UMOR-induced osteomalacia (also known as oncogenic osteomalacia) 1 is a rare disorder characterized by phosphaturia, hypophosphatemia, and osteomalacia mimicking the clinical phenotype of either X-linked 2 or autosomal dominant 3 hereditary hypophosphatemic rickets. Tumor-induced osteomalacia develops because of tumors that are predominantly of benign mesenchymal origin 4 but that may occasionally be malignant, as was recently reported. 5 Surgical removal of the tumor relieves all symptoms. Hemangiopericytoma is the most dominant histologic entity in tumor-induced osteomalacia. 4,6 Paraneoplastic secretion by the tumor of an unknown factor or factors -termed "phosphatonins" -causing renal tubular phosphate wasting has been proposed as the pathogenic mechanism. 7 We describe an adult man who had hypophosphatemic osteomalacia for several years before an octreotide scan revealed a mesenchymal tumor in his left thigh. Moreover, subcutaneous administration of octreotide, a synthetic somatostatin analogue, abolished renal tubular phosphate wasting before subsequent surgical removal of the tumor. CASE REPORTA 50-year-old man presented with chronic pain of the spine, ribs, femurs, and tibias. The clinical examination was otherwise normal. There was no family history of metabolic bone disease.The initial evaluation in July 1997 revealed elevated urinary phosphorus excretion, low serum phosphorus levels, and elevated serum alkaline phosphatase and osteocalcin levels. The serum values for calcium, parathyroid hormone, 25-hydroxyvitamin D 3 , and calcitonin were normal; the serum value for 1,25-dihydroxy-T vitamin D 3 was inappropriately low (6.9 pg per milliliter; normal range, 35 to 80). The diagnostic evaluation at this time provided no evidence of tumor. Multiple rib fractures were identified. A bone scan with technetium-99m-labeled 2,3-dicarboxypropane-1,1diphosphonate showed a pattern of focal, late-phase enhancement in the spine and ribs; this was suggestive of metabolic bone disease. The patient was given the diagnosis of idiopathic hypophosphatemic osteomalacia with renal phosphate wasting. Continuous oral supplementation with phosphate and 1,25-dihydroxyvitamin D 3 (1.25 µg per day) was initiated. Three years after the initial diagnosis, progressive metabolic bone disease prompted another extensive evaluation. METHODS AssaysSerum, plasma, and urinary constituents were measured by standard techniques. Hormone measurements were performed with the use of commercial immunoassay kits. Assays of serum parathyroid hormone, 25-hydroxyvitamin D 3 , 1,25-dihydroxyvitamin D 3 , and calcitonin were performed with commercial kits (DPC Biermann, Bad Nauheim, Germany), as were those for osteocalcin (Diagnostic Systems Laboratories, Sinsheim, Germany) and urinary type I collagen C-telopeptides (Beckmann Coulter, Krefeld, Germany). For calculation of renal clearance of phosphate, serum and urinary concentrations of phosphorus were determined together with the excreted urinary volume during two one-hour collection periods (Table 1)....
Incomplete intestinal absorption of fructose might lead to abdominal complaints such as pain, flatulence and diarrhoea. Whether defect fructose transporters such as GLUT5 or GLUT2 are involved in the pathogenesis of fructose malabsorption is a matter of debate. The hydrogen production by colonic bacteria is used for diagnosis with the hydrogen breath test. However, the appropriate fructose test dose for correct diagnosis is unclear. Subjects with fructose malabsorption show increased breath hydrogen levels and abdominal symptoms after fructose administration but do not report any symptoms when fructose is given together with glucose. This beneficial effect of glucose, however, cannot be explained yet but might be used for clinical care of these subjects.
