tbuckley/cabot-search huggingface dataset:
Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia‐Reperfusion Injury in Mice
Authors: Zhen‐Zhen Yan, Yong‐Ping Huang, Xin Wang, Hai‐Ping Wang, Fei Ren, Rui‐Feng Tian, Xu Cheng, Jie Cai, Yan Zhang, Xue‐Yong Zhu, Zhi‐Gang She, Xiao‐Jing Zhang, Zan Huang, Hongliang Li
Journal: Hepatology (2019)

Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.
Abstract P2-14-28: Local surgery improves survival in patients with primary metastatic breast cancer: A population-based study
Authors: Y Zhao, H Sun, X Yang, Y Zhao, M Chen, W Jin
Journal: Cancer Research (2019)

Abstract Background The aim of this study was to assess the prognosis of breast cancer patients with distant metastasis after surgery of the primary tumor and provide new understanding of treatment for these patients. Methods We retrospectively analyzed 8922 primary metastatic breast cancer (PMBC) patients from Surveillance, Epidemiology, and End Results (SEER) Database. The patients' clinical and pathological characteristics were investigated. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated by Kaplan-Meier method. Independent risk factors associated with disease special mortality were identified by Cox regression analysis. Results A total of 8922 PMBC patients from SEER database were identified, while 1724 (19.3%) of them received surgery therapy (ST) and 7198 (80.1%) patients were identified as no surgery therapy group (NST). Patients' underwent ST had dramatically increased OS (P&amp;lt;0.001) and BCSS (P&amp;lt;0.001) compared with those in NST group. And the result figured out that the patients with 1 or 2 distant metastatic sites might benefit most from local surgery, while the prognosis of patients with 3 or more showed no significant difference (p= 0.073 for OS, p= 0.091 for BCSS). Furthermore, no differences were found in the survival rates between different surgical procedure groups (p= 0.886 for OS, p= 0.943 for BCSS). PMBC patients with ST tented to have increased OS (hazard ratio [HR] = 0.642; 95% confidence interval [CI], 0.583-0.707, p &amp;lt; 0.001) and BCSS (HR = 0.649; 95% CI, 0.587-0.718, p &amp;lt; 0.001), while age, grade, T stage, breast subtype, radiation, the number of metastatic site were also independent prognostic factors. Conclusions The current study demonstrated the survival benefit of ST in PMBC patients, especially those has 1 or 2 distant metastatic sites. Enlarged surgical range could not prolong survival. However, a large randomized clinical trial to validate the efficacy of ST in PMBC is essential in the future. Key words: primary metastatic breast cancer; SEER Database; survival; surgery Citation Format: Zhao Y, Sun H, Yang X, Zhao Y, Chen M, Jin W. Local surgery improves survival in patients with primary metastatic breast cancer: A population-based study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-28.
GMC clarifies UK medical school guidance
Authors: Harriet Vickers
Journal: BMJ (2011)

Schools asked professional standards regulator for extra help The General Medical Council (GMC) has published two documents aiming to smooth the transition from medical student to junior doctor. These supplements should help medical schools improve the way they assess students and get them practical clinical experience. The GMC wrote the documents after some medical schools asked for help meeting the standards set out for them in Tomorrow’s Doctors . In Clinical Placements for Medical Students , the GMC recommends schools properly differentiate between types of placements (box) to ensure students get the most out of them. #### Types of placement
Abstract MS2-2: Missed opportunities - The perils of under-treatment
Authors: R Freedman
Journal: Cancer Research (2019)

