tbuckley/cabot-search huggingface dataset:
CD1c bypasses lysosomes to present a lipopeptide antigen with 12 amino acids
Authors: Ildiko Van Rhijn, David C. Young, Annemieke De Jong, Jenny Vazquez, Tan-Yun Cheng, Rahul Talekar, Duarte C. Barral, Luis León, Michael B. Brenner, Joel T. Katz, Richard Riese, Ruth M. Ruprecht, Peter B. O'Connor, Catherine E. Costello, Steven A. Porcelli, Volker Briken, D. Branch Moody
Journal: The Journal of Experimental Medicine (2009)
Prognostic potential of thyroid receptor TRα2 in breast cancer.
Authors: Katarzyna Joanna Jerzak, Sukhbinder K. Dhesy-Thind, Anita Bane
Journal: Journal of Clinical Oncology (2014)

e11535 Background: Thyroid receptors (TRs) influence cell metabolism and gene transcription, with potential prognostic value in malignancy. We characterized the expression of three TR isoforms in breast cancer tissue and investigated their prognostic significance. Methods: 131 formalin fixed paraffin embedded breast tumors were selected sequentially starting from January 2007, to allow for collection of 5-year clinical outcomes. Tumors were analysed for TRα1, TRα2 and TRβ1 expression by immunohistochemistry; the Allred score was assessed in triplicate (average score ≥ 6 was defined as high expression). TR expression was correlated with pathological features and clinical factors of known prognostic and predictive significance using correlation analyses and regression models. Results: The age of patients was 65±15 years. The majority had T1c (31%) or T2 (56%) disease and 39% had positive lymph nodes. 60% of tumors were ER positive and 13% were HER2 positive. TRα1, TRα2 and TRβ1 were expressed in 74%, 40% and 15% of tumors, respectively. High TRα2 expression correlated with 5-year DFS and OS, as well as ER/PR positivity. Absent or low TRα2 expression correlated with HER2 positivity, high tumor grade and a mitotic count >10 (Table). In a regression model incorporating patient age, tumor stage, grade, HER2 status, chemotherapy treatment and hormone therapy, tumor stage [OR 8.5 (95%CI 1.2-58.8), p=0.03] and TRα2 expression [OR 11.1 (95%CI 1.7–74.1), p=0.03] predicted favorable 5-year DFS. Tumor stage [OR 24.4 (95%CI 1.8–333.3), p=0.02] and TRα2 expression [OR 11.1 (95%CI 1.7–74.1), p=0.01] also predicted favorable 5-year OS. In a subset of ER positive and HER2 negative tumors (n=84), TRα2 predicted improved 5-year OS [OR 8.6 (95%CI 1.2-63.3), p=0.04]. Conclusions: High TRα2 expression predicts favorable 5-year DFS and OS in breast cancer patients. Down-regulation of thyroid mediated cell signalling and gene transcription by TRα2 (due to its inability to bind thyroid hormone) may explain these improved outcomes and may suggest a benefit of targeting TR expression for therapy. TRα2 expression ER+ PR+ HER2+ Grade 3 Mitotic count >10 5-year DFS 5-year OS High OR 10.9, p<0.01 OR 7.3, p<0.01 OR 2.8, p=0.03 OR 5.4, p=0.01 Low OR 13.5, p<0.01 OR 6.7, p<0.01 OR 3.0, p=0.05
Online GP service prescribed drugs without safety checks, says CQC
Authors: Gareth Iacobucci
Journal: BMJ (2017)

An online GP service that offers patients video consultations and online prescriptions has prescribed high risk medicines without proper checks and tests, inspectors have reported.

After an inspection of the service of the PushDoctor app the Care Quality Commission (CQC) found that it was not providing safe, effective, or well led services. “We found that GPs had prescribed high risk medicines without checking whether the patient had received the correct monitoring and blood tests,” the inspection report said.1

The inspection, carried out on 1 March …
David Oliver: What might the Queen’s speech mean for hospital doctors?
Authors: David Oliver
Journal: BMJ (2017)

The Queen’s speech contained little consolation for the NHS, with no meaningful pledges about funding, sustainability, or workforce gaps.1

Since she became prime minister, Theresa May has repeatedly made clear that the NHS has received budgetary protection in contrast with other departments, as well as the widely disputed “£10bn it asked for in its own plan.”23 I see little hope that healthcare will be a priority during the Brexit turmoil, not least because a system funded from general taxation is intrinsically dependent on economic growth and stability. I expect to see decisions and accountability increasingly delegated to arm’s length NHS leadership bodies.

