tbuckley/cabot-search huggingface dataset:
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma
Authors: Jae‐Kyung Won, Su Jong Yu, Chae Young Hwang, Sung‐Hwan Cho, Sang‐Min Park, Kwangsoo Kim, Won‐Mook Choi, Hyeki Cho, Eun Ju Cho, Jeong‐Hoon Lee, Kyung Bun Lee, Yoon Jun Kim, Kyung‐Suk Suh, Ja‐June Jang, Chung Yong Kim, Jung‐Hwan Yoon, Kwang‐Hyun Cho
Journal: Hepatology (2017)

Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low-PDI-expression group.These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. (Hepatology 2017;66:855-868).
HIV services are at risk from fragmentation, report warns
Authors: Anne Gulland
Journal: BMJ (2017)

Fragmentation of services is putting England’s world class HIV care at risk, a report by the King’s Fund has said.

The report on the future of HIV services in England warns that the Health and Social Care Act 2012 created a “fragmented and complex system,” making it harder to “deliver HIV care in the way that will be needed in future.”1

Before the act, services for HIV prevention, treatment, and support were commissioned by primary care trusts and some specialist HIV services but, since the act was implemented in 2013, responsibility has been split between clinical commissioning groups, local authorities, and NHS England.

The report says that this division of responsibilities has so far not had a …
Cryptic Philadelphia Chromosome in Newly Diagnosed Chronic Phase CML (CML-CP): Clinical Characteristics and Treatment Outcome after Treatment with 5 TKI Modalities
Authors: Ahmad N. Ghorab, Hagop M. Kantarjian, Preetesh Jain, Courtney D DiNardo, Farhad Ravandi, Guillermo Garcia-Manero, Elias J. Jabbour, Jorge E. Cortes
Journal: Blood (2016)
Clinical Features and Outcomes of Patients with Colorectal Cancers Harboring NRAS Mutations
Authors: Andrea Cercek, Maria Ignez Braghiroli, Joanne F. Chou, Jaclyn F. Hechtman, Nancy Kemeny, Leonard Saltz, Marinela Capanu, Rona Yaeger
Journal: Clinical Cancer Research (2017)

Purpose:NRAS mutations are now routinely included in RAS testing prior to EGFR inhibitor therapy for metastatic colorectal cancer (mCRC). The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy, however, are not known. We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS-mutant mCRC.Experimental Design: We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008 to 2015. Comparison groups consisted of RAS wild-type and KRAS-mutant mCRC consecutive cases genotyped from 2008 to 2012.Results: Three percent (87/2764) of mCRC patients had NRAS-mutant tumors (45% exon 2 and 55% exon 3), including three cases with concurrent NRAS and KRAS mutations. Left-sided primary site and African American self-reported race were associated with NRAS mutation (P < 0.01). Resection rate at 12 months was lower for NRAS-mutant mCRC than for RAS wild-type or KRAS-mutant mCRC. Median survival from time of first known metastasis was 33 months for NRAS-mutant, 47 months for KRAS-mutant, and 78 months for RAS wild-type cases (P < 0.001). Multivariate analysis assigned an HR for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation (P < 0.01).Conclusions:NRAS defines a molecular subset with distinct clinical characteristics from KRAS-mutant and wild-type mCRC. NRAS mutations are enriched in left-sided primary tumors and among African Americans. Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS-mutant or wild-type mCRC. Clin Cancer Res; 23(16); 4753-60. ©2017 AACR.
Nerve Growth Factor and Pain Mechanisms
Authors: Franziska Denk, David L. Bennett, Stephen B. McMahon
Journal: Annual Review of Neuroscience (2017)

