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Lipid disorders and cardiovascular disease (CVD) risk are known to be increased in patients with diabetes mellitus. The effects of statins on serum lipid levels are well known; however, previous studies did not compare the effects of statins on serum lipid levels in diabetic patients with non-diabetic patients. To investigate the effects of Atorvastatin on serum lipid profiles in hyperlipidemic patients with type 2 diabetes mellitus in comparison with hyperlipidemic patients without diabetes.This study was conducted on 33 type 2 diabetic patients & 34 non-diabetic patients; their age range was 40-80 years, all of them were hyperlipidemic, who had been administered 10, 20, & 40 mg daily of Atorvastatin and completed a 6-month follow-up. Serum lipids were measured before and after treatment at 1, 3, and 6 months.It was found that the reduction in S. Total Cholesterol and S. LDL-C were less in diabetic patients than that in non-diabetic patients when they are using the same doses of Atorvastatin, while the changes in S. HDL-C and S. Triglyceride were nearly similar in both. Furthermore, it is noticed that nearly the same responses of S. Cholesterol and S. LDL-C reduction were achieved in diabetic patients when they are using doubled doses that are used for non-diabetic patients.So,higher doses of Atorvastatin (double doses) are needed to improve serum lipid levels in diabetic patients as compared to non-diabetic patients. Key words: Diabetic , Lipids , Atorvastatin.

Abstract: Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-γ) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFN-γ-induced CD38 upregulation depends on interferon regulatory factor 1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T-cell engager (BN-CD38) designed to promote an effective immunological synapse between CD38pos AML cells and both CD8pos and CD4pos T cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts, leading to T-cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFN-γ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, although BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient-derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multilineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Chemotherapy, the treatment of choice in non-operable cases, achieves a dismal success rate, raising the need for new therapeutic options. In about 25% of NSCLC, the activating mutations of the KRAS oncogene define a subclass that cannot benefit from tyrosine kinase inhibitors (TKIs). The tumor suppressor miR-16 is downregulated in many human cancers, including NSCLC. The main objectives of this study were to evaluate miR-16 treatment to restore the TKI sensitivity and compare its efficacy to MEK inhibitors in KRAS -mutated NSCLC., Methods: We performed in vitro and in vivo studies to investigate whether miR-16 could be exploited to overcome TKI resistance in KRAS-mutated NSCLC. We had three goals: first, to identify the KRAS downstream effectors targeted by mir-16, second, to study the effects of miR-16 restoration on TKI resistance in KRAS-mutated NSCLC both in vitro and in vivo, and finally, to compare miR-16 and the MEK inhibitor selumetinib in reducing KRAS-mutated NSCLC growth in vitro and in vivo., Results: We demonstrated that miR-16 directly targets the three KRAS downstream effectors MAPK3 , MAP2K1 , and CRAF in NSCLC, restoring the sensitivity to erlotinib in KRAS -mutated NSCLC both in vitro and in vivo. We also provided evidence that the miR-16-erlotinib regimen is more effective than the selumetinib-erlotinib combination in KRAS -mutated NSCLC., Conclusions: Our findings support the biological preclinical rationale for using miR-16 in combination with erlotinib in the treatment of NSCLC with KRAS -activating mutations.

Sildenafil citrate, a widely-used oral therapy for erectile dysfunction, is a cytochrome P3A4 (CYP3A4) enzyme substrate. Studies have reported that this substrate has an inhibitory effect on CYP3A4 enzymes in long-term cigarette and cannabis smokers, which predominantly mediate the hepatic elimination of sildenafil. Cigarette and/or cannabis smoking could therefore alter the exposure of sildenafil. The aim of this study was to examine the effect of smoking cigarettes and/or cannabis on the pharmacokinetics, pharmacodynamics, safety and tolerability of sildenafil. Thirty-six healthy human subjects were equally divided into three groups: non-smokers, cigarette smokers and cannabis smokers. Each group was administered a single dose of sildenafil (50 mg tablets). The primary outcome measures included the maximum concentration of sildenafil in plasma (C max ), the elimination half-life (t1/2) and the area under the plasma concentration time curve from zero to time (AUC 0-t ). The pharmacodynamics were assessed by the International Index of Erectile Function (IIEF-5). The exposure of sildenafil (AUC 0-t ) showed a statistically significant increase in cigarette smokers (1156 ± 542 ng·h/mL) of 61% ( p < 0.05) while in cannabis smokers (967 ± 262 ng·h/mL), a non-significant increase in AUC 0-t of 35% ( p > 0.05) was observed relative to non-smokers (717 ± 311 ng·h/mL). Moreover, the C max of sildenafil increased by 63% ( p < 0.05) and 22% ( p > 0.05) in cigarette smokers and cannabis smokers, respectively. Cigarette smoking increases the exposure of sildenafil to a statistically significant level with no effect on its pharmacodynamics, safety and tolerability.

Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP + signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138 + /CD38 + plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target., Competing Interests: C.C.H. reports grants from Janssen, Bristol-Meyers Squibb, and Oncolytics Biotech, grants and personal fees for membership of a marketing advisory board from Celgene, personal fees for membership of a research advisory board from Karyopharm, personal fees for membership of a research advisory board from Oncopeptides and Imbrium Therapeutics, and personal fees for membership of a regulatory advisory board from Adaptive Biotechnologies, all outside the submitted work. D.W.S. reports grants from Oncolytics Biotech, Bristol-Meyers Squibb, GlaxoSmithKline, and Janssen, all outside the submitted work. L.H.B reports research funding from AstraZeneca and personal fees for membership of advisory boards from AstraZeneca and Genentech., (© 2021 The Authors.)

In this population-based study, we compared the incidence of distal radius fracture in 2016 with that in the same region's adult general population in 2001 using radiographs to identify fracture cases. We showed that the incidence decreased by 24% in 2016 compared with 2001 indicating an important development., Introduction: We conducted an epidemiological study on residents of northeastern Skåne in southern Sweden (population 182,000) to determine the overall incidence of distal radius fracture and the incidence according to age, sex, and fracture characteristics in the region's adult population during 2016, and to study the change in incidence in the same general population between 2001 and 2016 using wrist radiographs to identify fracture cases., Methods: Two orthopedic surgeons examined all wrist radiographs performed at the only two emergency hospitals in the study region to identify individuals, above 18 years of age, who sustained fracture of the distal radius during 2016. We used Poisson regression analysis adjusting for age, sex, and at-risk population to compare the incidence in 2016 with the incidence in 2001, previously estimated using similar methodology., Results: The overall incidence in 2016 was 22 (95% CI 20-25) per 10,000; the incidence in women was 34 (95% CI 30-39) and in men was 10 (95% CI 8-12) per 10,000. The overall incidence in 2016 was 0.76 (95% CI 0.70-0.82) of the incidence in 2001 (p < 0.0001). The incidence in the 3 age groups 19-49, 50-79, and ≥ 80 years was 0.91 (95% CI, 0.69-1.20), 0.67 (95% CI, 0.55-0.82), and 0.49 (95% CI, 0.25-0.97) of the incidence in 2001, respectively., Conclusion: In a general population in Sweden, a statistically significant and clinically important decrease in the incidence of distal radius fracture occurred between 2001 and 2016, driven by lower incidence in individuals 50 years or older.

In neuroblastoma, the interplay between immune cells of the tumor microenvironment and cancer cells contributes to immune escape mechanisms and drug resistance. In this study, we show that natural killer (NK) cell-derived exosomes carrying the tumor suppressor microRNA (miR)-186 exhibit cytotoxicity against MYCN-amplified neuroblastoma cell lines. The cytotoxic potential of these exosomes was partly dependent upon expression of miR-186. miR-186 was downregulated in high-risk neuroblastoma patients, and its low expression represented a poor prognostic factor that directly correlated with NK activation markers (i.e., NKG2D and DNAM-1). Expression of MYCN, AURKA, TGFBR1, and TGFBR2 was directly inhibited by miR-186. Targeted delivery of miR-186 to MYCN-amplified neuroblastoma or NK cells resulted in inhibition of neuroblastoma tumorigenic potential and prevented the TGFβ1-dependent inhibition of NK cells. Altogether, these data support the investigation of a miR-186-containing nanoparticle formulation to prevent tumor growth and TGFβ1-dependent immune escape in high-risk neuroblastoma patients as well as the inclusion of ex vivo -derived NK exosomes as a potential therapeutic option alongside NK cell-based immunotherapy. Significance: These findings highlight the therapeutic potential of NK cell-derived exosomes containing the tumor suppressor miR-186 that inhibits growth, spreading, and TGFβ-dependent immune escape mechanisms in neuroblastoma., (©2018 American Association for Cancer Research.)

