tbuckley/cabot-search huggingface dataset:
Failure of initial VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC): What next?
Authors: M. M. Vickers, T. K. Choueiri, I. Zama, T. Cheng, S. North, J. J. Knox, C. Kollmannsberger, D. F. McDermott, B. I. Rini, D. Y. Heng
Journal: Journal of Clinical Oncology (2009)

5098 Background: The characterization and efficacy of second-line targeted therapy in patients with metastatic RCC who failed first-line VEGF-targeted therapy in a population-based setting is of clinical relevance but remains to be assessed. Methods: Provincial registries and clinical databases from seven cancer centers (3 in US and 4 in Canada) identified patients with mRCC who received first-line anti-VEGF targeted therapy between 2005–2007. Patient characteristics, data on second-line therapy and outcomes were analyzed. Results: 645 patients with mRCC who received initial VEGF-targeted therapy were identified (sunitinib, sorafenib or bevacizumab) and had a median follow-up of 25 mos. Of these, 218 patients (34%) received second-line targeted therapy: the median age was 62 yrs (range, 41–87), median KPS was 90%, 90% had prior nephrectomy, 3.8% had non-clear cell histology, 5.8% had brain metastases and 79% had &gt; 1 metastatic site. Second-line therapy included anti-VEGF agents (sunitinib n = 93, sorafenib n = 80, bevacizumab n = 11, axitinib n = 8) and mTOR-inhibiting agents (temsirolimus n = 21, everolimus n = 3). Patient characteristics were similar aside from more non-clear cell histology in patients receiving second-line mTOR-inhibiting agents (14% vs 3% p = 0.045). On multivariable analysis, only a higher baseline KPS score prior to first-line therapy predicted which patients were more likely to receive second-line therapy (p &lt; 0.0001). The median time to treatment failure (TTF) of second-line therapy was 4.9 mos for anti-VEGF therapy and 2.5 mos for mTOR inhibitors (p = 0.014). After adjusting for MSKCC prognostic profile (favorable, intermediate, poor), the hazard ratio for TTF was 0.52 (95%CI:0.29–0.91) in pts receiving anti-VEGF therapy. Overall survival from start of second-line therapy was not different between anti-VEGF or anti-mTOR drugs (14.2 vs 10.6 respectively; p = 0.38). 70 patients (10%) received third-line therapy. Conclusions: Baseline KPS is an independent predictor of receiving second-line targeted therapy. Patients who receive a second-line anti-VEGF drug appear to have a longer TTF than those who receive a second-line anti-mTOR drug. However, patient selection may account for this finding and overall survival was not significantly different. Results of ongoing randomized trials are awaited. [Table: see text]
Prospective study of pattern of invasive fungal infections (IFI) and role of latex agglutination (LA) in galactomannan (GM) and candidamannan (CM) antigen detection in patients presenting with high-risk neutropenic fever (FN): Tata Memorial Hospital experience
Authors: N. V. Karanth, R. Nair, R. Kelkar, P. Karanth, Y. Gawade, C. Mathure, S. Biswas, P. Kurkure, P. M. Parikh
Journal: Journal of Clinical Oncology (2008)

20534 Background: IFI is a common cause of morbidity & mortality in hematolymphoid malignancy. This study was initiated to document the profile of IFI and to test LA in diagnosis. Methods: Prospective study of IFI in acute leukemia, high grade lymphoma and stem cell transplant with high risk FN. Sample size was calculated to be 270 with an assumed probability of 20% IFI. Consecutive consenting patients, without serious comorbid conditions were included. In a subset of 96 patients serial serum samples were tested for GM,CM. Endpoints were afebrile for 2 days, neutrophil > 1,000/cumm and clearance of infection or death. Episodes were classified as proven, probable, possible IFI and nonIFI based on the EORTC/MSG criteria. Results: From Feb 2006 to Jan 2007, 269 high risk FNs were studied. 85% of the episodes had acute leukemia. 14 (5.2%), 12 (4.5%) and 78 (29%) episodes had proven, probable and possible IFI. Halo sign, nodules and cavity were seen in 22%, 17% and 15% of chest CT scans and liver, spleen or kidney hypodensities in 5, 7 and 3 episodes respectively by abdominal imaging (n-37) in IFI group. Blood culture grew candida in 14 and mold in 4 in IFI. 3/64 respiratory (all IFI) and 7/84 stool samples also cultured candida (3 IFI). 2/3rd of the candida were non albicans. A total of 39 and 57 patients underwent LA assay in IFI and nonIFI group respectively. Sensitivity and specificity were 31%, 88% for GM and 5%,91% for CM detection respectively. The predictive values were 63%–65% for GM and 29%–61% for CM. In multivariate model presence of infectious focus, prolonged neutropenia and fever, poor PS and albumin <3.5gm/dl were associated with increased risk of IFI. Conclusion: IFI is on rise in hematolymphoid malignancy as chemotherapy regimens get more aggressive. LA for GM, CM detection is a simple test but had a low predictive value and sensitivity in our experience. IFI % (n: 104) * Non IFI % (n:165) Focus of infection Any 100 60 Chest 90 28 Abnormal Chest Xray 64 8 Abnormal Chest CT scan 97(n: 69) 40(n:20) Neutropenia > 10days 92 51 Fever > 10days 65 23 Death 33 1 * p value <.001 in all No significant financial relationships to disclose.
There is more to memory than inaccuracy and distortion
Authors: Brady Wagoner
Journal: Behavioral and Brain Sciences (2017)