Nerve growth factor (NGF) antagonism is on the verge of becoming a powerful analgesic treatment for numerous conditions, including osteoarthritis and lower back pain. This review summarizes the historical research, both fundamental and clinical, that led to our current understanding of NGF biology. We also discuss the surprising number of questions that remain about NGF expression patterns and NGF's various functions and interaction partners in relation to persistent pain and the potential side effects of anti-NGF therapy.
Unique and Novel Urinary Metabolomic Features in Malignant versus Benign Adrenal Neoplasms
Authors: Dhaval Patel, Matthew D. Thompson, Soumen K. Manna, Kristopher W. Krausz, Lisa Zhang, Naris Nilubol, Frank J. Gonzalez, Electron Kebebew
Journal: Clinical Cancer Research (2017)

Purpose: Adrenal incidentalomas must be differentiated from adrenocortical cancer (ACC). Currently, size, growth, and imaging characteristics determine the potential for malignancy but are imperfect. The aim was to evaluate whether urinary small molecules (<800 Da) are associated with ACC.Experimental Design: Preoperative fasting urine specimens from patients with ACC (n = 19) and benign adrenal tumors (n = 46) were analyzed by unbiased ultraperformance liquid chromatography/mass spectrometry. Creatinine-normalized features were analyzed by Progenesis, SIMCA, and unpaired t test adjusted by FDR. Features with an AUC >0.8 were identified through fragmentation patterns and database searches. All lead features were assessed in an independent set from patients with ACC (n = 11) and benign adrenal tumors (n = 46) and in a subset of tissue samples from patients with ACC (n = 15) and benign adrenal tumors (n = 15) in the training set.Results: Sixty-nine features were discovered and four known metabolites identified. Urinary creatine riboside was elevated 2.1-fold (P = 0.0001) in patients with ACC. L-tryptophan, Nε,Nε,Nε-trimethyl-L-lysine, and 3-methylhistidine were lower 0.33-fold (P < 0.0001), 0.56-fold (P < 0.0001), and 0.33-fold (P = 0.0003) in patients with ACC, respectively. Combined multivariate analysis of the four biomarkers showed an AUC of 0.89 [sensitivity 94.7% (confidence interval {CI}, 73.9%-99.1%), specificity 82.6% (CI, 68.6%-92.2%), PPV 69.2% (CI, 48.2%-85.6%), and NPV 97.4% (CI, 86.5%-99.6%)] for distinguishing ACC from benign tumors. Of the four, creatine riboside and four unknown features were validated. Creatine riboside, Nε,Nε,Nε-trimethyl-L-lysine, and two unknown features were elevated in ACC tumors.Conclusions: There are unique urinary metabolic features in patients with ACC with some metabolites present in patient tumor samples. Urinary creatine riboside can differentiate benign adrenal neoplasms from ACC. Clin Cancer Res; 23(17); 5302-10. ©2017 AACR.
Pentraxin 3 As a Novel Diagnostic and Prognostic Biomarker for Acute GvHD and Fungal Infections in Adult Allogeneic HSCT Recipients
Authors: Raffaella Greco, Elisa Sala, Lara Crucitti, Mara Morelli, Maria Teresa Lupo Stanghellini, Luca Vago, Andrea Angelo Assanelli, Fabio Giglio, Matteo Giovanni Carrabba, Giorgia Levati, Francesca Lorentino, Michela Giulia Tassara, Barbara Bottazzi, Roberto Leone, Consuelo Corti, Massimo Bernardi, Jacopo Peccatori, Alberto Mantovani, Fabio Ciceri, Cecilia Garlanda
Journal: Blood (2016)
Phase I Study of the Combination of 5-Azacitidine Sequentially with High-Dose Lenalidomide in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML)
Authors: Guillermo Garcia-Manero, Naval G. Daver, Gautam Borthakur, Marina Konopleva, Farhad Ravandi, William G. Wierda, Zeev Estrov, Stefan Faderl, Tapan Kadia, Kristy Rey, Cora Cheung, Hagop M. Kantarjian
Journal: Blood (2011)
P08.43 Understanding the aggressive nature of glioblastoma tumors associated with the subventricular zone
Authors: K. Gollapalli, S. Ghantasala, S. Kumar, R. Srivastava, S. Rapole, E. Sridhar, S. Srivastava, A. Moiyadi
Journal: Neuro-Oncology (2017)

