tbuckley/cabot-search huggingface dataset:
Abstract 5259: Fatty acid oxidation represents a metabolic vulnerability in glioblastoma in nutrient-deprived conditions
Authors: Shiva Kant, Antony Dayalan, Pravin Kesarwani, Prakash Chinnaiyan
Journal: Cancer Research (2019)

Abstract Glioblastoma represents an aggressive, primary brain tumor with limited treatment options. We performed an integrative, cross-platform analysis coupling global metabolomics and gene expression profiling in &amp;gt;100 patient-derived gliomas to begin to understand the diverse metabolic programs driving the aggressive phenotype of this malignancy. Alterations in fatty acid β-oxidation (FAO) emerged as a key metabolic node differentiating glioblastoma from low-grade astrocytoma, as demonstrated by an accumulation of acylcarnitines. Metabolic heterogeneity was observed within glioblastoma that could further define tumors as FAO ‘high’ and ‘low’. Integrative analyses identified these metabolic subtypes to be enriched with mesenchymal (MES) and proneural (PN) glioblastoma subtypes, respectively. These findings were metabolomically and functionally recapitulated in molecular subtype-specific preclinical models. Analysis of gene expression profiles from these lines uncovered an orchestrated transcriptional program designed to promote fatty acid uptake, activation, and mitochondrial oxidation. Studies designed to determine the biologic consequence of enhanced FAO in glioblastoma only identified a role in glucose-deprived conditions, where it served as a vital, alternate source for ATP synthesis. Based on these findings, we tested the hypothesis that dual targeting of glycolysis and FAO would elicit energetic stress-mediated cell death in glioblastoma. Accordingly, the glycolysis inhibitor 2DG and the FAO inhibitor etomoxir only demonstrated anti-proliferative activity in MES glioblastoma cell lines when used as single agents in vitro, while the combination resulted in robust, necroptosis-mediated cell death. Synergistic anti-tumor activity was observed following combined glycolysis and FAO inhibition when extended in vivo in an orthotopic model. Collectively, our findings suggest FAO provides metabolic plasticity in MES glioblastoma, allowing these cells to adapt to nutrient-deprived microenvironments. Combinatorial strategies designed to inhibit glycolysis and FAO represents an attractive therapeutic approach in glioblastoma. Citation Format: Shiva Kant, Antony Dayalan, Pravin Kesarwani, Prakash Chinnaiyan. Fatty acid oxidation represents a metabolic vulnerability in glioblastoma in nutrient-deprived conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5259.
Abstract 1299: Potential antitumor effects of a Golgi disrupting agent, M-COPA, <i>via</i> targeting cell-extracellular matrix interaction under the spheroid culture conditions
Authors: Yoshimi Ohashi, Kazuma Takeuchi, Mutsumi Okamura, Akinobu Akatsuka, Isamu Shiina, Kentaro Yoshimatsu, Shingo Dan
Journal: Cancer Research (2019)