Although increased dietary fructose consumption is associated with metabolic impairments, the mechanisms and regulation of intestinal fructose absorption are poorly understood. GLUT5 is considered to be the main intestinal fructose transporter. Other GLUT family members, such as GLUT7 and GLUT9 are also expressed in the intestine and were shown to transport fructose and glucose. A conserved isoleucine-containing motif (NXI) was proposed to be essential for fructose transport capacity of GLUT7 and GLUT9 but also of GLUT2 and GLUT5. In assessing whether human GLUT2, GLUT5, GLUT7, and GLUT9 are indeed fructose transporters, we expressed these proteins in Xenopus laevis oocytes. Stably transfected NIH-3T3 fibroblasts were used as second expression system. In proving the role of the NXI motif, variants p.I322V of GLUT2 and p.I296V of GLUT5 were tested as well. Sugar transport was measured by radiotracer flux assays or by metabolomics analysis of cell extracts by GC-MS. Fructose and glucose uptakes by GLUT7 were not increased in both expression systems. In search for the physiological substrate of GLUT7, cells overexpressing the protein were exposed to various metabolite mixtures, but we failed to identify a substrate. Although urate transport by GLUT9 could be shown, neither fructose nor glucose transport was detectable. Fructose uptake was decreased by the GLUT2 p.I322V variant, but remained unaffected in the p.I296V GLUT5 variant. Thus, our work does not find evidence that GLUT7 or GLUT9 transport fructose or glucose or that the isoleucine residue determines fructose specificity. Rather, the physiological substrate of GLUT7 awaits to be discovered.
The molecular mechanism of action of the HER2‐targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream‐acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI‐N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET‐amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.
Genetic alterations in the carboxypeptidase A1 gene (CPA1) are associated with early onset chronic pancreatitis (CP). Besides CPA1, there are two other human pancreatic carboxypeptidases (CPA2 and CPB1). Here we examined whether CPA2 and CPB1 alterations are associated with CP in Japan and Germany. All exons and flanking introns of CPA2 and CPB1 were sequenced in 477 Japanese patients with CP (234 alcoholic, 243 nonalcoholic) and in 497 German patients with nonalcoholic CP by targeted next-generation sequencing and/or Sanger sequencing. Secretion and enzymatic activity of CPA2 and CPB1 variants were determined after transfection into HEK 293T cells. We identified six nonsynonymous CPA2 variants (p.V67I, p.G166R, p.D168E, p.D173H, p.R237W, and p.G388S), eight nonsynonymous CPB1 alterations (p.S65G, p.N120S, p.D172E, p.R195H, p.D208N, p.F232L, p.A317V, and p.D364Y), and one splice-site variant (c.687+1G>T) in CPB1. Functional analysis revealed essentially complete loss of function in CPA2 variants p.R237W and p.G388S and CPB1 variants p.R110H and p.D364Y. None of the CPA2 or CPB1 variants, including those resulting in a marked loss of function, were overrepresented in patients with CP. In conclusion, CPA2 and CPB1 variants are not associated with CP.
Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a basis for the assessment of gastric cancer signaling and possibly for the development and discovery of predictive biomarkers.
The therapeutic options for advanced gastric cancer are still limited. Several drugs targeting the epidermal growth factor receptor family have been developed. So far, the HER2 antibody trastuzumab is the only drug targeting the HER-family that is available to gastric cancer patients. The pan-HER inhibitor afatinib is currently investigated in clinical trials and shows promising results in cell culture experiments and patient-derived xenograft (PDX) models. However, some cell lines do not respond to afatinib treatment. The determination of resistance factors in these cell lines can help to find the best treatment option for gastric cancer patients. In this study, we analyzed the role of MET as a resistance factor for afatinib therapy in a gastric cancer cell line. MET expression in afatinib-resistant MET-amplified Hs746T cells was reduced by means of siRNA transfection. The effects of MET knockdown on signal transduction, cell proliferation and motility were examined. In addition to the manual assessment of cell motility, a computational motility analysis involving parameters such as (approximate) average speed, displacement entropy or radial effectiveness was realized. Moreover, the impact of afatinib was compared between MET knockdown cells and control cells. MET knockdown in Hs746T cells resulted in impaired signal transduction and reduced cell proliferation and motility. Moreover, the afatinib resistance of Hs746T cells was reversed after MET knockdown. Therefore, the amplification of MET is confirmed as a resistance factor in gastric cancer cells. Whether MET is a useful resistance marker for afatinib therapy or other HER-targeting drugs in patients should be investigated in clinical trials.
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