Introduction: Subventricular zone (SVZ) in the brain is niche of neural stem cells. From recent reports it is evident that the glioma patients with tumors (both low-grade and high-grade glial tumors) in close proximity to the SVZ region (SVZ+) exhibit lower survival rate than those patients with tumors away from the SVZ region (SVZ-). In order to understand the molecular features responsible for aggressive nature of SVZ+ tumors over SVZ- tumors, serum and tissue proteomic analyses of glioblastomas (GBM) were performed. Materials and Methods: Serum proteomic analysis of SVZ- and SVZ+ GBMs was performed using two dimensional difference gel electrophoresis (2D-DIGE) and isobaric tags for relative and absolute quantitation (iTRAQ) methods. Tissue proteomic analysis of SVZ- and SVZ+ GBMs was performed using 2D-DIGE method, whereas in iTRAQ method, SVZ- and SVZ+ GBM tissue proteins were compared with peri-tumoral control tissue proteins. Validation of a few significantly altered proteins was performed using immunoblotting approach. Results: Serum levels of lipid binding proteins like apolipoproteins and acute phase proteins like hemopexin and alpha-1-antichymotrypsin were found to be altered in SVZ+ GBMs with respect to SVZ- GBMs. Tissue proteomic analysis revealed various metabolic pathways affected in SVZ- and SVZ+ GBMs, which includes glycolysis, gluconeogenesis, complement and coagulation cascades, aminoacid metabolism, extracellular matrix - receptor interactions etc. Various DNA repair enzymes like X-ray repair cross-complementing proteins and histone proteins were found to be highly up-regulated in SVZ- GBMs with respect to SVZ+ GBMs, while proteins like thymosin beta-4-like protein 3, alpha-1-antitrypsin, ferritin heavy and light chains and haptoglobin which are associated with the aggressive nature of tumors were found to be up-regulated in SVZ+ GBMs with respect to SVZ- GBMs. Conclusions: Increased tumor levels of various proteins associated with cell proliferation, migration, invasion and anti-apoptosis, while decreased levels of apoptotic and DNA damage repairing enzymes in SVZ+ GBMs provides a plausible explanation to their increased aggressiveness over SVZ- GBM tumors. Further understanding of these complex subtypes of GBM tumors can prove beneficial towards development of therapeutic targets and in deciding treatment modalities.
Abstract 241: Acetylomic and Metabolomic Alterations in Aged Hearts: Role for Silent Information Regulator (SIRT) 3
Authors: Jimmy Zhang, William R Urciuoli, Paul S Brookes, George A Porter, Sergiy M Nadtochiy
Journal: Circulation Research (2015)

Introduction: SIRT3 is a mitochondrial metabolic regulator, and a decline in function of SIRT3 may play a role in age-related mitochondrial alterations. The aim of this study was to investigate the possible down-regulation of SIRT3 activity in aged hearts, and to identify which metabolic pathways in aged hearts may be impaired due to SIRT3 dysfunction. Methods: Mitochondria were isolated from WT adult (7 mo.), SIRT3 -/- adult (7 mo.) and WT aged (18 mo.) hearts. Acetylated proteins in mitochondrial samples were identified using 2D gels and mass spectrometry. Metabolite concentrations and carbon fluxes through core metabolic pathways were determined using 13 C-labeled substrates and LC-MS/MS. Results: Mitochondrial acetylation patterns in the SIRT3 -/- adult group matched those found in the WT aged group; the level of acetylation was significantly higher than in WT adult. While the SIRT3 -/- samples exhibited zero SIRT3 protein content, no difference in SIRT3 protein level was seen between adult and aged WT hearts. Mechanistically, this suggests that alterations in mitochondrial acetylation during aging were not caused by lower SIRT3 protein levels, but rather by a lower SIRT3 enzymatic activity. Furthermore, aged myocardium exhibited 40% lower NAD + levels, which may underlie compromised SIRT3 activity. ATP levels were decreased in both SIRT3 -/- and WT aged hearts, suggesting possible defects in energy metabolism. Using metabolomics, we demonstrated that alterations of TCA cycle intermediates were similar in SIRT3 -/- and WT aged hearts (relative to WT adult), and included a substantial decline of carbon flux through α-ketoglutarate and malate. Furthermore, regulation of energy production might also be impaired at the level of the electron transport chain, where Complex I was significantly inhibited in both SIRT3 deficient and aged hearts. Conclusions: Collectively these data suggested that acetylomic and metabolomic fingerprints observed in SIRT3 -/- hearts were recapitulated in aged hearts.
Using tumor-associated antigen (TAA) chip technology to enhance antibody detection in immunodiagnosis of hepatocellular carcinoma
Authors: Koksun Looi, Ernesto Nakayasu, Hugo Villanueva, Igor Almeida, Jianying Zhang
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3972 