Abstract Although we have seen improvements in breast cancer survival over time, the pace of improvement has varied among patients with breast cancer, and disparities in breast cancer outcomes have widened for some sub-groups. In particular, black women, those without easy access to medical care, and those at the extremes of age (youngest and oldest patients), are at higher risk for sub-optimal treatment and consequent sub-optimal breast cancer outcomes. These disparities have evolved during an era of significant treatment advances in breast cancer such as hormonal therapy and HER2-directed therapy, with a concern that under-treatment has contributed to differences in breast cancer-specific survival. Though there are cases when over-treatment and over-diagnosis result in undue toxicity, worsened quality of life, and possible detrimental outcomes, there are also many cases where patients are simply under-treated. This under-treatment manifests in a number of ways, and not only in a lack of treatment receipt all together, but also in receipt of lower intensity, non-standard, delayed, or incomplete treatment, which may be most apparent in the setting of longer-term treatments such as hormonal therapy or maintenance HER2-directed therapy. The reasons for under-treatment are complex, highly variable, and may include clear and appropriate medical contraindications but also poor treatment adherence, social stressors which limit treatment completion, the high cost of care, and limited access to high-quality care. In addition, under-treatment likely occurs due to a lack of available prospective evidence to support ideal treatments in different patient sub-groups with the need to uncomfortably extrapolate and apply data from clinical trials where many subgroups are under-represented. We need to urgently improve the evidence base for populations at risk for under-treatment so that we can better understand the side effects and outcomes experienced for both standard treatments and alternative treatment strategies. We will never realize improved survival from breast cancer for all patients until we can assure that each patient is individually receiving the right therapy at the right time with the right amount and for the right duration. Citation Format: Freedman R. Missed opportunities - The perils of under-treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr MS2-2.
Abstract P1-05-06: Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with breast cancer
Authors: M Gunaldi, N Isiksacan, S Pehlivan, S Binboga
Journal: Cancer Research (2019)

Abstract Background: Endothelial nitric oxide synthase (eNOS), also known as NOS3 is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. Nitric oxide (NO) is synthesized from L-arginine by eNOS in the vascular endothelium and plays crucial roles in cellular proliferation. In the present study, it is hypothesized that polymorphisms of the Intron4b/a variable number of tandem repeat (VNTR) polymorphism Intron4b/a in the eNOS gene may be associated with an increased risk in the developing breast cancer. Methods: We included 38 (38 F/Female) patients with breast cancer and 70 (44M/26F) healthy controls. The VNTR polymorphism in intron4 (intron4b/a) was analyzed by PCR. The results were statistically analyzed by calculating the odds ratios (OR) and 95% confidence intervals using the χ2 test. Results: The distributions of genotype and allele frequency was compared among the groups. The bb, ab and aa genotypes were observed in 29 [76.3%], 9 [23.7%], 0 [0%] patients with breast cancer and in 33 [47.1%], 15 [21.4%], 22[31.5%] healthy controls respectively. The b and a alleles were observed in 67 [88.2%], 9 [11.8%] patients with breast cancer and in 81 [57.8%], 59 [42.2%] healthy controls respectively. The susceptibility to patients with breast cancer had significantly higher frequencies in bb genotype (p=0.004 OR=3.613). The patients with breastcancer had significantly lower frequencies in aa genotype (p=0.001,OR=1.458). The frequency of the a allele was significantly lower in the patients with breast cancer (p=0.001, OR=4.070). Comparison of eNOS / VNTR polymorphism between patients with Breast and healthy control subjects.eNOS VNTRBreastHealthy ControlsOR*%95 CI*pGenotypesn=38 (%)n=70 (%) BB29 (76.3)33 (47.1)3.613 a1.494-8.735 a0.004 a 3.065 b1.440-6.520 b0.004 bAB9 (23.7)15 (21.4)0.879 a0.343-2.252 a0.812 a 0.9020.388-2.096 b0.832 bAA0 (0)22 (31.5)1.458 a1.244-1.709 a0.001 a 12.375 b2.764-55.396 b0.001 bAllele B67 (88.2)81 (57.8)5.422 a2.505-11.740 a0.001 aA9 (11.8)59 (42.2)4.070 b2.199-7.533 b0.001 b* Fisher's Exact Test a, comparison of genotype and allele frequencies between breast and healthy control groups Conclusion: We conclude that there was sensible correlation between eNOS gene intron 4b/a VNTR polymorphism and the risk of breast cancer and bb genotype frequency was significantly higher in these patients than healthy controls. Citation Format: Gunaldi M, Isiksacan N, Pehlivan S, Binboga S. Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-05-06.
Synergistic effect of selenium compounds with radiation therapy in human A549 lung xenografts
Authors: Farukh Durrani, Shousong Cao, Young-Mee Park, Gail Thompson, Joyce Martin, Gary Yang, Michael Kuettel, Youcef Rustum
Journal: Cancer Research (2007)

