tbuckley/cabot-search huggingface dataset:
Sarcopenia as a predictor of mortality in advanced pancreatic cancer.
Authors: Ashley Baldwin, Madappa N. Kundranda, Eric Todd, Robert P. Whitehead, Rachel Winston, Jeffery Weber, David J Weitz, Melinda Kelly, Toufic Kachaamy
Journal: Journal of Clinical Oncology (2015)

268 Background: Pancreatic cancer (PC) patients have multiple risk factors for malnutrition including digestive enzyme deficiency, gastric outlet obstruction and post prandial abdominal pain. In order to assess prognosis and triage patients at risk for malnutrition, accurate nutrition assessment is crucial. Overweight (Ow) or obese (Ob) patients pose a particular challenge and weight status should not be the only determining nutritional assessment tool. Sarcopenia (Sp) is defined as muscle mass (MM) two standard deviations below the healthy adult mean. It has been demonstrated in multiple studies to be a more accurate indicator of nutritional status. Sp is associated with poor clinical outcomes and lower survival in other conditions such as cirrhosis. Radiologic assessment of MM can be obtained reliably from computed tomography (CT) scans. Methods: All patients with advanced PC who had baseline CT scans were included in this study. MM assessment was performed using an automated software (SliceOmatic, Tomovision, Montreal) and the skeletal muscle index(SMI) was calculated at level of the 3rd lumbar (L3) vertebrae. Multiple patient characteristics were assessed including demographics, weight, body mass index (BMI), cancer stage, treatment received and survival. Sp was defined as an L3 SMI of less than 38.5 in women and 52.4 in men. Survival analysis was performed using SAS software and Log-rank and Wilcoxon statistics. Results: 167 patients, 49% female, 62% with sarcopenia (S+), 44% Ow/Ob (O+) and 14% sarcopenic and Ow/Ob (S+O+). Patients received a variety of treatments including surgery, chemotherapy and radiation. There was a trend towards lower survival in S+O+ patients while patients who were S-O+ survived the longest. Median survival in months was 6.2 for S+O+, 7.1 for S+O-, 7.8 for S-O- and 10 for S-O+. Conclusions: Patients with sarcopenia appear to have decreased survival especially if overweight/obese. This suggests that overweight/obese pancreatic cancer patients with sarcopenia may derive the most benefit from aggressive nutritional interventions. Well powered prospective studies are needed to confirm this observation and study the effects of aggressive nutritional interventions in this subgroup of patients.
Obinutuzumab (GA101) Significantly Improves Survival In CD20 Positive Pre-B Cell Lymphoblastic Leukemia (pre-B-ALL) Xenograft Models Compared To Rituximab (RTX): Potential Targeted Therapy In Patients With High Risk Pre-B-ALL
Authors: Aradhana Awasthi, Janet Ayello, Carmella van de Ven, Stefan Hovy, Mitchell S. Cairo
Journal: Blood (2013)
Effect of sex steroid hormones on serum levels of vascular endothelial growth factor (VEGF) in a murine model.
Authors: M. Á. Berciano Guerrero, J. De la Haba Rodriguez, J. Castellano, I. Porras, G. Pulido, J. Jimenez, M. Tena Sempere, I. Barneto, E. Aranda
Journal: Journal of Clinical Oncology (2010)

e21097 Background: There is an increasing interest in knowing the relationship between sexual hormones and the mechanisms that regulate angiogenesis. This association and the potential regulatory pathways may have important therapeutical implications in the management of hormone-dependent tumors. Objective: To determine how sex steroid hormones alone and in combination change the serum levels of VEGF in a murine animal model. Methods: We analyzed serum levels of VEGF (Quantikine VEGF rat inmunoassay ref: RRVV00) in 30 male Wistar cyclic orchiectomized rats and 70 female oophorectomised rats. The animals were pretreated with subcutaneous placement of hormonal silastic capsules (Dow Corninc Midland, MI). Extraction was performed on day +7, as well as diestrous and late proestrous phases. Results: For male rats, highest levels of VEGF were obtained in those treated with estrogen compared to the control group and treated with testosterone. For female rats, highest serum levels of VEGF were obtained in those treated with progesterone, estrogen, and their combination versus control group (p<0.05). Conclusions: Estrogens and progestogens increase the serum levels of VEGF in murine model. These data support the connection between hormonal status and angiogenesis. Groups Control Empty capsule Testosterone Estrogens Progestogens Both Male - 11.42 13.97 22.31 - 13.96 Female 6.91 2.62 - 14.47 25.60 28.10 No significant financial relationships to disclose.
Well-Being: An Important Concept for Psychotherapy and Psychiatric Neuroscience
Authors: Gregor Hasler
Journal: Psychotherapy and Psychosomatics (2016)

