Hyperammonemia, an under-recognized complication and adverse prognostic marker in Multiple Myeloma

Hyperammonemia, a well-known complication of liver failure causing encephalopathy, has rarely been reported as a complication of multiple myeloma. We report four additional cases of hyperammonemia in patients with treatment refractory multiple myeloma. In these cases, we found that hyperammonemia remains a morbid complication of resistant disease without directed myeloma therapy. Our brief review has reaffirmed that hyperammonemia is a poor prognostic marker in myeloma with an undetermined mechanism. This complication’s poor response to traditional therapies, including rifaximin and lactulose, prompts our discussion urging early recognition and myeloma directed therapy. Clinical observations may support that proteasome inhibitors may be most effective in the treatment of these patients.

Central Obesity, Inflammation and Angiogenesis in Adult Men

Obesity is known to link with low-grade inflammation. Experimental studies revealed that inflammation was associated with angiogenesis process in adipose tissue. We investigate the correlation between inflammation and angiogenesis in Indonesian adult men with central obesity. A cross-sectional study was undertaken on 161 healthy Indonesian adult men (age: 23-53 y, waist circumference: 64-125 cm). Clinical parameters; biochemical markers; anthropometric parameters (weight, height and abdominal circumference); inflammatory biomarkers (tumor necrosis factor-α (TNF-α) and its soluble tumor necrosis factor receptor-2 (sTNFR-2), interleukin (IL)-1β); and biomarkers of angiogenesis (leptin, vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1 and Ang-2 were measured. Obese II, Obese I subjects had higher concentrations of fasting blood glucose and triglycerides (P<0.005) than those Non-obese subjects. Obese II subjects had higher concentrations of hsCRP (P<0.05) than obese I subjects; and obese I subjects had higher concentration of hsCRP (P<0.05) than Non-obese subjects. sTNFR-2 correlated positively with leptin and Ang-2 (rs = 0.376, P< 0.001 and rs = 0.281, P = 0.003, respectively) and negatively with Ang-1 in obese subjects. High concentration of sTNFR-2 also correlated with increased concentrations of leptin, VEGF and Ang-2 in all subjects (P= 0.001, P= 0.033, and P= 0.005, respectively). In obese subjects, high concentration of sTNFR-2 had correlated with increased leptin and Ang-2, and decreased Ang-1 (7.4 %, 10.9% and 9.2%, respectively). This study was able to demonstrate the relations between inflammation and angiogenesis in Indonesian adult men with central obesity. Findings of this study suggest that inflammation and angiogenesis were mutually supportive processes contribute to systemic low grade inflammation in central obesity.

Cellular metabolism and lysosomal mTOR signaling

Over the last few years extensive studies have linked the activity of mTORC1 to lysosomal function. These observations propose an intriguing integration of cellular catabolism, sustained by lysosomes, with anabolic processes, largely controlled by mTORC1. Interestingly, lysosomal function directly affects mTORC1 activity and is regulated by ZKSCAN3 and TFEB, two transcription factors and substrates of mTORC1. Thus, the lysosomal mTOR signaling complex represents a hub of cellular energy metabolism, and its dysregulation may lead to a number of human diseases. Here, we discuss the recent developments and highlight the open questions in this growing field.

N-cadherin in cancer dormancy

N-cadherin is an adhesion protein, which is important for intercellular interaction. It is involved in cell migration and motility during embryonic development, neuronal synapsis and cancer metastasis. There are several signaling cascades affected by N-cadherin including TGF-β, Rho family. N-cadherin is associated at the cytoplasmic domain with catenins (α, β, γ and p120) to facilitate metastasis. An increase in N-cadherin with down regulation of E-cadherin occurs during epithelial mesenchymal transition. Overexpression of N-cadherin is associated with cell cycle arrest, which correlates with a similar property of cancer stem cells (CSC). Connexin expression, which is important in CSC dormancy, is regulated by N-cadherin. This review discusses the potential of N-cadherin to be involved in maintaining CSCs, and to investigate pathways in N-cadherin expression. A better understanding of the role of N-Cadherin in CSC biology may identify new targets for the treatment of cancer.

An Orchestrated Response To Tumor Signals By Macrophages and Mesenchymal Stem Cells Potentiates Interleukin-6 Secretion In Glioblastoma

The tumor microenvironment plays a critical role in the survival, growth, invasion, and metastasis of solid tumors. However, the mechanisms by which it influences these aspects of tumor progression remain incompletely characterized. In this study, we show that human glioblastoma cells secrete soluble factors that alter the phenotype and cytokine secretion profile of both macrophages and mesenchymal stem cells (MSCs). Macrophages and MSCs respond to tumor-secreted factors by increasing the release of interleukin-6 (IL-6) and this response is potentiated when macrophages and MSCs are combined in co-culture. In glioblastoma, IL-6 has been associated with tumor cell invasion, angiogenesis, tumor cell proliferation, immune suppression, and poor prognosis. Our results suggest that the orchestrated response of macrophages and stromal elements to neoplastic cells enhances tumor progression through the release of soluble factors.