tbuckley/cabot-search huggingface dataset:
PLAC8 Localizes to the Inner Plasma Membrane of Pancreatic Cancer Cells and Regulates Cell Growth and Disease Progression through Critical Cell-Cycle Regulatory Pathways
Authors: Brajesh P. Kaistha, Holger Lorenz, Harald Schmidt, Bence Sipos, Michael Pawlak, Berthold Gierke, Ramona Kreider, Brigitte Lankat-Buttgereit, Melanie Sauer, Lisa Fiedler, Anja Krattenmacher, Bettina Geisel, Johann M. Kraus, Kristopher K. Frese, Sabine Kelkenberg, Nathalia A. Giese, Hans A. Kestler, Thomas M. Gress, Malte Buchholz
Journal: Cancer Research (2015)

Pancreatic ductal adenocarcinoma (PDAC) carries the most dismal prognosis of all solid tumors and is generally strongly resistant to currently available chemo- and/or radiotherapy regimens, including targeted molecular therapies. Therefore, unraveling the molecular mechanisms underlying the aggressive behavior of pancreatic cancer is a necessary prerequisite for the development of novel therapeutic approaches. We previously identified the protein placenta-specific 8 (PLAC8, onzin) in a genome-wide search for target genes associated with pancreatic tumor progression and demonstrated that PLAC8 is strongly ectopically expressed in advanced preneoplastic lesions and invasive human PDAC. However, the molecular function of PLAC8 remained unclear, and accumulating evidence suggested its role is highly dependent on cellular and physiologic context. Here, we demonstrate that in contrast to other cellular systems, PLAC8 protein localizes to the inner face of the plasma membrane in pancreatic cancer cells, where it interacts with specific membranous structures in a temporally and spatially stable manner. Inhibition of PLAC8 expression strongly inhibited pancreatic cancer cell growth by attenuating cell-cycle progression, which was associated with transcriptional and/or posttranslational modification of the central cell-cycle regulators CDKN1A, retinoblastoma protein, and cyclin D1 (CCND1), but did not impact autophagy. Moreover, Plac8 deficiency significantly inhibited tumor formation in genetically engineered mouse models of pancreatic cancer. Together, our findings establish PLAC8 as a central mediator of tumor progression in PDAC and as a promising candidate gene for diagnostic and therapeutic targeting.
Ticagrelor Crushed Tablets Administration in STEMI Patients
Authors: Guido Parodi, Ioanna Xanthopoulou, Benedetta Bellandi, Vassilios Gkizas, Renato Valenti, Stavros Karanikas, Angela Migliorini, Christos Angelidis, Rosanna Abbate, Sotirios Patsilinakos, Giorgio J. Baldereschi, Rossella Marcucci, Gian Franco Gensini, David Antoniucci, Dimitrios Alexopoulos
Journal: Journal of the American College of Cardiology (2015)
HIV infection must be destigmatised
Authors: R. Danziger
Journal: BMJ (1996)

abstained from sex immediately after their diagnosis, for periods ranging from a few months to two years, with a return to sex coinciding with a return of confidence and self esteem and a greater knowledge of the risks involved.Almost all participants observed that the frequency with which they had sex had declined since their diagnosis.Indeed, five men reported that they had not had a sexual relationship since their diagnosis.We are aware that the self selected nature of our sample may have biased the results obtained.Our study strongly suggests, however, that the sexual practices of many HIV positive homo- sexual and bisexual men may not correspond to those described by Catchpole and colleagues.Nevertheless, we agree with the authors' conten- tion that their data highlight the need for more effective health education messages, and we have found that this need was also expressed by the patients we surveyed.
Abstract 9509: Heart Fat, but Not Peri-Aortic Fat Depots Were Significantly Associated With Presence and Severity of Coronary Calcification in Women at Midlife: The Study of Women’s Health Across the Nation (SWAN) Ectopic Cardiovascular Fat Ancillary Study
Authors: Samar R El Khoudary, Kelly Shields, Matthew Budoff, Emma Barinas-Mitchell, Imke Janssen, Susan Everson-Rose, Karen A Matthews
Journal: Circulation (2014)

