tbuckley/cabot-search huggingface dataset:
Triptolide to induce cell death of pancreatic cancer cells via inhibition of 14-3-3γ expression.
Authors: Wei Wang, Jinbing Luo, Yinghui Liang, Yubin Chen, Wenjie Lin
Journal: Journal of Clinical Oncology (2015)

425 Background: Pancreatic cancer is one of the malignant tumors which exhibit resistance to chemotherapy. Gemcitabine-based therapy is a standard for advanced pancreatic cancer though it brings severe side-effect and average median survival is only 6 months. Hence increasing interest has focused on new agent with targeted therapies. Here we investigated the growth-inhibitory and apoptotic effect of triptolide, a diterpenoid triepoxide, and the role of 14-3-3γ expression in the apoptotic pathway induced by triptolide in human pancreatic cancer cells (AsPC-1 and PANC-1). Methods: Cell proliferation was measured by SRB, apoptotic cells were assessed by flow cytometry for Annexin V/PI staining and western blot for cleaved caspase-8, 9, 3 and fluorescent substrate assay for activities of caspase-8, 9, 3. To explore further mechanism of triptolide triggering death receptor pathway, specific siRNA targeted for 14-3-3γ was used to knock down 14-3-3γ expression measured by ELISA. In vivo, AsPC-1 xenografts in the absence or presence of stable down-regulation of 14-3-3γ expression by RNAi were treated with triptolide for 4 weeks and the tumor growth was compared, tumor samples were tested by ELISA and western blot for 14-3-3γ level. Results: Triptolide inhibits the proliferation at extremely low concentrations (12.5-50 nM) and induces apoptosis of pancreatic cancer cells through activating the caspase cascade associated with Bid cleavage. Moreover triptolide inhibited 14-3-3γ expression at dose and time-dependent manner and 14-3-3γ down-regulation sensitized cells to triptolide-induced apoptosis. Likewise, in vivo experiment of AsPC-1 xenografts, stable down-regulation of 14-3-3γ expression by RNAi significantly enhances triptolide-induced apoptosis and tumor growth delay. Conclusions: Triptolide exerted significant growth inhibitory effects and induced apoptosis in vitro and in vivo. Triptolide may have a potential to be an effective agent against pancreatic cancer and its mechanism of action is mediated by the inhibition of 14-3-3γ expression. The role of 14-3-3γ expression involved in resistance to apoptosis pathway make it be a potential therapeutic target in pancreatic cancer.
Routine appendectomy could be abandoned for uncomplicated appendicitis, study finds
Authors: J. Wise
Journal: BMJ (2015)

An appendectomy may not be needed in patients with uncomplicated acute appendicitis, researchers have reported in JAMA .1

Appendectomy has been the standard treatment for acute appendicitis for more than a century. Although it is generally well tolerated, it is still a major surgical intervention and can be associated with postoperative complications.

The APPAC trial was performed in six Finnish hospitals and included 530 patients aged 18-60 with uncomplicated acute appendicitis confirmed by a computed tomography (CT) scan. Complicated appendicitis was defined as the presence of an appendicolith, perforation, or abscess, …
Emerging macrolide-resistant mycoplasma pneumoniae in Thailand
Authors: Pornanan Domthong, Anan Wattanathum, Poonapong Harnsiripan, Sudaluck Tanyaharn, Varunya Wutthichan
Journal: European Respiratory Journal (2014)

