tbuckley/cabot-search huggingface dataset:
GNPAT p.D519G variant and iron metabolism during oral iron tolerance test
Authors: Raffaela Rametta, Paola Dongiovanni, Silvia Fargion, Luca Valenti
Journal: Hepatology (2016)

We read with interest the letter by Hsiao et al.,1 reporting that the rs11558492 polymorphism coding for the p.D519G protein variant of GNPAT is associated with higher serum iron and higher transferrin saturation (TS) after iron challenge in healthy women. This genetic variant had been reported to worsen iron overload in homozygotes for the p.C282Y+/+ HFE mutation of hereditary hemochromatosis (HH), even if evidence is still controversial.2-4 These new data suggest that the p.D519G variant may be involved in the regulation of hepcidin secretion independently of the presence of HFE mutations. The oral iron tolerance test (OITT) under normal iron stores, with measurement of serum iron parameters and hepcidin at baseline and at 4, 8, and 24 hours after the administration of 105 mg of ferrous sulfate, was able to discriminate HH and subtle alterations in iron metabolism related to dysmetabolic iron overload.5 To further clarify its impact on iron metabolism, we evaluated whether the p.D519G protein variant of GNPAT may influence iron metabolism in European individuals in this recently described cohort.5 The G allele frequency was 0.22 (0.22 in non-HH subjects and 0.20 in HH patients). In the 59 individuals not carrying HFE genotypes predisposing to HH (absence of mutations or p.H63D mutation present in heterozygosity), basal serum iron did not differ between p.519G variant carriers and negative subjects (101 ± 36 versus 94 ± 38 μg/dL, respectively, P = 0.48), whereas at 8 hours after challenge it was higher in p.519G carriers than in negative subjects (153 ± 67 versus 114 ± 50 μg/dL, respectively, P = 0.02). Moreover, p.519G carriers had a higher area under the curve (AUC) of serum iron and TS during the OITT (Table 1). The AUC of hepcidin during the OITT was nonsignificantly lower in p.519G carriers than in noncarriers. However, the presence of the p.519G variant was associated with reduced hepcidin production in response to TS as a hepcidin release index5 was lower in p.519G carriers than in noncarriers (P = 0.040). In conclusion, even in European individuals who do not carry HFE genotypes at risk of iron overload, the GNPAT p.D519G variant increases iron absorption by impairing hepcidin release. The OITT seems to represent a useful tool to study iron metabolism in humans. Raffaela Rametta, Ph.D. Paola Dongiovanni, B.S. Silvia Fargion, M.D. Luca Valenti, M.D. Department of Pathophysiology and Transplantation Università degli Studi di Milano Internal Medicine and Metabolic Diseases Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan, Italy Author names in bold designate shared co-first authorship.
Abstract 3482: Inhibition of glucose metabolism in neuroendocrine tumors by lanreotide, sunitinib, and rapamycin
Authors: Tami Rubinek, Ayelet Shabtay-Orbach, Arkadi Hesin, Tammi Rubinstein, Ido Wolf
Journal: Cancer Research (2016)

