tbuckley/cabot-search huggingface dataset:
Confusing Terminology—Neuroleptic Malignant Syndrome vs Malignant Hyperthermia—Reply
Authors: Philippe Damier, Jasem Al-Hashel
Journal: JAMA Neurology (2017)

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Long-Acting Reversible Contraception for Adolescents
Authors: Jenny K. R. Francis, Melanie A. Gold
Journal: JAMA Pediatrics (2017)

<h3>Importance</h3> Adolescents have higher rates of unintended pregnancies than any other age group. Contraceptive implants and intrauterine devices (IUDs) are long-acting reversible contraceptives (LARCs) that are known to be highly effective in preventing pregnancy. New devices have recently been approved for use in adolescents, yet pediatricians may be less familiar with how to counsel adolescents about implants and IUDs. <h3>Observations</h3> LARC methods should be described in basic terms to adolescents, including hormone dose, method of insertion, and method of pregnancy prevention. Clinicians should appreciate the developmental stages of adolescents, discuss the most effective methods of contraception, and ensure confidentiality from their parents. Short-acting contraception methods (eg, oral contraceptives) can be used as a temporary bridge to provide coverage until a LARC method can be placed. The most common adverse effect of LARC is nuisance bleeding, which can be managed with short courses of oral contraceptives or nonsteroidal anti-inflammatory drugs. <h3>Conclusions and Relevance</h3> LARC devices constitute first-line contraceptive methods for adolescents. All clinicians, including pediatricians, can counsel about LARC even before suggesting an oral contraceptive or another less effective contraceptive method. Effective, confidential communication with sensitive language to inform adolescents of the different types of LARC is necessary to normalize offering LARC as a contraceptive option and improve its uptake among adolescents. Special clinical populations can also be offered appropriate contraceptive options inclusive of LARC.
ETV1-Positive Cells Give Rise to <i>BRAFV600E</i>-Mutant Gastrointestinal Stromal Tumors
Authors: Leili Ran, Devan Murphy, Jessica Sher, Zhen Cao, Shangqian Wang, Edward Walczak, Youxin Guan, Yuanyuan Xie, Shipra Shukla, Yu Zhan, Cristina R. Antonescu, Yu Chen, Ping Chi
Journal: Cancer Research (2017)

Abstract Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA–mutant GIST, similar progress against KIT/PDGFRA wild-type GIST, including mutant BRAF-driven tumors, has been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E, a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse gastrointestinal tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention, and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents. Cancer Res; 77(14); 3758–65. ©2017 AACR.
MEDU-44. TARGETING SHH SIGNALING VIA PI3K/MTOR INHIBITION IN MEDULLOBLASTOMA AND EWING SARCOMA
Authors: Jessica Clymer, Frank Eckerd, Jonathan Bell, Rishi Lulla, Stewart Goldman, Leonidas Platanias
Journal: Neuro-Oncology (2017)

BACKGROUND: The phosphoinositide 3-kinase (PI3K) and sonic hedgehog (SHH) pathways play important roles in medulloblastoma (MB) and other pediatric cancers. Aberrant activation of the PI3K pathway has been shown to be an important regulator of cancer cell proliferation, metabolism, protein synthesis and apoptosis. Additionally, mTOR activation contributes to therapy resistance likely in part through SMO-independent activation of the transcription factor GLI. Thus we sought to evaluate the effects of combined PI3K/mTOR inhibition in medulloblastoma and Ewing sarcoma. METHODS: Medulloblastoma (DAOY and D556) and Ewing Sarcoma cell lines (TC71, RDES) were grown in 2-D culture to investigate the effects of pharmacologic inhibition of PI3K and mTOR (using BYL-719, a p110α isoform specific PI3K inhibitor and OSI-027, a catalytic inhibitor of mTOR1/2, respectively) on protein kinase signaling, cell proliferation, colony formation, intracellular localization of GLI, and GLI target gene expression. RESULTS: Of all four class I PI3Ks only the p110α isoform is required for MB cell proliferation and colony formation. Pharmacologic targeting of the p110α isoform of PI3K with BYL-719 synergized with the catalytic mTORC1/2 inhibitor OSI-027, resulting in inhibition of effector pathways, and blocked cell proliferation and colony formation in both medulloblastoma and Ewing Sarcoma. Moreover, dual PI3K/mTOR inhibition resulted in decreased nuclear localization of GLI and reduced GLI target gene expression in both pediatric tumor cell lines. CONCLUSIONS: Inhibition of p110α and mTOR exerts potent antineoplastic effects on cancer cell proliferation and transformation. This effect may be due in part to inhibition of GLI nuclear localization. Thus, besides established roles in inhibition of cancer cell proliferation and protein synthesis, dual inhibition of p110α and mTOR is particularly promising for targeting SHH-driven cancers such as medulloblastoma and Ewing sarcoma.
TRTH-32. COMBINATION IMMUNOTHERAPY TO ACTIVATE THE INNATE IMMUNE MICROENVIRONMENT AGAINST PEDIATRIC BRAIN TUMORS
Authors: Sharareh Gholamin, Rogelio Esparza, Samuel Cheshier, Siddhartha Mitra
Journal: Neuro-Oncology (2017)

