tbuckley/cabot-search huggingface dataset:
Insulin-Associated Weight Gain in Type 2 Diabetes Is Associated With Increases in Sedentary Behavior
Authors: Yvonne A.W. Hartman, Henry J. Jansen, Maria T.E. Hopman, Cees J. Tack, Dick H.J. Thijssen
Journal: Diabetes Care (2017)

The insulin therapy–mediated weight gain in patients with type 2 diabetes (T2D) may relate to altered physical activity patterns (1). In this study, we examined the hypothesis that initiation of insulin therapy would be associated with an increase in sedentary behavior (i.e., sitting time) and lower low-, moderate-, and vigorous-intensity physical activity, which would subsequently relate to weight gain.

We included 40 T2D patients who started insulin therapy and followed these patients for a period of 12 months. Patients were randomly selected from one university hospital, three nonuniversity teaching hospitals, and four primary care practices. The decision to start insulin treatment was at the discretion of the responsible physician and was always based on failure of glycemic control while on oral glucose-lowering agents and diet. Measurements were performed before and 6 months and 12 months after initiation of insulin therapy. We examined body weight, waist-to-hip circumference, fasting glucose, and HbA1c using standardized procedures. Free-living daytime physical activity was objectively measured (SenseWear Pro3 Armband, BodyMedia, Pittsburgh, PA) (2). We examined 1 ) time (hours/day) spent in sitting ( 3.0 METs); 2 ) steps per day; and 3 ) sit-to-stand maneuvers (transition from …
Evaluating pulmonary nodules to detect lung cancer: Does Fleishner criteria really work?
Authors: Muhammad Azharuddin, Aamir Malik, Noor Adamo, Douglas S Livornese
Journal: Journal of Clinical Oncology (2017)

e13053 Background: The Fleishner Society recommends interval computed tomography (CT) follow-up for managing incidental small pulmonary nodules detected in CT scans. This study evaluates the clinical application of 2013 Fleishner criteria using a large cohort of patients at high risk for lung cancer with low-dose CT screening. Methods: During 2012-2016, a retrospective study of 176 patients was reviewed for incidental lung nodules. Patient eligibility included: men and women aged 55-74; 30 pack-year smoking history who quit in the last 15 years; no cancer history in the last 5 years; and no previous CT chest scan done. Follow-up and management was calculated using the Fleishner criteria. Nodules were classified based on several features including size and shape. Nodule characteristics were tabulated and analyzed. Results: Out of 176 patients, 117 had nodules and a total of 210 nodules were detected. Table 1 categorizes all nodule features including Fleishner Criteria. Of the entire cohort, two patients (1.1%) showed malignancy: one part-solid nodule of 10.2mm, and one multiple subsolid groundglass nodule (GGN) of 20.1mm. Twenty-one patients (17.9%) had undergone unnecessary follow-up CT scans, including those with solid nodules, and solitary pure GGNs. Conclusions: This study emphasizes the need to revise the Fleishner guidelines to more accurately estimate the risk of malignancy, including minimizing over-diagnosis, unnecessary follow-up CTs, and invasive procedures for benign pulmonary nodules. Further analysis of lung cancer contributory factors is also required. [Table: see text]
Conjunctival cystectomy assisted by pattern scan laser photocoagulation
Authors: Hee Kyung Yang, Moosang Kim, Seung-Jun Lee, Sang Beom Han, Joon Young Hyon, Won Ryang Wee
Journal: Military Medical Research (2017)

To introduce a new technique of laser-assisted conjunctival cystectomy using pattern scan laser (PASCAL) photocoagulation. A 50-years-old Asian woman presented with a conjunctival cyst in the left eye. Slit-lamp examination revealed a 5 mm × 2 mm sized freely movable conjunctival cyst. After a 1 mm × 1 mm sized conjunctival opening was made using PASCAL photocoagulation, the cyst was extracted using a non-toothed forceps without rupture. Two weeks later, complete re-epithelialization of the conjunctiva was observed without any complications. No evidence of recurrence was noted over the 6-month follow-up period. Conjunctival cystectomy with the adjunctive use of PASCAL photocoagulation can be an effective and safe treatment method.
Abstract 314: The Interaction Of The Estrogen Receptor Alpha With The Cardiac Myosin Essential Light Chain Isoform 4 As A New Regulatory Mechanism In The Heart
Authors: Shokoufeh Mahmoodzadeh, Miriam Schanz, Hang Pham, Mercy M Davidson, Ingo Morano, George Petrov, Vera Regitz-Zagrosek
Journal: Circulation Research (2013)

