tbuckley/cabot-search huggingface dataset:
Secretome Analysis of Cardiomyocytes Identifies PCSK6 (Proprotein Convertase Subtilisin/Kexin Type 6) as a Novel Player in Cardiac Remodeling After Myocardial Infarction
Authors: Tim Christian Kuhn, Johannes Knobel, Sonja Burkert-Rettenmaier, Xue Li, Ingmar Sören Meyer, Andreas Jungmann, Florian Sicklinger, Johannes Backs, Felix Lasitschka, Oliver J. Müller, Hugo A. Katus, Jeroen Krijgsveld, Florian Leuschner
Journal: Circulation (2020)

Acute occlusion of a coronary artery results in swift tissue necrosis. Bordering areas of the infarcted myocardium can also experience impaired blood supply and reduced oxygen delivery, leading to altered metabolic and mechanical processes. Although transcriptional changes in hypoxic cardiomyocytes are well studied, little is known about the proteins that are actively secreted from these cells. We established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis. Further functional validation experiments included ELISA measurement of human samples, murine left anterior descending coronary artery ligation, and adeno-associated virus 9-mediated in vivo overexpression in mice. The presented approach is feasible for analysis of the secretome of primary cardiomyocytes without serum starvation. A total of 1026 proteins were identified to be secreted within 24 hours, indicating a 5-fold increase in detection compared with former approaches. Among them, a variety of proteins have not yet been explored in the context of cardiovascular pathologies. One of the secreted factors most strongly upregulated upon hypoxia was PCSK6 (proprotein convertase subtilisin/kexin type 6). Validation experiments revealed an increase of PCSK6 on mRNA and protein level in hypoxic cardiomyocytes. PCSK6 expression was elevated in hearts of mice after 3 days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements in human serum also indicate distinct kinetics for PCSK6 in patients with acute myocardial infarction, with a peak on postinfarction day 3. Transfer of PCSK6-depleted cardiomyocyte secretome resulted in decreased expression of collagen I and III in fibroblasts compared with control treated cells, and small interfering RNA-mediated knockdown of PCSK6 in cardiomyocytes impacted transforming growth factor-β activation and SMAD3 (mothers against decapentaplegic homolog 3) translocation in fibroblasts. An adeno-associated virus 9-mediated, cardiomyocyte-specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis, as well as decreased left ventricular function, after myocardial infarction. A novel mass spectrometry-based approach allows investigation of the secretome of primary cardiomyocytes. Analysis of hypoxia-induced secretion led to the identification of PCSK6 as being crucially involved in cardiac remodeling after acute myocardial infarction.
Selepressin for Patients With Septic Shock
Authors: Sebastian Rehberg, Andrea Morelli, Gerrit Jansen
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
Vitamin C for Sepsis and Acute Respiratory Failure—Reply
Authors: Alpha A. Fowler, Bernard J. Fisher, Markos G. Kashiouris
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
Neoadjuvant chemotherapy-induced sarcopenia to predict perioperative complications following radical cystectomy for bladder cancer.
Authors: Miki Haifler, Yossi Ventura, Kamil Malsha, Sagi Shpitzer, Amnon Zisman, Jack Baniel, Gilad Amiel, Azik Hoffman, Shay Golan
Journal: Journal of Clinical Oncology (2020)