Introduction: Increasing evidence demonstrates a role of cardiovascular fat in the pathogenesis of CAD. It is unknown whether heart and vascular fat depots are related to atherosclerotic burden in women transitioning through menopause, a time of increasing CAD risk. Hypothesis: We hypothesize that volumes of epicardial (EAT), pericardial (PAT), total heart (TAT=EAT+PAT) and peri-aortic (PVAT) adipose tissues are associated with presence and severity of coronary artery calcification (CAC) in a sample of white and black midlife women. Methods: CAC and cardiovascular fat depots were quantified by electron beam CT. Outcomes were presence of CAC (none vs. any: Agatston score &gt;0), and severity of CAC (CAC Agatston score). Logistic and tobit regression were used. Final models were adjusted for age, race, study site, menopausal status, obesity (BMI ≥30 Kg/m 2 ), systolic blood pressure, lipids, homeostasis model assessment insulin resistance index, current smoking, physical activity, comorbidity (history of hypertension, stroke, angina, heart attack or diabetes) and medication use (cholesterol lowering, antihypertensive or antidiabetic medications). Results: The study included 509 women (37.9% black; 58.4% pre-/early perimenopausal, 41.6% late peri-/postmenopausal) aged 46-59 years with data on any of the 4 fat depots. CAC was found in 47.4% of the participants. Odds ratios (95% CI) from final logistic regression models showed that higher volumes of EAT (2.43 (1.22, 4.86), PAT (1.57 (1.04, 2.37), and TAT (2.43 (1.22, 4.87), were significantly associated with higher odds of presence of CAC. Similarly, tobit regression models showed that higher volumes per 1 log-unit increase of EAT (β (SE): 28.0 (10.7)), PAT (16.5 (6.6)), and TAT (30.0 (10.7)), were significantly associated with greater severity of CAC in final adjusted models. PVAT was not associated with either CAC presence or severity in final models. Conclusions: Heart fat (EAT, PAT and TAT), but not peri-aortic fat were independently associated with greater presence and severity of CAC in women at midlife, suggesting that local cardiovascular fat depots may contribute to CAD in midlife women. Future work is warranted to understand the underlying mechanistic pathways.
Abstract 19572: Obese Female Patients Have Higher Rates of Lead Dislodgement After ICD or CRT-D Implantation
Authors: Hiro Kawata, Jigar Patel, Navinder Sawhney, David Krummen, Sanjiv Narayan, Gregory Feld, Ulrika Birgersdotter-Green
Journal: Circulation (2012)

Background: While there is significant data available regarding the effects of gender and obesity in cardiovascular disease, research focusing on defibrillators has been limited. Obese patients (pts) are considered at higher risk for complications of cardiac implantable electronic devices (CIED). However, no study has been published regarding the relationship between gender, obesity and risk of CIEDs implantation. The aim of this study was to evaluate complications of defibrillator implantation (ICD and CRT-D) and their rationship to gender and body mass index (BMI). Methods: We analyzed all complications related to ICD or CRT-D implantation from 2005 to 2012 at University of California San Diego Health System. Only ICD or CRT-D implants with a new lead were included in the analysis. Four hundred twenty nine consecutive pts were included. We divided these 429 pts into 4 groups based on gender and BMI (Group1=Male, BMI≥30, Group 2=Male, BMI&lt;30, Group 3=Female, BMI≥30, Group 4=Female, BMI&lt;30) and compared rate of complications among these 4 groups. Results: During 26.8±23.7 months follow-up, complications were observed in 75 patients (17.5 %). Lead dislodgement (32 patients), diaphragmatic pacing (9 patients), pocket hematoma or bleeding (8 patients), infection (8 patients) and pneumothorax (6 patients) accounted for &gt;80% of all complications. Fifty-four of these 75 pts needed additional surgical procedures or eariler generator exchange. No significant differences were observed in overall complication rates among the 4 groups (15.6%, 16.1%, 24.6% and 31.3%). However, lead dislodgement occurred at a significantly higher rate (p&lt;0.001) in group 4 (27.5%) compared to the other groups (5.7%, 6.7% and 7.7%). Conclusions: In our retrospective, single-center study there was a higher risk of lead dislodgement in obese female pts undergoing ICD or CRT-D implantation. Careful attention to lead and device anchoring, particularly with larger cardiac devices, may be more important in this group of pts to avoid lead dislodgement.
Central venous catheters---time for a change?
Authors: M. O'Leary, D. Bihari
Journal: BMJ (1998)