Abstract The Golgi apparatus plays an essential role in the transport, processing, and sorting of cell surface proteins. We previously demonstrated that a Golgi disrupting agent, 2-methylcoprophilinamide (M-COPA), exhibited antitumor effect in human cancer cells in vitro and in vivo; however, in vivo antitumor efficacy of M-COPA did not simply reflect its in vitro efficacy, probably due to the lack of microenvironmental features of tumor tissues in the monolayer culture conditions. To bridge the gap between in vitro and in vivo efficacies, we exploited 3-dimensional (3D) spheroid culture models, which can recapitulate physiological characteristics of tumor tissues; i.e., nutrient/oxygen gradient, cell-cell interaction and cell-extracellular matrix (ECM) interaction, if cancer cells synthesize their own ECM molecules. Interestingly, human gastric cancer MKN1 cells displayed hypersensitivity to M-COPA under the 3D culture conditions compared to those in the monolayer culture conditions. Especially, we found that M-COPA caused loss of spheroid integrity. We previously demonstrated that M-COPA exerted antitumor effects via inhibiting intracellular transport of receptor tyrosine kinases onto the cell surface. Therefore, we examined the involvement of cell adhesion molecules in the antitumor effect of M-COPA. As a result, we found that specific integrins, which serve as cell surface receptors responsible for cell-ECM adhesion, were overexpressed and their downstream signaling molecules such as Src, Akt and MEK/ERK were highly phosphorylated in the cells under the 3D culture conditions compared to those under the monolayer culture conditions. Upon exposure to M-COPA, cell surface expression of these integrins was efficiently decreased and the downstream signaling molecules were dephosphorylated along with loss of spheroid integrity. Moreover, expression knockdown or neutralizing antibody of the integrins clearly suppressed sphere formation of MKN1 cells. These results suggest that M-COPA exerted in vivo antitumor effects via targeting specific integrins that mediate cell-matrix adhesion and its downstream intracellular signaling pathway observed in 3D spheroid culture models. Citation Format: Yoshimi Ohashi, Kazuma Takeuchi, Mutsumi Okamura, Akinobu Akatsuka, Isamu Shiina, Kentaro Yoshimatsu, Shingo Dan. Potential antitumor effects of a Golgi disrupting agent, M-COPA, via targeting cell-extracellular matrix interaction under the spheroid culture conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1299.
Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells
Authors: Annabell Bachem, Christina Makhlouf, Katrina J. Binger, David P. de Souza, Deidra Tull, Katharina Hochheiser, Paul G. Whitney, Daniel Fernandez-Ruiz, Sabrina Dähling, Wolfgang Kastenmüller, Johanna Jönsson, Elise Gressier, Andrew M. Lew, Carolina Perdomo, Andreas Kupz, William Figgett, Fabienne Mackay, Moshe Oleshansky, Brendan E. Russ, Ian A. Parish, Axel Kallies, Malcolm J. McConville, Stephen J. Turner, Thomas Gebhardt, Sammy Bedoui
Journal: Immunity (2019)
Abstract 1311: Inhibition of gankyrin-tumor suppressor protein interactions due to small molecule induced conformational change
Authors: Abbas Kabir, Aaron Muth
Journal: Cancer Research (2019)

Abstract Introduction: Gankyrin is a highly conserved, 25 kDa protein containing 7 ankyrin repeats that binds to the S6 ATPase subunit of the 26S proteasome. It plays a crucial role in cellular growth, proliferation and metastasis. It is found to be largely overexpressed in a variety of malignancies and its abnormal overexpression makes it a biomarker in certain cancers. Gankyrin promotes cellular growth and proliferation through a variety of protein-protein interactions. Specifically, it binds to and promotes degradation of numerous tumor suppressor proteins (TSPs) such as p53 and retinoblastoma protein by promoting their proteasomal degradation. In 2016, a small molecule binder of gankyrin (cjoc42), demonstrated an ability to inhibit gankyrin activity in a dose dependent manner by inhibiting gankyrin’s interaction with certain TSPs as well as the proteasome. Methods: In this research, we hypothesize that small molecule binding of gankyrin brings about a conformational change that inhibits its interaction with certain TSPs as well as the proteasome. In order to test this hypothesis, we have performed a series of fluorescence based experiments. We investigated the effect cjoc42 binding to gankyrin has on its intrinsic tryptophan fluorescence as well as its effect on fluorescently conjugated gankyrin. Follow up experiments consisted of both simple western blotting and co-immunoprecipitation assays to further investigate the ability of cjoc42 to induce a conformational change in gankyrin. Discussion: We observed a diminished fluorescence intensity for both the intrinsic and labeled gankyrin experiments when in the presence of cjoc42. Western blot and Co-IP experiments are currently underway to further support our findings. Conclusion: Cjoc42, a small molecule binder of gankyrin, appears to induce a conformational change. This conformational change appears to play a prominent role in regulating certain protein-protein interactions. Furthermore, this suggests that gankyrin's binding to specific TSPs and the proteasome are modulated by this mechanism. Citation Format: Abbas Kabir, Aaron Muth. Inhibition of gankyrin-tumor suppressor protein interactions due to small molecule induced conformational change [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1311.
Abstract 716: Chakasaponin I from tea (<i>Camellia sinensis</i>) flower induce anti-proliferative effect and apoptosis of cisplatin-resistant ovarian cancer cells
Authors: Yi C. Chen
Journal: Cancer Research (2019)