This shouldn’t stop doctors from campaigning relentlessly, highlighting problems …
Indications for Surgical Management of Hyperparathyroidism
Authors: Antonia E. Stephen, Michael Mannstadt, Richard A. Hodin
Journal: JAMA Surgery (2017)

Primary hyperparathyroidism (pHPT) is a common clinical entity, with approximately 100 000 new cases diagnosed each year in the United States. Most patients with pHPT have a relatively mild form of the disease and present with few if any overt signs or symptoms. This has led to a dilemma regarding which patients should be considered for parathyroid surgery. In this article, we review the established literature on the indications for surgery in asymptomatic pHPT and discuss the most recent consensus conference guidelines.The reviewed literature suggests that there were improved outcomes among patients with asymptomatic pHPT who underwent curative surgery.Most patients with pHPT should be considered for parathyroidectomy. More randomized clinical trials are needed to strongly support a surgical recommendation for all asymptomatic patients with pHPT.
Juvenile onset arthritis and pregnancy outcome: a population-based cohort study
Authors: Katarina Remaeus, Kari Johansson, Johan Askling, Olof Stephansson
Journal: Annals of the Rheumatic Diseases (2017)

Reports on pregnancy outcomes among women with juvenile onset arthritis (JIA) have been few and small. The aim of this study was to assess pregnancy outcomes in a large and contemporary cohort of women diagnosed with JIA.In a nationwide Swedish population-based cohort study between 1992 and 2011, we identified 1807 births among women with JIA and 1 949 202 control births. Since JIA is a heterogenic condition, births to women with JIA was divided into JIA paediatric only (n=1169) and JIA persisting into adulthood (n=638). ORs and 95% CIs were estimated with generalised estimating equations.Women with JIA were at increased risk of preterm birth, especially medically indicated, in both subgroups: adjusted OR (aOR) 1.74 (1.35-2.67) for JIA paediatric and aOR 4.12 (2.76-6.15) for JIA persisting into adulthood. JIA persisting into adulthood was associated with very preterm birth (aOR 3.14, 1.58-6.24), spontaneous preterm birth (aOR 1.63, 1.11-2.39), small for gestational age birth (aOR 1.84, 1.19-2.85), early-onset pre-eclampsia (aOR 6.28, 2.68-13.81) and late-onset pre-eclampsia (aOR 1.96, 1.31-2.91). Women with JIA paediatric only were at increased risk of delivery by caesarean section (aOR 1.42, 1.66-1.73) and induction of labour (aOR 1.45, 1.18-1.77).We found increased risks of both maternal and infant complications among women with JIA confined to childhood and in women with JIA persistent into adulthood as compared with population controls. Pregnancies in women with JIA should thus be subject to increased surveillance during pregnancy and delivery.
Frequency of methicillin-resistant staphylococcus aureus carriage state in patients of a cancer hospital.
Authors: Tatyana A. Zykova, Michail L. Maleyko, Olga A. Bogomolova, Natalia I. Panova, Sergei A. Ilchenko, Vladimir A. Dontsov, Igor V. Goncharov
Journal: Journal of Clinical Oncology (2014)

