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Proper management and selection of a single drug or multiple drugs for the treatment of diabetes is very important. The choice of treatment depends on a number of factors. With the proper treatment, the state of diabetes can be managed very smoothly. The main objective of this study was to compare the efficacy of insulin, biguanides and sulfonylurea on HbA1C in diabetic patients. This interventional type of study was carried out among 102 diabetic patients attending at different hospitals in Rajshahi of Bangladesh. In this case purposive sampling technique was followed and data revealed that mean age of the patients was 45.98±11.23 years and most of them (35.30) were housewife. Among the insulin receiving group, 41.18% were male and 58.82% were female. In case of the biguanide receiving taking group 44.12% were male and 55.88% were female while for the sulfonylurea receiving group 35.29% were male and 64.71% were female. Regarding body mass index (BMI) among the respondents, it was found that 0.98% had BMI

Understanding racial disparities in cancer outcomes continues to be a challenge, with likely many factors at play, including socioeconomic factors and genetic polymorphisms impacting basic cellular and molecular functions. Additionally, it is possible that specific combinations of environment and genetics have specific impacts. T-cell receptor (TCR) gene segment usage, HLA allele combinations have been associated with autoimmune and infectious disease courses, and more recently, TCR gene segment usage, HLA allele combinations have been associated with distinct survival outcomes in cancer as well. We examined several such, previously reported cancer-related TCR gene segment usage, HLA allele combinations for evidence of racial disparities, with regard to the prevalence of the combination in different racial groups. Results indicated that TCR gene segment usage, potentially reflecting environmental factors related to previous pathogen exposure, in combination with certain HLA alleles or independently, may represent a novel explanation for racial disparities in cancer outcomes. Overall, at this point, a genetic connection to racial disparities in cancer outcomes is detectable but remains modest, suggesting that other factors, such as socioeconomic factors, remain as important considerations.

Cancer testis antigens have been of interest as possible targets for cancer immunotherapies. To better understand the opportunities for the use of such immunotherapy targets, we used a chemical complementarity scoring algorithm and an original web tool to establish aspects of electrostatic complementarity of the CTAs, MAGEA3 and MAGEA6, with melanoma specimen resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3) amino acid sequences. Greater electrostatic complementarity between T-cell receptor CDR3 and tumor CTAs MAGEA3/6 was associated with a greater probability of overall survival, for both the cancer genome atlas and Moffitt Cancer Center samples; and was associated with high levels of T-cell cytotoxicity-related gene expression. Most importantly, this approach allowed for the highly efficient screening of specific segments of the MAGEA3/6 antigens which indicated that certain MAGE segments would have either more or less risk of auto-reactivity. In sum, the chemical complementarity algorithm, and its efficient application via the web tool, adaptivematch.com, offers a convenient opportunity to identify likely parameters important for immunotherapy considerations and melanoma patient risk stratifications.

Supplementary tables to show combination index values for combination treatments of indicated compounds. Supplementary Table 1. Combination Index values for initial combination treatment of ZMC1 with chemotherapy drugs; Supplementary Table 2. Combination Index values for combination treatment of ZMC1 with chemotherapy drugs in the presence of GSH; Supplementary Table 3. Combination Index values for combination treatment of ZMC1 with Irinotecan with or without GSH in Detroit 562 cells; Supplementary Table 4. Combination Index values for combination treatment of MEE or DEE with Etoposide; Supplementary Table 5. Combination Index values for combination treatment of ZMC1 with the indicated compounds

Suppl. Fig. S1 display ZMC1 structure. Suppl. Fig. S2 showed no synergy in combination treatment of ZMC1 and Adriamycin or IR. Suppl. Fig. S3 showed synergy in Detroit 562 cells by combination treatment of ZMC1 and Irinotecan in the presence of GSH. Suppl. Fig. S4 showed combination response of ZMC1 and DNA damaging reagent (Irinotecan) in the presence of GSH. Suppl. Fig. S5 showed combination response to ZMC1 and Etoposide is mutant p53 dependent. Suppl. Fig. S6 showed measurement of KCuZMC1 using EGTA competition assay. Suppl. Fig. S7 displayed NTA competition assay for determining KCuC12. Suppl. Fig. S8 showed combination response to MEE or DEE and Etoposide is mutant p53 dependent. Suppl. Fig. S9 showed 5 combination treatments of ZMC1 and other targeted therapy drugs (A) b-Lapachone (b-Lap), (B) ThioNa, (C) 6-AN, (D) ABT-199, (E) Nutlin 3a. Suppl. Fig. S10 showed that the combination treatment of ZMC1 and ABT-199 promoted more apoptosis.

Suppl. Methods included the methods used in the paper, Cell growth inhibition assay, Immunofluorescent staining, Synthesis of ZMC1, Synthesis of 2,2'-((2-Ethoxy-2-oxoethyl)azanediyl)diacetic acid (NTA-MEE) and NTA-DEE, Zn2+-Kd measurements by competition, Metal binding experiments, Colony formation assays, Oxidative stress detection, Apoptosis assay (Annexin V staining).