Abstract Exaggerated claims about inaccuracy and downplaying veracity can also be found in research on memory. This commentary on Jussim's 2012 book analyzes these developments in connection with schema and the misinformation effect's purported role in memory distortion. It concludes by looking back to the locus classicus of memory distortion (viz. Bartlett 1932), which in fact provides a more nuanced account of inaccuracy.
The impact of the pandemic influenza A(H1N1) 2009 virus on seasonal influenza A viruses in the southern hemisphere, 2009
Authors: C C Blyth, A Kelso, K A McPhie, V M Ratnamohan, M Catton, J D Druce, D W Smith, S H Williams, Q S Huang, L Lopez, B D Schoub, M Venter, D E Dwyer
Journal: Eurosurveillance (2010)

Data collected over winter 2009 by five World Health Organisation National Influenza Centres in the southern hemisphere were used to examine the circulation of pandemic and seasonal influenza A strains during the first pandemic wave in the southern hemisphere.There is compelling evidence that the pandemic influenza A(H1N1) 2009 virus significantly displaced seasonal influenza A(H1N1) and, to a lesser extent, A(H3N2) viruses circulating in the southern hemisphere. Complete replacement of seasonal influenza A strains, however, was not observed during the first pandemic wave.
Government should apologise to junior doctors, says health policy expert
Authors: Nigel Hawkes
Journal: BMJ (2016)

The UK government should apologise for alienating England’s junior doctors, the leading US health policy expert Don Berwick has said.

Speaking at the health think tank the King’s Fund at a launch of a new report on improving quality in the NHS in England, Berwick said that it was vital to “de-escalate” the conflict between the government and the junior doctors, which would otherwise stand in the way of the quality improvement the NHS needs.

“The government should apologise” he said. “It would be an act of generosity and courage.” The junior doctors, for their part, should find a way to make seven day services work and embrace the policies outlined in NHS England’s Five Year Forward View .

Berwick, founder of the US Institute for Healthcare Improvement, is a long term enthusiast for the …
Abstract 12594: Impact of Surgical Stroke on Early and Late Outcomes After Thoracic Aortic Surgery
Authors: Noritaka Okada, Hideki Oshima, Yoshimori Araki, Yuji Narita, Akihiko Usui
Journal: Circulation (2013)

Introduction: Despite recent improvements in surgical technique and cerebral protection methods, surgical thoracic aortic repair is still an invasive procedure with a substantial rate of mortality and neurologic injury. The aim of this study is to investigate the impact of surgical stroke on early and late outcomes including ADL and QOL as well as mortality after thoracic aortic surgery. Methods: We retrospectively analyzed consecutive 500 cases (male: 350, mean age: 62.9±13.2 years) of open aortic repair from 1986 to 2008 performed in our institute. Urgent status was 20.6%. Type of aneurysm was atherosclerotic in 68%, dissected in 32%. Replacement segment was root and ascending (31%), arch (39%), extended arch (10%), descending and its distal (19%). Brain protection method was retrograde cerebral perfusion (RCP) (58%), antegrade cerebral perfusion (ACP) (26%), deep hypothermic circulatory arrest (DHCA) (16%). Surgical stroke was defined as neurological deficit persist over 72 hours after surgery. We anal...
Problems of students must not be ignored
Authors: G. C. Jenkins
Journal: BMJ (1995)

