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Oncolytic viruses are genetically engineered viruses that target myeloma-affected cells by detecting specific cell surface receptors (CD46, CD138), causing cell death by activating the signaling pathway to induce apoptosis or by immune-mediated cellular destruction. Although MM is a highly treatable but incurable disease, therapeutic advances with oncolytic viruses are an innovative treatment approach.Areas covered: This article summarizes oncolytic virotherapy advancements such as the therapeutic use of viruses by targeting cell surface proteins of myeloma cells as well as the carriers to deliver viruses to the target tissues safely. The major classes of viruses that have been studied for this include measles, myxoma, adenovirus, reovirus, vaccinia, vesicular-stomatitis virus, coxsackie, and others. The measles virus acts as oncolytic viral therapy by binding to the CD46 receptors on the myeloma cells to utilize its surface H protein. These H-protein and CD46 interactions lead to cellular syncytia formation resulting in cellular apoptosis. Vesicular-stomatitis virus acts by downregulation of anti-apoptotic factors (Mcl-2, BCL-2). Based upon the published literature searches till December 2020, we have summarized the data supporting the advances in viral oncolytic for the treatment of MM.Expert opinion: Oncolytic virotherapy is an experimental approach in multiple myeloma (MM); many issues need to be addressed for safe viral delivery to the target tissue.

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

e22002 Background: Hematopoietic stem cell transplant (HSCT) is indicated in pediatric acute lymphoblastic leukemia (ALL) patients who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning have been employed before HSCT: total body irradiation (TBI) based regimens and chemotherapy alone (CHT). The use of TBI is favorable in adults with ALL, and it has also demonstrated excellent efficacy in the pediatric population. However, the lifelong adverse events of TBI are a substantial concern in younger patients. This study compares the efficacy and safety of TBI and CHT conditioning in pediatric, adolescent and young adult ALL patients (0-24 years old). Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane, and Clinicaltrials.gov from inception to November 25, 2021, using MeSH terms and keywords for ‘acute lymphoblastic leukemia’, ‘whole body irradiation’, ‘child’, ‘adolescent’ and ‘young adult’. Efficacy outcomes considered were overall survival (OS), event-free survival (EFS), and relapse. Safety outcomes were acute (a) and chronic (c) graft-versus-host disease (GVHD), and non-relapse mortality/transplant-related mortality (NRM/TRM). Estimates of risk ratios (RR) for dichotomous variables and hazard ratios (HR) for OS and EFS were pooled using a random-effects model in Revman v5.4. Results: The initial search revealed 1544 articles. After excluding reviews, duplicates, and non-relevant articles, we included data from 16 studies (2 randomized controlled trials, 1 non-randomized prospective study and 13 retrospective studies). TBI based and CHT conditioning were evaluated in 4656 and 1500 patients, respectively. The most common TBI and CHT regimens were TBI + cyclophosphamide (Cy) + etoposide (3 studies) and busulfan + Cy (6 studies), respectively. The TBI dose utilised ranged from 8-12 Gy, with 12 Gy being the most common (8 studies). The median age ranged from 4 months to 13.3 years; and the median follow up was 1.2-9.7 years. In comparison with TBI conditioning, CHT alone was associated with significantly worse OS (HR 1.61, 95% CI 1.06-2.44; p = 0.03; I2 = 79%), EFS (HR 2.01, 95% CI 1.26-3.20; p = 0.003; I2 = 60%) and risk of relapse (RR 1.44, 95% CI 1.23-1.68; p = 0.00001; I2 = 37%). There was reduced risk of aGVHD with CHT (RR 0.79, 95% CI 0.66-0.93; p = 0.006; I2 = 51%), but the difference was not significant when only grade 3-4 aGVHD was considered (RR 1.01, 95% CI 0.80-1.27; p = 0.95; I2 = 0%). The two regimens were comparable in terms of risk of cGVHD (RR 0.87, 95%CI 0.64-1.18; p = 0.38; I2 = 43%) and NRM/TRM (RR 1.24, 95% CI 0.99-1.55; p = 0.06; I2 = 66.8%). Conclusions: In pediatric and young adult ALL patients undergoing HSCT, TBI conditioning has better efficacy and similar safety compared to CHT alone.

Objective. Copy number variation (CNV) is a structural variation in the human genome that has been associated with multiple clinical phenotypes. B cells are important components of rheumatoid arthritis- (RA-) mediated immune response; hence, CNV in the regulators of B cells (such as VPREB1) can influence RA susceptibility. In this study, we aimed to explore the association of CNV in the VPREB1 gene with RA susceptibility in the Pakistani population. Methods. A total of 1,106 subjects (616 RA cases, 490 healthy controls) were selected from three rheumatology centers in Pakistan. VPREB1 CNV was determined using the TaqMan® CN assay (Hs02879734_cn, Applied Biosystems, Foster City, CA, USA), and CNV was estimated by using CopyCaller® (version 2.1; Applied Biosystems, USA) software. Odds ratio (OR) was calculated by logistic regression with sex and age as covariates in R. Results. A significant association between >2 VPREB1 CNV and RA risk was observed with an OR of 3.92 (95% CI: 1.27 - 12.12; p=0.01746) in the total sample. Whereas p=0.00381). Conclusion. CNV>2 of VPREB1 is a risk factor for RA in the total Pakistani population, while CNV<2 is protective in women.