750  This laboratory has confirmed synergistic antitumor activity of selenium containing compounds, Se-(methyl)-Selenocysteine (MSC) and Seleno-L-Methionine (SLM) with a wide range of anticancer drugs including taxanes, fluoropyrimidines, irinotecan, platinum compounds and cyclophosphamide (Cao et.al., Cl Cancer Res., 2004; 10:2561-2569). This synergism was only observed in vivo but not in vitro with tumor cells evaluated to date and the effects were neither drug nor host or tumor specific. Studies with anticancer drugs were extended to determine whether therapeutic synergy also exists between selenium and radiation (RT) in xenografts bearing human non-small cell lung cancer, A549. Tumor bed (~200 mg in size) was radiated with the maximum tolerated dose (MTD) of 8 Gy/d x 5 and selenium was administered orally at 0.2 mg/mouse/d x 19 (MTD) with the first dose administered daily for seven days prior to and concurrent with radiation treatment. Treatment outcome was assessed 90 days after termination of therapy and quantitated as partial response (PR, ≥50% reduction in tumor size), complete tumor response (CR), and the results are as tabulated below.  Results indicate that while 10% of xenografts treated with RT alone, achieved CR; in combination with either SLM or MSC, CR rate increased significantly to 46 and 60% respectively. In addition, the total response rate (CR+PR) with RT alone and in combination with selenium was increased from 30% to 100%. Similar to what was achieved therapeutically with anticancer drugs, MSC appears to be a better modulator of therapeutic synergy in this tumor model than SLM and similar results were achieved with lower doses of radiation and selenium. The observed increase in therapeutic synergy was achieved without toxicity to the host. The therapeutic data generated provide the rationale for clinical validation of this new and novel approach.
Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus
Authors: Rebekah M. Dedrick, Carlos A. Guerrero-Bustamante, Rebecca A. Garlena, Daniel A. Russell, Katrina Ford, Kathryn Harris, Kimberly C. Gilmour, James Soothill, Deborah Jacobs-Sera, Robert T. Schooley, Graham F. Hatfull, Helen Spencer
Journal: Nature Medicine (2019)
A child with a painful limp
Authors: Adam M Ali, Ali Hani, Htwe Zaw
Journal: BMJ (2019)

A 10 year old boy presented to the paediatric emergency department with a one week history of a limp and increasing pain in his left thigh. He first noticed this while running at school. Over the following week his pain worsened and began to affect his knee. He had no history of hip, knee or lower back pain, was otherwise well and had no known medical conditions. On examination he was able to weight bear fully but with an antalgic gait. Internal rotation of the left …
Exploration and electives
Authors: Oliver Ellis
Journal: BMJ (2011)

One of the reasons medicine is so great is the massive variety of things that you can do as a doctor. In this issue we take a look at those medics who have gone off the beaten track, and we give you some pointers on how to do the same.