Currently combinations of surgery, chemotherapy, and irradiation are utilized to treat pediatric malignant brain tumors; resulting in significant and permanent morbidity. Recently we published the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: Group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Disabling the inhibitory signals transduced by SIRPa by blocking anti-CD47 antibodies we reduce the threshold for macrophage activation and promote phagocytic response driven by tumor-specific antibodies. Consequently, a number of approaches to augment macrophage responses to therapeutic antibodies are under investigation, including the exploration of new targets and development of antibodies with enhanced functions. We tested a unique paradigm to fully utilize the innate immune system by utilizing a three-pronged approach. a) Increase the infiltration of macrophages into the tumor. b) Block the anti-phagocytic signals and c) Stimulate pro-phagocytic signals. RESULTS: To determine the in vivo efficacy of combinatorial anti-CD47 and anti-CD40 therapies, Group 3 medulloblastoma xenografts were treated by, i.p. injections with either PBS (control), anti-CD47, anti-CD40 or anti-CD47+ anti-CD40 mAbs. Mice receiving anti-CD47 anti-CD40 duotherapy demonstrated increased survival as compared to both monotherapies and control cohorts. Immunohistochemical staining with the macrophage marker F4/80 demonstrated varying patterns of macrophage infiltration and combined anti-CD47 anti-CD40 therapy demonstrated increase macrophage recruitment and intra-tumor macrophage distribution in comparison to both monotherapeutic approaches. Antibody- dependent phagocytosis of solid tumors has also been demonstrated in vitro using anti-Her2 antibodies against breast cancer. To test if Herceptin (Trastuzumab) had similar opsonizing effect on MB cells, we carried out in-vitro in-vivo assays in combination with anti-CD47 and observe a synergistic effect of combination treatment.
Abstract 65: Desmin Preamyloid Oligomers in Experimental Heart Failure and Cultured Cardiac Myocytes
Authors: Peter Rainer, Dong I Lee, Matteo Sorge, Carlo Guarnieri, Charles G Glabe, Brian O’Rourke, Gordon F Tomaselli, David A Kass, Jennifer E Van Eyk, Giulio Agnetti
Journal: Circulation Research (2015)