Papers p1944 

It is often difficult to ascertain exactly where a particular medical practice or policy originates. Thus it is with routine scheduled changes of central venous catheters in patients requiring prolonged intensive care. If we are to believe the telephone survey by Cyna et al in this week's issue (p 1944),1 the policy of routinely replacing central venous catheters to reduce a perceived high incidence of catheter related sepsis appears to be ingrained in many British intensive care units. That this policy continues is surprising, since it is impossible to find a published randomised trial in the past 12 years supporting the contention that the incidence of catheter related sepsis increases with duration of catheterisation.

Indeed, there are now several randomised controlled trials comparing routine catheter change with change when clinically indicated, and these have …
Strategy to reformulate waiting lists
Authors: J. Cochrane, G. Mariotti, R. Sommadossi, T. Langiano, R. Raggi
Journal: BMJ (1999)

Editor—I have some suggestions that the BMA might like to consider when it designs the NHS priority system for elective surgery.1 My four suggestions are: use a scoring system instead of “banding” patients; don’t use the words “severity score”—instead use “priority score”; include consumers in the groups for developing the priorities; and set up a booking system when you introduce priority assessment.

I recommend that patients are scored instead of banded because clinicians will be compelled to use the assessment tool to get a score (the alternative is to determine a category for the patient, based on the current clinical decision making). If you have to ration (determine to which level you can provide publicly funded operations) it is much easier to work with a scoring system as opposed to, for example, 25% of D category.

We have found that the assessment tool (and score) should reflect ability to benefit from surgery as well as “need” factors. If you use only severity as an indicator then all patients for day surgery will wait for a long time or miss out on their surgery. This, in fact, is a group who benefit greatly for each health dollar/pound spent on them, both directly and indirectly (days off work, quality of life, etc). To determine your priority assessment tool, please include consumers. Consumers are good at prioritising benefit and need and are essential to getting the community to “buy in” to the scheme and for transparency to priority setting.

Giving people an idea of when they will receive their treatment means changing the way that waiting lists are managed. The main impact in our system has been projecting out our surgical booking lists to six months. I don’t think that you can introduce a priority assessment tool without looking at capacity and booking issues. If you start prioritising patients and give people certainty you need to be able to say, “Yes, we can carry out surgery on all of these people and the new patients expected each month within this time frame.” If you are not able to do this then you have to determine the level to which you will be providing elective surgery.
In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa
Authors: Benjamin Bakondi, Wenjian Lv, Bin Lu, Melissa K Jones, Yuchun Tsai, Kevin J Kim, Rachelle Levy, Aslam Abbasi Akhtar, Joshua J Breunig, Clive N Svendsen, Shaomei Wang
Journal: Molecular Therapy (2015)

Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (RhoS334) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of RhoS334, which prevented retinal degeneration and improved visual function. Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (RhoS334) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of RhoS334, which prevented retinal degeneration and improved visual function.
Response to Letter Regarding Article, “East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina: Possible Roles of Reactive Aldehydes and Implications of Alcohol Flushing Syndrome”
Authors: Yuji Mizuno, Eisaku Harada, Sumio Morita, Kenji Kinoshita, Mariko Hayashida, Makoto Shono, Yoshinobu Morikawa, Toyoaki Murohara, Masafumi Nakayama, Michihiro Yoshimura, Hirofumi Yasue
Journal: Circulation (2015)
A phase I study of bortezomib (PS-341) in pediatric patients with relapsed or refractory leukemia: A Children’s Oncology Group study
Authors: T. M. Horton, P. A. Thompson, L. R. Bomgaars, P. C. Adamson, M. Krailo, A. Ingle, S. M. Blaney
Journal: Journal of Clinical Oncology (2006)

