Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.

PSLS at rest was significantly lower in patients with left main or three-vessel CAD without RWMA, and might be useful for identifying patients with a severe CAD.

SUMMARYEach vertebrate species displays specific tooth patterns in each quadrant of the jaw: the mouse has one incisor and three molars, which develop at precise locations and at different times. The reason why multiple teeth form in the jaw of vertebrates and the way in which they develop separately from each other have been extensively studied, but the genetic mechanism governing the spatial patterning of teeth still remains to be elucidated. Sonic hedgehog (Shh) is one of the key signaling molecules involved in the spatial patterning of teeth and other ectodermal organs such as hair, vibrissae and feathers. Sostdc1, a secreted inhibitor of the Wnt and Bmp pathways, also regulates the spatial patterning of teeth and hair. Here, by utilizing maternal transfer of 5E1 (an anti-Shh antibody) to mouse embryos through the placenta, we show that Sostdc1 is downstream of Shh signaling and suggest a Wnt-Shh-Sostdc1 negative feedback loop as a pivotal mechanism controlling the spatial patterning of teeth. Furthermore, we propose a new reaction-diffusion model in which Wnt, Shh and Sostdc1 act as the activator, mediator and inhibitor, respectively, and confirm that such interactions can generate the tooth pattern of a wild-type mouse and can explain the various tooth patterns produced experimentally.

Background/Aims: People may have symptoms of multiple disorders at the same time. We aimed to determine prevalence and risk factors for overlaps between gastroesophageal reflux disease (GERD), dyspepsia and irritable bowel syndrome (IBS) in a Korean population. Methods: A cross-sectional survey was performed on 1,688 randomly selected Korean subjects. Data on 1,443 subjects could be analyzed. Dyspepsia and IBS were diagnosed using modified Rome II criteria. Results: The prevalences of GERD, dyspepsia and IBS were 8.5, 9.5 and 9.6%. Overlaps between GERD and dyspepsia, GERD and IBS, and dyspepsia and IBS were observed in 2.3 (95% CI 1.4–3.0), 2.0 (95% CI 1.2–2.6%) and 1.3% (95% CI 0.6–1.8%) of the population. 27 and 24% of GERD subjects suffered from dyspepsia and IBS. 24 and 14% of dyspeptic subjects had GERD and IBS. 21 and 14% of IBS subjects had GERD and dyspepsia. Anxiety was significantly associated with GERD overlap (OR 2.73, 95% CI 1.13–6.57), dyspepsia overlap (OR 3.19, 95% CI 1.33–7.63) and IBS overlap (OR 4.92, 95% CI 2.04–11.84), compared with GERD alone, dyspepsia alone and IBS alone. Conclusions: Overlaps between GERD, dyspepsia, and IBS are common in the general population. These overlaps occur predominantly in individuals with anxiety.

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Background/Aims: Psychological factors and subtle histopathological changes have been implicated in irritable bowel syndrome (IBS). The aims of the present study were to investigate whether the numbers of enterochromaffin (EC) cells, mast cells, and lamina propria T lymphocytes are altered in IBS, and evaluate the relationship of such alterations with psychological factors. Methods: Forty-two consecutive IBS patients (M : F = 17:25, mean age 48 years) fulfilling the Rome III criteria and twelve asymptomatic healthy controls underwent rectal biopsy. Immunostaining was performed for EC cells, mast cells, and lamina propria T lymphocytes. Results: The IBS group included five post-infectious (PI) IBS and 37 non-PI IBS patients. Significantly more EC cells, mast cells and lamina propria T lymphocytes were observed in PI IBS patients. Mast cells significantly increased in non-PI IBS-D (diarrhea) patients, but not in non-PI IBS-C (constipation) and non-PI IBS-M (mixed) patients. Enterochromaffin cell numbers were not significantly altered in non-PI IBS patients. Anxiety and depression scores did not differ between IBS patients with and without abnormal increase in EC cell or mast cell counts, defined as more than the mean of controls + 2 standard deviations. Enterochromaffin cell, mast cell, or lamina propria T lymphocyte numbers were poorly correlated with anxiety and depression scores in the IBS group. Conclusions: Enterochromaffin cells, mast cells, and lamina propria T lymphocytes significantly increase in PI IBS, whereas only mast cells significantly increase in non-PI IBS-D. Such histopathological changes do not seem to be directly associated with psychological factors.

The GWAS and the subsequent validation study identified new variants associated with the risk of CHB. These findings may advance the understanding of genetic susceptibility to CHB.

To identify and characterize a serologic glycoprotein biomarker for hepatocellular carcinoma (HCC), multi-lectin affinity chromatography was used to isolate intracellular N-linked glycoprotein fractions from five paired non-tumor and tumor tissues. From the series of 2-D DIGE targeted differentially expressed N-linked glycoproteins, we identified human liver carboxylesterase 1 (hCE1), which was remarkably down-regulated in tumor tissues, a finding confirmed by Western blot, a quantitative real-time RT-PCR, and immunohistochemical staining of non-tumor and tumor tissues from total 58 HCC patients. To investigate whether hCE1 is also present in human plasma, we employed a magnetic bead-based immunoprecipitation followed by nano-LC-MS/MS analysis, and we found for the first time that hCE1 is present in human plasma as opposed to that in liver tissues. That is, from normalization of hCE1 signal by the immunoprecipitation and Western blot analysis, hCE1 levels were increased in plasma specimens from HCC patients than in plasma from other disease patient groups (e.g. liver cirrhosis, chronic hepatitis, cholangiocarcinoma, stomach cancer, and pancreatic cancer). From the receiver operating characteristic analysis in HCC, both sensitivity and specificity were shown to be greater than 70.0 and 85.0%, respectively. Thus, the high-resolution proteomic approach demonstrates that hCE1 is a good candidate for further validation as a serologic glycoprotein biomarker for HCC.