478 Background: Radical cystectomy (RC) with neoadjuvant chemotherapy (NAC) is the standard of care for muscle invasive bladder cancer and has a high rate of complications. Malnutrition is common among RC patients and is an established risk factor for peri-operative complications. The association of NAC and nutritional status and its effect on post-operative complications is not fully understood. We hypothesize that NAC hinders nutritional status and thus increases complication rates after RC. Methods: We retrospectively examined the records of NAC/RC patients. We included demographic, clinical and pathologic data and type and cycle number of NAC. Nutritional status was assessed with the smooth muscle area (SMA) of the psoas muscle at the level of L4 vertebrae measured on cross-sectional imaging. Patients with missing imaging data were excluded. SMA was measured pre and post NAC. The difference between the measurements was used as a predictor variable (delta_SMA). The outcomes assessed were ileus, infection, rehospitalization and a composite outcome of any complication. Results: The study included 50 patients, from 3 high volume centers in Israel. Median delta_SMA was -197 (-366, -88) mm 2 . Demographic, clinical and pathologic parameters were similar in patients with and without complications. delta_SMA was an independent predictor of ileus (OR = 0.98, p=0.003), peri-operative infection (OR = 0.98, p=0.0015) and any complications (OR = 0.98, p = 0.011) on univariable analysis. Delta_SMA remained an independent predictor of ilieus (OR 0.97, p=0.014), peri-operative infections (OR 0.95, p=0.023) and any complications (OR 0.98, p=0.01) on multivariable regression analysis. Delta_SMA was not a significant predictor of rehospitalization. Conclusions: In patients undergoing RC, NAC causes a measurable nutritional insult. The change in SMA predicts significant peri-operative complications. Future studies should examine the role of nutritional intervention during NAC in the framework of a clinical trial.
Myelodysplastic Syndrome Presenting With Diffuse Bone Marrow Uptake on 68Ga-PSMA PET/CT
Authors: İpek Arslan, Emre Demirci, Selvinaz Özkara, Neslihan Taşdelen, Nalan Alan Selçuk
Journal: Clinical Nuclear Medicine (2020)

Abstract We present the case of a 67-year-old man with prostate cancer who had no findings of recurrence, except diffuse radiotracer uptake in the bone marrow in 68 Ga-PSMA PET/CT. Bone marrow uptake was also represented as multiple focal increased spots without any corresponding lytic or sclerotic lesions in CT. MRI revealed a high and homogeneous T2 signal within the bone marrow, without any contrast-enhanced or diffusion-restricted lesions. Further workup, including a bone marrow biopsy, revealed the diagnosis of myelodysplastic syndrome.
Helen Salisbury: Prestidigitation
Authors: Helen Salisbury
Journal: BMJ (2020)

This week Matt Hancock, secretary of state for health and social care, welcomed the introduction of the Medicines and Medical Devices Bill, tweeting a Daily Express headline that proclaimed, “NHS red tape slashed to boost patient care.” While I’d hate to be branded a Luddite, I admit to scepticism when it comes to medicine’s digital revolution. In the rush to approve new devices and apps, who defines what is red tape and what is due diligence?

Some patients are keen to take control of their health and to avoid bothering their GP, especially …
Family history and germline alterations in metastatic prostate cancer patients.
Authors: Whitley Hatton, Ellen Jaeger, Marcus W. Moses, Alexa Zaheri, Patrick Cotogno, Charlotte Manogue, Brian E. Lewis, Pedro C. Barata, Jodi Lyn Layton, Elisa Marie Ledet, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2020)

231 Background: Recent literature has highlighted the importance of germline genetic testing in metastatic prostate cancer (PCa)patients (pts). This retrospective study evaluated family history (FH), evaluate treatment outcomes in metastatic patients with pathogenic germline mutations, and compared family history in Caucasian (CA) and Africans Americans (AA). Methods: At Tulane Cancer Center, 428 metastatic PCa pts had germline testing in at least 79 genes. Comprehensive family histories were obtained in all. Analysis of prevalent FH, including breast, ovarian, prostate, and pancreatic cancers was assessed for all metastatic pts. Statistical analyses including chi square were performed. Results: 64 (64/428; 14.9%) pts had at least one or more pathogenic mutations, while 166 (166/428; 38.7%) had were normal. The remaining 199 (199/428; 46.4%) of pts had a variant of uncertain significance (VUS). Pts with a DNA repair pathogenic mutation were more likely to have &gt;2 family members affected by cancer, regardless of cancer type or degree of relationship (p=0.0047); 6 pts without any family history of cancer had a pathogenic mutation. In CA, the presence of either a breast or PCa family history was associated with pathogenic germline findings (p=.022/.0367) However, in AAs neither breast nor prostate cancer predicted pathogenic germline alterations. Conclusions: The correlation between family history of breast and PCa cancer in CA pts with pathogenic mutations is notable as is the finding of &gt;2 family members with cancer predicting germline pathogenic alterations. With AA pathogenic pts, there was no correlation of family history of breast and PCa, which highlights the need to learn more about the genetic factors which influence AA prostate cancer risk.[Table: see text]
Fermentation Products of Commensal Bacteria Alter Enterocyte Lipid Metabolism
Authors: João R. Araújo, Asmaa Tazi, Odile Burlen-Defranoux, Sophie Vichier-Guerre, Giulia Nigro, Hélène Licandro, Sylvie Demignot, Philippe J. Sansonetti
Journal: Cell Host & Microbe (2020)
Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Long-term follow up of secondary endpoints.
Authors: Benjamin Louis Maughan, Andrew W Hahn, Roberto Nussenzveig, John Hoffman, Kathryn Morton, Sumati Gupta, Julia Anne Batten, Jared Thorley, Josiah Hawks, Victor Sacristan Santos, Gayatri Nachaegari, Xuechen Wang, Kenneth M. Boucher, Benjamin Haaland, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2020)

