Mohammed Naseemuddin

Protective Role of Toll-like Receptor 4 during the Initiation Stage of Cutaneous Chemical Carcinogenesis

Toll-like receptors (TLR) activate multiple steps in inflammatory reactions in innate immune responses. They also activate signals that are critically involved in the initiation of adaptive immune responses. Many tumorigenic chemicals have been associated with endotoxin hypersensitivity mediated through TLR4. To determine the role of TLR4 in cutaneous skin carcinogenesis, we treated TLR4-deficient C3H/HeJ mice and the TLR4-normal C3H/HeN mice with the carcinogenic polyaromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA). TLR4-deficient C3H/HeJ mice developed more tumors relative to the TLR4-normal C3H/HeN mice. Both C3H/HeN and C3H/HeJ mice developed a T-cell-mediated immune response to topically applied DMBA. Interestingly, the cell-mediated immune response was mediated by IFN-gamma in C3H/HeN mice and by interleukin (IL)-17 in C3H/HeJ mice. Moreover, C3H/HeN mice had elevated circulating levels of IFN-gamma following topical application of DMBA, whereas IL-17 was elevated in C3H/HeJ mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA skin tumorigenesis and that this is associated with differences in the T-cell subtype activated. Efforts to divert the cell-mediated immune response from one that is IL-17 mediated to one that is IFN-gamma mediated may prove to be beneficial in the prevention of DMBA-induced cutaneous tumors.

Cell mediated immune responses through TLR4 prevents DMBA‐induced mammary carcinogenesis in mice

Toll‐like receptors (TLRs) activate signals that are critically involved in the initiation of adaptive immune responses and many tumorigenic chemicals have been associated with activation of those pathways. To determine the role of TLR‐4 (TLR4) in mammary carcinogenesis, we subjected TLR4 deficient and wild type (WT) mice to oral gavage with carcinogenic polyaromatic hydrocarbon 7,12‐dimethylbenz(a)anthracene (DMBA). TLR4 deficient mice developed more tumors relative to the WT mice. T cells of TLR4 deficient mice produced elevated levels of IL‐17 and lower levels of IFN‐γ relative to WT mice. IL‐12 secreted by CD11c+ cells was higher in WT mice, whereas greater amounts of IL‐23 were produced by CD11c+ cells from TLR4 deficient mice. Moreover, there was higher incidence of regulatory T cells in TLR4 deficient mice than WT mice. Similarly, various markers of angiogenesis [matrix metalloproteinases (MMP)‐2 and MMP‐9, CD31 and vascular endothelial growth factor] were highly expressed in tumors from TLR4 deficient mice than WT mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA induced mouse mammary tumorigenesis and efforts to divert the cell‐mediated immune response may, therefore, prove to be beneficial in the prevention of mammary tumors.

PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum.

Abstract Background and Aims: Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease. Methods: Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) and NAFLD were included. Pooled data are reported as odds ratios (ORs) with 95% confidence intervals. Results: Of 393 potentially relevant studies, 35 on NAFLD were included in the analysis. Compared to healthy controls, the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL) were 1.46 (1.16–1.85) and 2.76 (2.30–3.13), and were 1.75 (1.24–2.46) and 4.44 (2.92–6.76) among patients with non-alcoholic steatohepatitis respectively. The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90–6.13) and 5.05 (1.47–17.29) when comparing non-alcoholic hepatocellular carcinoma to NAFL patients. Among the NAFLD patients, the ORs for G allele frequency when comparing steatosis grade 2–3 to grade 0–1 NAFL, when comparing the NAFLD activity score of ≥ 4 to score ≤ 3, when comparing NASH to NAFLD, when comparing the presence of lobular inflammation to absence, and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43–3.80), 1.80 (1.36–2.37), 1.66 (1.42–1.94), 1.58 (1.19–2.10), and 2.63 (1.87–3.69) respectively. Subgroup analysis based on ethnicity showed similar results. Conclusions: PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs. PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD.

Case series on multimodal endoscopic therapy for gastric antral vascular ectasia, a tertiary center experience

AIM To study and describe patients who underwent treatment for gastric antral vascular ectasia (GAVE) with different endoscopic treatment modalities. METHODS We reviewed patients with GAVE who underwent treatment at University of Alabama at Birmingham between March 1, 2012 and December 31, 2016. Included patients had an endoscopic diagnosis of GAVE with associated upper gastrointestinal bleeding or iron deficiency anemia. RESULTS Seven out of 15 patients had classic watermelon description for GAVE, 1/15 with diffuse/honeycomb pattern and 6/15 with nodular GAVE per EGD description. Seven out of 15 patients required multimodal treatment. Four out of six of patients with endoscopically nodular GAVE required multimodal therapy. Overall, mean pre- and post-treatment hemoglobin (Hb) values were 8.2 ± 0.8 g/dL and 9.7 ± 1.6 g/dL, respectively (P ≤ 0.05). Mean number of packed red blood cells transfusions before and after treatment was 3.8 ± 4.3 and 1.2 ± 1.7 (P ≤ 0.05), respectively. CONCLUSION Patients with nodular variant GAVE required multimodal approach more frequently than non-nodular variants. Patients responded well to multimodal therapy and saw decrease in transfusion rates and increase in Hb concentrations. Our findings suggest a multimodal approach may be beneficial in nodular variant GAVE.

An Uncommon and Challenging Case of Duodenal Variceal Bleeding

A 59-year-old man with a history of alcohol-induced cirrhosis presented to an outside institution with complaints of hematochezia and hematemesis. Notable laboratory results included hemoglobin 2.8 g/dL, international normalized ratio 1.39, albumin 1.7 g/dL, and total bilirubin 2.2 mg/dL. Esophagogastroduodenoscopy at the outside hospital did not reveal a source of the bleed. He was transferred to our institution for further management. Esophagogastroduodenoscopy was repeated, which showed blood oozing from large duodenal varices in the second part of the duodenum (Figure 1). Abdominal computed tomography showed large periduodenal varices during the arterial phase imaging (Figure 2). Patient emergently underwent transjugular intrahepatic portosystemic shunt (TIPS) placement. The appearance of the periduodenal varices before and after TIPS placement is shown in Figure 3. Patient improved over the next few days with resolution of his acute gastrointestinal bleed.

Abstract 3459: Loss of p16INK4a gene renders mice more susceptible to DMBA-induced mammary carcinogenesis

Breast cancer is the most common type of cancer diagnosed in women. The incidence of breast cancer varies with environmental influences, including carcinogen exposure. Polyaromatic hydrocarbons (PAH), have been implicated as etiologic agents in breast cancer. Exposure occurs primarily through the smoking of tobacco, inhalation of polluted air, and ingestion of charred foods. One such example of a carcinogenic polyaromatic hydrocarbon is 7,12-dimethylbenz(a)anthracene (DMBA) which in animal models, induces mammary adenocarcinoma. p16, a low molecular weight tumor suppressor protein, and a major CDK inhibitor, is the product of a tumor suppressor p16/INK4a gene. It is frequently inactivated in the human tumors. In the present study, we were interested to evaluate the role of p16INK4a in DMBA-induced mammary carcinogenesis. Tumor latency was higher in p16INK4a −/− compared to WT (C3H/HeN) counterparts. Tumors from p16INK4a −/− mice were very aggressive as revealed by PCNA and Ki67 staining and qRT-PCR analysis. The levels of angiogeneic markers CD31 and VEGF were also higher in the tumors of p16INK4a −/− mice as compared to WT mice. These results indicate that restoration of p16INK4a −/− function can be helpful in reducing mammary tumors caused by environmental pollutants like DMBA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3459.