The Modes of Dysregulation of the Proto-Oncogene T-Cell Leukemia/Lymphoma 1A

Incomplete biological concepts in lymphoid neoplasms still dictate to a large extent the limited availability of efficient targeted treatments, which entertains the mostly unsatisfactory clinical outcomes. Aberrant expression of the embryonal and lymphatic TCL1 family of oncogenes, i.e., the paradigmatic TCL1A, but also TML1 or MTCP1, is causally implicated in T- and B-lymphocyte transformation. TCL1A also carries prognostic information in these particular T-cell and B-cell tumors. More recently, the TCL1A oncogene has been observed also in epithelial tumors as part of oncofetal stemness signatures. Although the concepts on the modes of TCL1A dysregulation in lymphatic neoplasms and solid tumors are still incomplete, there are recent advances in defining the mechanisms of its (de)regulation. This review presents a comprehensive overview of TCL1A expression in tumors and the current understanding of its (dys)regulation via genomic aberrations, epigenetic modifications, or deregulation of TCL1A-targeting micro RNAs. We also summarize triggers that act through such transcriptional and translational regulation, i.e., altered signals by the tumor microenvironment. A refined mechanistic understanding of these modes of dysregulations together with improved concepts of TCL1A-associated malignant transformation can benefit future approaches to specifically interfere in TCL1A-initiated or -driven tumorigenesis.

Characterisation of Drug-Induced Liver Injury in Patients with COVID-19 Detected by a Proactive Pharmacovigilance Program from Laboratory Signals

Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical manifestations. An elevation of liver damage markers has been observed in numerous cases, which could be related to the empirical use of potentially hepatotoxic drugs. The aim of this study was to describe the clinical and analytical characteristics and perform a causality analysis from laboratory signals available of drug-induced liver injury (DILI) detected by a proactive pharmacovigilance program in patients hospitalised for COVID-19 at La Paz University Hospital in Madrid (Spain) from 1 March 2020 to 31 December 2020. The updated Roussel Uclaf Causality Assessment Method (RUCAM) was employed to assess DILI causality. A lymphocyte transformation test (LTT) was performed on 10 patients. Ultimately, 160 patients were included. The incidence of DILI (alanine aminotransferase >5, upper limit of normal) was 4.9%; of these, 60% had previous COVID-19 hepatitis, the stay was 8.1 days longer and 98.1% were being treated with more than 5 drugs. The most frequent mechanism was hepatocellular (57.5%), with mild severity (87.5%) and subsequent recovery (88.1%). The most commonly associated drugs were hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone. The highest incidence rate of DILI per 10,000 defined daily doses (DDD) was with remdesivir (992.7/10,000 DDD). Some 80% of the LTTs performed were positive, with a RUCAM score of ≥4. The presence of DILI after COVID-19 was associated with longer hospital stays. An immune mechanism has been demonstrated in a small subset of DILI cases.

Coexistence of Mycobacterium Tuberculosis and Mycobacterium Leprae in a Patient- an Alarm of Inadequate Innate Immune Response?

Mycobacterium tuberculosis (M.Tb) and Mycobacterium leprae (M.Leprae) are Gram-positive aerobic Acid-Fast Bacilli (AFB) causing chronic granulomatous infections like Tuberculosis (TB) and Leprosy respectively. They can present with varied manifestations according to the host’s immune status and response.[1] Both are prevalent in clusters in developing countries; however, the simultaneous occurrence of both infections in an individual is rare even in endemic areas (0.02 per 100,000 population).[2] Few case reports showing the coexistence of TB and leprosy, majority are TB developing following immunosuppressive treatment of leprosy reactions. Of which pure neuritic presentation of leprosy in an old treated case of Pulmonary Tuberculosis (PTB) has not been reported yet. Here we are reporting a case of PTB while on treatment developed neurological manifestations, diagnosed to be a case of poly neuritic leprosy (PNL). PNL is a rare form of leprosy, characterised by an area of sensory loss along the distribution of single/multiple thickened nerve trunks with or without motor deficit in the absence of skin lesions. Keywords: TB with Pure Neuritic Hansen, SNP- PPTN22, Defective Lymphocyte Transformation, SNP- Granulomatous infection