Background:  Mycoplasma pneumoniae  is a common etiological agent of respiratory tract infection. Although prevalence of macrolide-resistant  M. pneumoniae  (MRMP) isolated has increased rapidly in Asia, there have been no reports concerning MRMP infection in Thailand. The study aimed to evaluate the prevalence of MRMP in Thailand.  Methods: Forty-four  M. pneumoniae  strains were isolated from 420 patients with respiratory tract infections by real-time PCR assay from February 2012 to January 2013. We developed sequencing analysis to detect point mutations in 23S rRNA conferring resistant genotypes.  Results: Of 44 clinical isolates, 16 (36.4%) were resistant to macrolide. All MRMP strains harbored an A-to-G transition mutation at position 2063 in 23S rRNA genes. Sixteen patients with MRMP were retrospectively analyzed ( 9 males and 7 females ; mean age 7.1 years) and were compared with macrolide-susceptible  M. pneumoniae  (MSMP) patients. The mean febrile days were 4.1 days. Rate of hospitalization in the MRMP patients was 62.5%. Interestingly, the MRMP patients were more likely than the MSMP patients to have had a change of the initially prescribed antimicrobial agents to levofloxacin (50% versus 0%; P   Conclusion: Macrolide-resistant  M. pneumoniae  is a common infection in Thailand. Physicians should absolutely pay close attention to MRMP in case of lower respiratory tract infection. The future prospectively epidemiological monitor of this species is recommended.  Key words: macrolide-resistant  Mycoplasma pneumoniae , respiratory tract infection.
Abstract 1353: The Phosphoinositide 3-Kinases (PI3K)-AKT Signaling Pathway may Explain Arrhythmic Changes in Cardiac-Specific Angiotensin Converting Enzyme (ACE) Overexpression Mice (ACE 8/8)
Authors: Shahriar Iravanian, Hong D Xiao, Kenneth E Bernstein, Samuel C Dudley
Journal: Circulation (2007)
Characteristics Associated With Maintenance of Mean A1C &amp;lt;6.5% in People With Dysglycemia in the ORIGIN Trial
Authors: Origin Trial Investigators
Journal: Diabetes Care (2013)

To assess the success and baseline predictors of maintaining glycemic control for up to 5 years of therapy using basal insulin glargine or standard glycemic care in people with dysglycemia treated with zero or one oral glucose-lowering agents.Data from 12,537 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were examined by baseline glycemic status (with or without type 2 diabetes) and by therapeutic approach (titrated insulin glargine or standard therapy) using an intention-to-treat analysis. Median values for fasting plasma glucose (FPG) and A1C and percentages with A1C<6.5% (48 mmol/mol) during randomized treatment were calculated. Factors independently associated with maintaining updated mean A1C<6.5% were analyzed with linear regression models.Median A1C in the whole population was 6.4% at baseline; at 5 years, it was 6.2% with glargine treatment and 6.5% with standard care. Of those with diabetes at baseline, 60% using glargine and 45% using standard care had A1C<6.5% at 5 years. Lack of diabetes and lower baseline A1C were independently associated with 5-year mean A1C<6.5%. Maintaining mean A1C<6.5% was more likely with glargine (odds ratio [OR] 2.98 [95% CI 2.67-3.32], P<0.001) than standard care after adjustment for other independent predictors.Systematic intervention with basal insulin glargine or standard care early in the natural history of dysglycemia can maintain glycemic control near baseline levels for at least 5 years, whether diabetes is present at baseline or not. Keeping mean A1C<6.5% is more likely in people with lower baseline A1C and with the glargine-based regimen.
IMMUNE RESPONSES IN VITRO
Authors: Carl W. Pierce, Judith A. Kapp, Susan M. Solliday, Martin E. Dorf, Baruj Benacerraf
Journal: The Journal of Experimental Medicine (1974)

