. Prior work has shown that chest compressions (CC) when synchronized with native systole results in significant hemodynamic improvement, most notably coronary perfusion pressure (CPP), and hence it is plausible that standard dyssynchronous CC may be detrimental to hemodynamics. Furthermore, retrospective clinical data has shown that LS patients treated with vasopressors and no CC, may have better outcomes. We compared epinephrine only versus epinephrine and chest compression, in a porcine model of LS. Methods: Our porcine model of hypoxic LS has previously been described. We randomized pigs to episodes of LS treated with epinephrine only (control) (0.0015 mg/kg) versus epinephrine plus standard external chest compressions (intervention). Animals were endotracheally intubated and mechanically ventilated, and the fraction of inspired oxygen (FiO 2 ) was gradually lowered from room air (20-30% O 2 ) to a target FiO 2 of 3-7% O 2 . This target FiO 2 was maintained until the systolic blood pressure (SBP) dropped to 30 mmHg for 30 seconds, or the animal became bradycardic (HR less than 40), which was defined as the start of LS. FiO 2 was then raised to 100%, and then animal would receive control or intervention. Return of spontaneous circulation (ROSC) was defined as SBP 60 mmHg, stable after 2 minutes. Results: Twenty-six episodes of LS in 11 animals received epinephrine only control and 21 episodes the epinephrine plus chest compression intervention. The rates of ROSC in two minutes or less were 5/26 (19%) in the control arm vs 14/21 (67%) in the intervention arm (P=0.001;95% CI 19.7 %-67.2%). Conclusions: In a swine model of hypoxia induced LS, epinephrine plus CPR may be superior to epinephrine alone.
Gene Therapy for Hemophilia A
Authors: Madhusudana G Sanal, Arun Srivastava
Journal: New England Journal of Medicine (2022)

Hemophilia A is an X-linked bleeding disorder caused by defective coagulation Factor VIII (FVIII). Although the efficacies of existing treatment using purified or recombinant FVIII are good, there remain shortcomings in using this particular form of treatment. A few FVIII gene therapy clinical trials have been initiated with modest improvements recorded, but these are no longer being continued due to insufficient efficacy. However, with the progress in the development of gene delivery vectors and the availability of mouse and canine hemophilia A models, gene therapy of hemophilia A remains an area of hot pursuit.
Abstract 10645: Left Atrial Booster-Pump Function as a Predictive Parameter for New-Onset Postoperative Atrial Fibrillation in Patients With Severe Aortic Stenosis
Authors: Junichi Imanishi, Hidekazu Tanaka, Yoshiki Yamadori, Takuma Sawa, Yoshiki Motoji, Tatsuya Miyoshi, Yasuhide Mochizuki, Yuko Fukuda, Kensuke Matsumoto, Kazuhiro Tatsumi, Yutaka Okita, Hiroya Kawai, Ken-ichi Hirata
Journal: Circulation (2013)