e15086 Background: Methicillin-resistant staphylococcus aureus (MRSA) is one of the most frequent multi-drug resistant pathogens of nosocomial infections. Examination of all coming patients for MRSA carriage state is not obligatory in Russia, though it is the necessary part of MRSA prevention programs. The purpose of the study was to assess the level of methicillin-resistant staphylococcus aureus carriage state in patients of a cancer hospital. Methods: Nasal and throat washings, secretions from surgical wound drainage were used as the material for the study. Presence and content of staphylococcus aureus DNA fragments and mecA gene were detected with Real-time PCR method. 141 samples were examined. Results: 56% of patients coming to the hospital were initially colonized with MRSspp., including MRSA in 12%. During the next examination of nasal washings, MRSA colonization was detected in 30% of patients while in hospital. During the examination of secretions from drainage, MRSspp. were detected in 44,2% of the samples, including MRSA in 16,3%. Frequency of MRSspp. carriage state in stomach cancer patients was 69,6%, including MRSA – 4,3%. MRSspp. was detected in secretions from drainage in that patients in 55,6%, including MRSA in 22,0%. Frequency of MRSspp. carriage state in patients with colon cancer was 44,0%, including MRSA – 14,0%. MRSspp. was detected in secretions from drainage in that patients in 45,7%, including MRSA in 11,4%. Conclusions: High level of nasal MRSA (coagulase-negative mostly) carriage state was detected in patients of the cancer hospital.
Epidemiology of time loss groin injuries in a men’s professional football league: a 2-year prospective study of 17 clubs and 606 players
Authors: Andrea B Mosler, Adam Weir, Cristiano Eirale, Abdulaziz Farooq, Kristian Thorborg, Rod J Whiteley, Per Hӧlmich, Kay M Crossley
Journal: British Journal of Sports Medicine (2017)

Groin injury epidemiology has not previously been examined in an entire professional football league. We recorded and characterised time loss groin injuries sustained in the Qatar Stars League.Male players were observed prospectively from July 2013 to June 2015. Time loss injuries, individual training and match play exposure were recorded by club doctors using standardised surveillance methods. Groin injury incidence per 1000 playing hours was calculated, and descriptive statistics used to determine the prevalence and characteristics of groin injuries. The Doha agreement classification system was used to categorise all groin injuries.606 footballers from 17 clubs were included, with 206/1145 (18%) time loss groin injuries sustained by 150 players, at an incidence of 1.0/1000 hours (95% CI 0.9 to 1.1). At a club level, 21% (IQR 10%-28%) of players experienced groin injuries each season and 6.6 (IQR 2.9-9.1) injuries were sustained per club per season. Of the 206 injuries, 16% were minimal (1-3 days), 25% mild (4-7 days), 41% moderate (8-28 days) and 18% severe (>28 days), with a median absence of 10 days/injury (IQR 5-22 days). The median days lost due to groin injury per club was 85 days per season (IQR 35-215 days). Adductor-related groin pain was the most common entity (68%) followed by iliopsoas (12%) and pubic-related (9%) groin pain.Groin pain caused time loss for one in five players each season. Adductor-related groin pain comprised 2/3 of all groin injuries. Improving treatment outcomes and preventing adductor-related groin pain has the potential to improve player availability in professional football.
A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients.
Authors: Ravi K. Amaravadi, Neil N. Senzer, Lainie P. Martin, Russell J. Schilder, Patricia LoRusso, Kyriakos P. Papadopoulos, David Edward Weng, Martin Graham, Alex A. Adjei
Journal: Journal of Clinical Oncology (2013)

2504 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m 2 . The MTD of B for each arm was CP (47 mg/m 2 ); I (22 mg/m 2 ); D (47 mg/m 2 ). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B &gt; 35mg/m 2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (&gt;2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.
Prognostic Value of Bone Marrow Angiogenesis in Newly Diagnosed Multiple Myeloma: A Comparison with Conventional Prognostic Factors.
Authors: Shaji Kumar, Jessica L. Haug, Linda Wellik, Thomas E. Witzig, John A. Lust, Michael Kline, Martha Q. Lacy, Angela Dispenzieri, Morie A. Gertz, Philip R. Greipp, S. Vincent Rajkumar
Journal: Blood (2005)
Ultrasound‐Triggered Destruction of Folate‐Functionalized Mesoporous Silica Nanoparticle‐Loaded Microbubble for Targeted Tumor Therapy
Authors: Yongjiu Lv, Yang Cao, Pan Li, Jianxin Liu, Huali Chen, Wenjing Hu, Liangke Zhang
Journal: Advanced Healthcare Materials (2017)