Estrogen (17β-estradiol, E2) is one of the key regulators of growth, differentiation and physiological function in different tissues, including the heart. The effects of E2 are mainly mediated by estrogen receptor (ER) alpha and beta, which act in concert with many cofactors to mediate estrogenic effects. So far, only a few cofactors of ER have been described in the human heart. To gain a better understanding of E2-mediated ERα action in the human heart, we identified and characterized the novel interaction partners of ERα Yeast two hybrid screening of a human heart cDNA library revealed that ERα interacts with the cardiac myosin essential light chain isoform 4 (ALC1) in presence of E2. ALC1, as a member of contractile proteins, is expressed in the fetal heart and becomes restricted to the atria of the adult heart under physiological conditions, and is reexpressed in ventricle of adult hypertrophic hearts. This switch is accompanied by alteration of contractile performance, thus improving the heart function. Retransformation experiments showed that ALC1 interacts with full-length ERα and ERα-EF domain in presence of E2. The interaction of ERα with ALC1 was also confirmed by Co-IP in human atrium. Double irnmunofluorescence (IF) analysis of paraffin-embedded sections from human atrium tissues showed co-localization of ERα and ALC1 proteins in a striated sarcomeric pattern. Co-localization corresponds most likely to the H-zone of sarcomere. IF analysis of AC16 cells (a human cardiomyocytes cell line) showed that ERα and ALC1 were mainly localized in the cytoplasm in the absence of E2. However, E2 treatment of AC16 cells led to a translocation of ALC1 and ERα into the nuclei of AC16 cells, where they also co-localized. Expression analysis in AC16 cells showed that E2 increases the expression of ALC1 gene (MYL4). Using ERE-based luciferase reporter assays we showed that E2-induced interaction of ERα with the ALC1 represses the transcriptional activity of ERα. We characterize for the first time an E2-regulated interaction of ALC1 with ERα in cardiomyocytes that may be crucial in physiological and/or pathological processes by regulating of transcriptional activity of ERa in the heart and/or by modulating contractile properties of cardiomyocytes.
A randomized, placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with AZD 1775 (MK 1775) in women with recurrent, platinum-resistant epithelial ovarian, primary peritoneal, or Fallopian tube cancers: Trial of Princess Margaret, Mayo, Chicago, and California consortia.
Authors: Stephanie Lheureux, Johanne Ingrid Weberpals, Andrea Elisabeth Wahner Hendrickson, Gini F. Fleming, Alexander Olawaiye, Irene Brana, Helen Mackay, Neesha C. Dhani, Michelle K. Wilson, Victor Rodriguez-Freixinos, Cristina Martin-Lorente, Jacklyn Ward, Karen Chang, Lisa Wang, Vanessa Speers, Katherine Karakasis, Valerie Lydia Bowering, Alice Chen, James Brenton, Amit M. Oza
Journal: Journal of Clinical Oncology (2015)