Chemotherapy and radiation are more effective in wild-type (WT) p53 tumors due to p53 activation. This is one rationale for developing drugs that reactivate mutant p53 to synergize with chemotherapy and radiation. Zinc metallochaperones (ZMC) are a new class of mutant p53 reactivators that restore WT structure and function to zinc-deficient p53 mutants. We hypothesized that the thiosemicarbazone, ZMC1, would synergize with chemotherapy and radiation. Surprisingly, this was not found. We explored the mechanism of this and found the reactive oxygen species (ROS) activity of ZMC1 negates the signal on p53 that is generated with chemotherapy and radiation. We hypothesized that a zinc scaffold generating less ROS would synergize with chemotherapy and radiation. The ROS effect of ZMC1 is generated by its chelation of redox active copper. ZMC1 copper binding (KCu) studies reveal its affinity for copper is approximately 108 greater than Zn2+. We identified an alternative zinc scaffold (nitrilotriacetic acid) and synthesized derivatives to improve cell permeability. These compounds bind zinc in the same range as ZMC1 but bound copper much less avidly (106- to 107-fold lower) and induced less ROS. These compounds were synergistic with chemotherapy and radiation by inducing p53 signaling events on mutant p53. We explored other combinations with ZMC1 based on its mechanism of action and demonstrate that ZMC1 is synergistic with MDM2 antagonists, BCL2 antagonists, and molecules that deplete cellular reducing agents. We have identified an optimal Cu2+:Zn2+ binding ratio to facilitate development of ZMCs as chemotherapy and radiation sensitizers. Although ZMC1 is not synergistic with chemotherapy and radiation, it is synergistic with a number of other targeted agents.

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PDF file - 76K, Supplemental Table 1. Clinicopathologic characteristics of prostate cancer patients. Supplemental Table 2. Complimentary sequences in 3'UTRs of genes for miR-34b and sequences of primers and probes.

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PDF file - 325K, Supplemental Figure 1: Downregulation of miR-34b expression, its potential diagnostic and prognostic significance and methylation status in PCa. A) Box plot representation of mir-34b expression in a cohort of unmatched tissue samples. B) Box plot representation of ISH results of tissue samples. (Ave- Average; T/N- Tumor/Normal). C) Chi-square test showing correlation of clinicopathological characteristics with miR-34b expression. D) CpG islands within the 1.0 kb region upstream of the miR-34b gene. Arrow indicates the start of the miR-34b gene. Locations for primers and probes are also shown on the miR-34b gene. F- Forward, R-Reverse, M/U Methylation and Unmethylation probes, CF1, CF2, CR1, CR2- ChiP Forward1-2, ChIP Reverse 1-2. E) Correlation of miR-34b expression with average percent methylation indicating cases with low miR-34b expression have higher methylation and vice versa.

PDF file - 141K, miR-23b directly targets Akt in prostate cancer

Supplementary Figure Legend from Regulation of Minichromosome Maintenance Gene Family by MicroRNA-1296 and Genistein in Prostate Cancer

PDF file - 65K, Clinicopathological characteristics of patients and their correlation with miR-23b

PDF file - 967K, Depletion of Src kinase by an additional siRNA sequence

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Supplementary Figure 4 from MicroRNA-205 Inhibits Src-Mediated Oncogenic Pathways in Renal Cancer

Supplementary Figure Legends 1-4 from MicroRNA-205 Inhibits Src-Mediated Oncogenic Pathways in Renal Cancer

Supplementary Figure 1 from Regulation of Minichromosome Maintenance Gene Family by MicroRNA-1296 and Genistein in Prostate Cancer

PDF file - 567K, miR-708 induces morphological changes indicative of increased apoptosis in PCa cell lines

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PDF file - 145K, AKT2 expression in CD44-ve and CD44+ve subpopulations of PC3 xenografts

Supplementary Figure 3 from MicroRNA-205 Inhibits Src-Mediated Oncogenic Pathways in Renal Cancer

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Supplementary Figure 2 from MicroRNA-205 Inhibits Src-Mediated Oncogenic Pathways in Renal Cancer

PDF file - 73K, Clinicopathologic characteristics of prostate cancer patients

PDF file - 91K, Correlation of miR-708 expression with serum PSA levels

Supplementary Figure 1 from MicroRNA-205 Inhibits Src-Mediated Oncogenic Pathways in Renal Cancer

Supplementary Table 1 from MicroRNA-205 Inhibits Src-Mediated Oncogenic Pathways in Renal Cancer

PDF file - 402K, In situ hybridization analysis of miR-708 expression in PCa tissues

We mined a set of neuroblastoma (NBL) exomes for immune receptor recombinations representing all seven, human adaptive immune receptor genes, using a very high standard for identifications of V- and J-gene segments in sequencing reads. Results indicated an unusually large number of TRD recombination reads in the NBL samples, possibly related to the younger age of the patients. In general, recovery of immune receptor (IR) recombination reads representing any of the immune receptors, from either blood or tumor samples, was associated with a lower overall survival rate, consistent with an emerging literature indicating that systemic immunology parameters can be informative for cancer evaluations. Despite the overall negative association of IR recombination frequencies and outcomes, survival rate distinctions could still be established as associated with certain chemical features of IR complementarity determining region-3 (CDR3) amino acid sequences, thereby likely revealing a distinction between the negative impacts of a general adaptive immune response versus the positive aspects of specific CDR3 chemical interaction potentials. These data underscore the relevance of gamma-delta T cells in the development of cancer in younger patients. And for the first time, these data allow a distinction within an NBL cohort with active disease, between two contrasting systemic immune states: (i) general and likely harmful adaptive immunity development versus (ii) a likely positive, adaptive immune response with particular antigenic specificities.