Bacterial Infection and Non-Hodgkin B-Cell Lymphoma: Interactions between Pathogen, Host and the Tumor Environment

Non-Hodgkin B-cell lymphomas (NHL) are a heterogeneous group of lymphoid neoplasms with complex etiopathology, rich symptomatology, and a variety of clinical courses, therefore requiring different therapeutic approaches. The hypothesis that an infectious agent may initiate chronic inflammation and facilitate B lymphocyte transformation and lymphogenesis has been raised in recent years. Viruses, like EBV, HTLV-1, HIV, HCV and parasites, like Plasmodium falciparum, have been linked to the development of lymphomas. The association of chronic Helicobacter pylori (H. pylori) infection with mucosa-associated lymphoid tissue (MALT) lymphoma, Borrelia burgdorferi with cutaneous MALT lymphoma and Chlamydophila psittaci with ocular adnexal MALT lymphoma is well documented. Recent studies have indicated that other infectious agents may also be relevant in B-cell lymphogenesis such as Coxiella burnettii, Campylobacter jejuni, Achromobacter xylosoxidans, and Escherichia coli. The aim of the present review is to provide a summary of the current literature on infectious bacterial agents associated with B-cell NHL and to discuss its role in lymphogenesis, taking into account the interaction between infectious agents, host factors, and the tumor environment.

IMPACT OF MERCURY CHLORIDE EXPOSURE ON SOME OF IMMUNOLOGICAL AND BIOCHEMICAL ASSAYS OF COMMON CARP, CYPRINUS CARPIO

This work was designed to evaluate the influence of mercury chloride on some of biochemical and immunological biomarkers in common cap, Cyprinus carpio. Around of 120 fish were randomly allocated into four groups (30 fish per group) in triplicates as follows; first group act as control group provided with water only without adding HgCl2; G1, G2 and G3 were exposed to waterborne HgCl2 at levels of 0.01, 0.05 and 0.1 mg l-1 respectively. After one month exposure to HgCl2, there were significantly decreased (P<0.05) in lymphocyte transformation index and in phagocytic and lysozyme activities. Besides, biochemically, Albumin and globulin content exhibited significantly declined (P<0.05) particularly at higher dose of HgCl2. In contrast, blood glucose value and urea showed significantly increased (P<0.05) especially in G3. On the other hand, variable changes were observed in total count of leucocytes included lymphopenia and neutrophilia in G1 and G2 compared to control. In conclusion, this investigation indicated that mercury chloride has immune suppressive effects and is extremely toxic to common carp.

Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Adverse drug reactions are a public health issue that draws widespread attention, especially for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which have high mortality and lack of efficacious treatment. Though T-cell-mediated HLA-interacted immune response has been extensively studied, our understanding of the mechanism is far from satisfactory. This review summarizes infection (virus, bacterial, and mycoplasma infection), an environmental risk factor, as a trigger for SJS/TEN. The mutations or polymorphisms of drug metabolic enzymes, transporters, receptors, the immune system genes, and T-cell-mediated apoptosis signaling pathways that contribute to SJS/TEN are discussed and summarized. Epigenetics, metabolites, and mobilization of regulatory T cells and tolerogenic myeloid precursors are emerged directions to study SJS/TEN. Ex vivo lymphocyte transformation test has been exploited to aid in identifying the causative drugs. Critical questions on the pathogenesis of SJS/TEN underlying gene polymorphisms and T cell cytotoxicity remain: why some of the patients carrying the risky genes tolerate the drug and do not develop SJS/TEN? What makes the skin and mucous membrane so special to be targeted? Do they relate to skin/mucous expression of transporters? What is the common machinery underlying different HLA-B alleles associated with SJS/TEN and common metabolites?