TPS5613 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. The majority of high grade serous OC (HGSOC) harbor TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with AZD 1775 (MK 1775) induces G2 checkpoint escape. Gemcitabine is an antimetabolite therapy that kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S phase boundary. Preclinical data have shown that the addition of AZD 1775 to gemcitabine increased activity in platinum resistant OC cell lines and xenograft models. We propose to evaluate the combination of gemcitabine/AZD 1775 in patients (pts) with platinum resistant OC. Methods: A multicenter 2:1 randomized phase 2 trial was designed to evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant/refractory OC receiving gemcitabine in combination with AZD 1775 compared to subjects receiving gemcitabine in combination with placebo (NCT02151292). Eligibility requires measurable disease with progression and disease amenable to a paired biopsy for correlative analyses. There is no limitation in the number of prior lines of therapy, but pts with prior gemcitabine are excluded. All histologic subtypes are eligible, but only pts with HGSOC are considered for the statistical analysis. AZD 1775/Placebo is given orally at 175mg on D1-2, D8-9 and D15-16 with gemcitabine 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. The primary objective is an improvement in median PFS (from 3.5 to 7 months). Integrated biomarkers will evaluate loss-of-function TP53 mutations by three complementary methodologies: Sanger sequencing, TAm-Seq and IHC as potential predictive factors of benefit to AZD 1775 and gemcitabine. The concordance of TP53 mutations in tumor specimens is also determined and followed by TAm-Seq in ctDNA. Current status: This trial was activated in Sept 2014. A total of 10 pts with a median age of 66 are enrolled, all HGSOC. Clinical trial information: NCT02151292.
Increased Inflammatory Properties of Neutrophils in Patients with Venous Thromboembolism and the Effect of Simvastatin on Abrogating Inflamed Neutrophils Adhesiveness
Authors: Kiara Cristina Senger Zapponi, Fernanda Andrade Orsi, Ingrid Rafaela de Brito, Anna Virginia Calazans Romano, José Luiz Rosenberis Cunha Junior, Silmara Aparecida De Lima Montalvão, Fernanda Dutra Santiago Bassora, Luis Fernando Bittar, Erich Vinicius De Paula, Carla Fernanda Franco Penteado, Joyce Maria Annichino-Bizzacchi
Journal: Blood (2016)
Self-Assembly DNA Polyplex Vaccine inside Dissolving Microneedles for High-Potency Intradermal Vaccination
Authors: Jing-Fong Liao, Jin-Ching Lee, Chun-Kuang Lin, Kuo-Chen Wei, Pin-Yuan Chen, Hung-Wei Yang
Journal: Theranostics (2017)

The strong immunogenicity induction is the powerful weapon to prevent the virus infections.This study demonstrated that one-step synthesis of DNA polyplex vaccine in microneedle (MN) patches can induce high immunogenicity through intradermal vaccination and increase the vaccine stability for storage outside the cold chain.More negative charged DNA vaccine was entrapped into the needle region of MNs followed by DNA polyplex formation with branched polyethylenimine (bPEI) pre-coated in the cavities of polydimethylsiloxane (PDMS) molds that can deliver more DNA vaccine to immune-cell rich epidermis with high transfection efficiency.Our data in this study support the safety and immunogenicity of the MN-based vaccine; the MN patch delivery system induced an immune response 3.5-fold as strong as seen with conventional intramuscular administration; the DNA polyplex formulation provided excellent vaccine stability at high temperature (could be stored at 45ºC for at least 4 months); the DNA vaccine is expected to be manufactured at low cost and not generate sharps waste.We think this study is significant to public health because there is a pressing need for an effective vaccination in developing countries.
Lessons Learned From the VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) Study
Authors: Maurizio Fava
Journal: JAMA (2017)

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Strict tropism for CD71+/CD234+ human reticulocytes limits the zoonotic potential of Plasmodium cynomolgi
Authors: Varakorn Kosaisavee, Rossarin Suwanarusk, Adeline C. Y. Chua, Dennis E. Kyle, Benoit Malleret, Rou Zhang, Mallika Imwong, Rawiwan Imerbsin, Ratawan Ubalee, Hugo Sámano-Sánchez, Bryan K. S. Yeung, Jessica J. Y. Ong, Eric Lombardini, François Nosten, Kevin S. W. Tan, Pablo Bifani, Georges Snounou, Laurent Rénia, Bruce Russell
Journal: Blood (2017)
Prognostic value of plasma circulating tumor (ct) DNA <i>KRAS</i> mutations and serum CA19-9 in unresectable pancreatic cancer (PC) patients.
Authors: Julia S. Johansen, Cecile Rose T. Vibat, Saege Hancock, Inna Markovna Chen, Latifa Hassaine, Errin Samuelsz, Eric Andrew Collisson, Benny Vittrup Jensen, Timothy T. Lu, Vlada Melnikova, Mark G. Erlander
Journal: Journal of Clinical Oncology (2015)

