tbuckley/cabot-search huggingface dataset:
Abstract 15092: Increased Cysteine Sulfonation of Complex I Mediates Mitochondrial Dysfunction in the Post-Ischemic Rat Heart
Authors: Patrick T Kang, Chwen-Lih Chen, Paul Lin, Yeong-Renn Chen
Journal: Circulation (2017)

A serious consequence of ischemia-reperfusion (IR) is oxidative damage causing mitochondrial dysfunction, which is observed as • O 2  -  overproduction and impaired ATP generation. The cascading ROS can propagate cysteine oxidation on mitochondrial enzymes and add insult to injury. Herein we employed LC-MS/MS to identify protein sulfonation focusing on mitochondrial complex I (Cx1) of sham control and the infarct region of rat hearts subjected to 30 min coronary ligation and 24 h reperfusion. Mitochondria from IR region had increased sulfonation of cysteine ligands of Cx1 iron-sulfur clusters, including N3 (C 425 ), N1b (C 92 ), N4 (C 226 ), N2 (C 158 ), and N1a (C 139 ). The clusters N3, N4, N1a, N2 are key redox-active components of Cx1, S-sulfonation of metal-binding sites impaired the main electron transfer pathway. N1a has a very low redox potential, and functions as an antioxidant to prevent accumulation of FMNH • , reducing  • O 2  -  generation by FMNH •  autooxidation. Increased C 139  sulfonation by IR impaired the cluster N1a, increasing  • O 2  -  generation by CxI. LC-MS/MS also identified IR increased sulfonation of regulatory thiols at the core subunits of Ndufv1 (C 125 , C 187 , C 206 , C 238 , C 255 , C 286 ), Ndus1 (C 367 , C 554 , C 564 , C 727 ), and Ndufs2 (C 146 , C 347 ). The results confirmed the consensus of Ndufv1 and Ndus1 are two major subunits hosting regulatory thiols, and enhanced S-sulfonation by IR predisposed heart a more oxidized status. LC-MS/MS further showed IR enhanced sulfonation at the supernumerary subunits of Ndufa10 (C 112 , C 183 ), Ndufs5 (C 43 ), and Ndufs6 (C 79 ). The Ndufa10 is metazoan-specific with functional implication of stabilizing mammalian Cx1. IR intensely increased Ndufa10 sulfonation, thus destabilizing Cx1 structure. C 43  of Ndufs5 forms intramolecular disulfide bonds with C 56 , which is critical for Cx1 stability. IR-induced C 43  sulfonation thus destabilized Cx1. C 79  of Ndufs6 is involved in Zn 2+ -binding, which is crucial for complex I assembly. C 79  sulfonation by IR impaired Zn 2+ -binding, thus blocking Cx1 assembly and biogenesis. In conclusion, suflonation of specific cysteines of Cx1 mediates IR-induced mitochondrial dysfunction via impaired activity, increased pro-oxidant activity, impaired stability, assembly, and biogenesis of Cx1.
Tumor regression and growth rates of advanced prostate cancer in African American patients treated with docetaxel and prednisone.
Authors: Achuta Kumar Guddati, Deepali Sharma
Journal: Journal of Clinical Oncology (2018)

e17049 Background: Tumor growth rates and regression rates in patients with advanced prostate cancer have been shown to correlate with efficacy of treatment. However, few studies have compared the efficacy of treatment in African American (AA) patients with Caucasian patients. In this study we have compared the growth and regression rates of AA patients with Caucasian patients treated with docetaxel and prednisone. Methods: Treatment data pertaining to the clinical trials: VENICE, ASCENT-2 and MAINSAIL was extracted from publicly available datasets hosted by Project Data Sphere LLC. The calculation of growth rate (g) and regression rate (d) have been described by Wilkerson et al (Lancet Oncology, 2017 Jan;18). ‘g’ and ‘d’ were calculated using the package ‘tumgr’ in ‘R’ statistical software. 32 Caucasian patients and 11 AA patients were excluded from the original data set due to insufficient data points or failure in curve-fit. The median
Identification of pleckstrin homology domain-mediated phosphoinositide binding by human DIP13α/APPL and DIP13β
Authors: Heidi J. Chial, Yong Q. Chen
Journal: Cancer Research (2004)