Abstract Ovarian cancer has the highest rate of death among gynecological malignancy and ranks fifth in cancer deaths among women. Adverse side effects and acquired resistance to conventional chemotherapy based on platinum drive the exploration of other anticancer therapies,thus natural products have drawn greater attention for cancer treatment in recent years. Tea (Camellia sinensis) flower being an abundant agricultural by-product in China and Japan, has been studied for its bio-functional effects. A recent research showed that tea flower saponins (TFS) could induce anti-proliferative effect and cell cycle arrest in human ovarian cancer cells. In the present study, Chakasaponin I, one of the major constituents in TFS, whose main structure is oleanane-type triterpene, showed strong growth inhibitory effects on cisplatin-resistant OVCAR-3 cells at 3 μM by MTS assay. Such inhibitory effects might result from the induction of apoptosis. Western blot assay, Hoechst 33342 staining assay, and flow cytometry analysis were used to examine the effects of Chakasaponin I on apoptosis. The results showed that Chakasaponin I treatment dose-dependently activated the pro-apoptotic proteins (Bad and Bax) and therefore induced apoptosis might by the intrinsic apoptotic pathway. Citation Format: Yi C. Chen. Chakasaponin I from tea (Camellia sinensis) flower induce anti-proliferative effect and apoptosis of cisplatin-resistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 716.
Abstract 029: Age-Related Blood Pressure Changes at the Incipient Stages of Westernization in Yanomami and Yekwana Tribes
Authors: Noel T Mueller, Oscar Noya-Alarcon, Monica Contreras, Lawrence J Appel, Maria Gloria Dominguez-Bello
Journal: Circulation (2018)

Introduction: Studies of isolated hunter-gatherers have found little evidence of the age-related rise in blood pressure (BP) that is common to Western societies, but none of these studies have included children or, for comparison, neighboring tribes exposed to Western culture. We tested the hypothesis that BP does not rise with age in isolated, hunter-gatherer Yanomami, and the age-BP slope is greater in neighboring Yekwana tribes that have some Western exposure. Methods: In the Upper Caura basin, a remote area of the Venezuelan Amazon, we sampled 438 participants from 5 isolated Yanomami-Sanema villages, accessible only by foot or canoe, and 3 Yekwana villages, 1 of which had a grass landing strip for small-engine planes, allowing for delivery of medicine and aspects of Western lifestyle, including salt. Trained researchers measured ausculatory sitting BP in triplicate per standard protocols, and height and weight to determine BMI (kg/m 2 ). We used ANCOVA to compare the age-BP slope between the Yanomami and Yekwana. Results: 154 participants (83 Yekwana; 71 Yanomami) ages 2-60 y (53% female) had data on age and sitting systolic BP (SBP). Age-SBP slopes were significantly different (p=0.02): in Yekwana, a 1-y age increment was associated with a 0.25±0.08 mmHg (p=0.003) increase in SBP ( Figure ), whereas in Yanomami age was not associated with SBP (1-y increment: 0.00±0.07mmHg; p=0.98). These results indicate that at age 10 y, mean sitting SBP was, on average, 5.8 mmHg lower for Yanomami compared to Yekwana, and that the average difference increased to 15.9 mmHg by age 50 y. BP differences between Yanomami and Yekwana remained after control for BMI. Conclusion: In isolated Yanomami with hunter-gatherer-grower lifestyles, BP does not increase with age over ages 2 to 60 y. Yet, among the Yekwana—the closest geographic neighbors of the Yanomami in whom Westernization is at the incipient stages—age is positively associated with BP, suggesting that the rise in BP with age may result in part from cumulative exposure to Western lifestyle.
Necrotizing skin and soft-tissue infections in the intensive care unit
Authors: M. Peetermans, N. de Prost, C. Eckmann, A. Norrby-Teglund, S. Skrede, J.J. De Waele
Journal: Clinical Microbiology and Infection (2019)