125 Background: RA, a bone targeting alpha radiopharmaceutical, and EZ, are approved for mCRPC. Per phase 3 SWOG0421 trial, men with mCRPC and a significant decline in serum bone metabolism markers (BMM) had improved survival with atrasentan, a bone targeting agent (PMID 24565955). We hypothesized that RA+EZ is safe, and decrease bone metabolism markers compared to EZ alone. Here we report the long-term follow up of the secondary clinical endpoints. Methods: In this phase 2 trial (NCT02199197), men with progressive mCRPC were treated with EZ (160 mg daily) ± RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives: 1) changes in N-telopeptide compared from baseline to end of treatment; 2) safety. Secondary objectives: changes in 4 other markers of bone resorption or formation, and PSA progression free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). Results: After a safety lead in phase (n=8), 39 men were randomized (2:1) to RA+EZ vs EZ. Median follow up is 19.3 months (range 3 – 24 months). Combining RA+EZ was safe (2018 ASCO annual meeting abstract: 5057) and met the primary endpoint (2018 ESMO annual meeting: Annals of Oncology). There was a consistent trend regarding PSA-PFS, rPFS and OS favoring RA+EZ over EZ. . . (Table). Notably, no bone fractures have occurred in either group with extended follow up. Conclusions: The use of RA+EZ was safe with a longer follow up with no increase in skeletal related events including fractures. All secondary endpoints, numerically favored RA+EZ vs EZ. Clinical trial information: NCT02614859.
Stalled Federal Efforts to End Surprise Billing — The Role of Private Equity
Authors: Erin C. Fuse Brown
Journal: New England Journal of Medicine (2020)

Interview with Prof. Erin Fuse Brown on Congress's failure to address surprise medical bills in 2019 and renewed efforts in 2020. (13:31)Download Though U.S. legislation targeting the problem of surprise medical bills advanced out of key congressional committees in 2019 with support from leaders in both parties, Congress ultimately failed to pass a law to end such bills.
Targeting resistant prostate cancer with ATR and PARP inhibition (TRAP trial): A phase II study.
Authors: Zachery R. Reichert, Stephanie Daignault, Benjamin A. Teply, Michael Edward Devitt, Elisabeth I. Heath
Journal: Journal of Clinical Oncology (2020)