A multifunctional drug delivery vehicle, which combines the active targeted mesoporous silica nanoparticle (MSN) and microbubble (MB) drug delivery system, is proposed and fabricated. The resulting delivery vehicle integrates the merits of high drug loading capacity, multitargeting, and ultrasound‐guided releasing. Folate (FA), which serves as an active ligand, is modified to the surface of MSN (MSN‐FA) to enhance cell membrane translocation. MSN‐FA is loaded with tanshinone IIA (TAN), then encapsulated in a microbubble (denoted as MSN‐FA‐TAN‐MB) for more precise tumor targeting. The conjunction between FA and MSN is confirmed by fourier transform infrared spectroscopy (FTIR). The characteristics and morphology of MSN‐FA‐TAN‐MB are investigated by confocal microscopy and transmission electron microscopy. In vitro cytotoxicity and cellular uptake studies of MSN‐FA‐TAN‐MB are conducted on A549 and HeLa tumor cells. FA‐facilitated MSN‐FA‐TAN uptake is shown by HeLa cells that overexpress FA receptors via a FA‐receptor‐mediated endocytosis mechanism. The ultrasound response property of MSN‐FA‐TAN‐MB is also verified. MSN‐FA‐TAN‐MB shows significant antitumor efficacy in vivo with the assistance of FA, MB, and an external ultrasound irradiation. Thus, this multifunctional vehicle may provide a novel strategy for tumor targeting and imaging in tumor therapy.
Do Low Risk Upper GI Haemorrhage Patients Discharged for Outpatient Endoscopy Come to Harm?
Authors: S Bhat, TCK Tham
Journal: Endoscopy (2006)

Aims: Patients admitted with upper GI haemorrhage assessed to be at low risk of further haemorrhage are often discharged to have outpatient endoscopy. Our aim was to ascertain if such patients suffered adverse outcomes while awaiting endoscopy.
Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis
Authors: Shengbing Zang, Jia Li, Haiyan Yang, Hongxiang Zeng, Wei Han, Jixiang Zhang, Minjung Lee, Margie Moczygemba, Sevinj Isgandarova, Yaling Yang, Yubin Zhou, Anjana Rao, M. James You, Deqiang Sun, Yun Huang
Journal: Journal of Clinical Investigation (2017)

Angioimmunoblastic T cell lymphoma (AITL) represents a distinct, aggressive form of peripheral T cell lymphoma with a dismal prognosis. Recent exome sequencing in patients with AITL has revealed the frequent coexistence of somatic mutations in the Rho GTPase RhoA (RhoAG17V) and loss-of-function mutations in the 5-methylcytosine oxidase TET2. Here, we have demonstrated that TET2 loss and RhoAG17V expression in mature murine T cells cooperatively cause abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression, phosphorylation, and subcellular localization, an abnormality that is also detected in human primary AITL tumor samples. Reexpression of FoxO1 attenuated aberrant immune responses induced in mouse models adoptively transferred with T cells and bearing genetic lesions in both TET2 and RhoA. Our findings suggest a mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells that may account for immunoinflammatory responses associated with AITL patients.
Outcomes from 735 patients with breast cancer brain metastases (BM) according to biological subtype, number of BMs, and systemic treatment after local therapy.
Authors: Anna Niwinska, Katarzyna Pogoda, Halina Rudnicka, Agnieszka Irena Jagiello-Gruszfeld, Sebastian Rybski, Zbigniew Nowecki
Journal: Journal of Clinical Oncology (2017)