9021 Background: Bortezomib is a 26S proteasome inhibitor that is effective as a single agent for the treatment of multiple myeloma in adults. Bortezomib at a dose of 1.2 mg/m 2 is well tolerated as a single agent in pediatric patients with solid tumors. This phase 1 study examined the tolerability and efficacy of bortezomib in pediatric patients with relapsed/refractory leukemia. Methods: Cohorts of 3–6 patients received bortezomib administered twice weekly (days 1, 4, 8 and 11) for two weeks every 21 days. Pharmacokinetics and NF-κB activation status were examined in peripheral blood mononuclear cells (PBMC) at 6, 12, and 24 hours following the first dose of bortezomib, and from bone marrow leukemic cells before treatment and on days 8 and 18 of the first treatment cycle. Results: Twelve patients (4 female, 8 male) (ALL=9, AML=3), median age 11y (range 1–18y), were enrolled at the 1.3 mg/m 2 (6 enrolled, 3 evaluable) or 1.7 mg/m 2 (6 enrolled, 2 evaluable) dose levels. Patients not fully evaluable for toxicity experienced disease progression prior to completing the first 21-day cycle of therapy. Two DLTs occurred at the 1.7 mg/m 2 dose level. One patient had altered mental status and the other patient had febrile neutropenia associated with Grade 3 hypotension, Grade 4 renal insufficiency and hypoxia, followed by death on day 9 of cycle 1. No CRs or PRs were observed in the 10 patients evaluable for response. One patient had SD for 2 cycles. PK analysis (n= 5) revealed a Cl of 0.62 L/min/m 2 , V d of 13 L/m 2 , and a terminal T 1/2 of 12.6 h. NF-κB activation was inhibited in the leukemic blasts of 2 patients examined to date. Conclusions: Bortezomib was tolerated at 1.3 mg/m 2 in children with relapsed/refractory leukemia. Although bortezomib appeared to inhibit NF-κB activation, it was ineffective as a single agent for pediatric leukemia treatment. No significant financial relationships to disclose.
NHS England chooses 13 hospital groups to drive improvement at district level
Authors: Gareth Iacobucci
Journal: BMJ (2015)

Several leading NHS hospitals are to provide clinical and organisational support to chains of smaller acute care trusts as part of the next phase of NHS England’s national drive to implement new integrated models of healthcare.

The plans, announced on 25 September by NHS England’s chief executive, Simon Stevens, mark the next phase of the NHS’s push to create higher quality and more efficient models of care, as set out in the Five Year Forward View .1

NHS England has selected 13 new “vanguards” (box) from a total of 65 bids from hospitals across England, each of which will test one of three new approaches to integrated care. These will add to the 37 areas that are already piloting new ways to integrate care between general practice, social and community care, mental health, and hospitals.2

The first new approach will see individual high performing NHS hospitals forming new groups with smaller organisations to try to raise standards and improve efficiency across chains …
Cytogenetic Studies of Human Breast Cancer Lines: MCF-7 and Derived Variant Sublines
Authors: J Whang-Peng, E C Lee, C S Kao-Shan, K Seibert, M Lippman
Journal: JNCI Journal of the National Cancer Institute (1983)

Cytogenetic studies of the human breast cancer cell line MCF-7 and the sublines derived from it demonstrated extensive aneuploidy with both numerical and structural abnormalities and a wide range of heteroploidy. Detailed G-banding analyses showed that loss of marker chromosomes was a rare event, while formation of additional structural abnormalities was very common in these long-term cultures. All chromosomes were involved in these abnormalities. Loss of a morphologically normal X-chromosome may be related to the loss of estrogen receptors in these cell lines. With the exception of one subline, all cell lines had a short homogeneously staining region (HSR) on chromosome 7. Although the parent MCF-7 line had tetrahydrofolate dehydrogenase levels within the normal range, a lengthened HSR has been found in MCF-7 lines that are resistant to methotrexate. This observation strongly favors the association of an increased level of tetrahydrofolate dehydrogenase with HSR. In conclusion, the inherent genetic instability in this group of related cell lines may explain the heterogeneity found in this tumor. Continuous chromosomal rearrangements and numerical changes may reflect an ongoing process of selection and adaptation in these cell lines established from a breast carcinoma and may be characteristic of the aggressiveness of this neoplasm.
Nintedanib (BIBF 1120) prevents TGF-β-induced pro-fibrotic effects in primary human lung myofibroblasts derived from patients with idiopathic pulmonary fibrosis
Authors: Katrin Hostettler, Eleni Papakonstantinou, Jun Zhong, George Karakiulakis, Didier Lardinois, Michael Tamm, Michael Roth
Journal: European Respiratory Journal (2014)

