tbuckley/cabot-search huggingface dataset:
The Objective of Local Therapy in Oligometastatic Cancer Is a Moving Target—Reply
Authors: Zabi Wardak, Puneeth Iyengar
Journal: JAMA Oncology (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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Duplication of hsp-110 Is Implicated in Differential Success of Globodera Species under Climate Change
Authors: Laura M Jones, Sebastian Eves-van den Akker, Patricija van-Oosten Hawle, Howard J Atkinson, Peter E Urwin
Journal: Molecular Biology and Evolution (2018)

Managing the emergence and spread of crop pests and pathogens is essential for global food security. Understanding how organisms have adapted to their native climate is key to predicting the impact of climate change. The potato cyst nematodes Globodera pallida and G. rostochiensis are economically important plant pathogens that cause yield losses of up to 50% in potato. The two species have different thermal optima that may relate to differences in the altitude of their regions of origin in the Andes. Here, we demonstrate that juveniles of G. pallida are less able to recover from heat stress than those of G. rostochiensis. Genome-wide analysis revealed that while both Globodera species respond to heat stress by induction of various protective heat-inducible genes, G. pallida experiences heat stress at lower temperatures. We use C. elegans as a model to demonstrate the dependence of the heat stress response on expression of Heat Shock Factor-1 (HSF-1). Moreover, we show that hsp-110 is induced by heat stress in G. rostochiensis, but not in the less thermotolerant G. pallida. Sequence analysis revealed that this gene and its promoter was duplicated in G. rostochiensis and acquired thermoregulatory properties. We show that hsp-110 is required for recovery from acute thermal stress in both C. elegans and in G. rostochiensis. Our findings point towards an underlying molecular mechanism that allows the differential expansion of one species relative to another closely related species under current climate change scenarios. Similar mechanisms may be true of other invertebrate species with pest status.
Abstract 64: Macrophage perceive tumor-intrinsic glutamine metabolism and orchestrate immunosuppression through IL-23 inclear cell renal cell carcinoma
Authors: Qiang Fu
Journal: Cancer Research (2018)

Abstract The signaling mechanisms between renal cancer cell metabolism and infiltrating immune cells may illuminate novel therapeutic approaches. Here, we showed the idiomatic glutamine metabolism of clear cell renal cell carcinoma (ccRCC) suppress immune surveillance through nonautonomous IL-23. Through analyzing multiple ccRCC clinical cohorts and human tumor samples, we uncovered SLC1A5 (solute carrier family 1 member 5) promotes ccRCC consumption of extrinsic glutamine, predicts patient prognostication, and associates with reduction of cytotoxic T cells and NK cells in the tumor microenvironment. Specifically, the immune surveillance suppression of tumor-intrinsic SLC1A5 is considerably conducted by IL-23, which could directly induce intratumoral accumulation of T helper 17 cells and regulatory T cells. Intriguingly, we identified macrophages as the major source of intratumoral IL-23, and macrophages secrete large amount of IL23 under low glutamine condition, as the consequence of tumor-driven glutamine consumption. Furthermore, blocking IL-23 using specific antibody in syngeneic mice tumor model prolonged their survival, and blocking IL-23 in an in vitro culture model of human tumors promote anti-tumoral T and NK cells reaction. Our results demonstrate that macrophage-secreting IL-23 is a key immune effector as the response to tumor-driving glutamine metabolism, and IL-23 profoundly facilitate an immunosuppressive microenvironment which suggest it as a promising target for cancer immunotherapy in ccRCC. Citation Format: Qiang Fu. Macrophage perceive tumor-intrinsic glutamine metabolism and orchestrate immunosuppression through IL-23 inclear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 64.
LDL subclass distribution is associated with coronary calcification in postmenopausal women
Authors: Rachel H. Mackey, Lewis H. Kuller, Kim Sutton-Tyrrell, Karen A. Matthews, Rhobert W. Evans, Richard Holubkov, James D. Otvos
Journal: Circulation (2001)