Necrotizing skin and soft-tissue infections (NSTI) are rare but potentially life-threatening and disabling infections that often require intensive care unit admission.To review all aspects of care for a critically ill individual with NSTI.Literature search using Medline and Cochrane library, multidisciplinary panel of experts.The initial presentation of a patient with NSTI can be misleading, as features of severe systemic toxicity can obscure sometimes less impressive skin findings. The infection can spread rapidly, and delayed surgery worsens prognosis, hence there is a limited role for additional imaging in the critically ill patient. Also, the utility of clinical scores is contested. Prompt surgery with aggressive debridement of necrotic tissue is required for source control and allows for microbiological sampling. Also, prompt administration of broad-spectrum antimicrobial therapy is warranted, with the addition of clindamycin for its effect on toxin production, both in empirical therapy, and in targeted therapy for monomicrobial group A streptococcal and clostridial NSTI. The role of immunoglobulins and hyperbaric oxygen therapy remains controversial.Close collaboration between intensive care, surgery, microbiology and infectious diseases, and centralization of care is fundamental in the approach to the severely ill patient with NSTI. As many aspects of management of these rare infections are supported by low-quality data only, multicentre trials are urgently needed.
Clinicopathological factors associated with death from thin (≤ 1·00 mm) melanoma
Authors: M. Claeson, P. Baade, S. Brown, H.P. Soyer, B.M. Smithers, A.C. Green, D.C. Whiteman, K. Khosrotehrani
Journal: British Journal of Dermatology (2019)

Thin cutaneous melanomas (≤ 1·00 mm) are increasing worldwide, causing around a quarter of all melanoma deaths in the U.S.A. and Australia. Identification of predictive factors for potentially fatal thin melanomas could allow better use of resources for follow-up.To identify the clinicopathological factors associated with fatal thin melanomas.This large, nested case-case study extracted data from the population-based Queensland Cancer Registry, Australia. Our cohort consisted of Queensland residents aged 0-89 years who were diagnosed with a single, locally invasive thin melanoma (≤ 1·00 mm) between 1995 and 2014. Fatal cases (eligible patients who died from melanoma) were individually matched to three nonfatal cases (eligible patients who were not known to have died from melanoma) according to sex, age, year of diagnosis and follow-up interval. Using conditional logistic regression, we calculated odds ratios (ORs) for melanoma-specific death, adjusting for all collected clinicopathological variables.In the cohort, 27 660 eligible patients were diagnosed with a single, thin melanoma. The final case-case series included 424 fatal cases and 1189 nonfatal cases. Fatal cases were sixfold as likely to arise on the scalp as on the back [OR 6·39, 95% confidence interval (CI) 2·57-15·92] and six times as likely to be of thickness 0·80-1·00 mm as of < 0·30 mm (OR 6·00, 95% CI 3·55-10·17).Scalp location is a strong prognostic factor of death from thin melanoma. Further, this study provides support that melanomas with a thickness of 0·80-1·00 mm are the more hazardous thin lesions. Patients with these tumour characteristics require specific attention during follow-up. What's already known about this topic? Thin invasive melanomas (≤ 1·00 mm) contribute a substantial proportion of melanoma fatalities, owing to the high volume of disease. There is a need to find prognostic factors that will better identify fatal thin melanomas at the time of diagnosis. What does this study add? In this large population-based study, fatal thin tumours were sixfold as likely to be located on the scalp as on the back. Thin melanomas of 0·80-1·00 mm thickness were six times as likely to be associated with death as tumours < 0·30 mm. Scalp location and increasing thickness are strong predictive factors of fatal thin melanomas, indicating that patients with these tumour characteristics require close follow-up.
Image Gallery: <scp>AL</scp> amyloidosis presenting as bilateral periorbital plaques and ecchymoses
Authors: J.K. Winkler, F. Toberer
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none to declare. Dear Editor, A 64‐year‐old man presented with bilateral periorbital plaques and ecchymoses (a, b). The patient had an IgG‐lambda‐type multiple myeloma, which was treated with four cycles of bortezomib, cyclophosphamide and dexamethasone followed by high‐dose melphalan and autologous stem cell transplantation. At the time of presentation, the patient was in near complete remission. Histopathology showed amorphous dermal material with positive staining for Congo red consistent with a cutaneous manifestation of AL amyloidosis. Atraumatic facial ecchymoses, particularly in the periorbital region, should raise the suspicion of AL amyloidosis. Early diagnosis of this condition may improve patients’ prognosis.
Correlation of BRAF V600E mutation with cardiac involvement assessed by heart imaging in a monocentric series of 205 patients with Erdheim-Chester disease.
Authors: Marine Bravetti, Levi-Dan Azoulay, Fleur Cohen-Aubart, Jean-François Emile, Zahir Amoura, Philippe Cluzel, Julien Haroche
Journal: Journal of Clinical Oncology (2019)