istential issues were crucial in patients with eating disorders, and overall, well-being outcomes were particularly important for women [3,4] .Recent empirical evidence confirms Engel's assumptions on well-being as an important aspect of health and disease to an extent that I have never dared to imagine.The authors of the World Happiness Report 2016 Update found that positive affect, autonomy, generosity and social support were highly correlated with quality of life and well-being, while there was almost no correlation between negative affect -an important criterion in the definition of psychiatric disorders -and overall happiness [5] .A study including all 3.9 million US personnel who served during the Operation Enduring Freedom or Operation Iraqi Freedom points in the same direction.It demonstrated that the direct involvement in acts of war was not associated with the rate of suicide at all [6] .Instead, socially positive experiences such as marriage, social support, long-term employment and ascending in the military hierarchy were the main drivers of survival.This means that resiliency and quality of life may be better explained by social well-being than by combat trauma.Unsurprisingly, books about resiliency, personal growth, mindfulness, flow and well-being dominate nonfiction bestseller lists across the world.In contrast, most
Artemisinin-Based Treatments in Pregnant Women with Malaria
Authors: Adeshina I Adekunle, Deborah Cromer, Miles P Davenport
Journal: New England Journal of Medicine (2016)

To the Editor: The Pregnancy Artemisinin-Based Combination Treatments (PREGACT) Study Group compared the polymerase-chain-reaction (PCR)-adjusted "recrudescence" rates of Plasmodium falciparum infection after treatment and suggest that this indicates the failure to eradicate the initial infection (March 10 issue). 1 However, analysis of the PCR-adjusted and PCR-unadjusted survival curves of time to "treatment failure" (Fig. S1 in the Supplementary Appendix, available with the full text of the article at NEJM.org) suggests that the curves are equally well explained by a constant rate of new infections, a proportion of which are misclassified as recrudescent.The percentage of infections classified as recrudescent is 9.9% (68 of 686) across the cohort (Table 2 of the article) and does not differ significantly among the four drug regimens (P = 0.64 by the chi-square test).Nor is there evidence of an early clustering of PCR-adjusted infection, as might be expected from treatment failure. 2,3In fact, the only significant difference between drugs appears to be their duration of post-treatment prophylaxis.It is important to clarify terminology, because assuming that all PCR-adjusted infections indicate failure to eradicate existing parasites may exaggerate estimates of the recrudescence rate and therefore of drug resistance.Parasite genotyping may perform poorly in areas of high transmission, 4 and consideration of the underlying infection kinetics can provide additional insights.
P1173 : Mait cells are enriched in portal tracts and respond to biliary epithelial cells presenting bacterial ligands during liver inflammation
Authors: H. Jeffery, B. van Wilgenburg, S. Hunter, A. Kurioka, K. Parekh, K. Stirling, S. Roberts, D. Adams, P. Klenerman, Y.H. Oo
Journal: Journal of Hepatology (2015)
The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature
Authors: André F. Carvalho, Manu S. Sharma, André R. Brunoni, Eduard Vieta, Giovanni A. Fava
Journal: Psychotherapy and Psychosomatics (2016)

Newer generation antidepressant drugs (ADs) are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents. In this critical review, we evaluated the literature on adverse events, tolerability and safety of selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, bupropion, mirtazapine, trazodone, agomelatine, vilazodone, levomilnacipran and vortioxetine. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms (nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances (heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system disturbances (lowering of seizure threshold, extrapyramidal side effects, cognitive disturbances), sweating, sleep disturbances, affective disturbances (apathy, switches, paradoxical effects), ophthalmic manifestations (glaucoma, cataract) and hyperprolactinemia. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. Other areas of concern involve suicidality, safety in overdose, discontinuation syndromes, risks during pregnancy and breast feeding, as well as risk of malignancies. Thus, the rational selection of ADs should consider the potential benefits and risks, likelihood of responsiveness to the treatment option and vulnerability to adverse events. The findings of this review should alert the physician to carefully review the appropriateness of AD prescription on an individual basis and to consider alternative treatments if available.
Pharmacokinetics and pharmacodynamics of the dual syk/jak inhibitor PRT062070 (cerdulatinib) in patients with advanced B-cell malignancies.
Authors: Ian Flinn, Manish R. Patel, Nina D. Wagner-Johnston, Anjali Pandey, Greg Coffey, Janet Leeds, Stanley Hollenbach, Sandra Russell, Dale Baker, Gallia G. Levy, John T Curnutte
Journal: Journal of Clinical Oncology (2014)