4022 Background: Median overall survival (OS) time of patients with unresectable PC varies widely. Diagnostic tools are presently lacking to predict outcomes. The majority of pancreatic tumors have KRAS mutations. The study aim was to evaluate the utility of baseline and serial measurements of ctDNA KRAS mutation load, alone or in combination with serum CA 19-9, as an outcome prognostic biomarker in patients with unresectable PC undergoing palliative chemotherapy. Methods: In the Danish BIOPAC prospective biomarker study, plasma was collected from 182 unresectable PC patients (85 females, 97 males, median age 68, range 45-89 years; locally advanced disease n = 48; metastatic n = 134) undergoing treatment with gemcitabine (n = 151) or FOLFIRINOX (n = 31). ctDNA KRAS G12/13 mutation levels in archival ( ≤ 6 years) plasma was assessed with enrichment PCR followed by next generation sequencing and standardized reporting of copies per 105 genome equivalents (GE). Results: In a prospective-retrospective study of 182 patients, interim analysis of ctDNA KRAS was conducted (after 168 deaths). 176 of 182 patients had evaluable baseline plasma samples. Of 176 patients, 143 (81%) had > 1 copy mutant KRAS G12/13 ctDNA at baseline. To assess associations between KRAS, CA 19-9 and OS, KRAS and CA 19-9 values were dichotomized by finding thresholds maximizing similarity of OS in each group (thresholds: 41 KRAS copies/105 GE; 314 U/ml, CA 19-9). Both KRAS and CA 19-9 negatively predicted OS (Cox proportional hazards model). KRAS with CA 19-9 was a stronger predictor of death than either marker alone. The hazard rate (HR) of death for patients with KRAS > 41 c/105GE and CA 19-9 > 314 U/ml was 3.0 times as high (95% CI: 2.0 to 4.6) as those with KRAS < 41 c/105GE and CA 19-9 < 314 U/ml. This is compared to HR 2.1 (95% CI: 1.5 to 2.8) for patients with high KRAS vs low KRAS, and HR 1.8 (95% CI: 1.3 to 2.6) for patients with high CA 19-9 vs low CA 19-9. Shorter OS tend to associate with elevated KRAS and CA 19-9 during chemotherapy. Conclusions: Combination of pre-treatment plasma ctDNA KRAS mutation load and CA 19-9 is a strong prognostic factor in patients with unresectable PC receiving palliative treatment with gemcitabine or FOLFIRINOX.
Individualizing Cancer Therapies Using PET Imaging
Authors: Richard Wahl
Journal: Clinical Cancer Research (2007)

ED01-02   PET/CT imaging using the radiotracer 18F-Fluoro-2-deoxy-D glucose (FDG) has been established as a clinically useful tool for imaging a wide range of cancers offering quantitative functional and anatomical information. In general, PET imaging is able to detect smaller cancers than detected with anatomic imaging, with greater specificity. It has been shown in a diverse array of neoplasms that effective therapies of a wide variety of types generally rather quickly reduce glucose metabolism in cancers, before tumor shrinkage occurs, and these reductions in glucose metabolism are quite predictive of the ultimate success of the treatments. The use of PET with FDG for the early assessment of treatment response includes a baseline PET scan with a follow up PET scan after 1 or 2 cycles of treatment. Rapid and large declines in tumor glycolysis early after treatment is initiated have been generally associated with a continued response to treatment and a superior progression free survival period than seen in patients who do not have rapid reductions or in whom glycolysis does not decline with treatment. The obvious advantage of imaging this approach is that there is a prompt and direct biological read out of cancer treatment efficacy in the individual tumor of an individual patient. Thus, host, therapeutic and tumor factors contribute to the PET signal observed. This “read out” of treatment effect appears to be rather robust and general predictor of the efficacy of treatment regimens in the diseases in which it has been studied, particularly lymphoma, esophageal and breast cancers. Thus, if this approach were widely adopted, effective treatments can be continued while ineffective treatments can be changed at earlier time points than currently is the case, “response adaptive therapy”. Dose de-intensification might also be possible. This approach using PET with FDG also is potentially applicable using other tracers, such as those for proliferation, protein or membrane synthesis, etc. This early readout of treatment efficacy is also of considerable interest in drug development and may help achieve more quick determinations of which candidate agents to continue development of and which to not pursue. Other PET approaches include “response predictive” therapies which may be able to predict before treatment the receptor status, hypoxic state, etc. for cancers before treatments are started and adjust the treatment appropriately. This lecture will briefly review the available data on monitoring cancer response with PET, response adaptive therapy with PET, and will also address briefly the potential for response predictive PET algorithms.
Abstract 16529: Coupling of Mitochondrial Respiration and Superoxide Production in Healthy and Failing Hearts
Authors: Guohua Gong, Xiaoyun Liu, Georgios Karamanlidis, Wang Wang
Journal: Circulation (2012)