The effects of alloantisera against leukocyte alloantigens on plaque-forming cell (PFC) responses to sheep erythrocytes and the terpolymer of L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10) (GAT) by mouse spleen cells in vitro have been investigated. Polyspecific antibodies against both H-2 and non-H-2 alloantigens on responding spleen cells suppressed both IgM and IgG PFC responses; antisera against alloantigens coded for by the K and I regions, but not the D region, of the H-2 complex also effectively suppressed PFC responses. The suppression was not due to cytotoxicity to the spleen cells or anti-immunoglobulin activity in the sera and was directly related to the amount of antiserum added to the cultures. The suppression was specific for spleen cells against which the alloantiserum was directed. The alloantisera suppressed responses most effectively when present during the first 24 h of incubation, and although not rendering lymphoid cells incapable of developing PFC responses after removal of noncell-bound antibody, did act by interfering with successful initiation of the PFC response. The alloantisera suppressed both IgM and IgG PFC responses when directed against alloantigens only on macrophages, but selectively suppressed IgG responses when directed against alloantigens only on lymphoid cells. The alloantisera did not interfere with the ability of macrophages to bind GAT or to support the viability of the lymphoid cells, but did interfere with the ability of macrophage-associated antigen to effectively stimulate antibody responses by the lymphoid cells. Possible mechanisms for the effects of alloantisera on macrophages and the selective suppression of IgG responses when the antisera are directed against alloantigens on lymphoid cells are discussed with reference to our current understanding of genetic restrictions governing cell interactions in the development of antibody responses in mice.
Allogeneic Hematopoietic Stem Cell Transplantation Following Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)
Authors: Anthony Stein, Max S. Topp, Nicola Goekbuget, Ralf C. Bargou, Hervé Dombret, Adele K. Fielding, Richard A. Larson, Alessandro Rambaldi, Gary Schiller, Gerhard Zugmaier, Catherine Jia, Tapan Maniar, Birgit Huber, Dirk Nagorsen, Hagop Kantarjian, Stephen J. Forman
Journal: Blood (2014)
Antitumor response and new lesions in advanced melanoma patients on ipilimumab treatment
Authors: J. D. Wolchok, R. Ibrahim, V. DePril, M. Maio, P. Queirolo, K. Harmankaya, L. Lundgren, A. Hoos, R. Humphrey, O. Hamid
Journal: Journal of Clinical Oncology (2008)

3020 Background: Antitumor immune responses have been observed in response to ipilimumab (ipi), an anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody. Per modified World Health Organization (mWHO) criteria, new lesions during cancer therapy are indicative of progressive disease (PD) and treatment failure. Final data from a single-arm, phase II study showed that ipi-treated patients (pts) with advanced melanoma who developed new lesions can go on to achieve responses with subsequent shrinkage of the new lesions. Methods: All pts were treated in study CA184008 with 10 mg/kg dosing every 3 weeks (Q3W) × 4; eligible pts received 10 mg/kg maintenance Q12W starting at Week (Wk) 24. If PD per mWHO was seen at Wk 12, ipi was withdrawn, but tumor assessments (TAs) continued in some cases for pts who were not switched to other anticancer therapies on-study, or for pts who chose to enter a roll-over study, CA184025. Immune-related response criteria (irRC) were developed based on measurements by independent radiologists. Per irRC, total tumor burden (TB, index + new lesions, when relevant) was compared at each TA to baseline measurements. irRC responses were categorized as complete or partial (irCR/PR) or stable disease (irSD25 - stable TB with > 25% reduction compared with baseline at the last TA). Results: 53/155 pts had a mWHO best overall response of PD and developed new lesions at the first TA (most at Wk 12, some earlier at an unscheduled visit). Of these, 26 were followed beyond mWHO PD at Wk 12 and 7 of these achieved irCR/PR (n = 4) or irSD25 (n = 3). Most of the irRC responders had stable or declining index lesions at Wk 12 despite new lesions. Shrinking and stabilization of new lesions was observed. This was observed in every study in which new-lesion measurements were captured. Conclusions: In pts receiving ipi, new lesions may not always indicate treatment failure, particularly in pts with decreasing or stable index lesions when new lesions appear. Shrinkage and/or eradication of new lesions after they appear has not been described in oncology. New criteria for evaluation of efficacy of ipi and related drugs are needed to fully capture clinical activity and guide treatment choices. irRC require prospective validation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb
Sued and nonsued physicians' self-reported reactions to malpractice litigation
Authors: Sara C. Charles, Jeffrey R. Wilbert, Kevin J. Franke
Journal: American Journal of Psychiatry (1985)