EDITOR,--K G M M Alberti's editorial draws a depressing picture of the current situation with regard to ethics committees,1 and the three accompanying short papers paint a familiar picture instantly recognisable by all trying to carry out research in the NHS.2 3 4 Problems that Alberti does not mention include research projects labelled as reviews to avoid the need for referral to, scrutiny by, and approval of ethics committees. Clinicians and others, bound by their NHS contracts, …
Identification of prognostic factors for patients with advanced pancreatic cancer by proteomics
Authors: J. Matsubara, M. Ono, H. Ueno, T. Okusaka, J. Furuse, K. Furuta, J. Sawada, N. Saijo, S. Hirohashi, T. Yamada
Journal: Journal of Clinical Oncology (2009)

4615 Background: Gemcitabine monotherapy is the current standard for patients with advanced pancreatic cancer (PC). Its efficacy, however, varies significantly depending on individuals. This study was aimed at discovering a new diagnostic biomarker that can estimate the outcome of patients after receiving the therapy. Methods: All patients included in this study (304 patients) had metastatic PC and received at least two cycles of gemcitabine monotherapy. We compared the baseline plasma proteome between representative 29 short-term survivors (survived for less than 100 days) and 31 long-term survivors (survived for more than 400 days) using quantitative mass spectrometry (MS). Results: Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities were significantly different (p&lt;0.001, Welch's t-test). The 2 MS peaks with the highest statistical significance (p=2.57×10 -4 and 5.03×10 -4 ) were revealed to be derived from α1-antitrypsin (AT) and α1-antichymotrypsin (ACT), respectively, by tandem MS. The levels of AT and ACT, WBC count, platelet count, alkaline phosphatase, and ECOG performance status were selected using a forward stepwise procedure by Akaike's information criterion, and a scoring system (nomogram) was constructed to estimate the prognosis of individual patients. Among the selected parameters the AT level was found to be the second most significant contributor to the nomogram (p=0.0003; Table ). This survival prediction model was internally validated using a bootstrap approach with 200 resamples. Conclusions: Our survival prediction model including values of AT and ACT seems to have high practical utility and may lead to tailoring the treatment of patients with advanced PC. Modification of therapeutics may need to be taken into consideration for patients with increased AT and ACT. [Table: see text] [Table: see text]
Abstract 15163: The p110α[[Unable to Display Character: ]]Selective PI3K Inhibitor PIK75 Reverses SU5416/Hypoxia-Induced PH
Authors: Eva M Berghausen, Arnica Behringer, Marius Vantler, Stephan Baldus, Stephan Rosenkranz
Journal: Circulation (2014)

Rationale:  Pulmonary arterial hypertension (PAH) is characterized by chronically elevated pulmonary artery pressure and pulmonary vascular resistance due to vascular remodeling in small pulmonary arteries. We previously reported that genetic ablation of the PI 3-kinase (PI3K) isoform p110α[[Unable to Display Character: ]]in smooth muscle cells (SMCs) or pharmacological inhibition of p110α prevents hypoxia-induced PH in mice.[[Unable to Display Character: ]]Here, we characterized the effects of selective p110α inhibition on growth factor-induced downstream signaling events in human PASMCs related to proliferation. Furthermore we investigated the effects of (therapeutic) p110α inhibition on disease development in the SU5416/hypoxia-induced rat model of established severe PH.   Methods:  Rats were subcutaneously injected with SU5416 (20 mg/kg) and exposed to hypoxia (21 days) and normoxia (14 days). Treatment was carried out form day 21 via intraperitoneal injection of 50mg/kg of the p110α selective PI3K inhibitor PIK75 or same amounts of vehicle. RV systolic pressure (RVSP) was measured using a millar pressure catheter inserted via the jugular vein. RV hypertrophy was demonstrated as the ratio of RV weight to LV + septum weight. Additionally, starved PASMCs were pre-incubated with PIK75 and then stimulated with multiple growth factors for 16 hours or 5 minutes. Western blots were probed with various antibodies.   Results:  Western blot analysis of downstream relays in growth factor stimulated hPASMCs demonstrated a profoundly reduced phosphorylation of AKT (threonine 308 and serine 473), GSK3s and ERK in the PIK75 (300nM) exposed cells. Furthermore, expression of cyclin D1 as well as phosphorylation of Rb were prevented by PIK75.  Additionally, SU5416/hypoxia caused a robust elevation of the RVSP (81,0mmHg) which was significantly reduced by p110α inhibition (41,2mmHg). Furthermore, SU5416/hypoxia-induced RV hypertrophy was reversed.   Conclusion:  These results reveal that inhibition of p110α prevents growth factor-induced signaling events leading to an increased PASMC proliferation furthermore it reverses severe PH in the SU5416/hypoxia model. Therefore, p110α inhibition may represent a capable strategy for the treatment of PAH.
Bipolar Illness: Factors in Drinking Behavior
Authors: David L. Dunner, Bruce M. Hensel, Ronald R. Fieve
Journal: American Journal of Psychiatry (1979)