5153   Interactions between proteins and phosphoinositides can affect subcellular localization, protein-protein interactions, enzymatic activity, and downstream signaling events in a spatially and temporally controlled manner. Intracellular phosphoinositide levels are tightly controlled by specific phosphoinositide kinases and phosphatases and the importance of this regulation is reflected by their association with many human diseases. Several forms of cancer, including breast, colon, ovarian, pancreatic, lymphoid, prostate, multiple myeloma, and head and neck cancers are associated with dysregulation of phosphoinositide-mediated signaling pathways via mutations in phosphoinositide kinases and phosphatases such as phosphatidylinositol 3-kinase (PI3K) and the phosphatase and tensin homolog (PTEN). Pleckstrin homology (PH) domains play a key role in mediating phosphoinositide binding of proteins with diverse cellular functions, including cell proliferation, apoptosis, cytoskeletal remodeling, cell motility, vesicular transport, and metabolism. Human DIP13α/APPL and DIP13β are members of a novel family of proteins that contain a central PH domain and a C-terminal phosphotyrosine binding (PTB) domain. DIP13α was identified by our lab as a protein that interacts with the intracellular domain of the deleted in colorectal cancer (DCC) protein via its PTB domain and is required for DCC-mediated apoptosis. DIP13α has also been identified by other labs as a protein that interacts with AKT protein kinases and with PI3K regulatory and catalytic subunits. Our  in vitro  phosphoinositide binding studies demonstrate that isolated PH domains from DIP13α and DIP13β bind immobilized PtdIns(4)P, PtdIns(5)P, PtdIns(3,4)P2, and PtdIns(3,5)P2. To our knowledge, this is a novel PH domain-mediated phosphoinositide binding profile. We have expressed enhanced cyan fluorescence protein (ECFP) fusions of isolated PH domains and full-length DIP13α and DIP13β proteins in human cell lines and observe patterns of subcellular localization in living cells consistent with membrane and phosphoinositide association  in vivo . Therefore, DIP13α and DIP13β may act as adapter proteins by linking proteins with phosphoinositides and play a role in phosphoinositide-mediated signaling pathways.
The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility
Authors: Mark J. Wall, Dawn R. Collins, Samantha L. Chery, Zachary D. Allen, Elissa D. Pastuzyn, Arlene J. George, Viktoriya D. Nikolova, Sheryl S. Moy, Benjamin D. Philpot, Jason D. Shepherd, Jürgen Müller, Michael D. Ehlers, Angela M. Mabb, Sonia A.L. Corrêa
Journal: Neuron (2018)

Highlights•Mutation of Arc ubiquitination sites slows Arc degradation•Arc knockin mice have enhanced mGluR-LTD•The persistence of Arc reduces cognitive flexibilitySummaryNeuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.Graphical abstract
Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft-tissue sarcomas
Authors: S. Le Guellec, T. Lesluyes, E. Sarot, C. Valle, T. Filleron, P. Rochaix, T. Valentin, G. Pérot, J.-M. Coindre, F. Chibon
Journal: Annals of Oncology (2018)

Prediction of metastatic outcome in sarcomas is challenging for clinical management since they are aggressive and carry a high metastatic risk. A 67-gene expression signature, the Complexity INdex in SARComas (CINSARC), has been identified as a better prognostic factor than the reference pathological grade. Since it cannot be applied easily in standard laboratory practice, we assessed its prognostic value using nanoString on formalin-fixed, paraffin-embedded (FFPE) blocks to evaluate its potential in clinical routine practice and guided therapeutic management. A code set consisting of 67 probes derived from the 67 genes of the CINSARC signature was built and named NanoCind®. To compare the performance of RNA-seq and nanoString (NanoCind®), we used expressions of various sarcomas (n = 124, frozen samples) using both techniques and compared predictive values based on CINSARC risk groups and clinical annotations. We also used nanoString on FFPE blocks (n = 67) and matching frozen and FFPE samples (n = 45) to compare their level of agreement. Metastasis-free survival and agreement values in classification groups were evaluated. CINSARC strongly predicted metastatic outcome using nanoString on frozen samples (HR = 2.9, 95% CI: 1.23-6.82) with similar risk-group classifications (86%). While more than 50% of FFPE blocks were not analyzable by RNA-seq owing to poor RNA quality, all samples were analyzable with nanoString. When similar (risk-group) classifications were measured with frozen tumors (RNA-seq) compared with FFPE blocks (84% agreement), the CINSARC signature was still a predictive factor of metastatic outcome with nanoString on FFPE samples (HR = 4.43, 95% CI: 1.25-15.72). CINSARC is a material-independent prognostic signature for metastatic outcome in sarcomas and outperforms histological grade. Unlike RNA-seq, nanoString is not influenced by the poor quality of RNA extracted from FFPE blocks. The CINSARC signature can potentially be used in combination with nanoString (NanoCind®) in routine clinical practice on FFPE blocks to predict metastatic outcome.
Continuing to Improve Appropriateness of Continuous Electrocardiographic Monitoring (Telemetry)
Authors: Sanket S. Dhruva
Journal: JAMA Internal Medicine (2018)