Expedition medicine is arguably the most intrepid and daring of all the specialties. Yassar Mustafa takes a look at this exciting discipline and finds that even in the modern world there are still plenty of adventures to be …
Transmission of Nipah Virus — 14 Years of Investigations in Bangladesh
Authors: Birgit Nikolay, Henrik Salje, M. Jahangir Hossain, A.K.M. Dawlat Khan, Hossain M.S. Sazzad, Mahmudur Rahman, Peter Daszak, Ute Ströher, Juliet R.C. Pulliam, A. Marm Kilpatrick, Stuart T. Nichol, John D. Klena, Sharmin Sultana, Sayma Afroj, Stephen P. Luby, Simon Cauchemez, Emily S. Gurley
Journal: New England Journal of Medicine (2019)

Nipah virus is a highly virulent zoonotic pathogen that can be transmitted between humans. Understanding the dynamics of person-to-person transmission is key to designing effective interventions.
Addition of Platinum Derivatives to Fluoropyrimidine-Based Neoadjuvant Chemoradiotherapy for Stage II/III Rectal Cancer: Systematic Review and Meta-Analysis
Authors: Felix J Hüttner, Pascal Probst, Eva Kalkum, Matthes Hackbusch, Katrin Jensen, Alexis Ulrich, Jürgen Debus, Dirk Jäger, Markus K Diener
Journal: JNCI Journal of the National Cancer Institute (2019)

Current guidelines recommend neoadjuvant therapy for patients with stage II or III rectal cancer. The addition of platinum derivatives to fluoropyrimidine-based chemoradiotherapy has been frequently investigated, but their role in this setting remains controversial.PubMed, Cochrane Library, and Web of Science were systematically searched for randomized trials comparing chemoradiotherapy with or without platinum agents in stage II or III rectal cancer. Main outcome parameters were overall and disease-free survival, additional outcomes included pathological complete response, isolated local recurrence, distant recurrence, toxicity, and perioperative morbidity. Time-to-event data were pooled as hazard ratios (HRs) by the inverse variance method and binary outcomes as odds ratios (ORs) by the Peto method with their respective 95% confidence interval (CI). All statistical tests were two-sided.Ten randomized controlled trials with data on 5599 patients were included in the meta-analysis. Platinum derivatives did not statistically significantly improve overall survival (HR = 0.93, 95% CI = 0.82 to 1.05, P = .23), disease-free survival (HR = 0.91, 95% CI = 0.83 to 1.01, P = .07), or local recurrence (OR = 0.83, 95% CI = 0.66 to 1.05, P = .12). However, it led to a statistically significant increase of pathological complete response (OR = 1.31, 95% CI = 1.10 to 1.55, P = .002) and a statistically significant reduction of distant recurrence (OR = 0.78, 95% CI = 0.66 to 0.92, P = .004). Benefits were accompanied by higher rates of grade 3 or 4 toxicities.Intensified neoadjuvant chemoradiotherapy with the addition of platinum derivatives cannot be recommended routinely because it did not improve overall or disease-free survival and was associated with increased toxicity. It needs to be elucidated whether the benefits in distant recurrence and pathological complete response may be advantageous for selected high-risk patients.
Abstract SY19-04: A systems biology approach reveals master regulators of the mesenchymal phenotype of glioblastoma
Authors: Andrea Califano
Journal: Cancer Research (2010)

Abstract A key challenge in cancer research is the identification of master regulators associated with oncogenesis and tumor progression, i.e., gene products that are necessary and/or sufficient to induce these events. We show that this problem can be successfully tackled by reverse-engineering and unbiased interrogation of context-specific maps of molecular interactions, commonly known as Interactomes. Specifically, it has been shown that a mesenchymal phenotype is the hallmark of tumor aggressiveness in human malignant glioma. Yet, the regulatory programs determining the associated signature are unknown. We used the ARACNe reverse-engineering algorithm to infer a genome-wide transcriptional interactome, from a large collection of high-grade glioma samples. Interactome-based analysis of the mesenchymal signature of high-grade gliomas revealed a regulatory module causally related to its transcriptional activation. Two transcription factors (C/EBP and Stat3) emerged as synergistic initiators and master regulators of mesenchymal transformation. Indeed, ectopic co-expression of C/EBPβ and Stat3 was sufficient to reprograms neural stem cells along an aberrant mesenchymal lineage. Conversely, co-silencing of these transcription factors in high-grade glioma cells led to collapse of the mesenchymal signature and systematic reduction in tumor aggressiveness. In human glioma, expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation and predicts poor clinical outcome. Citation Format: Andrea Califano. A systems biology approach reveals master regulators of the mesenchymal phenotype of glioblastoma [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY19-04
Abstract LB-300: In vivo evaluation of the intravenous MDM2-p53 antagonist RO6839921 alone and in combination with temozolomide in <i>TP53</i> wild-type orthotopic models of neuroblastoma
Authors: Lindi Chen, Fabio Pastorino, Philip Berry, Jennifer Bonner, Katrina Wood, Gareth Veal, Mirco Ponzoni, John Lunec, David R. Newell, Deborah A. Tweddle
Journal: Cancer Research (2017)