BACKGROUND: Accumulating evidence suggests that alternative RNA splicing has an important role in cancer development and progression by driving the expression of a diverse array of RNA and protein isoforms from a handful of genes. However, our understanding of the clinical significance of cancer-specific RNA splicing in renal cell carcinoma (RCC) is limited. OBJECTIVE: To characterize and validate a novel oncogene RNA splicing event discovered in patients with RCC and to correlate expression with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Using DNA and RNA sequencing, we identified a novel epidermal growth factor receptor (EGFR) splicing alteration (EGFR_pr20CTF) in RCC tumor tissue. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We confirmed the frequency and specificity of the EGFR_pr20CTF variant by analyzing cohorts of patients from our institution (n = 699) and The Cancer Genome Atlas (TCGA; n = 832). Furthermore, we analyzed its expression in tumor tissue and a human kidney cancer cell line using reverse transcriptase-polymerase chain reaction. Variant expression was also correlated with survival and response to systemic therapy. RESULTS AND LIMITATIONS: EGFR_pr20CTF expression was identified in 71.7% (n = 71/99) of patients with RCC in our institutional cohort and in 56.7% (n = 279/492) of patients in the TCGA cohort. EGFR_pr20CTF was found to be specific to clear cell renal cell carcinoma (ccRCC), occurring in

Multiple myeloma (MM) immunogenomics studies related to T-cell characterizations and involving large patient sets have been lacking, particularly in comparison to solid tumor types. Thus, we evaluated (i) HLA alleles, and (ii) T-Cell Receptor (TCR) V- and J-gene segment, HLA allele combinations, based on TCR recombinations in blood samples, for their potential associations with overall survival distinctions among an MM cohort. Two HLA alleles, and seven TCR V- or J-gene segment, HLA allele combinations were found to be associated with distinct overall survival rates. For examples, HLA-C*08:02, and the TRAV19, HLA-C*07:01 combination, were found to be associated with negative outcomes. In addition, anti-cytomegalovirus immune receptor sequences, from blood samples, were found to be associated with a positive outcome (

Common or dominant, T-cell receptor (TCR), V and J usage, in combination with particular human leukocyte antigen (HLA) alleles, has been associated with differing outcomes in viral infections, autoimmunity, and more recently, in cancer. Cervical cancer in particular represents the most dramatic series of distinctions of outcomes associated with differing combinations of dominant V or J usage and HLA alleles, possibly because of the strong association of cervical cancer with human papilloma virus (HPV), in turn leading to a likely molecular consistency in the mechanism of HPV antigen presentation. Thus, we considered assessing TRB V and J usage, HLA allele combinations, for their associations with survival rates and related data, in the cancer genome atlas head and neck cancer dataset. We obtained the TRB VDJ recombination reads from both the blood and tumor exome files and determined the V and J identities. We then established case ID (patient) subsets of V or J usage, HLA alleles, and determined, for example, that the TRBJ2-7, HLA-B*40:01 combination was associated with a better disease free survival rate than were either the TRBJ1-3, HLA-DPB1*03:01 or the TRBJ2-1, HLA-DPB1*02:01 combinations. Furthermore, these analyses led to the conclusion that TRBJ1-5 usage, and the HLA-C*08:02 and HLA-DRB1*03:01 alleles, had independent associations with distinct overall survival rates. In sum, the results suggest that dominant V or J usage, HLA allele combinations, and in certain cases, dominant V or J usage independently of HLA, could be useful in prognosis and in guiding immunotherapies.

Immunogenomics and earlier, pioneering studies, particularly by Whiteside and colleagues, have indicated a positive role for B-cells in breast cancer, as well as a positive role for gamma-delta T-cells. However, these studies have been completely limited to assessing breast cancer tumor tissue. Our analyses here has shown that blood-borne T-cell receptor gamma (TRG) chain sequences were associated with greater overall survival, of particular note due to the comparative longevity of primary breast cancer patients, whereby assessments of disease-free, but rarely overall survival parameters are possible. Additional immunogenomics approaches narrowed the overall survival correlations to specific, TRG complementarity determining region-3, amino acid (AA) sequence chemical features, independently of many common, confounding variables in the breast cancer setting, such as estrogen or progesterone receptor status. These results are discussed in the context of patient age and with regard to potential antigenic targets, based on the chemistry of the TRG CDR3 AA sequences associated with the higher survival rates.