Person: Gautam, Shiva
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Gautam
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Shiva
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Gautam, Shiva
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Publication Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status(Mary Ann Liebert Inc, 2017) Gavrila, Alina; Hasselgren, Per-Olof; Glasgow, Allison; Doyle, Ashley N.; Lee, Alice J.; Fox, Peter; Gautam, Shiva; Hennessey, James; Kolodny, Gerald; Cypess, AaronBackground: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. Methods: The study subjects underwent 18F-FDG PET-CT scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following thyroid hormone withdrawal at the time of the radioactive iodine treatment and then 3-6 months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. We measured thermogenic and metabolic parameters in both phases. Results: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4 out of 6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, P = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, P = 0.34). Importantly, circulating T3 was a stronger predictor of energy expenditure changes compared to cold-induced BAT activity. Conclusions: Iatrogenic hypothyroidism lasting 2-4 weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.Publication Electrical impedance myography as a biomarker to assess ALS progression(Informa UK Limited, 2012) Rutkove, Seward; Caress, James B.; Cartwright, Michael S.; Burns, Ted M.; Warder, Judy; David, William; Goyal, Namita; Maragakis, Nicholas J.; Clawson, Lora; Benatar, Michael; Usher, Sharon; Sharma, Khema R.; Gautam, Shiva; Narayanaswami, Pushpa; Raynor, Elizabeth; Watson, Mary Lou; Shefner, Jeremy M.Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.Publication Widespread Climate Change in the Himalayas and Associated Changes in Local Ecosystems(Public Library of Science, 2012) Shrestha, Uttam Babu; Gautam, Shiva; Bawa, Kamaljit S.Background: Climate change in the Himalayas, a biodiversity hotspot, home of many sacred landscapes, and the source of eight largest rivers of Asia, is likely to impact the well-being of \(\sim\)20% of humanity. However, despite the extraordinary environmental, cultural, and socio-economic importance of the Himalayas, and despite their rapidly increasing ecological degradation, not much is known about actual changes in the two most critical climatic variables: temperature and rainfall. Nor do we know how changes in these parameters might impact the ecosystems including vegetation phenology. Methodology/Principal Findings: By analyzing temperature and rainfall data, and NDVI (Normalized Difference Vegetation Index) values from remotely sensed imagery, we report significant changes in temperature, rainfall, and vegetation phenology across the Himalayas between 1982 and 2006. The average annual mean temperature during the 25 year period has increased by 1.5\(^\circ\)C with an average increase of 0.06\(^\circ\)C yr\(^{−1}\). The average annual precipitation has increased by 163 mm or 6.52 mmyr\(^{−1}\). Since changes in temperature and precipitation are immediately manifested as changes in phenology of local ecosystems, we examined phenological changes in all major ecoregions. The average start of the growing season (SOS) seems to have advanced by 4.7 days or 0.19 days yr\(^{−1}\) and the length of growing season (LOS) appears to have advanced by 4.7 days or 0.19 days yr\(^{−1}\), but there has been no change in the end of the growing season (EOS). There is considerable spatial and seasonal variation in changes in climate and phenological parameters. Conclusions/Significance: This is the first time that large scale climatic and phenological changes at the landscape level have been documented for the Himalayas. The rate of warming in the Himalayas is greater than the global average, confirming that the Himalayas are among the regions most vulnerable to climate change.Publication Prevalence and Predictors of Loss of Wild Type BRCA1 in Estrogen Receptor Positive and Negative BRCA1-Associated Breast Cancers(BioMed Central, 2010) Fetten, Katharina; Yassin, Yosuf; Buraimoh, Ayodele; Kim, Ji-Young; Legare, Robert D; Tung, Nadine; Miron, A; Schnitt, Stuart; Gautam, Shiva; Kaplan, Jennifer; Szasz, Attila M.; Tian, R; Wang, Zhigang C.; Collins, Laura; Brock, Jane; Krag, Karen; Sgroi, Dennis; Ryan, Paula D.; Silver, Daniel P.; Garber, Judy; Richardson, AndreaIntroduction: The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers. Methods: Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers. Results: Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞). Conclusions: We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.