0030     Major lipoprotein classes consist of particles of various  sizes, densities and composition. Associations between lipoprotein  subclasses and coronary calcification were evaluated in 287 healthy  women, 8 years post-menopause (age 56.9 to 65.4, mean=61.7 y). Coronary  calcification score (CCS) was measured by electron beam CT and  lipoprotein subclasses were determined by NMR spectroscopy. The mean  CCS was 53 (range 0-1175) but 54% of the women had zero scores. CCS  was analyzed as categories (CCS: 0, 1-99, ≥100). Current smoking was  strongly associated with greater CCS but age and SBP were not  significantly associated. Higher CCS was associated with higher  triglycerides, total cholesterol and LDL-C, by NMR or usual methods,  and total HDL-C by usual methods at the same visit (p   100). The number of LDL  particles was also strongly related to CCS (p  27 mg/dL were more likely to be in a higher CCS category  than those without these risk factors (OR = 2.09, 95% CI: 1.18,  3.70; OR= 2.21, 95% CI: 1.19,4.10, respectively.) After adjustment,  higher CCS was still related to higher levels of small LDL (L1), but  not to mean (LDL) particle size. These relationships were confirmed  using linear regression with log-transformed variables. In  postmenopausal women the size and number of LDL particles may be better  predictors of atherosclerosis than total LDL-C. The level of large VLDL  triglyceride contributes to decreased LDL size and increased number of  LDL particles at a given level of LDL-C, via CETP and hepatic  lipase.
Upskill doctors to make the most of new medical technologies, report says
Authors: Abi Rimmer
Journal: BMJ (2018)

Doctors need training to make success of new technologies, a report on the digital future of the NHS has said.

As part of Health Education England’s (HHE) development of a 10 year strategy for the NHS, Eric Topol, a digital medicine researcher, was commissioned to set up a review of how the workforce needed to be prepared to work with new technologies.12

An interim report, published …
Abstract 2392: Evaluation of synergistic PI3K/Akt and MEK5/ERK5 inhibition in triple-negative breast cancer
Authors: Thomas D. Wright, Christopher Raybuck, Nathan Gartland, Katy Wendekier, Darlene Monlish, Suravi Chakrabarty, Patrick T. Flaherty, Matthew E. Burow, Jane E. Cavanaugh
Journal: Cancer Research (2018)

Abstract Triple negative breast cancers (TNBCs) represent 15-20% of all breast cancers and are often associated with a poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Therefore, there is a need to identify survival pathways that may be targeted in TNBCs. Aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. The crosstalk between PI3K/Akt and MEK1/2/ERK1/2 has been characterized in several systems. However, new evidence suggests that MEK5/ERK5, a member of the MAPK family, is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in three TNBC cell lines: MDA-MB-231, BT549, and MDA-MB-468. We achieved Akt inhibition by using the clinically relevant inhibitors MK-2206 and Ipatasertib. We used a novel compound synthesized in our lab, SC-1-181, and the research tool, XMD8-92, to inhibit MEK5 and ERK5, respectively. Our results indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Interestingly, this signaling pattern was observed without disturbing the ERK1/2 pathway. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. Additionally, the dual inhibition strategy was determined to be synergistic in TNBCs and was nontoxic in non-neoplastic cell lines. Lastly, we evaluated the contributions of Bromodomain 4 (BDR4), an off-target effect of XMD8-92, to the synergy mechanism. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs. Citation Format: Thomas D. Wright, Christopher Raybuck, Nathan Gartland, Katy Wendekier, Darlene Monlish, Suravi Chakrabarty, Patrick T. Flaherty, Matthew E. Burow, Jane E. Cavanaugh. Evaluation of synergistic PI3K/Akt and MEK5/ERK5 inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2392.
Abstract 522: Histone deacetylase 6-let-7i-5p-thrombospondin-1 signaling axis suppresses CD47-dependent tumorigenic behavior of liver cancer
Authors: Hee Doo Yang, Jung Woo Eun, Qingyu Shen, Hyung Seok Kim, Sang Yean Kim, Suk Woo Nam
Journal: Cancer Research (2018)