Background: Neuroendocrine tumors (NETs) represent a heterogeneous family of neoplasms, which may develop from different endocrine glands or endocrine cells dispersed throughout the digestive and respiratory tracts. Lanreotide is a somatostatin analog approved for the treatment of NETs. While Lanreotide extends survival of patients and slows tumor growth, controversy exists regarding its mechanism of action. We hypothesized that lanreotide can interfere with the metabolic activity of NETs, and compared its effect to that of rapamycin and sunitinib.Methods: The pancreatic carcinoid BON-1 cells and pulmonary carcinoid NCI-H727 cells were used. Viability was tested using colony formation assay. mRNA levels of the glycolytic enzymes hexokinase 2 (HK2), lactate dehydrogenase (LDH) and pyruvate kinase M2 (PKM2) was tested using real-time PCR. Phosphorylation levels of AMP-activated kinase (AMPK) and acetyl CoA carboxylase (ACC) were tested using Western blot. The activity of HK2 was tested using HK enzymatic assay. Lactate secretion was tested in the routine biochemistry laboratory of our institution.Results: Lanreotide, rapamycin and sunitinib significantly decreased colony formation. They also reduced relative expression levels of HK2, LDH and PKM2 24 and 48h after treatment and decreased HK2 activity after 24h. An increase in the phosphorylation levels of AMPK and ACC was observed shortly after treating the cells with lanreotide and rapamycin. All three agents also decreased lactate concentration in the media.Conclusions: These data indicate tumor metabolism as an attractive target for therapies against NET, and a novel mechanism of action of somatostatin analogs, namely, alteration of tumor metabolism.Citation Format: Tami Rubinek, Ayelet Shabtay-Orbach, Arkadi Hesin, Tammi Rubinstein, Ido Wolf. Inhibition of glucose metabolism in neuroendocrine tumors by lanreotide, sunitinib, and rapamycin. [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 3482.
Definitions for Sepsis and Septic Shock
Authors: Sean R. Townsend, Emanuel Rivers, Lemeneh Tefera
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Laboratory Testing in the Setting of Diabetic Scleredema
Authors: David Alter
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
“Freeze Only” — An Evolving Standard in Clinical In Vitro Fertilization
Authors: Christos Coutifaris
Journal: New England Journal of Medicine (2016)

In recent years, the rates of pregnancy and live birth after the transfer of frozen embryos have improved,1 probably as a result of the use of vitrification for embryo cryopreservation.2 In addition, multiple reports have shown that adverse perinatal outcomes are less common in pregnancies after frozen-embryo transfer than after fresh-embryo transfer.3,4 Analyses of in vitro fertilization (IVF) data from the Centers for Disease Control and Prevention and the Society for Assisted Reproductive Technology suggest that the differences in outcomes between frozen and fresh cycles may be explained by the nonphysiologic, hormonally hyperstimulated, periconceptional milieu of fresh IVF cycles, . . .
The 8.1 ancestral MHC haplotype is strongly associatied with colorectal cancer
Authors: J. Kocsis, K. E. Toth, B. Madaras, A. Biro, G. Füst, B. Blaskó, Z. Pocsai, R. Ádány, J. Laki
Journal: Journal of Clinical Oncology (2007)

10548 Background: The immune system is believed to play an important role in sufficiently or insufficiently inhibiting the multistep process of tumour development. The so-called 8.1 ancestral haplotype (8.1AH) in the main histocompatibility complex is associated with alterations of the immune response characterized by an increase in antibodies, circulating immune complexes and TNF-a, and lack of a complement protein component (C4A). Methods: To study the possible association of the 8.1AH with colorectal cancer the DNA samples of 183 hungarian patients (average age 67.99 ys; 63–74 ys) with colorectal cancer and 129 healthy hungarian controls (average age 66.5 ys; 60–73.5 ys) were genotyped for member alleles of the 8.1 AH: AGER -429C, HSP70–2 -1267G (HSP70–2G), TNF- a -308A (TNF2) and LTA+252G by SSP-PCR and PCR-RFLP. Simultaneous carriage of the four member alleles was considered carriage of the 8.1AH. Results: We found the frequency of the 8.1AH to be significantly higher in patients with colorectal cancer than in healthy controls (19.1% vs. 7%, P=0.002). After adjustment to age and gender individuals carrying the 8.1AH had a 2.81 (1.23–6.22, P=0.011) fold risk to develop colorectal cancer compared with non-carriers of the haplotype. None of the member alleles alone showed association with colorectal cancer (P AGER-429C =0.486; P HSP70–2G =0.898; P TNF2 =0.140; P LTA =0.376.) Conclusions: The 8.1AH by the genetically encoded alterations of the immune response may affect the development of colorectal cancer. The frequency of the 8.1AH is 5–10% in Hungary/Central Europe but, for instance, approx. 20–25% in the populations with Celtic origin. Our novel observation might contribute to cancer research and therapy when more information is available on which key components of the altered immune response encoded by the 8.1AH are not effective enough against tumor development. No significant financial relationships to disclose.
Abstract 2802: Exogenous pyruvate supports oxygen-independent tumor cell proliferation by serving as an oxygen surrogate to maintain homeostasis of NAD+/NADH
Authors: Chengqian Yin, Dan He, Shuyang Chen, Nianli Sang
Journal: Cancer Research (2016)