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 Internal Medicine 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 Internal Medicine journal
Therapeutic and protective efficacy of a dengue antibody against Zika infection in rhesus monkeys
Authors: Peter Abbink, Rafael A. Larocca, Wanwisa Dejnirattisai, Rebecca Peterson, Joseph P. Nkolola, Erica N. Borducchi, Piyada Supasa, Juthathip Mongkolsapaya, Gavin R. Screaton, Dan H. Barouch
Journal: Nature Medicine (2018)
Genome-wide sequencing for early stage lung cancer detection from plasma cell-free DNA (cfDNA): The Circulating Cancer Genome Atlas (CCGA) study.
Authors: Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Alex Aravanis, Nan Zhang, Oliver Venn, Anton Valouev, Ling Shen, Shilpen Patel, Arash Jamshidi, Karthik Jagadeesh, Samuel Gross, Darya Filippova, John F. Beausang, Minetta C. Liu, Donald A. Richards, Sylvia Plevritis, Richard Thomas Williams, Anne-Renee Hartman, Charles Swanton
Journal: Journal of Clinical Oncology (2018)

LBA8501 Background: Plasma cfDNA genomic analysis is used widely for the care of advanced lung cancer, but its suitability for early stage lung cancer detection is not well established. CCGA (NCT02889978) is a prospective, multi-center, observational study launched for the development of a noninvasive assay for cancer detection. Methods: Blood was prospectively collected (N = 1627) from 749 controls (no cancer diagnosis) and 878 participants (pts) with newly-diagnosed untreated cancer in this preplanned substudy, including 127 pts with lung cancer. Three prototype sequencing assays were performed: paired cfDNA and white blood cell (WBC) targeted sequencing (507 genes, 60,000X) for single nucleotide variants/indels; paired cfDNA and WBC whole genome sequencing (WGS) for copy number variation (30X); and cfDNA whole genome bisulfite sequencing (WGBS) for methylation (30X). For each assay, a classification model using 10-fold cross-validation was developed for all pts with cancer, then evaluated in the pts with lung cancer; sensitivity was estimated at 95% specificity. Results: We evaluated pts with lung cancer (127) and a subset of controls (580) with similar ages (mean±SD yrs: 67±9, 60±13), 85% and 43% were ever-smokers, and 46% and 22% were men, respectively. Of 3055 nonsynonymous mutations detected across 122 evaluable pts with lung cancer, &gt; 50% were detected in WBC consistent with clonal hematopoiesis (CH). Accounting for CH, sensitivity in 63 stage I-IIIA pts evaluable across all 3 assays was 48% (35-61, targeted), 54% (41-67, WGS), and 56% (43-68, WGBS); in 54 stage IIIB-IV pts it was 85% (73-93, targeted), 91% (80-97, WGS), and 93% (82-98, WGBS) . Similar sensitivities were observed across histological subtypes (adenocarcinoma, squamous cell, small cell). Comparison to tumor WGS and multi-assay classification will be reported. Conclusions: Early stage lung cancers are detectable in cfDNA using a genome-wide sequencing approach. For lung cancer detection using targeted assays, CH must be accounted for to minimize false positives. Assay optimization is ongoing to allow further clinical development in the intended use population. Clinical trial information: NCT02889978.
Activation of PI3K/AKT/mTOR pathway in ER+ breast cancer: Analysis of paired primary and metastatic tumor samples.
Authors: Teresa R. Pacheco, Afonso C. Fernandes, Suhail M. Ali, Mario Maia-Matos, Ana Lucia Gaspar Gomes da Costa, Catarina Abreu, Antonio Teixeira Alves, Lurdes Correia, Jonathan F. Lara, Richard Alan Michaelson, Arlindo Rebelo Ferreira, Margarida Matias, Kim Leitzel, Allan Lipton, Luis Costa
Journal: Journal of Clinical Oncology (2015)