TPS254 Background: Inhibition of poly(ADP-ribose) polymerase (PARP) shows promise in prostate cancer, but is limited to the ~20% of men with defects in genes encoding for DNA repair proteins BRCA1, BRCA2 or ATM (homologous recombination defect positive, HRD+). The effect is modest for HRD+ patients with a progression free survival of ~7 months. Pharmacologically simulating genetic DNA repair defects may expand who benefits to homologous recombination defect negative (HRD-) patients and improve HRD+ response. The ataxia telangiectasia and Rad3-related protein (ATR) is ideal with its roles in cell cycle regulation, replication fork resolution and both single and double strand break repair. Preclinical studies on HRD-/HRD+ cell lines support this. We hypothesize co-inhibition of ATR and PARP will respond regardless of HRD status. Methods: TRAP is a prospective, multi-institutional, phase 2 clinical trial testing AZD6738 combined with olaparib in HRD+ and HRD- mCRPC patients. Primary endpoint is the response rate (RR) by RECIST radiographic response or PSA decline ≥50% in 35 HRD- patients, with a secondary objective of RR in 12 HRD+ patients. HRD+ is mono/biallelic loss of ATM or biallelic loss of BRCA1/2. Tissue based sequencing is done unless completed prior in mCRPC, known BRCA germline loss, treating provider deems biopsy unsafe or biopsy fails. Those unable or failing biopsy are designated as HRD-, but BRCA1/2 and ATM are tested via circulating tumor DNA in a commercial test. Eligible patients must progress after ≥1 line of mCRPC therapy. Progression on a second generation anti-androgen (e.g. apalutamide), abiraterone or within 6 months of docetaxel in hormone sensitive disease are eligible. Treatment entails 160 mg PO daily of AZD6738 on days 1-7 and 300 mg PO BID of olaparib on days 1-28 of a 28-day cycle. Statistical analysis will provide RR with 95% binomial confidence intervals. Analysis of tumor specimens, circulating tumor cells and DNA will be performed for predictors of response and acquired resistance. The study is at four sites in the US, participates in the Prostate Cancer Clinical Trials Consortium, LLC, is managed by the University of Michigan and funded by AstraZeneca. Clinical trial information: NCT03787680.
タスキニモドは易感染性癌の微小環境内におけるHDAC4生存シグナル伝達のアロステリックな調節因子である | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: T Isaacs John, Antony Lizamma, L Dalrymple Susan, Brennen W. Nathaniel, Gerber Stephanie, Hammers Hans, Wissing Michel, Kachhap Sushant, Luo Jun, Xing Li, Bjoerk Per, Olsson Anders, Bjoerk Anders, Leanderson Tomas
Journal: Cancer Research (2013)
Antifungal susceptibility testing in Candida, Aspergillus and Cryptococcus infections: are the MICs useful for clinicians?
Authors: M. Bassetti, A. Vena, E. Bouza, M. Peghin, P. Muñoz, E. Righi, F. Pea, M. Lackner, C. Lass-Flörl
Journal: Clinical Microbiology and Infection (2020)
Point-of-care HIV viral load testing combined with task shifting to improve treatment outcomes (STREAM): findings from an open-label, non-inferiority, randomised controlled trial
Authors: Paul K Drain, Jienchi Dorward, Lauren R Violette, Justice Quame-Amaglo, Katherine K Thomas, Natasha Samsunder, Hope Ngobese, Koleka Mlisana, Pravikrishnen Moodley, Deborah Donnell, Ruanne V Barnabas, Kogieleum Naidoo, Salim S Abdool Karim, Connie Celum, Nigel Garrett
Journal: The Lancet HIV (2020)
Novel androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer: A network meta-analysis.
Authors: Amanda Elizabeth Hird, Diana E. Magee, Bimal Bhindi, Xiang Y. Ye, Thenappan Chandrasekar, Hanan Goldberg, Laurence Klotz, Neil Fleshner, Raj Satkunasivam, Zachary William Abraham Klaassen, Christopher J.D. Wallis
Journal: Journal of Clinical Oncology (2020)