2619 Background: Syk and Jak appear to have independent but cooperative roles in promoting the survival of certain B cell malignancies. Syk is upstream of BTK and PI3K on the B cell antigen receptor (BCR) signaling pathway, and Jak mediated survival signals have been observed in leukemia and lymphoma. Combined knockdown of Syk and Jak results in greater cell kill in B cell lymphoma cell lines relative to knock down of either alone (Ma, et al, 2013), suggesting dual pharmacological targeting of these pathways may be an effective treatment strategy. PRT062070 is a potent and selective inhibitor of Syk, JAK1, JAK3, and Tyk2. Here we present PK and PD data from a dose escalation study with PRT062070 in patients with NHL, CLL, and SLL. Methods: Patients were enrolled in a 3+3 dose escalation study beginning at 15 mg orally daily. PK/PD relationships were determined using a variety of whole blood assays measuring Syk (BCR-mediated) and Jak (IL2-, IL4-, and IL6-mediated) kinase activity. Specificity controls included GM-CSF (JAK2 mediated) and phorbol 12-myristate 13-acetate (PKC-mediated) stimulations. Plasma concentrations were assessed on Days 1, 8, 15, and 22 of the first treatment cycle with standard LC/MS/MS methods. Results: The average elimination T1/2 at steady state (SS) is ~12 hours and Tmax ~2 hours. The SS peak-to-trough ratio is 3:1. The mean Cmaxss value was 80% higher than the Day 1Cmax. Increases in Cmax and exposure were dose proportional from the 15 to 30 mg dose. Relative to pre-dose, assays measuring Syk (BCR) and Jak (IL2, IL4, IL6) activity at SS were inhibited by 25-50% at the 15 mg dose level, and 50-70% at the 30 mg dose level. No corresponding inhibition of JAK2 or PKC-mediated signaling was observed. The PK/PD relationship is consistent with pre-clinical in vitro experiments. Conclusions: PRT062070 demonstrates a favorable PK profile, supporting once daily dosing. The PD data demonstrate selective target inhibition with IC50’s consistent with that observed pre-clinically. Data to date suggest that high levels of Syk and Jak inhibition in peripheral blood can be safely achieved following oral dosing. Clinical trial information: NCT01994382.
Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of<i>CDKN2A</i>,<i>MC1R</i>and<i>MITF</i>
Authors: C. Mangas, M. Potrony, C. Mainetti, E. Bianchi, P. Carrozza Merlani, A. Mancarella Eberhardt, E. Maspoli-Postizzi, G. Marazza, A. Marcollo-Pini, F. Pelloni, C. Sessa, B. Simona, J.A. Puig-Butillé, C. Badenas, S. Puig
Journal: British Journal of Dermatology (2016)

Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease. To obtain information about genetic predisposition to CM in Ticino, the southern region of Switzerland, a zone with moderate‐to‐high CM incidence. We identified germline mutations in highly CM‐associated genes (CDKN2A and CDK4) and low/medium‐penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first‐ or second‐degree relatives. Healthy blood donors (n = 146) were included as a control group. From July 2010 to July 2012, 57 patients (41 pedigrees) were included. Twenty‐six were melanoma‐prone families (with at least two cases) and 15 had multiple CMs. Pancreatic cancer was found in six families. The CDKN2A mutation p.V126D was identified in seven patients (four families) with a founder effect, whereas CDKN2A A148T was detected in seven cases (five families) and seven healthy donors (odds ratio 2·76, 95% confidence interval 0·83–9·20). At least one MC1R melanoma‐associated polymorphism was detected in 32 patients (78%) and 97 healthy donors (66%), with more than one polymorphism in 12 patients (29%) and 25 healthy donors (17%). The MITF variant p.E318K was identified in four patients from three additional pedigrees (7%) and one healthy control (0·7%). Inclusion criteria for the Ticino population for genetic assessment should follow the rule of two (two affected individuals in a family or a patient with multiple CMs), as we detected a CDKN2A mutation in almost 10% of our pedigrees (four of 41), MITF p.E318K in 7% (three of 41) and a higher number of MC1R variants than in the control population.
Abstract A04: The tumor microenvironment is the main source of IL-6 for plasmacytoma development in mice.
Authors: Timothy R. Rosean, Van S. Tompkins, Ramakrishna Sompallae, Lyse A. Norian, Herbert C. Morse, Thomas J. Waldschmidt, Siegfried Janz
Journal: Clinical Cancer Research (2015)