7019 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm, is an histiocytosis associated with multisystem infiltration. Cardiovascular involvement in ECD is under-diagnosed and associated with poor outcome. The targetable BRAF V600E mutation is present in up to 70% of all ECD. Methods: Retrospective study of 205 patients (pts) with ECD who had cardiac imaging (195 MRI, 10 CT when MRI was contraindicated). We identified the types of lesions (infiltration, tumor, and effusion), localization (pericardial, myocardial, valvular) and consequences on cardiac function (coronary stenosis, atrial wall dyskinesia, diastolic and systolic functions). Results: 141 (68.8%) pts were male. 30 (14.6%) had mixed histiocytosis (mainly ECD + langerhans cell histiocytosis). BRAF mutation ( BRAFm) was found in 112 (54.6%) cases, while 59 pts (28.8%) were Wild Type (WT) and 34 pts (7.6%) had unknown BRAF status. Among the 205 cardiac imaging, 101 (49.3%) were abnormal. Cardiac involvement was found in 93 pts (49%). Among these, 72 had an impairment of the right ventricular atrioventricular sulcus (74%), 65 of the right atrium (RA) enclosure (69%). Alteration of Tricuspid Annular Plane Systolic Excursion was found in 15% and correlated with the size of the tumor. Pericardial involvement (effusion, thickening or contrast enhancement) was found in 59 pts (29%). Among BRAFm pts, 75 (67%) had a heart abnormality while 37 (33%) had normal imaging; Among WT pts 14 (23.7%) showed heart abnormality, whereas 45 (76.3%) had normal imaging (RR 2.8 (CI: 1.8-4.5); p = 1.8*10 -7 ). A RA tumor was present in 51 (45.5%) BRAFm but only 6 (10.2%) WT pts respectively (RR 4.5 (CI : 2.0-9.8); p = 7*10 -6 ). BRAFm was also associated with aortic infiltration (RR 1.76 (CI: 1.2–2.5)) and pericardial involvement (RR 2.12 (CI: 1.1–3.9), p = 0.0017). Conclusions: Cardiac infiltration is frequent in ECD (49.3%), especially RA tumor. BRAFm is associated with RA, aortic and pericardial involvements.
Global burden of melioidosis in 2015: a systematic review and data synthesis
Authors: Emma Birnie, Harjeet S Virk, Jelmer Savelkoel, Rene Spijker, Eric Bertherat, David A B Dance, Direk Limmathurotsakul, Brecht Devleesschauwer, Juanita A Haagsma, W Joost Wiersinga
Journal: The Lancet Infectious Diseases (2019)
Helen Salisbury: Talking about death
Authors: Helen Salisbury
Journal: BMJ (2019)

Any emergency hospital admission of frail, elderly patients means a decision about what to do if their heart stops beating. Should we attempt cardiopulmonary resuscitation (CPR)? The medical answer isn’t always clear, and the decision should involve the patient and sometimes relatives.12 For the admitting team, it would be useful if that discussion had already taken place with a doctor who knows the patient, with a decision recorded somewhere accessible.

This sounds like common sense, so why aren’t GPs routinely discussing end-of-life care with patients who may need it soon? NHS England encourages doctors to engage …