Background: Heart Failure (HF) is one of the main causes of morbidity and mortality in westernized countries but the molecular mechanisms underlying its development are still unclear. A paradigm-shifting view focuses on the accumulation of preamyloid oligomers (PAOs), similar to those observed in Alzheimer disease, as a potential mechanism of cardiac toxicity. We reported that differential desmin phosphorylation at serines (S) 27 and 31 could drive the formation of PAOs in the heart, in the absence of genetic mutations. We sought to establish the identity of the molecular seed triggering the nucleation of cardiac PAOs in an experimental model of HF and in cultured cardiac cells. Methods: Mice were subjected to transverse aortic constriction (TAC) for 4 weeks (FS% = 29.3±2.6, P=0.0001). Alternatively, neonatal rat ventricular myocytes were transduced with lentiviral vectors carrying alanine (A) or phospho-mimetic aspartate (D) desmin double mutants at S27 and S31, fused with GFP. Protein homogenates were subjected to western blot analysis with fluorescent co-staining using the A11 anti-PAOs and anti-desmin antibodies. Transduced cells were also subjected to live imaging to assess phenotype. Results: Co-western blot analysis of both TAC mice and phospho-mimetic mutant cells revealed the colocalization of PAOs with desmin modified (potentially cleaved) forms. Preamyloid oligomers and a desmin fragment were both increased in TAC mice vs. controls (2.8-fold, P=0.023 and 1.8-fold, P=0.038, respectively). The DD mutant, mimicking the doubly phosphorylated desmin that we hypothesized is the physiological form, showed a healthier phenotype in terms of number of spontaneously contracting cells (P=0.041) and incorporation of GFP-desmin at the Z-discs (P=0.0027), whereas the mono-phosphomimetic mutant (AD) resulted in the increase of desmin positive aggregates (P=0.0014). Conclusions: This preliminary evidence suggests that desmin modified forms represent the seed triggering the formation of cardiac PAOs, in the absence of genetic mutations. The accumulation of desmin PAOs could therefore represent an overarching mechanism underlying the deterioration of cardiac function in HF.
Albiflorin ameliorates obesity by inducing thermogenic genes via AMPK and PI3K/AKT in vivo and in vitro
Authors: Mi-Young Jeong, Jinbong Park, Dong-Hyun Youn, Yunu Jung, JongWook Kang, Seona Lim, Min-Woo Kang, Hye-Lin Kim, Hong-Seob So, Raekil Park, Seung-Heon Hong, Jae-Young Um
Journal: Metabolism (2017)
Remarks on the Barking Cough of Puberty: Cynobex Hebetis
Authors: A. Clark
Journal: BMJ (1890)

<h3>Background</h3> Tuberculosis (TB) cases in the United States are concentrated among underserved populations in the inner city. Grady Memorial Hospital (GMH) cares for 80% of patients with TB in Atlanta and 20% of all TB cases in Georgia. An unfortunate consequence of late diagnosis is that some patients are initially diagnosed with TB very late in their disease process, resulting in an unacceptably high mortality rate shortly thereafter. Regretfully, TB is sometimes diagnosed postmortem. Delayed diagnosis has major public health implications with regard to the persistent transmission of TB in the community and in hospital settings. <h3>Methods</h3> As part of a larger TB mortality study, we identified patients seen at Grady Memorial Hospital, a 1,000-bed inner-city university-affiliated public hospital in Atlanta, GA, who were diagnosed with TB postmortem by performing a retrospective review of medical records from June 1993 to June 2004. Death at diagnosis was confirmed by postmortem culture results, autopsy findings, and/or dying within 72 hours of presentation. <h3>Results</h3> In a preliminary study, over an 11-year period, 20 cases of missed diagnoses of TB were identified. All of the patients were African American, 13 (65%) were male, and the mean age at death was 47.8 (range 24-81). Eighteen (90%) were culture confirmed, whereas 2 (10%) were clinical cases. Of these 18, 13 (72%) had pulmonary TB, whereas 5 had extrapulmonary TB; among these 5, 4 had disseminated TB, whereas 1 had pleural. Five (25%) cases were identified at autopsy. Eleven (55%) were HIV positive with a mean CD4 of 89.8, median 51.5 (range 8-290). Eight (40%) patients were in the ICU, and 6 of the 8 (75%) were on ventilators. Radiologic findings at admission (<i>n</i> = 18) were as follows: miliary (2, 11%), interstitial (5, 28%), cavitary (1, 0.06%), lobar infiltrate (1, 0.06%), pleural effusion (8, 44%), and normal (1, 0.06%). Despite radiologic findings and admission diagnoses of AIDS, pneumonia, weight loss, or dyspnea, TB was considered for 8 patients and only 6 received presumptive therapy within 72 hours prior to death. <h3>Conclusions</h3> In areas of high prevalence, TB is frequently underdiagnosed. Furthermore, given the protean clinical features of TB and its ability to mimic other diseases, its diagnosis may be missed or overlooked. Our results demonstrate that in many cases, TB is diagnosed late or even at autopsy. Among these cases, there were many missed opportunities to diagnose and treat TB. Clinicians treating patients with TB risk factors should have a low threshold of suspicion in diagnosing TB and should consider treating empirically while awaiting the results of smears, cultures, and molecular tests in some cases.
Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence?
Authors: Dang Luan, Karen Willard-Gallo, Soizic Garaud, Hugues Duvillier, Jean-Nicolas Lodewyckx, Cinzia Solinas, Pushpamali De Silva, Chunyan Gu-Trantien, Catherine Sibille, Dominique Bron
Journal: Blood (2016)
Manchester doctors describe aftermath of bomb blast as NHS continues to treat casualties
Authors: Ingrid Torjesen, Anne Gulland
Journal: BMJ (2017)