Alcohol use and abuse was investigated in 73 patients with bipolar I manic-depressive illness who were attending a lithium clinic. Alcohol-related problems were identified in 7 of the male and none of the female patients. Family data revealed a higher morbid risk for alcoholism among relatives of patients with drinking problems than among relatives of patients without drinking problems. Morbid risks for affective disorder for these two groups of relatives were similar, suggesting that alcoholism among relatives of patients with bipolar illness is not solely "genotypically" related to the affective disorder.
A retrospective analysis evaluating the benefit of early palliative care for patients with advanced pancreatic adenocarcinoma.
Authors: Julia Quintin, Jaafar Bennouna, Hélène Senellart, Sandrine Hiret, Veronique Barbarot
Journal: Journal of Clinical Oncology (2014)

30 Background: Patients with advanced pancreatic carcinoma exhibit from the diagnosis and beyond severe clinical symptoms dominated by pain and weight loss, hampering quality of life. A recent study in metastatic lung cancer have shown a clear advantage of early palliative care in both quality of life and mood (Temel JS, et al. N Engl J Med 2010;363:733-42). Methods: Based on these data, we conducted a monocentric retrospective study including patients with advanced pancreatic cancer newly diagnosed and treated according with standard guidelines. The aim of this study was to determine the contribution of early palliative care visits (with supportive care physicians) on disease control symptoms, quality of life and overall survival. Results: From January 2006 to December 2010, 157 patients, PS 0, 1 or 2, with newly diagnosis of advanced pancreatic cancer were retrospectively enrolled. 126 patients (80.3 %) received at least one chemotherapy line. Out of 157 patients, 64 (40.7%) were seen in our palliative care department. Demographic patient characteristics between the two groups were well balanced; palliative care versus non palliative care: median age, 66.2 vs 66.7 years; PS 0,1 51 (79.5 %) vs 73 (79.7 %) ; male 34 (53.1 %) vs 47 (50.5 %) ; metastatic disease 39 (60.9%) vs 51 (54.8 %). Patients in the palliative care group showed more clinical symptoms at diagnosis, especially pain (73.4% patients in palliative care group versus 50.5%; p=0.004). They received less aggressive care at the end of their life: interruption of chemotherapy earlier (1.7 months before death versus 1.2 months) and less number of chemotherapy cycles in the month before death (22.7% versus 43.5%, p=0.042). However, no significant difference was observed for overall survival between both groups: 7.5 months in palliative care group versus 6.9 months (p=0.99). Conclusions: This study underlines the need of a multidisciplinary approach in advanced pancreatic cancer, promoting palliative care started initially at the diagnosis. It deserves to be completed by a largest prospective randomized study including a quality of life analysis.
Abstract 20563: Hyperhomocysteinemia Induces Vascular Remodeling During Atherosclerosis in Pon1 Knockout Mice
Authors: Srikanth Givvimani, Sathnur Pushpakumar, Sourav Kundu, Vivian Doyle, Nithya Narayanan, Naira Metreveli, Suresh C Tyagi
Journal: Circulation (2014)

Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for various cardiovascular diseases including hypertension, coronary artery disease and atherosclerosis. Previous studies have reported the anti-atherogenic properties of paraoxynase1 (PON1) through its homocysteine thiolactonase activity. Studies from our lab have shown abnormal matrix remodeling due to elevated MMP-9 expression, decreased vascular connexins (37 & 40) and endothelial dysfunction during HHcy. In the current study we examine the role of homocysteine and its effect on vascular remodeling during atherosclerosis in PON1 knockout mice. We hypothesize that PON1 knockout mice develop HHcy that induces MMP-9 expression and causes decreased Akt/ eNOS expression leading to vascular remodeling in atherosclerosis. Methods: PON1 knockout mice were fed on atherogenic diet for 15 weeks as atherosclerosis disease model and compared with C57BL/6J (wild type) controls. Blood pressure was measured by tail cuff method and cardiovascular fu...
Neoadjuvant chemotherapy for adult soft tissue sarcomas: A phase II trial.
Authors: Samuel Aguiar, Fabio Oliveira Ferreira, Ranyell Spencer Sobreira Batista, Alexsander Kurowa Bressan, Celso Lopes Mello, Ademar Lopes
Journal: Journal of Clinical Oncology (2012)