Abstract Background. Neuroblastoma is a predominantly TP53 wt tumor which supports the use of MDM2-p53 antagonists as a novel therapy for neuroblastoma patients. This is the first study to evaluate the efficacy of RO6839921, an IV prodrug of RG7388, alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma. Methods. Studies were conducted using a well-established orthotopic model of neuroblastoma, implanted with SHSY5Y-Luc (TP53 wt; non-MYCN amplified) and NB1691-Luc (TP53 wt; MYCN and MDM2 amplified) cells, and randomized into control, intravenous RO6839921, oral temozolomide or RO6839921 and temozolomide in combination. Tumor growth was monitored using bioluminescence imaging. Active RG7388 in plasma and tumor samples were detected using liquid chromatography-mass spectrometry, and p53 pathway activation assessed by MIC-1 ELISA assays, Western analysis and/or immunohistochemistry for p53, p21 and cleaved caspase 3. Results. Pharmacokinetic and pharmacodynamic analysis of RO6839921 observed peak plasma levels of active RG7388 at 1h posttreatment with maximal activation of the p53 pathway observed 3-6h posttreatment. RO6839921 had a favorable pharmacodynamic profile consistent with intermittent dosing. Assessment of anti-tumor efficacy demonstrated that RO6839921 was as effective as temozolomide and that RO6839921 in combination with temozolomide led to significantly greater tumor growth inhibition and survival than either agent given alone. RO6839921 alone and in combination with temozolomide was well tolerated. Conclusions. These preclinical studies support the evaluation of combining RO6839921 with temozolomide in early phase clinical trials of neuroblastoma patients with wt TP53. Citation Format: Lindi Chen, Fabio Pastorino, Philip Berry, Jennifer Bonner, Katrina Wood, Gareth Veal, Mirco Ponzoni, John Lunec, David R. Newell, Deborah A. Tweddle. In vivo evaluation of the intravenous MDM2-p53 antagonist RO6839921 alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-300. doi:10.1158/1538-7445.AM2017-LB-300
The story of Down’s syndrome
Authors: Mary Parkes
Journal: BMJ (2012)

In Down’s Syndrome: The Biography , retired GP Chris Nancollas traces the history of Down’s syndrome and psychiatric “care” as far back as 300 BC, more than 2000 years before Langdon Down qualified from the London Hospital and took a job at The Royal Earlswood Asylum for Idiots.

When Down began his medical career, psychiatric patients were divided into “lunatics”—those whose condition began after birth—and “idiots,” who were born with their condition and for whom there was no hope of treatment. Down was almost alone …
Is there a doctor on board?
Authors: David Douglas
Journal: BMJ (2011)

As a student I heard stories of doctors fashioning chest drains out of coat hangers (or some other implement) on an aeroplane and never having to pay for flights again—stories in which fear and human frailty did not have a role. They were always things that happened to other people, but a similar incident happened to me three days after my last week as a medical student. I was on board a ship with my wife celebrating completing medical school when the loudspeaker announced, “If there is a doctor on board please come to the purser’s office.”

My heart sank. What should I do? What would you do? …