To assess the impact of malpractice litigation on physicians' personal and professional lives, the authors surveyed a random sample of the Chicago Medical Society membership. Although both sued and nonsued physicians reported changes in professional behavior and emotional reactions to both the threat and actuality of litigation, sued physicians reported significantly more symptoms than nonsued physicians. Significantly more of them reported that they were likely to stop seeing certain types of patients, think of retiring early, and discourage their children from entering medicine. Malpractice litigation may affect not only physicians' personal and professional lives but also the delivery of health care.
Abstract 8395: Central Pressure Profiles as Predictors of Incident Cardiovascular Events and Heart Failure: The Multiethnic Study of Atherosclerosis
Authors: Julio A Chirinos, Jan Kips, David R Jacobs, Lyndia Brumback, Richard Kronmal, Daniel A Duprez, David A Bluemke, Raymond R Townsend, Sebastian Vermeersch, Patrick Segers
Journal: Circulation (2011)

Background: Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear. Methods: Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveforms recorded non-invasively at baseline from 5,958 participants in the Multi-Ethnic Study of Atherosclerosis. The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM=[reflected/forward wave amplitude]x100), augmentation index ([second/first systolic peak]x100) and pulse pressure amplification ([radial/aortic pulse pressure]x100) were assessed as predictors of cardiovascular events (CVE) and congestive heart failure (CHF). Results: During median 6.46 years of follow-up, aortic augmentation index and pulse pressure amplification did not independently predict CVE. After adjustment for established risk factors, RM was independently predictive of CVE (hazard ratio [HR] per 10%-increase=1.39; 95%CI=1.10-1.75; P=0.006) and strongly predictive of CHF (HR per 10%-increase=2.81; 95%CI=1.83-4.33; P&lt;0.0001). RM was a stronger predictor of CHF risk than hypertension (HTN) and other established modifiable risk factors, judging by various measures of model performance and population-attributable risk. In fully adjusted models, compared to non-hypertensive subjects with low RM, the HR for hypertensive subjects with low RM, non-hypertensive subjects with high RM and hypertensive subjects with high RM were 1.82 (95%CI=0.85-3.86), 2.31 (95%CI=1.07-5.01) and 4.55 (95%CI=2.28-10.0), respectively (Figure). Conclusions: Arterial wave reflections represent an important novel modifiable risk factor for CHF in the general population and a potential therapeutic target for primary CHF prevention.
Collapse in an Accident and Emergency Department
Authors: Andrew J McLaren, John Lear, R G Daniels
Journal: Journal of the Royal Society of Medicine (1994)

Collapse is a common presenting complaint to accident and emergency (A & E) departments. This retrospective study of 4180 new attendances at a district general hospital A & E showed that this accounted for 2.9%. A wide disease spectrum was implicated. This patient group has a high admission rate (47.8%) and a high mortality rate (31.3%). The deaths occurred largely in the elderly and it is suggested that elderly patients should either be admitted for observation, or a careful screening carried out for underlying pathology. The diversity of disease precludes a standard management protocol.
Ultrastructural Localization of IgA Deposits in Adult Linear IgA Disease
Authors: J N Leonard, Nicola Ring, G P Haffenden, Lionel Fry
Journal: Journal of the Royal Society of Medicine (1982)

Two cases of adult linear IgA disease are reported. They demonstrate the two sites of deposition of IgA at an ultrastructural level: sub-basal lamina and lamina lucida. This finding supports the view that there are subgroups of this disease. Clinical presentation and histological appearance of lesional skin are misleading, and the immunofluorescent appearance is unhelpful in predicting the ultrastructural localization of the IgA deposit.
Prediction of postoperative FEV1 and chronic dyspnoea using quantitative computed tomography (CT) in lung resection candidates
Authors: Chrysovalantis V. Papageorgiou, Georgios Kaltsakas, Panagiotis Misthos, Iris Tsangaridou, Dimitra Chaimala, Nikolaos G. Koulouris
Journal: European Respiratory Journal (2011)