Background: Postoperative atrial fibrillation (AF) has been reported to be associated with long-term mortality following aortic valve replacement (AVR), but its associated factors remains unknown. ...
REPLY
Authors: Liang Li, Yanpin Wei, Hongyang Wang
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. The relative expression levels and number of microRNA (miRNA) response elements (MREs) are important parameters to determine the magnitude of the competing endogenous RNA (ceRNA) effect.(1) We agree that circular RNAs (circRNAs) express much less than certain miRNAs and cannot be predicted to function as a sponge nearly as effectively as cerebellar degeneration–related protein 1 antisense RNA. Consistent with this understanding, of the 177 circRNAs that were abnormally expressed in the very early stage of hepatocellular carcinoma (HCC), bioinformatics analysis revealed that only 52 circRNAs may act as miRNA sponges, and circular chromodomain Y‐like (circ‐CDYL) was the one we confirmed experimentally in this study.(2) Circ‐CDYL shares multiple MREs targeted by multiple miRNAs (miR‐892a and miR‐328‐3p), which is an advantage to miRNA sponge regulation. miR‐892a and miR‐328‐3p are high‐abundance miRNAs in HCC cells. The highly circ‐CDYL expression is conducive to derepression of miR‐892a and miR‐328‐3p on heparin‐derived growth factor (HDGF) and hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN), respectively, and promotes hepatocarcinogenesis. Circ‐CDYL colocalized with miR‐892a and miR‐328‐3p in tumor tissues; miRNA pull‐down assay found that miR‐892a and miR‐328‐3p could pull down circ‐CDYL. In addition, RNA antisense purification assay confirmed that these two miRNAs were reversely pulled down by circ‐CDYL. These experimental evidences amply proved that circ‐CDYL can act as miRNA sponges in HCC. Nevertheless, considering the complexity of ceRNA regulation forms, there are still many unknown factors that need to be further discussed both in vivo and in vitro. More than 98% of the human genome is noncoding. One reason for the difficulties in treating HCC with current drugs, which usually target protein‐coding genes, is the possibility that the roles of noncoding RNA have not been adequately considered. Elucidating the molecular basis of the circ‐CDYL–driven noncoding regulatory RNAs network could naturally shed light on new options for HCC therapy. The high expressions of HDGF and HIF1AN, which are induced by circ‐CDYL, were inhibited after blocking miR‐892a and miR‐328‐3p binding sites, respectively. Furthermore, combining circ‐CDYL interference with a traditional enzyme inhibitor led to accredited inhibition of stem‐like characteristics and tumor growth in HCC. Because of the lack of 5′ and 3′ ends, circRNA can resist the digestion of exonuclease and is highly stable(3) and is thus considered as a potential biomarker in cancer. We searched the probability of surveillance of early‐stage HCC using circ‐CDYL. After combining circ‐CDYL with HDGF and HIF1AN, this set of biomarkers achieved accredited sensitivity and specificity for discrimination of early‐stage HCC. The early diagnostic efficiency is better than that of alpha fetoprotein here. Furthermore, we are now exploring the application value of circ‐CDYL in fluid biopsy.
PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.
Authors: Helena Margaret Earl, Anne-Laure Vallier, Wendi Qian, Louise Grybowicz, Stanly Thomas, Saba Mahmud, Caron Harvey, Karen McAdam, Luke Hughes-Davies, Rebecca Roylance, Ellen Copson, Jessica Brown, Elena Provenzano, Emma McMurtry, Marc Tischkowitz, Jean Abraham
Journal: Journal of Clinical Oncology (2017)

TPS591 Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 - Safety: both research arms combined. Stage 2 - Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the-winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~55-60% for all trial patients and ~60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 17 Sites activated: 12 [expected number of sites 30-50].
Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19)
Authors: Neil Mehta, Ankur Kalra, Amy S. Nowacki, Scott Anjewierden, Zheyi Han, Pavan Bhat, Andres E. Carmona-Rubio, Miriam Jacob, Gary W. Procop, Susan Harrington, Alex Milinovich, Lars G. Svensson, Lara Jehi, James B. Young, Mina K. Chung
Journal: JAMA Cardiology (2020)

The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use.To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation).Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included.History of taking ACEIs or ARBs at the time of COVID-19 testing.Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive.A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15).This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.
Avoiding a Health Care Financial Meltdown
Authors: Andrew Bindman
Journal: JAMA (2020)

The article discusses the financial impact of the coronavirus disease 2019 (COVID-19) pandemic on the U S  health care system  Topics explored include the challenges brought by the significant increase in the demand for COVID-19-related health services to hospitals, the way some health systems opted to lay off health care workers to reduce expenses, and the Public Health and Social Services Emergency Fund allotted to hospitals and physicians following the issuance of shelter-in-place orders
Bottom-Up and Top-Down Paradigms for Psychopathology: A Half-Century Odyssey
Authors: Thomas M. Achenbach
Journal: Annual Review of Clinical Psychology (2020)

Bottom-up paradigms prioritize empirical data from which to derive conceptualizations of psychopathology. These paradigms use multivariate statistics to identify syndromes of problems that tend to co-occur plus higher-order groupings such as those designated as internalizing and externalizing. Bottom-up assessment instruments obtain self-ratings and collateral ratings of behavioral, emotional, social, and thought problems and strengths for ages 1½–90+. Ratings of population samples provide norms for syndrome and higher-order scales for each gender, at different ages, rated by different informants, in relation to multicultural norms. The normed assessment instruments operationalize the empirically derived syndromes and higher-order groupings for applications to clinical services, research, and training. Because cross-informant agreement is modest and no single informant provides comprehensive assessment data, software compares ratings by different informants. Top-down paradigms prioritize conceptual representations of the nature and structure of psychopathology, as exemplified by psychodynamic, DSM/ICD, and HiTOP paradigms. Although these paradigms originated with observations, they tend to prioritize conceptual representations over empirical data.
Immunotherapy With Programmed Cell Death 1 vs Programmed Cell Death Ligand 1 Inhibitors in Patients With Cancer
Authors: David Bomze, Daniel Azoulay, Tomer Meirson
Journal: JAMA Oncology (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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Oncology journal
Decoding the Noncoding Cancer Genome
Authors: Peter van Galen
Journal: Cancer Discovery (2020)