NHS doctors in Manchester are still dealing with the aftermath of last week’s bomb attack as a number of patients remain in critical care in the city’s hospitals.

As of 6 am on Tuesday 30 May, NHS England disclosed that 50 people were still being treated in eight hospitals in Manchester, including 17 patients in critical care. The NHS said that 116 people had received inpatient care after the suicide bomb attack at the Manchester Arena on 22 May, which killed 22 people.

With emotions still raw after the attack, a consultant orthopaedic surgeon who spent 48 hours treating injured patients at Salford Royal Hospital said that he was subjected to racial abuse while travelling back to work to treat more victims of the attack. Naveed Yasin, who spoke of the “horrific” injuries that he treated including penetrating injuries from shrapnel, told the Sunday Times that he had been called a “brown, P\***| bastard” and a “terrorist” while driving back to work.1

But, despite being taken …
Concussion knowledge, attitudes, and perceived level of involvement by american youth sport coaches in concussion management
Authors: Melissa C Kay, Richelle M Williams, Tamara C Valovich McLeod, Johna K Register-Mihalik
Journal: British Journal of Sports Medicine (2017)

Objective To describe concussion knowledge and attitudes of youth sport coaches and relationships among knowledge, attitudes, and perceptions of coach involvement in concussion management. Design Cross-sectional survey. Setting Youth sport coaches in North Carolina and Arizona. Subjects 81 youth sport coaches (males: n=69; females: n=11; age=42, IQR=33,45). Intervention A validated survey identifying demographics, concussion knowledge, attitudes, and beliefs. Outcome measures The primary outcome was perceived level of coach involvement in concussion management. Descriptive and univariable statistics were used to examine knowledge and attitude differences by demographic factors and perceived involvement. Multivariable logistic regression examined associations between knowledge and attitude and perceived level of coach involvement (lower agreement vs. higher agreement). Results Knowledge was low-moderate (Median=13/23, IQR=11,14.5), with 75% indicating a loss of consciousness always occurs with concussion. Attitudes were positive (Median=42/42, IQR=40,42). Forty-seven (58%) strongly agreed or agreed that coaches should be involved in clinical decision-making. There were no differences in knowledge or attitudes across gender, age, previous concussion education, or previous concussion history. Knowledge and attitude were not correlated (r=0.114; p=0.343). There were no knowledge (Median=13, IQR=12,15 vs. Median = 12, IQR=11,14) or attitude (Median=42, IQR=41,42 vs. Median = 42, IQR=39,42) differences between lower and higher perceived involvement, respectively. No associations were observed in the multivariable model with perceived coach involvement (p&gt;0.05). Conclusions Coaches had limited knowledge, but expressed positive attitudes towards concussion. Educational efforts should target both knowledge and attitudes, as these constructs are not related, but are both key to improving the culture concerning concussion. Competing interests The project was funded in part by a grant from the National Operating Committee on Standards for Athletic Equipment.
Modulation of the p53 response by uncoupling protein-2 promotes chemoresistance in colon cancer cells
Authors: Zoltan Derdak, Nicholas Mark, Tamako Garcia, Guido Beldi, Simon Robson, Jack Wands, Gyorgy Baffy
Journal: Cancer Research (2008)