Abstract Histone deacetylase 6 (HDAC6) uniquely endows as tumor suppressor in liver tumorigenesis, but the underlying mechanisms leading to liver cancer are not fully understood. To identify the large-scale microRNA (miRNA) expression changes by HDAC6, we performed miRNA expression analysis in HDAC6-overexpressing Hep3B cells. From this, let-7i-5p was suggested as most highly associated miRNA with HDAC6 in liver cancer cells. We also found that let-7i-5p expression was up-regulated in a large cohort of HCC patients, and high expression of let-7i-5p was significantly associated with poor prognosis of HCC patients. Ectopic expression of antisense let-7i-5p (AS-let-7i-5p) caused cancer cell growth inhibition mediated by caspase-dependent cell death processing, and inhibited epithelial-mesenchymal transition (EMT) of liver cancer cells. Computational analysis suggested that thrombospondin-1 (TSP-1) is a specific target for let-7i-5p in liver cancer cells. Increased secretion of TSP1 was detected in AS-let-7i-5p transfected HCC cells. We found that partially purified TSP-1 from culture media (ppTSP-1) induced cellular death processing and simultaneously inhibited tumor angiogenesis and metastatic behavior of liver cancer cells. In addition, we observed that anti-TSP-1 antibody containing CD47 receptor binding motif (3F352) attenuated HDAC6, AS-let-7i-5p and TSP-1 effects on liver cancer cells. Furthermore, TSP-1 and ppTSP-1 treatments significantly enhanced macrophage phagocytosis through blocking CD47-dependent “Don't eat me” signal in liver cancer cells. Our findings suggest that HDAC6-let-7i-5p-TSP-1 signaling axis regulates CD47-dependent neoplastic and phagocytic behaviors of hepatocytes providing a novel target for the molecular treatment of liver malignancies. Citation Format: Hee Doo Yang, Jung Woo Eun, Qingyu Shen, Hyung Seok Kim, Sang Yean Kim, Suk Woo Nam. Histone deacetylase 6-let-7i-5p-thrombospondin-1 signaling axis suppresses CD47-dependent tumorigenic behavior of liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 522.
Abstract 1425: A multi-enzyme DNA repair mix improves library quality and sequencing accuracy in FFPE tumor samples
Authors: Pingfang Liu, Margaret Heider, Chen Song, Lixin Chen, Laurence Ettwiller, Lauren Higgins, Eileen Dimalanta, Theodore Davis, Thomas Evans
Journal: Cancer Research (2018)

Abstract Next-generation sequencing (NGS) methods are used extensively to profile mutations present in diseased human tissues. These genomic approaches hold great promise for personalized medicine but sequencing accuracy is essential for proper patient diagnosis and determining a treatment plan. A common source of DNA for genomic profiling is formalin-fixed, paraffin-embedded (FFPE) tissue samples obtained from patient biopsy. FFPE DNA poses important challenges for preparing NGS libraries including low input amounts and poor DNA quality, resulting from extensive fixation- and storage-induced DNA damage. Additionally, these damage-induced sequencing artifacts raise the background level of mutations, making it difficult to discern true, low frequency, disease-causing variants from noise. We previously showed that a major fraction of somatic mutations described in publicly available datasets are due to such sequencing artifacts (Chen et al., Science 2017). Furthermore, we showed that enzymatic repair of DNA before library preparation improves the library quality and reduces background noise. We developed a second-generation DNA repair enzyme mix (V2) that efficiently repairs the most prevalent damage types found in FFPE DNA and further improves the quality and yield of NGS libraries. Additionally, we tested the efficacy of the V2 repair mix in improving sequencing accuracy for FFPE DNA samples obtained from different cancer tissues. We performed target enrichment on a panel of 151 cancer genes, deep sequenced, and performed variant analysis. For a subset of variants, we further validated our results using a droplet digital PCR (ddPCR) assay. Both methods showed that the V2 repair mix did not alter the overall frequency of variants identified, thus it did not introduce bias, but significantly improved the sequencing accuracy by reducing the number of false variant calls. Therefore, enzymatic repair is a critical first step in preparing FFPE DNA sequencing libraries, allowing more sensitive and robust detection of low frequency, disease variants. Citation Format: Pingfang Liu, Margaret Heider, Chen Song, Lixin Chen, Laurence Ettwiller, Lauren Higgins, Eileen Dimalanta, Theodore Davis, Thomas Evans. A multi-enzyme DNA repair mix improves library quality and sequencing accuracy in FFPE tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1425.
An Annular Eruption in a Young Child
Authors: Nirali Patel, Hayley Goldbach, Marcia Hogeling
Journal: JAMA Dermatology (2018)

A young child had a 6-month history of an asymptomatic expanding erythematous eruption on the lower legs, abdomen, and buttocks; clinical examination was significant for faint, nonscaling annular serpiginous, erythematous plaques. What is your diagnosis?
CD1d-dependent natural killer T cells attenuate angiotensin II-induced cardiac remodelling via IL-10 signalling in mice
Authors: Hong-Xia Wang, Wen-Jun Li, Cui-Liu Hou, Song Lai, Yun-Long Zhang, Cui Tian, Hui Yang, Jie Du, Hui-Hua Li
Journal: Cardiovascular Research (2018)

