Gene expression profile of esophageal cancer in North East India by cDNA microarray analysis

AIM: To identify alterations in genes and molecular functional pathways in esophageal cancer in a high incidence region of India where there is a widespread use of tobacco and betel quid with fermented areca nuts. METHODS: Total RNA was isolated from tumor and matched normal tissue of 16 patients with esophageal squamous cell carcinoma. Pooled tumor tissue RNA was labeled with Cy3-dUTP and pooled normal tissue RNA was labeled with Cy5-dUTP by direct labeling method. The labeled probes were hybridized with human 10K cDNA chip and expression profiles were analyzed by Genespring GX V 7.3 (Silicon Genetics). RESULTS: Nine hundred twenty three genes were differentially expressed. Of these, 611 genes were upregulated and 312 genes were downregulated. Using stringent criteria (P ≤ 0.05 and ≥ 1.5 fold change), 127 differentially expressed genes (87 upregulated and 40 downregulated) were identified in tumor tissue. On the basis of Gene Ontology, four different molecular functional pathways (MAPK pathway, G-protein coupled receptor family, ion transport activity, and serine or threonine kinase activity) were most significantly upregulated and six different molecular functional pathways (structural constituent of ribosome, endopeptidase inhibitor activity, structural constituent of cytoskeleton, antioxidant activity, acyl group transferase activity, eukaryotic translation elongation factor activity) were most significantly downregulated. CONCLUSION: Several genes that showed alterations in our study have also been reported from a high incidence area of esophageal cancer in China. This indicates that molecular profiles of esophageal cancer in these two different geographic locations are highly consistent.     

Phylogenetic Analysis of Spread of Hepatitis C Virus Identified during HIV Outbreak Investigation,Unnao, India

An HIV outbreak investigation during 2017–2018 in Unnao District, Uttar Pradesh, India, unearthed high prevalence of hepatitis C virus (HCV) antibodies among the study participants. We investigated these HCV infections by analyzing NS5B and core regions. We observed no correlation between HIV–HCV viral loads and clustering of HCV sequences, regardless of HIV serostatus. All HCV isolates belonged to genotype 3a. Monophyletic clustering of isolates in NS5B phylogeny indicates emergence of the outbreak from a single isolate or its closely related descendants. The nucleotide substitution rate for NS5B was 6 × 10⁻³ and for core was 2 × 10⁻³ substitutions/site/year. Estimated time to most recent common ancestor of these isolates was 2012, aligning with the timeline of this outbreak, which might be attributable to unsafe injection practices while seeking healthcare. HIV–HCV co-infection underlines the need for integrated testing, surveillance, strengthening of healthcare systems, community empowerment, and molecular analyses as pragmatic public health tools.     

Ricolinostat (ACY‐1215) induced inhibition of aggresome formation accelerates carfilzomib‐induced multiple myeloma cell death

Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome‐proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti‐MM effects, even in bortezomib‐resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY‐1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ‐induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.     

Neuropathic pain and diabetes

Neuropathic pain is a common phenomenon resulting from injury to the central or peripheral nervous system. The means by which diabetes results in nerve injury is unclear but the effect is to cause injury at all levels of the nervous system from the level of the peripheral nerves to the brain. Nerve injury causes pain through a cascade of mechanisms resulting in altered processing of sensory input into the nervous system. This alteration occurs through chemical and anatomical changes in the nervous system that are similar to some of the processes seen in central sensitisation following acute pain. Following nerve injury, neuropathic pain occurs not only when these mechanisms are activated but also when sensitisation is maintained. Other processes occurring in neuropathic pain appear to be a loss of normal inhibitory controls as seen by a reduction in local GABA-ergic and descending monoaminergic influences. There are also important changes mediated via glial cells that can maintain neuropathic pain. Diabetes affects all areas of the nervous system and the contribution of higher levels of the nervous system is often overlooked. Neurophysiological and MRI evidence strongly suggest that these may contribute to the pain of diabetic neuropathy. Psychological dysfunction in diabetic patients is an important factor in increasing the suffering associated with all aspects of the disease, but treatment and control of pain can greatly improve the quality of life.     

The evidence for Mycobacterium paratuberculosis in Crohn's disease.

PURPOSE OF REVIEW: Though long hypothesized, the putative link between Mycobacterium avium paratuberculosis and Crohn's disease remains neither confirmed nor refuted. This article reviews published contributions that directly or indirectly address this question. RECENT FINDINGS: Epidemiologic studies, looking for M. avium paratuberculosis DNA in Crohn's tissue, show a strong association between the agent and this disease. Supporting data, however, are presently inconclusive on a causal role. Genetic studies provide indirect support for a role of mycobacteria in Crohn's disease, by identifying susceptibility genes that encode proteins implicated in innate immunity to intracellular bacteria. Clinical trial data support at least a short-term benefit for antimycobacterial therapy in Crohn's disease, but the microbial specificity of this response is presently unknown. SUMMARY: There appears to be a strong association between M. avium paratuberculosis and Crohn's disease, but the causality of this association is unknown. Consequently, the therapeutic implications of this association require further study. A number of critical questions about the biology of M. avium paratuberculosis remain unanswered. Data from studies of this organism, and its interaction with the immune system, can help address proposed reasons for or against a role of M. avium paratuberculosis in the etiology of Crohn's disease.     

PATCH TESTING WITH DERMATOPHAGOIDES AND ITS CORRELATION WITH CHRONIC ECZEMA AND ATOPIC DERMATITIS

Background:

Chronic eczema is commonly encountered in the Indian set up. So also is atopic dermatitis. House dust mites (Dermatophagoides) are implicated in various diseases like atopic dermatitis, asthma, and perennial rhinitis. It has also been proven that patch testing with Dermatophagoides pteronyssinus (DP) is important for detection of contact sensitization in chronic dermatitis.

Aims:

To study clinical characteristics of DP mix positive patients with regards to chronic dermatitis and atopic dermatitis.

Methods:

Dermatology outpatients presenting to the department of Skin and STD of Kasturba Medical College (KMC), with clinically diagnosed atopic dermatitis and chronic eczema were chosen for the study. Inclusion and exclusion criteria were well demarked. Eighty six randomly selected patients of dermatitis were subjected to patch testing with standard series and DP mix.

Results:

Of the 86, 50 (58%) showed positive reaction to DP mix. Among these positive patients, chronic dermatitis was seen in 42 (84%) with involvement of exposed parts in 37 (74%). Atopic dermatitis was seen in 19 patients (38%) from DP positive group whereas it was observed in 4 patients (17%) from the other group.

Conclusion:

Dermatophagoides mix positivity was statistically significant in chronic eczema as well as atopic dermatitis. Patch testing is an important tool to detect delayed type allergy to house dust mite.