131 Background: Novel non-steroidal anti-androgens (NSAAs) including enzalutamide, apalutamide, and darolutamide with androgen deprivation therapy (ADT) have proven efficacy in men with high-risk non-metastatic castrate resistant prostate cancer (nmCRPC). However, in the absence of direct comparative trials, there is little evidence to guide therapeutic choice. Our objective was to perform a network meta-analysis to compare agents and perform a class-level meta-analysis of NSAAs with androgen deprivation therapy (ADT) versus ADT-alone. Methods: We performed a systematic review of phase III parallel-group RCTs in men ≥18 years of age with nmCRPC using EMBASE and MEDLINE, indexed as of March 8, 2019. Our primary outcome was metastasis free survival (MFS). Secondary outcomes included OS, PSA progression free survival (PFS), and rates of grade 3-4 adverse events (AEs). Three RCTs were identified. We performed a random effects meta-analysis of NSAA versus ADT-alone using the inverse variance technique for meta-analysis for efficacy outcomes and the Mantel-Haenszel method for meta-analysis of dichotomous data for AEs. We then performed a network meta-analysis to compare outcomes between NSAAs using fixed-effect models in a Bayesian framework. We estimated the relative ranking of the different treatments for each outcome. Results: Pooled MFS, PSA-PFS, and OS were significantly greater with NSAA versus placebo (HR:0.32,95%CI:0.25-0.41, HR:0.08,95%CI:0.05-0.13, and HR:0.74,95%CI:0.61-0.90, respectively). Apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing MFS, respectively. There was a 44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide offered the greatest OS benefit, respectively. There was a 61% chance that darolutamide was preferred with respect to AEs. Conclusions: NSAAs improve survival outcomes in patients with high-risk nmCRPC. Apalutamide and enzalutamide may offer improved oncological outcomes. Darolutamide may result in fewer adverse events. These differences, if confirmed, would be meaningful to patients and practitioners when selecting treatment.
Impact of somatic <i>SPOP (</i>Speckle-Type POZ protein) mutation (mtSPOP) on response to systemic therapy and survival outcome in men with de novo metastatic castration-sensitive prostate cancer (d-mCSPC).
Authors: Umang Swami, Pedro Isaacsson Velho, Roberto Nussenzveig, Victor Sacristan Santos, Stephanie Erickson, Divya Dharmaraj, Ajjai Shivaram Alva, Ulka N. Vaishampayan, John Esther, Andrew W Hahn, Benjamin Louis Maughan, Emmanuel S. Antonarakis, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2020)

329 Background: Men with metastatic castration resistant prostate cancer harboring somatic mutant SPOP (mt SPOP) have improved progression free survival (PFS) on abiraterone than those with wild-type SPOP (wt SPOP) (Boysen et al, CCR 2018; PMID: 30068710). We hypothesized that mtSPOP will be associated with improved response to systemic therapy and outcomes in mCSPC. Methods: This retrospective study included patients from 4 academic institutions. Eligibility criteria: receipt of standard androgen deprivation therapy (ADT) without intensification (chemotherapy or novel hormonal agents) for the diagnosis of d-mCSPC, no prior history or treatment for prostate cancer, and established SPOP status determined by targeted next-generation sequencing. PFS was defined per PCWG2 defined PSA or investigator assessed radiographic progression. Overall survival (OS) was calculated from date of starting ADT for d-mCSPC to date of death. Kaplan-Meier analysis and t-test were used to compare variables in these two cohorts. Results: Of 110 mtSPOP men with advanced prostate cancer identified, 37 had d-mCSPC of which 25 received ADT. Of 353 wtSPOP patients, 184 had d-mCSPC of which 97 received ADT. Baseline demographics and disease characteristic were similar (table). mtSPOP was associated with significantly improved PFS [35 vs. 14 months, HR 0.519 (95% CI 0.312-0.861), p=0.011] and OS [97 vs. 69 months, HR 0.4392 (95% CI=0.207-0.931); p=0.032] with ADT as compared to wtSPOP patients. Conclusions: Men with d-mCSPC with somatic mtSPOP have improved outcomes with ADT than those with wtSPOP. Once validated, these hypothesis generating data may aid with counselling and treatment selection, as well as patient stratification in future trials in d-mCSPC.[Table: see text]
Mutanome engineered RNA immuno-therapy (MERIT) for patients with triple negative breast cancer
Authors: K. Frenzel, L. Heesen, S. Bolte, V. Bukur, M. Diken, E. Derhovanessian, S. Kreiter, A. Kuhn, K. Kuehlcke, M. Löwer, J. De Greve, H. Lindman, S. Pascolo, M. Schmidt, A. Schneeweiss, T. Sjöblom, K. Thielemans, L. Zitvogel, Ö Türeci, U. Sahin
Journal: Annals of Oncology (2017)