Abstract Aims CD1d is a member of the cluster of differentiation 1 (CD1) family of glycoproteins expressed on the surface of various antigen-presenting cells, which is recognized by natural killer T (NKT) cells. CD1d-dependent NKT cells play an important role in immune-mediated diseases; but the role of these cells in regulating cardiac remodelling remains unknown. Methods and results Cardiac remodelling was induced by angiotensin (Ang) II infusion for 2 weeks. Ang II-induced increase in hypertension, cardiac performance, hypertrophy and fibrosis, inflammatory response, and activation of the NF-kB and TGF-β1/Smad2/3 pathways was significantly aggravated in CD1d knockout (CD1dko) mice compared with wild-type (WT) mice, but these effects were markedly abrogated in WT mice treated with α-galactosylceramide (αGC), a specific activator of NKT cells. Adoptive transfer of CD1dko bone marrow cells to WT mice further confirmed the deleterious effect of CD1dko. Moreover, IL-10 expression was significantly decreased in CD1dko hearts but increased in αGC-treated mice. Co-culture experiments revealed that CD1dko dendritic cells significantly reduced IL-10 mRNA expression from NKT cells. Administration of recombinant murine IL-10 to CD1dko mice improved hypertension, cardiac performance, and adverse cardiac remodelling induced by Ang II, and its cardioprotective effect was possibly associated with activation of STAT3, and inhibition of the TGF-β1 and NF-kB pathways. Conclusion These findings revealed a previously undefined role for CD1d-dependent NKT cells in Ang II-induced cardiac remodelling, hence activation of NKT cells may be a novel therapeutic target for hypertensive cardiac disease.
Potential Underuse of the Sentinel Lymph Node Biopsy for High-Risk Squamous Cell Carcinoma of the Skin—Reply
Authors: Shera Feinstein, Adam Sutton, Ashley Wysong
Journal: JAMA Dermatology (2018)

In Reply We read with interest the response by Glazer et al regarding our study on the underuse of sentinel lymph node biopsy (SLNB) for high-risk cutaneous squamous cell carcinoma (cSCC)1 and noted several important inquiries and comments.
Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care
Authors: Lia Bally, Hood Thabit, Sara Hartnell, Eveline Andereggen, Yue Ruan, Malgorzata E. Wilinska, Mark L. Evans, Maria M. Wertli, Anthony P. Coll, Christoph Stettler, Roman Hovorka
Journal: New England Journal of Medicine (2018)

In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care.In this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge.The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group.Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565 .).
Novel therapeutic strategy for cancer and autoimmune conditions: Modulating cell metabolism and redox capacity
Authors: Xing-Xing Fan, Hu-Dan Pan, Ying Li, Rui-Jin Guo, Elaine Lai-Han Leung, Liang Liu
Journal: Pharmacology & Therapeutics (2018)

Dysregulation of cell metabolism and redox balance is implicated in the pathogenesis and progression of cancer and autoimmune diseases. Because the cell proliferation and apoptotic regulatory pathways are interconnected with metabolic and redox signalling pathways, the current mono-target treatment is ineffective, and multi-drug resistance remains common. Complex diseases are often implicated in a network-based context of pathology; therefore, a new holistic intervention approach is required to block multi-crosstalk in such complicated circumstances. The use of therapeutic agents isolated from herbs to holistically modulate metabolism and redox state has been shown to relieve carcinoma growth and the inflammatory response in autoimmune disorders. Multiple clinically applied or novel herbal chemicals with metabolic and redox modulatory capacity as well as low toxicity have recently been identified. Moreover, new metabolic targets and mechanisms of drug action have been discovered, leading to the exploration of new pathways for drug repositioning, clinical biomarker spectra, clinical treatment strategies and drug development. Taken together with multiple supporting examples, the modulation of cell metabolism and the redox capacity using herbal chemicals is emerging as a new, alternative strategy for the holistic treatment of cancer and autoimmune disorders. In the future, the development of new diagnostic tools based on the detection of metabolic and redox biomarkers, reformulation of optimized herbal compositions using artificial intelligence, and the combination of herbs with mono-targeting drugs will reveal new potential for clinical application.