Mitochondrial respiration through electron transport chain (ETC) activity critically regulates energy homeostasis and heart performance. Insufficient energy supply and excessive oxidative stress underlie the mechanism of heart failure. How mitochondrial respiration and reactive oxygen species production are fine-tuned in the healthy heart and dys-regulated in the failing heart remain largely unknown. Recently, we discovered stochastic and transient superoxide production events, named superoxide flashes, in single mitochondria of intact cardiac myocytes. Here, we show that superoxide flash is tightly coupled to mitochondrial respiration and diminished superoxide flash activity is a hallmark of the transition to heart failure. Increase in either metabolic substrate availability (glucose 10 mM, palmitate 0.5 mM, or pyruvate 10 mM) or energy demand (isoproterenol 1 µM or pacing) boosted superoxide flash activity. In permeabilized myocytes, addition of the specific substrates for each ETC complex (Complex I, II or IV) elevated superoxide flash activity 3-4 folds over basal level, indicating that superoxide flash arises from the ETC electron flow. Further, myocytes from a Complex I deficient mice (Ndufs4H-/-) showed significantly lower flash activity, which was stimulated by palmitate but not pyruvate. This indicates that Complex I is likely the primary site for electron entrance under normal conditions. However, when Complex I activity is compromised, electron entrance at other sites (associated with palmitate oxidation) may be enhanced. Interestingly, inhibition of the FoF1 ATP synthase by oligomycin A acutely increased flash activity followed by a decline to below normal level. Thus, ETC activity is transiently accelerated upon blockade of the downstream ATP generation. In the pressure overload induced heart failure model, the decline of superoxide flash precedes the contractile dysfunction, suggesting that impaired mitochondrial respiration occurs at the early stage of heart failure. In summary, our data support the mechanistic coupling of superoxide flash with mitochondrial respiration, and suggest that superoxide flash is a sensitive indication of single mitochondrial dysfunction in heart failure.
Complex Patterns of Admixture across the Indonesian Archipelago
Authors: Georgi Hudjashov, Tatiana M. Karafet, Daniel J. Lawson, Sean Downey, Olga Savina, Herawati Sudoyo, J. Stephen Lansing, Michael F. Hammer, Murray P. Cox
Journal: Molecular Biology and Evolution (2017)

Indonesia, an island nation as large as continental Europe, hosts a sizeable proportion of global human diversity, yet remains surprisingly undercharacterized genetically. Here, we substantially expand on existing studies by reporting genome-scale data for nearly 500 individuals from 25 populations in Island Southeast Asia, New Guinea, and Oceania, notably including previously unsampled islands across the Indonesian archipelago. We use high-resolution analyses of haplotype diversity to reveal fine detail of regional admixture patterns, with a particular focus on the Holocene. We find that recent population history within Indonesia is complex, and that populations from the Philippines made important genetic contributions in the early phases of the Austronesian expansion. Different, but interrelated processes, acted in the east and west. The Austronesian migration took several centuries to spread across the eastern part of the archipelago, where genetic admixture postdates the archeological signal. As with the Neolithic expansion further east in Oceania and in Europe, genetic mixing with local inhabitants in eastern Indonesia lagged behind the arrival of farming populations. In contrast, western Indonesia has a more complicated admixture history shaped by interactions with mainland Asian and Austronesian newcomers, which for some populations occurred more than once. Another layer of complexity in the west was introduced by genetic contact with South Asia and strong demographic events in isolated local groups.