Liver cancer, especially hepatocellular carcinoma (HCC), is one of the most malignant tumors, which affects the Hispanic population of the United States at a rate double that of the white population. The majority of people with HCC will die within 1 year of its detection. This high case fatality rate can in part be attributed to lack of diagnostic methods that allow early detection. Therefore, there is an urgent need for the development of more HCC sensitive and specific approaches in the early detection of this cancer. In the present study, the proteomic approach was applied to identify HCC-related TAAs as markers in HCC. Twenty HCC sera and 10 normal human sera were collected from the US-Mexico border region, and further used in proteomic approach to identify potential TAAs. A total of 34 immunoreactive protein spots of interest were excised from the 2-DE gel, digested with trypsin, and subsequently analyzed by mass spectrometry (LC-MS/MS). Of 34 immunoreactive protein spots, 29 were finally identified. In particularly, four proteins were reported to be associated with HCC, and 14 with other type of cancers. In order to evaluate whether these identified proteins can be used as candidate markers in HCC, we have integrated our TAA array with protein chip technology to develop a novel TAA chip for further screening HCC serum samples. A total of 19 TAAs which includes 17 TAAs used in previous studies, and 2 TAAs identified in the above study were printed on microscope slide using a robotic arrayer. In the subsequent study, this TAA chip was used to screen 20 HCC sera and 10 normal sera for evaluating the potential application of this approach. The results indicated that different HCC serum had a different anti-TAA profile. For example, one HCC serum had immunoreactions with cyclin D, cyclin E, p62, koc, c-myc, survivin, wnt, and RalA, and another serum had immunoreactions with p16, cyclin D, cyclin E, koc, c-myc, survivin, wnt, and RalA. Of ten normal sera screened, only one had weak immunoreactions with cyclin D and wnt protein. Of 20 HCC sera tested, six sera showed a much higher intensity value compared to normal controls, indicating that antibody responses to 19 TAAs in some cancer patients were quite robust, and not just mildly elevated. This preliminary study also provides a possibility that a customized TAA chip can be developed in the future for immunodiagnosis of certain type of cancer.
Incident Myocardial Infarction and Very Late Stent Thrombosis in Outpatients With Stable Coronary Artery Disease
Authors: Gilles Lemesle, Olivier Tricot, Thibaud Meurice, Robert Lallemant, Maxence Delomez, Octave Equine, Nicolas Lamblin, Christophe Bauters
Journal: Journal of the American College of Cardiology (2017)
Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies
Authors: N. Boeckx, R. Koukakis, K. Op de Beeck, C. Rolfo, G. Van Camp, S. Siena, J. Tabernero, J.-Y. Douillard, T. André, M. Peeters
Journal: Annals of Oncology (2017)