Abstract The development of targeted interventions for hematopoietic neoplasms of the B-lymphocyte lineage, such as multiple myeloma (MM), may benefit from preclinical experimental model systems in which complex interactions of neoplastic and nonmalignant bystander cells in the tumor microenvironment (TME) can be genetically dissected. Here we employ peritoneal plasmacytomagenesis in mice, which is strictly dependent on the pro-inflammatory cytokine, interleukine 6 (IL-6), to demonstrate that the nonmalignant bystanders are the main source of IL-6 for tumor development. B cell derived IL-6 is dispensable. The finding that lack of IL-6 in the TME significantly delays tumor onset in mice supports translational research efforts to target IL-6 production in bone marrow stroma cells for myeloma treatment and prevention. Citation Format: Timothy R. Rosean, Van S. Tompkins, Ramakrishna Sompallae, Lyse A. Norian, Herbert C. Morse, III, Thomas J. Waldschmidt, Siegfried Janz. The tumor microenvironment is the main source of IL-6 for plasmacytoma development in mice. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A04.
Extracellular vesicles carry microRNA‐195 to intrahepatic cholangiocarcinoma and improve survival in a rat model
Authors: Ling Li, Klaus Piontek, Masaharu Ishida, Michel Fausther, Jonathan A. Dranoff, Rongdang Fu, Esteban Mezey, Stephen J. Gould, Francis K. Fordjour, Stephen J. Meltzer, Alphonse E. Sirica, Florin M. Selaru
Journal: Hepatology (2016)

The cancer microenvironment plays a central role in cancer development, growth, and homeostasis. This paradigm suggests that cancer fibroblasts support cancers, probably in response to stimuli received from the cancer cells. We aimed at investigating whether extracellular vesicles (EVs) can shuttle microRNA (miR) species between cancer-associated fibroblasts (CAFs) and cancer cells. To this end, we extracted EVs according to published protocols. EVs were studied for their miR content by quantitative reverse-transcription polymerase chain reaction. EVs were transfected with select miR species and utilized in vitro as well as in vivo in a rat model of cholangiocarcinoma (CCA). We found that miR-195 is down-regulated in CCA cells, as well as in adjoining fibroblasts. Furthermore, we report that EVs shuttle miR-195 from fibroblasts to cancer cells. Last, we show that fibroblast-derived EVs, loaded with miR-195, can be administered in a rat model of CCA, concentrate within the tumor, decrease the size of cancers, and improve survival of treated rats.EVs play a salient role in trafficking miR species between cancer cells and CAFs in human CCA. Understanding of these mechanisms may allow devising of novel therapeutics. (Hepatology 2017;65:501-514).
Abstract 2825: Identification of CDK4/6-response biomarkers using estrogen receptor-positive breast cancer patient-derived xenografts (PDX)
Authors: Violeta Serra, Marta Palafox, Maria-Teresa Herrera, Martin A Rivas, Marta Guzmán, Olga Rodriguez, Judit Grueso, Meritxell Bellet, Mafalda Oliveira, Cristina Saura, Emmanuelle di Tomaso, Giordi Camponigro, Nicholas C. Turner, Javier Cortés, José Baselga
Journal: Cancer Research (2016)

