tbuckley/cabot-search huggingface dataset:
METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis
Authors: Hui-Ning Fan, Zhao-Yu Chen, Xiao-Yu Chen, Ming Chen, You-Cai Yi, Jin-Shui Zhu, Jing Zhang
Journal: Molecular Cancer (2022)

Abstract Background N6-methyladenosine (m 6 A) RNA methylation and circular RNAs (circRNAs) have been shown to act vital roles in multiple malignancies including gastric cancer (GC). However, there is little knowledge about how m 6 A modification of circRNAs contributes to GC progression. Methods The association of METTL14 expression with the clinicopathological characteristics and prognosis in patients with GC was assessed by Western blot, Immunohistochemistry and public datasets. In vitro and vivo function experiments were conducted to investigate the role of METTL14 in GC. Furthermore, m 6 A-circRNA epitranscriptomic microarray was utilized to identify METTL14-mediated m 6 A modification of circRNAs, which were validated by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in GC cells. The sponge of circORC5 with miR-30c-2-3p was confirmed by luciferase gene report and RNA immunoprecipitation assays. The expression, localization and prognosis of circORC5 in GC were evaluated by fluorescence in situ hybridization. The effects of METTL14 and (or) circORC5 on miR-30c-2-3p-mediated AKT1S1 and EIF4B were estimated by RT-qPCR and Western blot analyses. Results We found that METTL14 was downregulated in GC tissue samples and its low expression acted as a prognostic factor of poor survival in patients with GC. Ectopic expression of METTL14 markedly repressed growth and invasion of GC cells in vitro and in vivo , whereas knockdown of METTL14 harbored the opposite effects. Mechanically, m 6 A-circRNA epitranscriptomic microarray and Me-RIP identified circORC5 as the downstream target of METTL14. Silencing of METTL14 reduced the m 6 A level of circORC5, but increased circORC5 expression. Moreover, circORC5 could sponge miR-30c-2-3p, and reverse METTL14-caused upregulation of miR-30c-2-3p and downregulation of AKT1S1 and EIF4B. In addition, circORC5 possessed a negative correlation with miR-30c-2-3p and indicated a poor survival in GC. Conclusion Our findings demonstrate that METTL14-mediated m 6 A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.
Abstract 101: PHLPP Inhibitory Peptide Administered During CPR Improves Survival After Prolonged Cardiac Arrest
Authors: Jing Li, Xiangdong Zhu, Chunpei Lee, Rong-Wen Tain, Kejia Cai, Terry Vanden Hoek
Journal: Circulation (2018)

Introduction: Active cooling is more effective than targeted temperature management in improving sudden cardiac arrest (SCA) survival, but can be difficult to implement clinically. We are developing drugs that mimic cooling effects without the need for physical cooling. Cooling protection is mediated by Akt activation. PH domain and Leucine rich repeat Protein Phosphatases (PHLPP) is a phosphatase that negatively regulates Akt. We developed a cell-permeable peptide TAT-PHLPP9c that inhibits PHLPP and reaches heart and brain within 5 min of intravenous administration. Hypothesis: We hypothesize that TAT-PHLPP9c improves outcomes following SCA. This protection involves the improved early metabolic recovery. Methods: C57BL6 mice (n=20) were randomized to receive peptide treatment and appropriate blinding was ensured. A 12 min asystolic arrest was induced with KCl. CPR was started along with TAT-PHLPP9c (7.5 mg/kg) via i.v. Survival was evaluated. Cerebral blood flow (CBF) and metabolic chemical exchange saturation transfer (CEST) contrast were measured with endogenous and dynamic arterial spin labeling (ASL) and CEST MRI respectively. Glucose utilization was assessed by pyruvate dehydrogenase (PDH) phosphorylation and ATP generation. Further, blood taurine and glutamate were measured. Results: Compared to control, TAT-PHLPP9c significantly improved ROSC rates. 3 ROSC mice in the control group died within 10 min while 8 out of 10 ROSC mice in the treatment group survived over 1 h and 4 mice survived to 4 h despite a 12-min arrest. Progressively increased CBF and metabolic CEST contrast were observed in the treated mice compared to controls. p-PDH was decreased by TAT-PHLPP9c (increased activity) at 15 min post-ROSC in both heart and brain. ATP generation was replenished with the peptide treatment. Plasma taurine and glutamate concentrations was reduced by TAT-PHLPP9c as early as 5 min post-ROSC. Further, higher levels of taurine and glutamate were detected in the non-survivors than the survivors. Conclusions: This novel treatment strategy may have a high translational potential to reproduce critical outcomes of CPR cooling without physical cooling.
Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma.
Authors: Thomas Powles, Toni K. Choueiri, Mauricio Burotto, Bernard Escudier, Maria Teresa Bourlon, Amishi Yogesh Shah, Cristina Suárez, Alketa Hamzaj, Camillo Porta, Christopher Hocking, Elizabeth R Kessler, Howard Gurney, Yoshihiko Tomita, Jens Bedke, Joshua Zhang, Burcin Simsek, Christian Scheffold, Andrea B. Apolo, Robert J. Motzer
Journal: Journal of Clinical Oncology (2022)

