Hepatic glucose synthesis from glycogen, glycerol, and the tricarboxylic acid (TCA) cycle was measured in five overnight-fasted subjects by 1H,2H, and 13C NMR analysis of blood glucose, urinary acetaminophen glucuronide, and urinary phenylacetylglutamine after administration of [1,6-13C2]glucose,2H2O, and [U-13C3]propionate. This combination of tracers allows three separate elements of hepatic glucose production (GP) to be probed simultaneously in a single study: 1) endogenous GP, 2) the contribution of glycogen, phospho enolpyruvate (PEP), and glycerol to GP, and 3) flux through PEP carboxykinase, pyruvate recycling, and the TCA cycle. Isotope-dilution measurements of [1,6-13C2] glucose by 1H and 13C NMR indicated that GP in 16-h-fasted humans was 10.7 ± 0.9 μmol · kg−1 · min−1.2H NMR spectra of monoacetone glucose (derived from plasma glucose) provided the relative 2H enrichment at glucose H-2, H-5, and H-6 S, which, in turn, reflects the contribution of glycogen, PEP, and glycerol to total GP (5.5 ± 0.7, 4.8 ± 1.0, and 0.4 ± 0.3 μmol · kg−1 · min−1, respectively). Interestingly, 13C NMR isotopomer analysis of phenylacetylglutamine and acetaminophen glucuronide reported different values for PEP carboxykinase flux (68.8 ± 9.8 vs. 37.5 ± 7.9 μmol · kg−1 · min−1), PEP recycling flux (59.1 ± 9.8 vs. 27.8 ± 6.8 μmol · kg−1 · min−1), and TCA cycle flux (10.9 ± 1.4 vs. 5.4 ± 1.4 μmol · kg−1 · min−1). These differences may reflect zonation of propionate metabolism in the liver.

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Over the past two decades, detailed studies of mitochondrial DNA and the Y chromosome have increased our understanding of the history and population genetics of Native American populations. Variation in autosomal DNA has also been investigated, but to a more limited extent. A low level of genetic diversity in Native American populations is a robust finding from all lines of evidence. In contrast to the previous multiple migration scenarios for the Pleistocene peopling of the Americas, it now seems that a single migration satisfactorily explains the genetic data. Native Americans show greater genetic similarity to populations in east central Asia than they do to the current easternmost Siberian populations. Recent studies on the Y chromosome indicate a date of entry (about 17,000 years ago) into the Americas roughly consistent with the archaeological record. Native Americans experienced two episodes of reduced population size: one with the peopling of the Americas and the other with European contact. The former is the more important determinant for the number of gene lineages and founding haplotypes seen in populations. It may also be an important determinant of the genetic variation underlying common complex diseases, and especially diabetes. The tribal structure of contemporary Native American populations is relevant to the distribution of rare Mendelian disorders because most tribes constitute relatively small, semi-independent gene pools. This leads us to expect that the allelic spectrum for Mendelian diseases will be simple within individual tribes but complex for Native Americans as a whole.

Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier

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The past few years have been incredibly exciting in cancer research and care. Some of the advances highlighted in Clinical Cancer Advances 2016 are already improving the lives of patients today, and many others provide direction for further research. Compared with when I started my career in oncology, today we do the unthinkable. We no longer treat cancer simply by its type or stage. In the era of precision medicine, we selectand rule out-treatments based the genomic profile of each patient and the tumor. We manage once-debilitating adverse effects to the point that many, if not most, patients can continue their daily activities during treatment. No recent advance has been more transformative than the rise of immunotherapy, particularly over this past year, making immunotherapy the American Society of Clinical Oncology's (ASCO's) Advance of the Year. The immunotherapy concept is simple: unleash the body's immune system to attack cancer. It has proven extremely difficult, however, to develop treatments that deliver real, consistent results. Decades of bold ideas, dedication, and financial investment in research have been required to prove immunotherapy's worth as a treatment for people with an array of different cancers. Until the US Food and Drug Administration approved the first immune checkpoint blocker to treat advanced melanoma in 2011, life expectancy for patients with that disease was usually measured in months. But new immunotherapies have extended that time to yearsand melanoma was just the tip of the iceberg. In 2015, clinical trials showed that the approach holds promise for patients with other hard-to-treat cancers, including advanced lung, kidney, bladder, and head and neck cancers and Hodgkin lymphoma. Dizon et al.

Purpose Despite recent advances, multiple myeloma remains incurable and most patients eventually develop progressive disease. Allogeneic hematopoietic stem cell transplantation (allo HCT) offers a potentially curative option in 10–20% of patients with relapsed or refractory disease. We evaluated the outcome of patients undergoing allo HCT with reduced-intensity conditioning (RIC) for relapsed and/or refractory myeloma at our institution. Methods Fifty-one patients with heavily pretreated, relapsed myeloma, who received RIC allo HCT between 1996 and 2006, were included in this analysis. Results Median time from diagnosis to allo HCT was 34 months. Median follow-up in surviving patients was 27 months (3–98). Cumulative transplant-related mortality (TRM) at 1 year was 25%. Progression-free survival (PFS) and overall survival (OS) at 2 years were 19% and 32%, respectively. The incidence of grade II-IV acute or chronic graft-vs-host disease (GVHD) was 27% and 47%, respectively. At the time of this analysis, 12 patients (24%) were alive 7 of whom (14%) were in remission for up to 6 years after allo SCT. A lower β2 microglobulin (<3.3) and a prior autotransplant predicted a lower NRM, longer PFS and OS. Conclusion Allo HCT with RIC regimens is associated with acceptable toxicity and durable remission and survival in relapsed or refractory myeloma. Use of RIC allo HCT earlier in the course of the disease may offer greater benefit.