Abstract Hypoxia is usually associated with solid tumors and ischemic lesions. Because oxygen is the common final electron acceptor in a variety of metabolic reactions, hypoxia leads to cell injury and death in normal tissues but promotes tumor progression and metastasis. Hypoxic cells use pyruvate from glycolysis as electron acceptor to support ATP production; anaerobic glycolysis, in which the glycolytic product pyruvate is converted to lactate, has been well established as an adaptive energy strategy for hypoxic cells. In tumor cells, pyruvate may also be used as a substrate to support an active biosynthesis, as well as to maintain the homeostasis of NAD+/NAD. However, whether exogenous pyruvate promotes hypoxic tumor cell proliferation by serving as an electron acceptor or a biosynthetic substrate remains unclear. By using both hypoxia and ρ0 cell with defective mitochondrial electron transfer chain, we show that exogenous pyruvate sustains the proliferation of tumor cells that cannot use oxygen as the electron acceptor. Pyruvate-derived metabolites including acetyl-coA, α-ketoglutarate, succinate, alanine, and aspartate were not able to substitute pyruvate to support oxygen-independent proliferation. Knockdown of metabolic enzymes including pyruvate carboxylase, pyruvate dehydrogenase and citrate synthetase showed no negative effects on pyruvate-facilitated hypoxic cell proliferation, whereas knockdown of lactate dehydrogenase significantly inhibited proliferation, indicating that the crucial role of exogenous pyruvate is to serve as the electron acceptor other than a substrate for proliferating biosynthesis. Consisting with this notion, we show that exogenous pyruvate significantly increased lactate generation and increased the ratio of NAD+/NADH. We also show that in our model cells, hypoxia did not cause accumulation of reactive oxygen species, suggesting that pyruvate-facilitated proliferation of hypoxic cells is not achieved by alleviating oxidative stress. Finally, we show that well-oxygenated cells release pyruvate, providing an in vivo source of pyruvate exogenous to the hypoxic cells. Taken together, our data support a novel model that well-oxygenated cells release pyruvate, which is utilized by hypoxic cells as an electron acceptor to facilitate proliferation. This model provides a potential new therapeutic target to suppress tumor progression. Citation Format: Chengqian Yin, Dan He, Shuyang Chen, Nianli Sang. Exogenous pyruvate supports oxygen-independent tumor cell proliferation by serving as an oxygen surrogate to maintain homeostasis of NAD+/NADH. [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 2802.
Abstract 18896: The Clinical Course of the Rare Disorder of Segmental Arterial Mediolysis Through Retrospective Review
Authors: Gerges Makar, Salma Patel, Robert Hines, M'hamed Temkit, Waldemar E Wysokinski, Eddie L Greene, Christine Menias, Sailendra Naidu, Robert D McBane, Fadi Shamoun
Journal: Circulation (2015)