350 Background: First-line nivolumab plus cabozantinib (N+C) demonstrated superiority over sunitinib (SUN) in the primary disclosure of the phase 3 CheckMate 9ER trial (NCT03141177; 10.6 months minimum follow-up; Choueiri TK et al. N Engl J Med 2021) in patients (pts) with advanced renal cell carcinoma (aRCC). Here, we report the preplanned final overall survival (OS) analysis with updated efficacy and safety in intent-to-treat (ITT) pts, and an exploratory assessment of target lesions by organ site after extended follow-up. Methods: Pts with aRCC (clear cell component) were randomized to N 240 mg every 2 weeks + C 40 mg once daily vs SUN 50 mg once daily (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1–defined progression-free survival (PFS) by blinded independent central review (BICR) in ITT pts; secondary endpoints included OS, objective response rate (ORR) by BICR, and safety. The preplanned final OS analysis was set to occur after observing 254 events. Maximal reduction of target lung, lymph node, kidney, and liver lesions were evaluated per BICR via post hoc exploratory analyses. Results: After 25.4 months minimum follow-up (median, 32.9 months) for OS in ITT pts, a total of 271 OS events occurred, and N+C continued to demonstrate OS improvement vs SUN (N = 323 vs 328; median 37.7 vs 34.3 months; HR 0.70 [95% CI 0.55–0.90]). PFS (median 16.6 vs 8.3 months; HR 0.56 [95% CI 0.46–0.68]) and ORR (55.7% [95% CI 50.1–61.2] vs 28.4% [95% CI 23.5–33.6]) benefits were maintained with N+C vs SUN, and 12.4% (N+C) vs 5.2% (SUN) of pts had a complete response. Median duration of response was 23.1 months with N+C vs 15.1 months with SUN. A higher percentage of pts experienced any reduction and ≥30% reduction from baseline with N+C vs SUN in target lesions at all organ sites assessed (Table). Among all treated pts, 97.2% (N+C; N = 320) vs 93.1% (SUN; N = 320) had a treatment-related adverse event (TRAE) of any grade (65.0% vs 54.1% had a grade ≥ 3 TRAE). Conclusions: N+C continued to provide survival improvement vs SUN among ITT pts in the final OS analysis, additionally PFS and ORR benefits with N+C were sustained with minimum 2-year follow-up. A higher proportion of pts experienced tumor shrinkage benefit with N+C vs SUN across all 4 organ sites assessed. No new safety signals emerged with extended follow-up in either arm. These results highlight N+C as a first-line treatment for pts with aRCC. Clinical trial information: NCT03141177. [Table: see text]
Abstract 200: Glycopyrrolate Does Not Ameliorate Bradycardia During Prolonged Cooling in Awake Subjects
Authors: Jon C Rittenberger, Alex Weissman, Kate Flickinger, Francis X Guyette, Melissa Repine, Cameron Dezfulian, Ankur A Doshi, Jonathan Elmer, Kelly Sawyer, Clifton W Callaway
Journal: Circulation (2018)

Introduction: Hypothermia may help improve outcomes in patients with large vessel occlusion cerebrovascular accidents or other reversible ischemia. Dexmedetomidine infusion reduces shivering in awake subjects undergoing hypothermia but has dose-limiting bradycardia. If vagally mediated, anticholinergic drugs might reduce bradycardia. Hypothesis: Glycopyrrolate prevents bradycardia during dexmedetomidine-assisted prolonged hypothermia. Methods: Eight healthy subjects were randomly assigned to 0.4mg glycopyrrolate bolus, glycopyrrolate rescue (0.01mg every 3 minutes as needed for heart rate &lt;50), or no glycopyrrolate during three separate sessions of 3 hours cooling. Following 1mg/kg dexmedetomidine bolus, subjects received 20cc/kg of (4 0 C) cold saline and surface cooling (EM COOLS, Weinerdorf Austria). Dexmedetomidine infusion was titrated to suppress shivering but allow arousal to verbal stimuli. After 3 hours of cooling, we allowed subjects to rewarm. We compared heart rate, core temperature, and mean arterial blood pressure between groups using Kruskal-Wallis test and ANOVA. Results: Mean age was 27 (SD 6) years and most (N=6, 75%) were male. Mean pre-treatment resting heart rate was 73 [SD 13] bpm. Neither heart rate nor core temperature differed between the groups during the stable hypothermia period (p&gt;0.05). (Figure) Mean arterial blood pressure was higher in the glycopyrrolate bolus group than the other two groups during the study period (p&lt;0.048). Conclusions: Glycopyrrolate did not prevent the bradycardic response to hypothermia and dexmedetomidine. Mean arterial blood pressure was higher in subjects receiving a bolus of glycopyrrolate before induction of hypothermia.
Chloramphenicol-induced bone marrow suppression
Journal: JAMA (1970)