Previous studies have reported the prognostic impact of primary tumor sidedness in metastatic colorectal cancer (mCRC) and its influence on cetuximab efficacy. The present retrospective analysis of two panitumumab trials investigated a possible association between tumor sidedness and treatment efficacy in first-line mCRC patients with RAS wild-type (WT) primary tumors.Data from two randomized first-line panitumumab trials were analyzed for treatment outcomes by primary tumor sidedness for RAS WT patients. PRIME (phase 3; NCT00364013) compared panitumumab plus FOLFOX versus FOLFOX alone; PEAK (phase 2; NCT00819780) compared panitumumab plus FOLFOX versus bevacizumab plus FOLFOX. Primary tumors located in the cecum to transverse colon were coded as right-sided, while tumors located from the splenic flexure to rectum were considered left-sided.Tumor sidedness ascertainment (RAS WT population) was 83% (n = 559/675); 78% of patients (n = 435) had left-sided and 22% (n = 124) had right-sided tumors. Patients with right-sided tumors did worse for all efficacy parameters compared with patients with left-sided disease in the RAS WT population and also in the RAS/BRAF WT subgroup. In patients with left-sided tumors, panitumumab provided better outcomes than the comparator treatment, including on median overall survival (PRIME: 30.3 versus 23.6 months, adjusted hazard ratio = 0.73, P = 0.0112; PEAK: 43.4 versus 32.0 months, adjusted hazard ratio = 0.77, P = 0.3125).The results of these retrospective analyses confirm that in RAS WT patients, right-sided primary tumors are associated with worse prognosis than left-sided tumors, regardless of first-line treatment received. RAS WT patients with left-sided tumors derive greater benefit from panitumumab-containing treatment than chemotherapy alone or combined with bevacizumab, including an overall survival advantage (treatment difference: PRIME 6.7 months; PEAK 11.4 months). No final conclusions regarding optimal treatment could be drawn for RAS WT patients with right-sided mCRC due to the relatively low number of paxtients. Further research in this field is warranted.PRIME (NCT00364013), PEAK (NCT00819780).
Impact of hearing loss on medical consultations is largely overlooked, review finds
Authors: Susan Mayor
Journal: BMJ (2017)

The impact of older patients’ hearing loss on communication with doctors is largely overlooked in research studies, a review has found.1

Hearing loss is very common in older people, affecting one in four people aged 60-69 and 80% of those over 80. But only about one in five elderly people uses a hearing aid.

Researchers carried out a literature review analysing studies looking at doctor-patient communication with older …
Multimodal assessment of SERS nanoparticle biodistribution post ingestion reveals new potential for clinical translation of Raman imaging
Authors: Jos L. Campbell, Elliott D. SoRelle, Ohad Ilovich, Orly Liba, Michelle L. James, Zhen Qiu, Valerie Perez, Carmel T. Chan, Adam de la Zerda, Cristina Zavaleta
Journal: Biomaterials (2017)
Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation
Authors: Uma Mahesh Gundra, Natasha M Girgis, Michael A Gonzalez, Mei San Tang, Hendrik J P Van Der Zande, Jian-Da Lin, Mireille Ouimet, Lily J Ma, Jordan Poles, Nikollaq Vozhilla, Edward A Fisher, Kathryn J Moore, P'ng Loke
Journal: Nature Immunology (2017)
THE PREVENTION OF DIABETES MELLITUS
Journal: JAMA (1921)

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
Landscape of Combination Immunotherapy and Targeted Therapy to Improve Cancer Management
Authors: Leandro M. Colli, Mitchell J. Machiela, Han Zhang, Timothy A. Myers, Lea Jessop, Olivier Delattre, Kai Yu, Stephen J. Chanock
Journal: Cancer Research (2017)

Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic datasets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide nonsynonymous mutations (NsM) that exceed a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of U.S. annual incident cancer cases. Frequently targetable mutations were in PIK3CA, BRAF, NF1, NRAS, and PTEN We also noted a high burden of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and MET Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs. Cancer Res; 77(13); 3666-71. ©2017 AACR.