Aim:  Preoperative evaluation of lung function before lung resection is necessary in order to avoid postsurgery morbidity. The aim of the study is to evaluate the role of quantitative CT in predicting postoperative FEV1 and patient9s chronic dyspnoea.   Methods:  Twenty-eight patients with non-small cell lung cancer have been evaluated. Lung function tests (LFTs) and chest CT scan were performed preoperatively. Fifteen patients (group A) had normal LFTs, thirteen patients (group B) had impaired lung function, requiring further testing. Quantitative evaluation of CT using dual threshold (-910 up to -500 Hounsfield Units) estimated total functional lung volume and the volume of the lobe(s) to be resected. Postoperative FEV1 was predicted by reducing the preoperative value by the same fraction that the resected part contributed to the total lung volume, in both groups. Postoperative LFTs were performed 3 months after surgery. Postoperative dyspnoea was evaluated using the modified Medical Research Council (mMRC) scale.   Results:  The postoperative predicted and postoperative actual values of FEV1 were significantly correlated in both groups (Group A: r=0.897, p   Conclusion:  Quantitative CT in patients undergoing lung resection appears to be a useful tool in evaluating postoperative patient9s status as it predicts postoperative FEV1 and postoperative mMRC.
Double dose-intensive chemotherapy with autologous stem-cell support for metastatic breast cancer: no improvement in progression-free survival by the sequence of high-dose melphalan followed by cyclophosphamide, thiotepa, and carboplatin.
Authors: L J Ayash, A Elias, G Schwartz, C Wheeler, J Ibrahim, B A Teicher, E Reich, D Warren, C Lynch, P Richardson, L Schnipper, E Frei, K Antman
Journal: Journal of Clinical Oncology (1996)

Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/ m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration.Women with at least partial responses (PRS) to induction received melphalan (140 or 180 mg/ m2) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support.Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival times for the whole group are estimated at 11 and 20 months, respectively.Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agenting that may adversely influence outcome.
Prediction of survival by immunohistochemical stains (IHC) in stage D2 prostate cancer patients (pts): The importance of pTEN overexpression
Authors: B. Kasimis, V. Chang, S. Gounder, M. Gonzalez, C. Finch-Cruz, M. Blumenfrucht, S. Srinivas, J. Cogswell, E. Morales, S. Ahmed
Journal: Journal of Clinical Oncology (2009)

e16019 Background: Several signal transduction pathways,important for apoptosis and angiogenesis were idendified and their expression and correlation with survival was studied by IHC in archival prostate cancer biopsies. All pts has androgen deprivation for stage D2 disease and were followed at 3 month intervals. Methods: In an IRB approved study,42 pts had adequate tissue preserved between 1992 and 2006 and their charts were reviewed retrospectively.IHC stains to detect tumor expression of S6(ribosomal),p70s6,pTEN,AKT-1,BCL-1(Cyclin D1),VEGF,c-KIT,PDGFR-alpha and PDGFR-beta were performed by US Labs(Irvine,CA).All results were independently evaluated by two pathologists.Immunoreactivity was scored using a semiquantitative system combining intensity of staining(0–3+) and percentage of cells staining positive(0–3+).The total score was obtained by adding the scores for indensity and the percentage of positive cells,then averaging the resuts obtained by each reader.For the purpose of this study, stain intensity of 0–1+ was considered negative and the intensity of 2–3+ was considered positive.A Cox regression survival model for each stain was developed with variables known to predict survival :Gleason score,Hemoglobin(Hgb),Alkaline Phosphatase(Alk Phos),Prostate Specific Antigen(PSA),Lactate Dehydrogenase(LDH) levels. Results: The median values were: age 70yrs(56–92),Gleason score 8(6–10), LDH 171 IU/L(97–350),Hgb 12.9gm/dl (6.8–16.3), PSA 188ng/ml(2–5677),Alk Phos 139U/L(60–1756),survival 851 days(163- 6102).In univariate analysis,VEGF staining was predictive of survival (p&lt;0.037) but not in multivariate analysis.The pTEN staining correlated with survival (p&lt;0.0367) and a hazard ratio of 0.040 in multivariate analysis. Conclusions: In this small sample of pts, overexpression of S6,p70s6,AKT-1,BCL-1,VEGF,c-KIT,PDGFR-alpha and PDGFR-beta by IHC staining did not predict survival independently.The pTEN staining,however was strong predictor of survival in the multivariate analysis. No significant financial relationships to disclose.