Hepatoid esophagogastric adenocarcinoma and tumoral heterogeneity: a case report

Hepatoid adenocarcinoma of the stomach is an uncommon subtype of gastric cancer remarkably similar to hepatocellular carcinoma in histopathological analysis. It is also commonly associated with high serum alfa-fetoprotein and a poorer prognosis, despite the emergence of new therapeutic options. In recent years, next generation sequencing (NGS) technology has made it possible to identify and describe the genes and molecular alterations common to gastric cancer thereby contributing to the advancement of targeted therapies. A 62-year-old patient, with no prior risk factor for hepatocellular carcinoma (HCC), presented to the emergency room with dysphagia for solids, abdominal pain and weight loss of about 3 kilograms over 3 months. Histopathological analysis presented with disparities regarding HER2 and programmed death-ligand 1 (PD-L1) status in the primary and metastatic sites. We describe a case of a de novo metastatic, human epidermal growth factor receptor 2 (HER2) positive esophagogastric junction hepatoid adenocarcinoma. Although this is a rare subgroup of gastric cancer, treatment strategies were based in recent studies in immunotherapy and guided therapy, taking into consideration the molecular findings from the patient’s tumor NGS analysis. Data about HER2 and PDL1 heterogeneity were also reviewed. Despite the aggressiveness and rarity of this histology, the patient had a good response to treatment.     

Resveratrol inhibits rat aortic vascular smooth muscle cell proliferation via estrogen receptor dependent nitric oxide production

Vascular smooth muscle cell (VSMC) proliferation is pivotal in the progression of hypertension, atherosclerosis, and restenosis. Resveratrol is a grape polyphenol that is implicated as an important contributor to red wine's vascular protective effects. Its antimitogenic action on VSMC is attributed to an array of pleiotropic effects, including modulation of the estrogen receptor (ER). To elucidate the mechanisms underlying resveratrol-mediated ER modulation and its inhibition of VSMC proliferation, we treated VSMC with resveratrol with or without the ER antagonist ICI 182,780 and measured cell proliferation and nitric oxide (NO) production. Resveratrol dose-dependently decreased VSMC DNA synthesis, with a half maximal inhibitory concentration (IC50) of 3.73+/-0.57 microM, and dramatically slowed cell growth, but did not induce VSMC apoptosis. Resveratrol-mediated decrease in proliferation was reversed by cotreatment with ICI 182,780, and resveratrol effectively competed with 17beta-estradiol for binding to the ER, exhibiting an IC50 of 8.92+/-0.14 microM. Resveratrol induced a sustained increase in ER-dependent NO production. Further, resveratrol-mediated decrease in VSMC proliferation was blunted by cotreatment with the general nitric oxide synthase (NOS) inhibitor N5-(1-Iminomethyl)-L-ornithine, dihydrochloride or with the inducible NOS (iNOS)-selective inhibitor S,S'-1,4-phenylene-bis (1,2-ethanediyl)bis-isothiourea, dihydrobromide, but not with the neuronal NOS-selective inhibitor 7-nitroindazole. Though resveratrol did not alter iNOS protein levels, it dose-dependently increased levels of iNOS activity, of the iNOS cofactor tetrahydrobiopterin (BH4), and of guanosine triphosphate cyclohydrolase I protein, the rate-limiting enzyme in BH4 biosynthesis. In addition, all of these effects were abolished by cotreatment with ICI 182,780. Thus, the antimitogenic effects of resveratrol on VSMC may be mediated by an ER-induced increase in iNOS activity.     

The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys

Background and Purpose

Oligodendrocyte (OL) death is important in focal cerebral ischemia. TIMP-3 promotes apoptosis in ischemic neurons by inhibiting proteolysis of TNF-α superfamily of death receptors. Since OLs undergo apoptosis during ischemia, we hypothesized that TIMP-3 contributes to OL death.

Methods

Middle cerebral artery occlusion (MCAO) was induced in Timp-3 knockout (KO) and wild type (WT) mice with 24 or 72 h of reperfusion. Cell death in white matter was investigated by stereology and TUNEL. Mature or immature OLs were identified using antibodies against glutathione S-transferase-π (GST-π) and galactocerebroside (GalC), respectively. Expression and level of proteins were examined using immunohistochemistry and immunoblotting. Protein activities were determined using a FRET peptide.