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

2791 

Background and Aims. Cancer cells acquire chemoresistance by selection pressure in response to an unfavorable microenvironment. This process is modulated by oxidative stress that primarily originates from mitochondria. We studied if this critical adaptive response in cancer cells is linked to uncoupling protein-2 (UCP2), a recently established regulator of mitochondrial reactive oxygen species (ROS) production with enhanced expression in human colon cancer. Methods. We overexpressed the full-length human UCP2 in HCT116 human colon cancer cells and analyzed the effect of various chemotherapeutic agents in vitro and in vivo. We monitored the impact of UCP2 on intracellular ROS levels and apoptosis rates of cultured HCT116 cells in response to camptothecin (CPT), etoposide, cisplatin, and doxorubicin. In addition, we generated subcutaneous xenografts by inoculating HCT116 cells - stably overexpressing UCP2 - into NCr nu/nu mice and monitored in vivo tumor growth in response to irinotecan (CPT-11). Results. UCP2 overexpression resulted in lower ROS levels and markedly reduced apoptosis rates (including less abundance of PUMA) in HCT116 cells treated with chemotherapeutics. The protective effect of UCP2 was absent in p53-/- HCT116 cells. Moreover, UCP2 overexpression markedly diminished CPT-induced N-terminal phosphorylation of p53 at the Ser15, Ser33, and Ser46 residues and increased its proteasomal degradation. Inhibition of glycolysis, a newly discovered metabolic function of p53 was also altered by mitochondrial uncoupling, since the UCP2 overexpressing HCT116 cell line exhibited higher lactate production and increased susceptibility to the glycolysis inhibitor 2-deoxyglucose. Finally, inhibition of tumor growth by CPT-11 in mice receiving xenografts of UCP2-overexpressing cells was distinctly weakened compared to empty vector controls. Conclusions. These findings indicate that UCP2 has a protective effect in colon cancer cells treated with chemotherapeutics and this response involves modulation of the p53 response and promotion of the glycolytic phenotype (Warburg-effect). The association between increased UCP2 expression and chemoresistance suggests that UCP2 may become a novel target of our efforts to improve the treatment of advanced colon cancer. This work was supported by NIH grants DK-61890 and RR-17695.
Abstract 404: High-throughput Screening Reveals the Mitochondrial Complex I Inhibitor Nornicotine is Cardioprotective in Ischemia-reperfusion Injury When Delivered at Reperfusion
Authors: Jimmy Zhang, Marcin K Karcz, Sergiy M Nadtochiy, Paul S Brookes
Journal: Circulation Research (2015)

Background: To date, there are no FDA-approved therapies for the reduction of infarct size in acute myocardial infarction. Previously, we developed a cell-based phenotypic assay of ischemia-reperfusion (IR) injury, which was used to identify novel cytoprotective agents delivered prior to ischemia. Herein, we sought to identify cytoprotective agents in a more clinically relevant model: drug delivery at reperfusion, and to investigate possible underlying mechanisms of protection. Methods: Primary adult mouse cardiomyocytes were subjected to simulated IR injury using a modified Seahorse XF24 apparatus with drug addition at the onset of reperfusion. Cell death was estimated using LDH release. Drugs which protected cardiomyocytes in vitro were tested in a Langendorff model of IR injury, measuring functional recovery and infarct size. In separate experiments, metabolites extracted from perfused hearts were resolved by HPLC. Results: Nornicotine was identified as a cardioprotective agent in the screen. In perfused hearts, 10 nM nornicotine injected at the onset of reperfusion improved functional recovery and decreased in infarct size (13.1% ± 2.4 vs 49.2% ± 2.5 in non-treated hearts, p&lt;0.05, n=16-20). Nornicotine also exhibited profound inhibitory effects on mitochondrial complex I activity. Succinate is known to accumulate in ischemia, and its rapid consumption during early reperfusion exacerbates reperfusion injury via ROS generation from electron backflow through complex I [PMID: 25383517]. In non-treated hearts, we confirmed that high post ischemic levels of succinate rapidly declined during the first 2 min of reperfusion. In contrast, nornicotine slowed post-ischemic succinate consumption, suggesting that electron backflow through complex I is the major pathway driving succinate consumption. Conclusions: Herein, we demonstrated that nornicotine was cardioprotective when delivered at early reperfusion in vitro and ex vivo. The mechanism of cardioprotection may be due to inhibition of rapid succinate consumption during early reperfusion via reverse electron flow back through complex I.