577 Background: The activation of the mammalian target of rapamycin (mTOR) pathway is associated with resistance to endocrine therapy in breast cancer. Our aim was to evaluate changes in activation of the PIK3/AKT/mTOR pathway between primary and corresponding metastatic tumor samples in estrogen receptor (ER) positive breast cancer patients and to test whether phosphorylated protein levels are predictive of overall survival (OS). Methods: Phosphorylated forms of AKT (p-AKT) and S6 (p-S6) were assessed by immunohistochemistry on archival paraffin embedded samples of primary breast tumors and distant metastases collected from 132 breast cancer patients in two centers. A semi-quantitative scoring system (H-score) was used, combining the intensity of staining and the percentage of stained cells. The difference between expression of p-AKT and p-S6 in primary and metastatic tumor samples was analyzed using the Wilcoxon signed-rank test and the correlation of expression of p-S6 with OS using the Cox’s proportional hazards model. Results: Overall, 93 cases ER and/or PR positive were analyzed. The median age was 55 years; 66 patients were treated with endocrine therapy in adjuvant and/or palliative setting. The median time to relapse was 42.7 mo and the median follow-up was 73.4 mo. The median OS from time of metastatic sample collection was 26.2 mo. The p-AKT H-score index was higher in primary tumor samples when compared to metastases (p = 0.0003). The p-S6 H-score index at the primary tumor and metastatic samples was not significantly different (p = 0.26); concordance between paired samples was 60% using median as cut-off; only metastatic p-S6 H-score index associated with OS (p = 0.022) and the association was also significant when analyzed by quartiles (p = 0.001). Conclusions: Expression levels of p-AKT are significantly lower in metastatic tumor samples. Metastatic p-S6 higher expression might predict worse prognosis in ER+ breast cancer patients, and deserves further study as a novel predictive breast cancer biomarker.
Educating primary care providers about cancer survivorship.
Authors: Genevieve Chaput, Catherine Courteau, Tristan Williams, Vinita D'Souza, Blythe Fortier-McGill
Journal: Journal of Clinical Oncology (2018)

20 Background: Nearly 50% of cancer survivors (CS) experience psychosocial and physical treatment-related effects. CS are often afflicted with greater medical conditions than non-cancer patients: survivorship care is thus imperative. In addition to follow-up by specialists, 75% of CS also visit their primary care provider (PCP) during and after treatments. Despite their role in survivorship, insufficient knowledge and low confidence have been reported by PCPs, supporting the need to educate them. This study aimed to evaluate the educational benefit of a survivorship workshop (SW) targeting PCPs in Montreal, Canada. Methods: An accredited 60-minute SW based on common survivorship issues and recommended guidelines by recognized entities was developed and delivered to 167 PCPs at 6 sites. The same MD presented each SW. Brief matched pre, post and 3 month delayed post surveys were designed (Likert-scale and short-answer questions), and completed on a voluntary basis. Outcome measures targeted 3 levels of Kirkpatrick’s learning model: satisfaction, knowledge, and behavior. Data were analyzed with parametric (paired t-tests) and non-parametric (Wilcoxon Signed rank tests) comparisons as appropriate. Results: The pre and post survey response rate was 65.3% and the 3-month delayed post survey response rate was 56.9%. Immediately following the SW, participants were significantly more likely to be able to list standards of survivorship, t(108) = 10.50, p &lt; .001, and to name late-effects of cancer treatment, t(108) = 5.52 , p &lt; .001. High relevance and satisfaction of SW was reported (95%), and 99% expressed intent to incorporate survivorship information into practice. At 3 months post-SW, confidence remained significantly higher than pre-intervention levels for both knowledge of “late physical effects” ( Z = 6.08, p &lt; .001, n = 60) and “adverse psychosocial outcomes” of cancer and treatments (Z = 4.26, p &lt; .001, n = 62). Conclusions: Much literature has focused on determining PCP barriers to survivorship care, including limited topic proficiency, yet further initiatives are warranted to optimize PCP survivorship expertise. Our SW increased PCP survivorship knowledge, and confidence levels remained greater at 3 months post, indicating its educational merit.
Prescribing in pregnancy shows the weaknesses in pharmacovigilance
Authors: Alain Braillon, Susan Bewley
Journal: BMJ (2018)

Even the most recent of several commendable articles in The BMJ on epilepsy and valproate during pregnancy missed that regulatory agencies should have acted earlier.1