Results

Loss of OL-like cells was detected at 72 h only in WT ischemic white matter where TUNEL showed greater cell death. TIMP-3 expression was increased in WT reactive astrocytes. GST-π was reduced in ischemic white matter of WT mice compared with WT shams with no difference between KO and WT at 72 h. GalC level was significantly increased in both KO and WT ischemic white matter at 72 h. However, the increase in GalC in KO mice was significantly higher than WT; most TUNEL-positive cells in ischemic white matter expressed GalC, suggesting TIMP-3 deficiency protects the immature OLs from apoptosis. There were significantly higher levels of cleaved caspase-3 at 72 h in WT white matter than in KO. Greater expression of MMP-3 and -9 was seen in reactive astrocytes and/or microglia/macrophages in WT at 72 h. We found more microglia/macrophages in WT than in KO, which were the predominant source of increased TNF-α detected in the ischemic white matter. TACE activity was significantly increased in ischemic WT white matter, which was expressed in active microglia/macrophages and OLs.

Conclusions

Our results suggested that focal ischemia leads to proliferation of immature OLs in white matter and that TIMP-3 contributes to a caspase-3-dependent immature OL death via TNF-α-mediated neuroinflammation. Future studies will be needed to delineate the role of MMP-3 and MMP-9 that were increased in the Timp-3 wild type.     

Means of improving the chemoradiotherapy of small cell cancer of the lung

The report deals with an analysis of the results of treatment of 84 patients suffering small cell lung cancer. Four regimens of combination chemotherapy as well as radiation were used. Complete plus partial regression rates ranged 18-81% (mean-42%) following chemotherapy and 73-87% after radiation treatment. Platidiam-containing schemes proved most effective. Prophylactic cranial irradiation was followed by increased survival. A correlation between extent of tumor and effectiveness of treatment was established.     

Gene transfection of human mesenchymal stem cells with a nano‐hydroxyapatite–collagen scaffold containing DNA‐functionalized calcium phosphate nanoparticles

This study aimed to fabricate a growth factor‐releasing biodegradable scaffold for tissue regeneration. We prepared multishell calcium phosphate (CaP) nanoparticles functionalized with DNA, polyethyleneimine (PEI), protamine and octa‐arginine (R8) and compared their respective transfection activity and cell viability measures using human mesenchymal stem cells. DNA–protamine complexes improved the transfection efficiency of CaP nanoparticles with the exception of those functionalized with R8. These complexes also greatly reduced the cytotoxicity of PEI. In addition, we also fabricated DNA–protamine‐functionalized CaP nanoparticle‐loaded nano‐hydroxyapatite–collagen scaffolds and investigated their gene transfection efficiencies. These experiments showed that the scaffolds were associated with moderate hMSC cell viability and were capable of releasing the BMP‐2 protein into hMSCs following gene transfection. In particular, the scaffold loaded with protamine‐containing CaP nanoparticles showed the highest cell viability and transfection efficiency in hMSCs; thus, it might be suitable to serve as an efficient growth factor‐releasing scaffold.     

Influence of atorvastatin on fractional and subfractional composition of serum lipoproteins and MMP activity in mice with Triton WR 1339-induced lipaemia

Objectives The effects of atorvastatin on the atherogenic and anti‐atherogenic lipoprotein‐cholesterol (C‐LP) and lipoprotein‐triglyceride (TG‐LP) fractions and subfractions at the early stage of murine acute hyperlipidaemia, and its pleiotropic anti‐inflammatory effects via the activity of matrix metalloproteinases (MMPs) were studied. Methods Atorvastatin (75 mg/kg) was administered to ICR mice with acute lipaemia induced by a single injection of Triton WR 1339 (500 mg/kg). A novel small‐angle X‐ray scattering (SAXS) method was used for the determination of the fractional and subfractional composition of C‐LP and TG‐LP. Key finding In Triton WR 1339‐treated mice, there was a drastic increase in the atherogenic low‐density C‐LP (C‐LDL) fraction, intermediate density lipoprotein‐cholesterol (C‐IDL) subfraction, and very low‐density C‐LP (C‐VLDL) fractions (C‐VLDL_3–5 subfraction). Additionally, there was an increase in the C‐HDL₃ subfraction. Treatment of lipaemia with atorvastatin resulted in the normalization of the atherogenic C‐LDL fraction and the C‐IDL subfraction. A decrease in C‐VLDL (C‐VLDL_3–5 subfraction), total cholesterol and, especially, triglyceride (TG) concentrations was also demonstrated. Similar results were obtained with the TG‐LP fractions and subfractions. Additionally, atorvastatin treatment resulted in an increase in the serum and liver MMP activity. Conclusion High‐dose atorvastatin therapy exerts its rapid lipid‐lowering and pleiotropic effect(s) in the early stages of acute lipaemia induced with Triton WR‐1339.