Abstract Endocrine resistance is a clinical challenge for the treatment of estrogen receptor positive (ER+) breast cancer (BC). CDK4/6 blockade in combination with endocrine therapy has shown clinical activity in metastatic ER+ BC refractory to anti-hormonal treatment. However, there is a need for biomarkers that can predict the response to this treatment and improve patient stratification. We aimed to address this issue using xenograft models established from samples of ER+ BC patients. Six ER+ PDXs were treated with continuous doses of a CDK4/6 inhibitor (LEE011, 75mg/kg, 6IW) and a PI3K-alpha inhibitor (BYL719, 35mg/kg, 6IW) as single agents and in combination, and intrinsic sensitivity to these agents was evaluated. The models were then genomically characterized using a capture-based sequencing panel and by digital PCR. One PDX model was intrinsically sensitive to single-agent CDK4/6 inhibition and experienced tumor regression, but all individual tumors eventually escaped therapy after 50 days of treatment. This particular model harbored an ESR1-mutation and concomitant losses of CDKN2A/B. At relapse, we identified the acquisition of an RB1 frameshift mutation. Interestingly, upfront combined treatment with a PI3K-alpha inhibitor delayed the onset of tumor progression. Two out of the remaining five CDK4/6-resistant PDXs harbored either a frameshift mutation in RB1 (plus loss of heterozygosity) or had low pRb protein expression. Two other resistant models harbored CCND1 and MYC amplifications. The remaining one harbored a TSC1 loss. In all the CDK4/6-resistant PDX, however, the combination of CDK4/6 and PI3K-alpha inhibition resulted in tumor regression. From our results, we conclude that loss of G1-cell cycle checkpoint control, such as mutation/loss of RB1 and CCND1-amplification, is associated with lack of response to CDK4/6 blockade in ER+ BC PDX. The addition of a PI3K-alpha inhibitor results in improvement of disease control in all experimental models tested. Citation Format: Violeta Serra, Marta Palafox, Maria-Teresa Herrera, Martin A Rivas, Marta Guzmán, Olga Rodriguez, Judit Grueso, Meritxell Bellet, Mafalda Oliveira, Cristina Saura, Emmanuelle di Tomaso, Giordi Camponigro, Nicholas C. Turner, Javier Cortés, José Baselga. Identification of CDK4/6-response biomarkers using estrogen receptor-positive breast cancer patient-derived xenografts (PDX). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2825.
Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results
Authors: Claire N. Harrison, Alessandro M. Vannucchi, Jean-Jacques Kiladjian, Haifa Kathrin Al-Ali, Heinz Gisslinger, Laurent Knoops, Francisco Cervantes, Mark M. Jones, Kang Sun, Laurence Descamps, Viktoriya Stalbovskaya, Prashanth Gopalakrishna, Tiziano Barbui
Journal: Blood (2015)
Abstract 3532: Compound Tc inhibits ATG4 to attenuate autophagic flux and sensitize cancer cells to chemotherapy
Authors: Chih-Wen Shu.
Journal: Cancer Research (2016)

Abstract Autophagy is induced to protect cancer cells against stresses, including starvation, hypoxia and chemotherapy. Antimalarial drugs chloroquine and its derivative hydroxychloroquine are used to inhibit autophagy and being investigated with clinical trials for certain types of cancer. However, the tumor suppressive effects of the drugs might be autophagy independent, which require more specific inhibitors target autophagy components for clinical uses. Here, we screened FDA-approved drug library with both biochemical and cellular ATG4 reporter assays and found compound Tc blocked proteolysis activity of ATG4, essential proteases in autophagy machinery. Docking and MD simulation results appeared compound Tc was directly associated with active site of ATG4. Further, compound Tc obstructed the binding between ATG4 and MAP1LC3 and accumulated autophagosomes, which in turn reduce autophagic flux in cells. Moreover, compound Tc suppressed tumor viability and sensitized chemotherapy efficacy in two-dimensional and sphere culture model. Silencing ATG4 or overexpression of ATG4 catalytic mutant had no additional effects on tumor suppression compared to compound Tc alone, indicating compound Tc inhibited ATG4s activity to diminish tumor viability. In addition, compound Tc enhanced genotoxic stress-induced apoptosis to synergize chemotherapy efficacy in vitro and in vivo. Thus, we report that the clinical drug compound Tc is a potent ATG4 inhibitor, which could interrogate the role of autophagy in clinical setting and provide compound Tc as an anticancer drug or chemosensitizer. Citation Format: Chih-Wen Shu. Compound Tc inhibits ATG4 to attenuate autophagic flux and sensitize cancer cells to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3532.
England must support its community hospitals
Authors: David Seamark, Helen Tucker, Heather Penwarden
Journal: BMJ (2016)

Appleby highlights the plight of acute hospital patients with delayed discharge because of waiting for assessments and transfers to other NHS facilities.1 We note an overlooked and neglected NHS resource: community hospitals. The UK has around 500,2 and Simon Stevens, NHS England chief, made a statement supporting improved local access to services and full use of these hospitals.3

Of the 362 community hospitals …