Introduction: Segmental arterial mediolysis (SAM) is nonatherosclerotic and noninflammatory arteriopathy. It commonly affects the abdominal vasculature. There is uncertainty about its presentation, radiological findings, prognosis and management. Hypothesis: The goal of this study is to describe the clinical course and evaluate risk factors for disease progression. Method: Retrospective review of all cases diagnosed with SAM at the Mayo clinic between 2001 and 2014. Medical records were reviewed for demographics, risk factors, laboratory, imaging findings and treatment options at presentation and during follow-up visits. A non-parametric Wilcoxon-rank-sum test and the Chi-Square test were used. Results: Out of 247 reviewed cases, 114 patients were confirmed with SAM and included in the analysis. (69%) were male and a majority (84%) had no other connective tissue disorder. Mean age was (52) years old. Pre-existing hypertension was identified in (48%), hyperlipidemia (31%), migraine (11%) and smoking (32%). The most common symptoms at presentation were abdominal pain (70%), flank pain (21%), back pain (8%) and chest pain (5%). Only (30%) of patients had recurrent symptoms and most (89%) had negative inflammatory markers. On angiography the following arteries were commonly affected: renal (51%), celiac (43%), superior mesenteric (49%), and iliac (18%). At presentation (85%) of patients were found to have mesenteric arterial dissection; (45%) aneurysms; (14%) wind or wall thickening; (21%) occlusion; and (38%) with evidence of end organ ischemia or infarct. 82 patients were followed up with a CT angiogram for an average of 19 months, 17 (20.73%) had evidence of disease progression. (22%) required revascularization. Aspirin (47%) was the most common treatment used followed by anticoagulation (38%), beta blocker (35%) and ACEI/ARB (29%). Risk factors for disease progression are being male (P&lt;0.0173), Hypertension (P&lt;0.0128), hyperlipidemia (P&lt;= 0.0044). The use of antiplatelets and ACEI/ARB was not associated with disease stability. Conclusion: SAM is an arteriopathy that affects the mesenteric arteries in middle age men. Conservative management with control of risk factors and close follow up are preferred approach.
Abstract 5101: Tumor-secreted acids alter macrophage phenotype
Authors: Asmaa El-Kenawi, Arig Ibrahim-Hashim, Kimberly Luddy, Brian Ruffell, Shari Pilon-Thomas, Robert Gatenby, Robert Gillies
Journal: Cancer Research (2016)

Abstract Within tumors, tumor-associated macrophages (TAMs) usually adopt an M2 phenotype with tumor-promoting characteristics, as opposed to the M1 phenotype responsible for host protection. As acidic pH can affect the characteristics of immune cells, we aimed to test whether low pH as a common stress factor in the tumor microenvironment could be partially responsible for the phenotypic characteristics and/or functional activity of macrophages in prostate cancer. To test this hypothesis, we allowed TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice to develop neoplastic lesions of variable histologic severity. Thereafter, we isolated tumor-associated macrophages from control tumors and analyzed their expression of the M1 and M2 markers; iNos, Il-6, Cd206 and Arg1. Gene expression analysis confirms previous studies which reported higher expression of both M1 and M2 markers in TAMs compared with peritoneal macrophages. Treatment of TRAMP mice with sodium bicarbonate to continuously buffer acids secreted by neoplastic cells, decreased TAMs infiltration into the stromal compartment of prostate. In addition, sodium bicarbonate decreased iNos, Arg1, and Cd206 but not Il-6 expression in TAMs isolated from subcutaneously growing TRAMP-C2 tumors, a TRAMP-derived prostate tumor cell line injected into syngeneic male hosts. Since decreased expression of Arg1 and iNos has been shown to mediate the suppressive activity of myeloid cells, tumor acidity might promote the suppressive microenvironment by upregulating both enzymes. In conclusion, extracellular acidosis increases the density of macrophages and their L-arginine metabolic potential; coincident with delayed tumor progression in prostate tumors. Citation Format: Asmaa El-Kenawi, Arig Ibrahim-Hashim, Kimberly Luddy, Brian Ruffell, Shari Pilon-Thomas, Robert Gatenby, Robert Gillies. Tumor-secreted acids alter macrophage phenotype. [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 5101.
Hierarchical Analysis Of Recurrent Point Mutations In SF3B1 and TET2 In RARS Stem Cells
Authors: Teresa Mortera-Blanco, Marios Dimitriou, Petter Woll, Mohsen Karimi, Elli Papaemmanuil, Simona Conte, Oni Chowdhuri, Monika Jansson, Peter J. Campbell, Sten Eirik W Jacobsen, Eva Hellström-Lindberg
Journal: Blood (2013)
Abstract 2343: The immune modulatory roles of IAP inhibitor, LCL161, and its connection to immune-checkpoint molecules
Authors: Maria Pinzon-Ortiz, William Hastings, Tyler Longmire, Pamela Shaw, Xianhui Rong, Masato Murakami, Benjamin H. Lee, Glenn Dranoff, Kenzie MacIsaac, Z. Alexander Cao
Journal: Cancer Research (2016)