The first report of malformations due to valproate was in 1982.2 Despite many meetings and reports, no action was taken until 2015, when a legal case went public, thanks to a mother whose two children, one after the other, were damaged. She also …
Concordance of genomic alterations (GA) in synchronous tumor biopsies (tBx) and circulating tumor (ct) DNA from metastatic breast cancer (MBC) patients (pts).
Authors: Mafalda Oliveira, Meritxell Bellet, Anna Suñol, Fiorella Ruiz-Pace, Patricia Gomez, Santiago Escrivá, Laia Garrigós, Esther Zamora, Marta Capelán, Analía Azaro, Miriam Arumí, Carolina Ortiz, Judit Matito, Roberta Fasani, Francesco M Mancuso, Martin Espinosa, Paolo Nuciforo, Rodrigo Dienstmann, Ana Vivancos, Cristina Saura
Journal: Journal of Clinical Oncology (2018)

1073 Background: Next generation sequencing (NGS) of tBx is the basis for precision medicine. Most tBx used for NGS are archival primary tumors, often acquired several years before starting matched treatment. Analysis of ctDNA may better capture the GA landscape of MBC. We aimed to compare the concordance of GA detection by NGS in synchronously acquired tBx and ctDNA in MBC pts. Methods: MiSeq Amplicon-based NGS (panel of 59 cancer-related genes) was performed in both tBx and ctDNA at disease progression. The concordance of GA in tBx vs ctDNA was determined at patient level and at mutation (mut) level in clinically actionable genes (PIK3CA, AKT1, ERBB2, ESR1, PTEN). False negative result in ctDNA (FN-ctDNA) defined as mut detected in tBx but not in ctDNA. Results: 28 pts identified (luminal [lum] 21, HER2+ 5, triple negative 2), median prior lines of therapy 4.5 (0-15). Most pts had visceral metastasis (71%); most biopsies were from non-visceral sites (67%), mainly breast/nodes/skin (59%). In 16 pts (57%), tBx and ctDNA had complete concordant results (4 were wild-type). Concordance was 100% in non-lum and 43% in lum pts (P=0.01). Clinically actionable GA were found in 20/28 (71%) pts. FN-ctDNA rate was 25%; these pts had a trend towards having non-visceral metastasis (OR 3.1, P=0.32). Focusing in clinically actionable genes, concordance was 52% at mut level, being lower for ESR1 mut (Table). Interestingly, ctDNA analysis identified 6 ESR1 mut that were not detected in tissue, including 3 pts with a double ESR1 mut. Conclusions: NGS in ctDNA is feasible and the results may be informative for pts management. Our results suggest that ctDNA may be useful for assessing GA in non-lum MBC and the emergence of ESR1 mut in lum MBC. Double ESR1 mut in ctDNA suggests a mechanism of convergent evolution in acquired resistance to endocrine treatment. Causes of discordant tBx/ctDNA (e.g. tumor burden / heterogeneity, technical issues related to ctDNA isolation / processing), warrant further study in larger datasets. N mut detected Concordant mut tBx ctDNA Overall N (%) ERBB2 1 1 1 1 (100) PIK3CA 9 7 9 7 (78) ESR1 10 13 16 7 (44) AKT1 2 0 2 0 PTEN 0 1 1 0 Overall 22 22 29 15 (52)
WHO is “cautiously optimistic” about Ebola ring vaccination programme in DRC
Authors: Jacqui Wise
Journal: BMJ (2018)

Over 400 suspected contacts have been vaccinated against Ebola virus disease in the first stage of the ring vaccination programme in the Democratic Republic of the Congo (DRC). A senior World Health Organization official said that he was cautiously optimistic, as 90% of people at risk in the city of Mbandaka had now been vaccinated.

Latest WHO figures show that 54 cases of Ebola have occurred in DRC, including 25 deaths. Of these cases, 35 are confirmed, 13 are probable, and six are suspected.

The unlicensed rVSV-ZEBOV Ebola vaccine has so far been used only in Mbandaka, a provincial capital with …
Benefit of direct-acting antiviral therapy for hepatitis C virus (HCV) in monoinfected and HIV-HCV-coinfected patients with mixed cryoglobulinaemia
Authors: P. Miailhes, K. Hartig-Lavie, V. Virlogeux, P. Pradat, M. Diakite, A.-C. Uhres, F. Zoulim, M.-N. Sarda
Journal: Clinical Microbiology and Infection (2018)