10069 Background: Treatment of soft tissue sarcomas (STS) is characterized by high rates of local control, but poor overall survival because of distant relapses and high rates of wound complications, when preoperative radiation is used. The objective of this study was to test the effectiveness of a protocol with neoadjuvant chemotherapy for STS. Methods: A phase II single-arm prospective trial was carried out. Only adult patients with high grade extremity lesions and tumors deep and larger than 5 cm were included. A total of four cycles of chemotherapy was administered pre-operatively. The chemotherapeutic regimen was: ifosfamide – total of 9.0 g/m2 per cycle, infused in 2 hours from Day 1 to Day 5 (1.8 mg/m2/day). Half of the equivalent dose of mesna was infused 15 min pre-ifosfamide and 4 hours post-ifosfamide. Doxorubicin – total of 60mg/m2 per cycle, was infused in bolus on Day 1. Filgrastima 300 mcg, SC, was administered after the last dose of chemotherapy for 5 days. Radiation was given after surgery. Toxicity was classified by the NIH Toxicity Criteria and response was determined by the RECIST criteria. The others endpoints were the amputation and the wound-related complication rates. Results: Between January, 2005 and May, 2011, 42 patients were included. 21(50%) patients have completed the 4 cycles. Nineteen patients (45.2%) have grade 3 or 4 toxicity, and one (2.3%) death related to treatment had occurred. Between severe complications, febrile neutropenia was the most frequent. By using the RECIST criteria, we observed 10(24.5%) cases of progression, 24(58.5%) cases of stable disease, and 7(17%) partial responses. No complete clinical or radiological response was observed. In the pathological analysis of the surgical specimens, 4(9.7%) cases showed no residual disease (complete pathological response), and a total of 6 (14.6%) showed ≤ 5% of viable residual cells. The amputation rate was 4.8% (2 cases) and complications related to the wound were observed in 9 patients (21.9%). Conclusions: The protocol showed a good rate of objective and pathological response, low rate of complications related to the operative wound, and maintained an acceptable amputation rate. On the other hand, we observed high rate of progression, by RECIST criteria.
Analysis of a genetic hitchhiking model, and its application to DNA polymorphism data from Drosophila melanogaster.
Authors: T H Wiehe, W Stephan
Journal: Molecular Biology and Evolution (1993)

Begun and Aquadro have demonstrated that levels of nucleotide variation correlate with recombination rate among 20 gene regions from across the genome of Drosophila melanogaster. It has been suggested that this correlation results from genetic hitchhiking associated with the fixation of strongly selected mutants. The hitchhiking process can be described as a series of two-step events. The first step consists of a strongly selected substitution wiping out linked variation in a population; this is followed by a recovery period in which polymorphism can build up via neutral mutations and random genetic drift. Genetic hitchhiking has previously been modeled as a steady-state process driven by recurring selected substitutions. We show here that the characteristic parameter of this steady-state model is alpha v, the product of selection intensity (alpha = 2Ns) and the frequency of beneficial mutations v (where N is population size and s is the selective advantage of the favored allele). We also demonstrate that the steady-state model describes the hitchhiking process adequately, unless the recombination rate is very low. To estimate alpha v, we use the data of DNA sequence variation from 17 D. melanogaster loci from regions of intermediate to high recombination rates. We find that alpha v is likely to be > 1.3 x 10(-8). Additional data are needed to estimate this parameter more precisely. The estimation of alpha v is important, as this parameter determines the shape of the frequency distribution of strongly selected substitutions.
Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension
Authors: Fabrice Antigny, Aurélie Hautefort, Jolyane Meloche, Milia Belacel-Ouari, Boris Manoury, Catherine Rucker-Martin, Christine Péchoux, François Potus, Valérie Nadeau, Eve Tremblay, Grégoire Ruffenach, Alice Bourgeois, Peter Dorfmüller, Sandra Breuils-Bonnet, Elie Fadel, Benoît Ranchoux, Philippe Jourdon, Barbara Girerd, David Montani, Steeve Provencher, Sébastien Bonnet, Gérald Simonneau, Marc Humbert, Frédéric Perros
Journal: Circulation (2016)