2078 Background: To assess survival when BM is detected according to the biological subtype of breast cancer, number of BMs and systemic treatment after local therapy. Methods: Subjects were 735 consecutive breast cancer patients with BM treated during 2003-2015. Whole brain radiotherapy was undertaken in 97%, neurosurgery -19% and systemic therapy was performed in 74% cases. The biological subtypes: triple-negative (TNBC), HER2+ER/PR-, HER2+/ER/PR+ and ER/PR+HER2- (Luminal) were determined in 714 subjects. Survival after BM detection was assessed in the entire group, in patients with a single BM (1 brain lesion regardless of metastases in other organs) and those with a solitary brain metastasis (1 brain lesion but no metastases in other organs). Factors influencing survival upon detecting BM were assessed by Cox multivariate analysis. Results: The median survivals for all patients with TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal breast cancer BM were respectively 4, 8, 10 and 9 months (p &lt; 0.001). In those both treated and untreated systemically within the TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal subtypes survivals were correspondingly 6, 10, 14, 11 and 2, 3, 2, 2 months (p &lt; 0.001). Median survivals of 171 patients with a single BM treated and untreated systemically were respectively 15 and 5 months (p &lt; 0.001). Median survivals of 70 patients with solitary BM treated and untreated systemically were respectively 28 and 6 months (p &lt; 0.001). In patients with solitary brain metastasis, median survival within the TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal subtypes, with systemic treatment was respectively 16, 28, 28, 28 months and without systemic treatment 6, 7, 7 and 7 months (p &lt; 0.001). Conclusions: Patients with TNBC and BM had the worst prognosis. Systemic treatment performed after local therapy is an important factor prolonging survival of patients with breast cancer BM, even in those with solitary brain metastasis. Based on the present evidence and our recent publication, systemic treatment should be performed in all patients with BM after local treatment, even those with brain metastases as an isolated recurrence.
Overexpression of MCT1 oncogene contributes to increased tumorigenicity of MCF7 breast cancer cells
Authors: Anait S. Levenson, Ted E. Thurn, Laura A. Simons, Clodia Osipo, V. Craig Jordan, Robert L. Satcher, Ronald B. Gartenhaus
Journal: Cancer Research (2005)

2812  Introduction: Overexpression of MCT1 (multiple copies in a T-cell malignancy), a novel candidate oncogene, in murine fibroblasts is associated with malignant transformation (Prosniak et al, Cancer Res, 1998; Dierov et al, JCB, 1999). To establish the role of MCT1 in the pathogenesis of breast cancer, we stably transfected MCT1 cDNA into MCF7 breast cancer cells that lack endogenous expression of this protein. Three MCT1-overexpressing MCF7 clones (N1, N4 and N7) and empty-vector control were selected for in vitro and in vivo studies. Results: In vitro studies: Transfection of MCT1 gene into breast cancer cells resulted in slightly increased production of estrogen receptor α (ERα), increased levels of DNA synthesis and a higher growth rate in response to estradiol (E2) compared to empty-vector control and parental MCF7 cells. The pure antiestrogen ICI 182,780 (ICI, fulvestrant) inhibited the E2-stimulated proliferation of MCF7-MCT1 cells further substantiating that E2 stimulation of growth was through the functional ER.To examine invasive capacity of MCF7-MCT1 cells we used a 96-well Cell Invasion Assay. All three clones of MCT1-transfected cells showed increased invasiveness in the presence of 50% FBS compared to empty-vector control. Soft agar colony formation assay, however, did not display statistically significant differences of anchorage independent growth between MCT1-transfectants and empty-vector control. We next examined expression of procathepsin D (pCD) and cathepsin D (CD), both markers for invasive potential of MCF7-MCT1 cells. We found that while the expression of CD in MCF7-MCT1 clones was comparable with levels in MDA-MB-231 cells, the levels of pCD reached levels of those in MDA-MB-231 or higher only after stimulation with E2. ICI was able to block the E2-stimulated enhancement of pCD in MCT1-overexpressing cells. In vivo studies: When inoculated into the mammary fat pad of ovariectomized nude mice (10 mice/group), MCT1-overexpressing cells (N1 and N7) had higher tumor rates and formed tumors that were larger than those produced by empty-vector control cells injected under the same conditions. At week 17, the largest N1 tumor was 0.96 cm2 in size, the largest N7 tumor was 0.88 cm2 and empty-vector tumor was 0.25 cm2. To determine the metastatic potential of MCF7-MCT1 cells, we examined spontaneous metastases in lung and liver tissues isolated from sacrificed mice. No evidence of micrometastases was seen in any of the animals in all groups. Conclusion: MCT1 overexpression in breast cancer cells resulted in more aggressive growth characteristics and invasiveness in vitro, as well as greater tumorigenicity when injected into nude mice. The increase tumorigenesis induced by MCT1 transfection into breast cancer cells suggest that MCT1 overexpression may play a role in the pathogenesis and progression of human breast cancer.