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
Comparison of Sexually Transmitted Infections and Adverse Perinatal Outcomes in Underserved Pregnant Patients Before vs During the COVID-19 Pandemic in Texas
Authors: Irene A. Stafford, Jennie O. Coselli, Danielle F. Wilson, Courtney Y. Wang, Baha M. Sibai
Journal: JAMA Network Open (2022)

This cohort study assesses the rates of sexually transmitted infections (STI) and associated adverse perinatal outcomes among underserved pregnant patients during the COVID-19 pandemic in a public health system in Southeastern Texas.
Osteoarthritis.
Authors: W G Kernohan, R A Mollan
Journal: BMJ (1990)

SIR,-Dr Peter Held and colleagues' concluded that calcium blockers cannot be recommended for routine use to patients with acute myocardial infarction to reduce death and reinfarction.Results from the Danish verapamil infarction trial I (DAVIT I)2 were included, but the results from the Danish pilot study'4 were not.From the overview the reader who does not know DAVIT I might get a wrong impression of the design and outcome of that trial.We intended to treat patients admitted with acute myocardial infarction with verapamil or placebo for six months after admission.We knew that 40-50% of the patients admitted to coronary
Syringe and Needle Exchange to Prevent HIV Infection
Authors: Matthew Lopes
Journal: JAMA (1994)

<h3>To the Editor.</h3> —Despite scientific and meta-analytical studies supportive of needle and syringe exchanges as an HIV risk reduction strategy,<sup>1</sup>opposition to such programs remains. The recent<i>JAMA</i>article by Watters et al<sup>2</sup>is important in demonstrating to needle-exchange opponents that such programs do not undermine drug abuse prevention efforts while slowing the spread of HIV. Their conclusions are seconded by results from the legal NEP that has been operating in New Haven, Conn, since November 1990. In New Haven, the needle exchange operates as a mobile, neighborhood-based program in which individuals receive new syringes for old, supplies for safer injection, condoms, acquired immunodeficiency syndrome (AIDS) transmission and HIV testing information, and encouragement to enter drug treatment. Our evaluation reveals that the program actually hastens the entry of current IDUs into treatment without encouraging new IDUs as it decreases the transmission of HIV. During the initial 7.5 months
Low-value prostate cancer screening among young men with private insurance.
Authors: Jeffrey Vehawn, Suzanne Lange, Mouneeb Choudry, Jacob P. Ambrose, Benjamin Haaland, Niraj Paudel, Heidi A. Hanson, Brock O Neil
Journal: Journal of Clinical Oncology (2022)

240 Background: Debate remains about the value of Prostate-specific antigen (PSA) based prostate cancer screening among men aged 55-69 (USPSTF Grade C). However, no professional society or guideline recommends PSA based prostate cancer screening in men younger than age 40. This study aims to understand the risk of PSA testing exposure in young men, and we hypothesize that substantial low-value testing occurs in this population. Methods: We performed a retrospective analysis of claims data from the MarketScan database to identify men aged 18 to 39 without prostate cancer who received a PSA test from 2008 to 2017. For the primary analysis, men were required to be continuously in the database for least 5 years. Age groups were stratified to include: men less than 25, 25-29, 30-34, and 35-39 years. Secondary analysis did not limit subjects to those with 5 years of continuous data and explored the association of Charlson Comorbidity Index (CCI), lower urinary tract symptoms, erectile dysfunction, depression/anxiety, prostate cancer screening, infertility, and hypogonadism with PSA testing in young men. We used logistic regression to determine which of the factors were associated with PSA testing in young men. Results: We identified claims for 40,164,773 adult men who met study criteria. Of these men, 3,230,748 were continuously in the Marketscan database for at least 5 years. The cumulative risk for receiving a PSA over 5 years for men under 40 is 2.5%. Stratified by age, men aged 35-39 are at highest risk (Table). Logistic multivariable regression showed that, relative to all men between 18 and 40, patients in this age group who received a PSA were more likely to be diagnosed with hypogonadism (OR 20.55, 95% CI 20.39-20.71) or lower urinary tract symptoms (OR 9.34, 95% CI 9.26-9.41). Higher CCIs appeared to correlate with a decreased rate of PSA testing. This population was not significantly more likely to be diagnosed with infertility, depression, or anxiety. Conclusions: PSA screening for men under 40 is not uncommon, especially when associated with concomitant genitourinary symptoms. At a population level, this represents substantial low-value testing. Interventions aimed at clarifying the relationship between common urologic conditions and prostate cancer, the extremely low incidence of prostate cancer in this age group, and the lack of guidelines supporting this practice may help decrease low-value PSA testing. Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number K08CA234431. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.[Table: see text]
IP3 receptor orchestrates maladaptive vascular responses in heart failure
Authors: Haikel Dridi, Gaetano Santulli, Jessica Gambardella, Stanislovas S. Jankauskas, Qi Yuan, Jingyi Yang, Steven Reiken, Xujun Wang, Anetta Wronska, Xiaoping Liu, Alain Lacampagne, Andrew R. Marks
Journal: Journal of Clinical Investigation (2022)

Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC-/- mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC-/- mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC-/- mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC-/- mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.
St. Mary's Hospital
Authors: C. H. Jones
Journal: BMJ (1862)

Lzipus.This malady presents several interesting points for consideration.It is certainly a skin-disease, yet it seems to form a connectinig link between some of the ordinary eruptions and the graver and malignant affections.In several respects it approaches to syphilis, 'which, indeed, may be the actual cause of one form of it.Its soft, low, languidly inflamed tubercles are by no means unlike those of secondary syphilis; and its frightful ulcerations are only paralleled by those of phaged.Tnic chancre.Yet, on the other hand, it differs widely from it in its essential relation to the skin, and its non-dependence on any communicated virus.Though often affecting persons of scrofulotus constitution, it is un- questionable, as Cazenave states, that in a great number ,of cases it shows itself in persons in the primne of life, robust, and having always enjoyed excellent health.No previous disease of the skin seems to have any deter- mining influence.There is no doubt that the three forms of lupus, the exedens, superficial, and lhypertrophic, which are justly distinguished, are mere varie- ties of the same affection, as they may all exist at the same time in the same individual, and all cause more or -less structural alteration of the skin.The origin of lupus is just as obscure as that of a fatty, a fibrouis, or any other tumour.We have no ground whatever, that I can see, to suppose that it de- pends on a poison in the blood.The phenomena are more favourable to the view that it is a dynamic de- rangemenit of the nutrition of the skin, which issues eitber in a languid chronic inflammation, or in a conti- nually advancing ulceration.The absence of affection ,of distant parts, the non-impairment of the general health, atnd the good effect of a local treatment in many cases, are weighty arguments for regarding the disease 's a local degeneration, or disorder of nutrition, de- pending, in all probability, on failure of the vital power of the tissue itself.If we compare the inflammations of lupus with those of -psoriasis or other cutaneous eruptions, we must admit that the mere inflammation is not the essential thing, 'and that the peculiar tissue-change which ensues is of much more consequence.A patch of skini may be 'severely congested and inflamed even for a long time, -nd yet undergo no such alteration as l1Upus infallibly induces.The eroding tendency of lupus, which be- 'comes the chief feature of the exedens variety, points clearly to a low vitality of the skin and other tissues.'The power of repair is wanting; exudation, instead of 'organising into granulations and cicatrix structure, forms glutinous discharge, which concretes into a lifeless ,scab.We see the same tendency in the perforating ulcers of the cornea and stomach, where a local decay and wasting of tissue occurs in one particular spot, though all around the living parts maintain their vitality and normal composition.Such instances are very illustrative of the independent vitality of each separate part, and how this may fail primarily and per se.
Adder Bite
Authors: P. Szekely
Journal: BMJ (1942)

immediately and oxygen and carbon dioxide were administered, with rhythmic pressure on the bag, as, although the airway was clear, there was complete cessation of respiration.The pulse re- mained regular throughout, though the rate increased during the convulsions.The latter ceased, the patient's colour improved, and respiration recommenced in about three minutes.The operation was cortcluded under nitrous oxide and oxygen with no recurrence of the fits.The patient's condition seemed satisfictory on leaving the theatre, but he became cyanosed on return to the ward, where he was given oxygen intranasally.His recovery since then has been normal, and his condition now (a week later) is satisfactory.Morning and evening temperatures on the day of operation, and