Abstract Summary: In this issue of Cancer Discovery, Li and colleagues provide a blueprint for the identification and functional validation of cancer-associated mutations in noncoding regions of the genome. Integration of whole-genome sequencing and high-throughput epigenome editing screens is starting to reveal the extent to which noncoding genetic lesions contribute to cancer. See related article by Li et al., p. 724.
Chatbots in the fight against the COVID-19 pandemic
Authors: Adam S. Miner, Liliana Laranjo, A. Baki Kocaballi
Journal: npj Digital Medicine (2020)

We are all together in a fight against the COVID-19 pandemic. Chatbots, if effectively designed and deployed, could help us by sharing up-to-date information quickly, encouraging desired health impacting behaviors, and lessening the psychological damage caused by fear and isolation. Despite this potential, the risk of amplifying misinformation and the lack of prior effectiveness research is cause for concern. Immediate collaborations between healthcare workers, companies, academics and governments are merited and may aid future pandemic preparedness efforts.
Targeting telomerase for its advent in cancer therapeutics
Authors: Shalini Bajaj, Maushmi S Kumar, GJ Peters, YC Mayur
Journal: Medicinal Research Reviews (2020)

Abstract Telomerase has emerged as an important primary target in anticancer therapy. It is a distinctive reverse transcriptase enzyme, which extends the length of telomere at the 3′ chromosomal end, and uses telomerase reverse transcriptase (TERT) and telomerase RNA template‐containing domains. Telomerase has a vital role and is a contributing factor in human health, mainly affecting cell aging and cell proliferation. Due to its unique feature, it ensures unrestricted cell proliferation in malignancy and plays a major role in cancer disease. The development of telomerase inhibitors with increased specificity and better pharmacokinetics is being considered to design and develop newer potent anticancer agents. Use of natural and synthetic compounds for the inhibition of telomerase activity can lead to an opening of new vistas in cancer treatment. This review details about the telomerase biochemistry, use of natural and synthetic compounds; vaccines and oncolytic virus in therapy that suppress the telomerase activity. We have discussed structure‐activity relationships of various natural and synthetic telomerase inhibitors to help medicinal chemists and chemical biology researchers with a ready reference and updated status of their clinical trials. Suppression of human TERT (hTERT) activity through inhibition of hTERT promoter is an important approach for telomerase inhibition.
Pervasive Phenotypic Impact of a Large Nonrecombining Introgressed Region in Yeast
Authors: Christian Brion, Claudia Caradec, David Pflieger, Anne Friedrich, Joseph Schacherer
Journal: Molecular Biology and Evolution (2020)

To explore the origin of the diversity observed in natural populations, many studies have investigated the relationship between genotype and phenotype. In yeast species, especially in Saccharomyces cerevisiae, these studies are mainly conducted using recombinant offspring derived from two genetically diverse isolates, allowing to define the phenotypic effect of genetic variants. However, large genomic variants such as interspecies introgressions are usually overlooked even if they are known to modify the genotype-phenotype relationship. To have a better insight into the overall phenotypic impact of introgressions, we took advantage of the presence of a 1-Mb introgressed region, which lacks recombination and contains the mating-type determinant in the Lachancea kluyveri budding yeast. By performing linkage mapping analyses in this species, we identified a total of 89 loci affecting growth fitness in a large number of conditions and 2,187 loci affecting gene expression mostly grouped into two major hotspots, one being the introgressed region carrying the mating-type locus. Because of the absence of recombination, our results highlight the presence of a sexual dimorphism in a budding yeast for the first time. Overall, by describing the phenotype-genotype relationship in the Lachancea kluyveri species, we expanded our knowledge on how genetic characteristics of large introgression events can affect the phenotypic landscape.