Genome-wide association studies (GWAS) have identified multiple type 2 diabetes (T2D) loci, mostly among populations of European descent. There is a high prevalence of T2D among Pakistanis. Both genetic and environmental factors may be responsible for this high prevalence. In order to understand the shared genetic basis of T2D among Pakistanis and Europeans, we examined 77 genome-wide significant variants previously implicated among European populations. We genotyped 77 single-nucleotide polymorphisms (SNPs) by iPLEX® Gold or TaqMan® assays in a case-control sample of 1,683 individuals. Association analysis was performed using logistic regression. A total of 16 SNPs (TCF7L2/rs7903146, GLIS3/rs7041847, CHCHD9/rs13292136, PLEKHA1/rs2292626, FTO/rs9936385, CDKAL1/rs7756992, KCNJ11/rs5215, LOC105372155/rs12970134, KCNQ1/rs163182, CTRB1/rs7202877, ST6GAL1/rs16861329, ADAMTS9-AS2/rs6795735, LOC105370275/rs1359790, C5orf67/rs459193, ZBED3-AS1/rs6878122 and UBE2E2/rs7612463) showed statistically significant associations after controlling for the false discovery rate. While KCNQ1/rs163182 and ZBED3-AS1/rs6878122 showed opposite allelic effects, the remaining significant SNPs had the same allelic effects as reported previously. Our data indicate that a selected number of T2D loci previously identified among populations of European descent also affect the risk of T2D in the Pakistani population.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease. The interaction of genetic and environmental factors is likely necessary for RA. Among potential genetic factors, many major histocompatibility complex (MHC) and non-MHC variants may be involved in RA susceptibility. CTLA4 is involved in the regulation of T-cell response during an immune reaction, and multiple CTLA4 single nucleotide polymorphisms (SNPs) have been associated with numerous autoimmune diseases, including RA. To our knowledge, the genetic association of CTLA4 with RA risk has not been examined previously in the Pakistani population. In this study, we sequenced the entire CTLA4 gene and flanking regions in 95 Pakistani RA cases followed the screening of identified variants in Study 1 sample consisting of 350 RA cases and controls. Four common significant variants identified in Study 1 sample were further examined in a larger Study 2 replication sample comprising 1,678 independent RA cases and controls. We report significant associations of three variants from the combined analysis: rs3087243 (OR = 1.26, p = 4.47E-03), rs5742909 (OR = 1.78, p = 4.60E-03), and rs11571319 (OR = 1.48, p = 6.64E-03); the latter is a novel association in the Pakistani sample.

Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.

Objective Type 1 diabetes (T1D) and rheumatoid arthritis (RA) are autoimmune diseases. It is known that certain genetic loci and factors that increase the overall autoimmunity risk can be shared among different autoimmune diseases. We sought to replicate seven T1D-related SNPs that have been previously reported to be associated with RA susceptibility in a small set of mixed family-based and case-control Pakistani sample in a relatively large and independent RA case-control sample from the same population. Seven T1D-associted SNPs (GLIS3/rs7020673, BACH2/rs11755527, SKAP2/rs7804356, GDSMB/rs2290400, C6orf173/rs9388489, LOC399716/rs947474 and DLK1-MEG2/rs941576) were genotyped in a large Pakistani RA case-control sample (n=1,959) using TaqMan® SNP genotyping assays. Results None of the tested SNPs showed statistically significant association with RA susceptibility; however, one SNP (GLIS3/rs7020673) showed a trend for association (OR= 0.88, p=7.99E-02). Our study has failed to replicate the previously reported association of seven T1D-associted SNPs with RA risk in a large sample from the same population. Thus, our results do not support a major role of these T1D SNPs in affecting RA susceptibility in the Pakistani population.

Inflammation plays a significant role in the etiology of type 2 diabetes mellitus (T2DM). The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury, oxidative stress and beta cell apoptosis in T2DM. Among the recognized markers are interleukin (IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha (TNF-α), C-reactive protein, resistin, adiponectin, tissue plasminogen activator, fibrinogen and heptoglobins. Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance. Many single nucleotide polymorphisms (SNPs) in various genes including those of pro and anti-inflammatory cytokines have been reported as a risk for T2DM. Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups. The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene, gene-environment and gene-nutrient interactions. This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6, TNF-α, resistin and adiponectin in pathogenesis of T2DM.