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Nintedanib (BIBF 1120) is a tyrosine kinase inhibitor specific for platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor. Its effect on IPF disease progression measured by lung function decline has been investigated in two replicate Phase III clinical trials (INPULSIS-1 and INPULSI-2) in patients with IPF. Scant information is available on the in-vitro effect of nintedanib on transforming growth factor-beta (TGF-β) – induced pro-fibrotic effects.

Aim: To determine the in vitro effect of nintedanib on TGF-β1-stimulated primary human lung myofibroblasts.

Methods: Primary human lung myofibroblasts were isolated and propagated from lung parenchyma derived from patients with IPF and from non-fibrotic control lungs. After incubation with nintedanib (0.001 - 1µM) and stimulation with or without TGF-β1, the expression of matrix metalloproteinases (MMP) was assessed in the culture medium by gelatin zymography, collagen secretion was quantitated by the Sircol assay, and cell proliferation was assessed by automatic cell counting.

Results: In IPF myofibroblasts nintedanib prevented 1) the TGF-β1-induced reduction of pro-MMP2 expression, 2) the TGF-β1-induced enhanced secretion of collagen and 3) the pro-proliferative effect induced by TGF-β1.

Conclusion: Our data demonstrate that nintedanib significantly counteracts TGF-β-induced pro-fibrotic effects, and thus provide new insight into the mechanisms underlying the drug's clinically documented beneficial activity.
Long-term outcomes and prognostic factors for neuroendocrine G1 and G2 lung tumors
Authors: Julia Wälscher, Gerhard Weinreich, Dirk Theegarten, Saskia Ting, Andrea Tannapfel, Georgios Stamatis
Journal: European Respiratory Journal (2012)

Background: Bronchial neuroendocrine G1 and G2 tumors show a favorable outcome.However,survival depends on several prognostic factors such as histological sub-type,nodal involvement and other predictors.  Objectives:The presented study aimed to evaluate the long-term outcomes,survival rates and prognostic factors after resection of G1 and G2 neuroendocrine lung tumors according to the 7th edition of the TNM staging system.  Patients and methods: We conducted a retrospective review of 246 consecutive patients who underwent surgical treatment for G1 and G2 neuroendocrine tumors of the lung between 1998-2010.  Results: 246 patients(61% women)with G1 and G2 neuroendocrine lung tumor underwent thoracotomy. G1 tumors were found in 205(83%)patients,while 41(17%)had G2 disease.Follow-up was 65.9±40.3 months.In the total study cohort we analysed 5- and 10-year survival:G1 bronchopulmonary tumor(survival 96% and 94%)was significantly different(p I(survival 86% and 59%),nodal involvement(survival 83% and 57%)was significantly different(p=0.02)in comparison to patients without nodal involvement(survival 94% and 84%),distant metastases(survival 80% and 27%)was significantly different(p=0.001)compared to patients without distant metastases (survival 94% and 84%),occurrence of symptoms before operation(survival 96% and 84%)was significantly different from patients presenting no symptoms before operation(survival 86% and 67%).  Conclusion: Prognosis was influenced by histological subtype,stage of disease,occurrence of symptoms before operation,lymph node involvement and distant metastases.
Idiotype Immunization Combined With Granulocyte-Macrophage Colony-Stimulating Factor in Myeloma Patients Induced Type I, Major Histocompatibility Complex–Restricted, CD8- and CD4-Specific T-Cell Responses
Authors: Anders Österborg, Qing Yi, Lotta Henriksson, Jan Fagerberg, Susanne Bergenbrant, Mahmood Jeddi-Tehrani, Ulla Rudén, Ann-Kari Lefvert, Göran Holm, Håkan Mellstedt
Journal: Blood (1998)