Induction of angiogenesis by hyperplastic colonic mucosa adjacent to colon cancer

We determined whether hyperplastic mucosa adjacent to colon cancer contributes to neoplastic angiogenesis. Surgical specimens of human colon cancer (40 Dukes' stage B and 34 Dukes' stage C) were analyzed by immunohistochemistry for expression of proliferative and angiogenic molecules. The mucosa adjacent to Dukes' stage C tumors (but not Dukes' stage B tumors) had a higher Ki-67 labeling index and a higher expression of epidermal growth factor receptor and transforming growth factor-alpha than distant mucosa. The expression levels of vascular endothelial growth factor, basic fibroblast growth factor, interleukin-8, and the vascular density in the adjacent mucosa were similar to those in the tumor lesions and significantly higher than those in the distant mucosa. The expression of interferon-beta inversely correlated with the level of pro-angiogenic molecules and the vascular density. The injection of metastatic human colon cancer cells and murine colon cancer cells into the cecal wall of mice induced hyperplastic changes in the adjacent mucosa which expressed higher levels of epidermal growth factor receptor, basic fibroblast growth factor, and vascular endothelial growth factor, and lower levels of interferon-beta than did the control mucosa, which directly correlated with the degree of hyperplasia. These data suggest that metastatic human colon cancer cells can induce hyperplasia in the adjacent mucosa, which in turn produces angiogenic molecules that contribute to neoplastic angiogenesis.     

Dietary Patterns and Hepatocellular Carcinoma Risk among US Adults

The objective of this study was to assess the association between dietary patterns and risk of hepatocellular carcinoma (HCC) among US adults in a hospital-based case-control study. We analyzed data from 641 cases and 1002 controls recruited at The University of Texas MD Anderson Cancer Center during 2001–2018. Cases were patients with a pathologically or radiologically confirmed new diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck cancer. Cases and controls were frequency-matched by age and sex. Dietary patterns were identified by principal component analysis. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. A vegetable-based dietary pattern was inversely associated with HCC risk (highest compared with lowest tertile: OR 0.66, 95% CI 0.46–0.94). A Western diet pattern was directly associated with HCC risk (highest compared with lowest tertile: OR 1.79, 95% CI 1.19–2.69). These findings emphasize the potential role of dietary intake in HCC prevention and clinical management.     

β-Phorbol ester-induced enhancement of exocytosis in large mossy fiber boutons of mouse hippocampus

β-Phorbol esters (BPE), synthetic analogues of diacylglycerol (DAG), induce the potentiation of transmission in many kinds of synapses through activating the C₁ domain-containing receptors. However, their effects on synaptic vesicle exocytosis have not yet been investigated. Here, we evaluated the vesicular exocytosis directly from individual large mossy fiber boutons (LMFBs) in hippocampal slices from transgenic mice that selectively express synaptopHluorin (SpH). We found that the activity-dependent increment of SpH fluorescence (ΔSpH) was enhanced by 4β-phorbol 12,13-diacetate (PDAc), one of the BPEs, without influencing the recycled component of SpH. These PDAc effects on ΔSpH were almost completely inhibited by staurosporine, a non-selective antagonist of protein kinases. However, intermittent synaptic transmission was still potentiated through a staurosporine-resistant mechanism. The staurosporine-sensitive cascade may facilitate the vesicle replenishment, thus maintaining the fidelity of transmission at a high level during repetitive firing of the presynaptic neuron. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Kinetic evaluation of photosensitivity in genetically engineered neurons expressing green algae light-gated channels

Neurons become photosensitive by genetically introducing one of green algae-derived protein, channelrhodopsin-2 (ChR2). Here, we quantitatively investigated the rapidness of the light-gated current of ChR2 expressed in PC12 cells using blue light-emitting diode (LED) light. The light-gated current consists of two components, inactivating and non-inactivating. The magnitude of inactivating component was almost linearly related to the light intensity. The non-inactivating component showed a tendency to saturate at high illumination. Both the activation and inactivation rates of the light-gated current were linearly dependent on the light intensity. However, the activation rate (turning-on rate) is about 10-fold faster than the inactivation rate. Although the turning-off time constant was little dependent on the light intensity, that at the end of 1s light pulse was about two-fold larger than that at 20 ms. Neurons are also made photosensitive by the expression of ChR2 in the living animal. Since both the turning-on and turning-off time constants of light-gated current was smaller than the membrane time constant of neurons, the LED light illumination of the photosensitive neurons was enough to evoke action potentials in a pulse-to-pulse manner in an acute slice of hippocampus.     

Epidemiological risk factors for adrenocortical carcinoma: A hospital-based case–control study

Adrenocortical carcinoma (ACC) is a rare malignancy whose risk factors are unclear. We explored the association of ACC risk with exposure to selected environmental factors, with a focus on cigarette smoking. We conducted a hospital-based case–control study at The University of Texas MD Anderson Cancer Center. Cases (n = 432) patients with ACC treated at MD Anderson, and controls (n = 1,204) were healthy and genetically unrelated spouses of patients at MD Anderson who had cancers not associated with smoking. Information on the subjects’ demographic features and selected risk factors was collected using a structured, validated questionnaire and medical records review. Unconditional logistic regression was used to calculate adjusted odds ratios (AORs) via the maximum-likelihood method. Cases had a younger mean (± standard deviation) age than did controls (47.0 ± 0.7 and 60.0 ± 0.3 years, respectively), and the majority of cases were female (60.6%) and non-Hispanic white (82.4%). We found a markedly increased risk of ACC among male cigarette smokers, with an AOR = 1.8 (95% confidence interval [CI] =1.2–2.9), but not among female smokers (AOR = 1.1, 95% CI = 0.7–1.6). Family history of cancer was associated with increased risk of ACC (AOR = 2.8, 95% CI 1.9–4.3) and in both men and women, whereas alcohol consumption was associated with reduced risk in men (AOR = 0.2, 95% CI = 0.1–0.3) but not women (AOR = 0.7, 95% CI = 0.5–1.1). Understanding these risk factors and their underlying mechanisms may help prevent ACC in susceptible individuals and eventually identify new therapeutic options for ACC.     

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.