Abstract Tumor immunotherapy is a unique therapeutic modality in our fight against human cancers. The recent success of immune-checkpoint therapies highlights the value and potential of this approach. Previous studies have demonstrated positive immune-modulatory activities of the IAP inhibitor, NVP-LCL161. In this study, we sought to further explore the immune-modulatory activities of NVP-LCL161 in connection with immune-checkpoint molecules. In PBMC stimulation assays, NVP-LCL161 potently induced IFN and enhanced proliferation, while down-modulating IL-10 production. Additionally, the role of NVP-LCL161 on immune-checkpoint modulation was revealed in CyTOF analysis of in vitro stimulated PBMCs. NVP-LCL161 treatment led to increases in TIM-3 expression on multiple T cell subsets, and on cells of the myeloid lineage. These observations illustrate potential modulation of specific immune-checkpoint molecule by NVP-LCL161, thus suggesting possible synergy between TIM-3 immunecheckpoint blockade and NVP-LCL161. NVP-LCL161 was further combined in vivo with anti-PD1 antibody in the murine syngeneic tumor model, MC38. At multiple dosing schedules, synergy was observed with this combination, which appeared to be independent of single agent efficacy. Expression profiling of MC38 tumor tissues by a customized Nanostring panel revealed elevation of gene signatures in T cells, dendritic cells, cytokines and chemokines, amongst others. In summary, the preclinical data support the hypothesis that NVP-LCL161 is an active immune modulator. Its combination activity with immune_checkpoint inhibitors would warrant further exploration in both preclinical and clinical setting. Citation Format: Maria Pinzon-Ortiz, William Hastings, Tyler Longmire, Pamela Shaw, Xianhui Rong, Masato Murakami, Benjamin H. Lee, Glenn Dranoff, Kenzie MacIsaac, Z. Alexander Cao. The immune modulatory roles of IAP inhibitor, LCL161, and its connection to immune-checkpoint molecules. [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 2343.
Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis
Authors: Hyun-Kyung Chang, Pyung-Hwan Kim, Hyun-Min Cho, Soo-Young Yum, Young-Jin Choi, YeonSung Son, DaBin Lee, InSung Kang, Kyung-Sun Kang, Goo Jang, Je-Yoel Cho
Journal: Molecular Therapy (2016)

Mesenchymal stem cells (MSCs) promote therapeutic angiogenesis to cure serious vascular disorders. However, their survival period and cytokine-secretory capacity are limited. Although hepatocyte growth factor (HGF) can accelerate the rate of angiogenesis, recombinant HGF is limited because of its very short half-life (<3-5 minutes). Thus, continuous treatment with HGF is required to obtain an effective therapeutic response. To overcome these limitations, we produced genome-edited MSCs that secreted HGF upon drug-specific induction. The inducible HGF expression cassette was integrated into a safe harbor site in an MSC chromosome using the TALEN system, resulting in the production of TetOn-HGF/human umbilical cord blood-derived (hUCB)-MSCs. Functional assessment of the TetOn-HGF/hUCB-MSCs showed that they had enhanced mobility upon the induction of HGF expression. Moreover, long-term exposure by doxycycline (Dox)-treated TetOn-HGF/hUCB-MSCs enhanced the anti-apoptotic responses of genome-edited MSCs subjected to oxidative stress and improved the tube-formation ability. Furthermore, TetOn-HGF/hUCB-MSCs encapsulated by arginine-glycine-aspartic acid (RGD)-alginate microgel induced to express HGF improved in vivo angiogenesis in a mouse hindlimb ischemia model. This study showed that the inducible HGF-expressing hUCB-MSCs are competent to continuously express and secrete HGF in a controlled manner. Thus, the MSCs that express HGF in an inducible manner are a useful therapeutic modality for the treatment of vascular diseases requiring angiogenesis.