Human exposure to persistent organic pollutants (POPs) begins during pregnancy and may cause adverse health effects in the fetus or later in life. The present study aimed to assess prenatal POPs exposure to Tanzanian infants and evaluate the distribution of POPs between breast milk, maternal blood, placenta and cord blood. For assessment of prenatal exposure, 48 maternal blood samples from Mount Meru Regional Referral Hospital (MMRRH), Arusha Tanzania, were analyzed for organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs), dioxin-like (DL) activity and perfluorinated alkyl substances (PFASs). For evaluation of POPs distribution between maternal/infant compartments, breast milk, placenta and cord blood corresponding to the maternal blood were analyzed for OCPs, PCBs and BFRs. In maternal blood, p,p´- DDE was detected in 100% of the samples ranging between 29 and 1890 ng/g lipid weight (lw). PCB-153 was the only PCB detected in maternal blood, with detection rate of 29% and concentrations up to 116 ng/g lw. BDE-47 was detected in 65% of the maternal blood samples, ranging between

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The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis. Their mechanisms of action and the factors regulating their expression in cancers are poorly understood. Here we show that high expression of uc.339 correlates with lower survival in 210 non-small cell lung cancer (NSCLC) patients. We provide evidence from cell lines and primary samples that TP53 directly regulates uc.339. We find that transcribed uc.339 is upregulated in archival NSCLC samples, functioning as a decoy RNA for miR-339-3p, -663b-3p, and -95-5p. As a result, Cyclin E2, a direct target of all these microRNAs is upregulated, promoting cancer growth and migration. Finally, we find that modulation of uc.339 affects microRNA expression. However, overexpression or downregulation of these microRNAs causes no significant variations in uc.339 levels, suggesting a type of interaction for uc.339 that we call "entrapping". Our results support a key role for uc.339 in lung cancer.

This is the first study to report organochlorines (OCs), including chlorinated pesticides (OCPs) and polychlorinated biphenyls (PCBs) in human milk from Tanzania. The main aims of this study were to assess the level of contamination and the possible health risks related to OC exposure in nursing infants from the Northern parts of Tanzania. Ninety-five healthy mother-infant couples attending Mount Meru Regional Referral Hospital (MMRRH), Arusha, Tanzania, were assessed for associations between maternal/infant characteristics, i.e. mother's age, BMI, gestational weight gain, occupation, residence and fetal growth parameters and breast milk levels of OCPs, such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, dieldrin and PCBs. p,p'-DDE and p,p'-DDT were detected in 100% and 75% of the breast milk samples, respectively, and ranged between 24 and 2400ng/g lipid weight (lw) and

The main aim of this study was to assess brominated flame retardants (BFRs) in breast milk in the Northern parts of Tanzania. Ninety-five colostrum samples from healthy, primiparous mothers at Mount Meru Regional Referral Hospital (MMRRH), Arusha Tanzania, were analyzed for polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), hexabromobenzene (HBB), (2,3-dibromopropyl) (2,4,6-tribromophenyl) ether (DPTE), pentabromoethylbenzene (PBEB) and 2,3,4,5,6-pentabromotoluene (PBT). The Ʃ7PBDE (BDE 28, 47, 99, 100, 153, 154, 183) ranged from below level of detection (

Background: How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL)., Methods: Coculture experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts treated with Cisplatin and peritumoral exosomic miR-155 (n = 6 mice per group) CD163, miR-155, and TERF1 levels were assessed in 20 NBL primary tissues by Human Exon Arrays and quantitative real-time polymerase chain reaction. Student's t test was used to evaluate the differences between treatment groups. All statistical tests were two-sided., Results: miR-21 mean fold change (f.c.) was 12.08±0.30 (P < .001) in human monocytes treated with NBL derived exosomes for 48 hours, and miR-155 mean f.c. was 4.51±0.25 (P < .001) in NBL cells cocultured with human monocytes for 48 hours. TERF1 mean luciferase activity in miR-155 transfected NBL cells normalized to scrambled was 0.36 ± 0.05 (P <.001). Mean tumor volumes in Dotap-miR-155 compared with Dotap-scrambled were 322.80±120mm(3) and 76.00±39.3mm(3), P = .002 at day 24, respectively. Patients with high CD163 infiltrating NBLs had statistically significantly higher intratumoral levels of miR-155 (P = .04) and lower levels of TERF1 mRNA (P = .02)., Conclusions: These data indicate a unique role of exosomic miR-21 and miR-155 in the cross-talk between NBL cells and human monocytes in the resistance to chemotherapy, through a novel exosomic miR-21/TLR8-NF-кB/exosomic miR-155/TERF1 signaling pathway., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

miRNAs are small noncoding RNAs with gene regulatory functions, frequently dysregulated in human cancers. Specific signatures of differentially expressed miRNAs can be used in the diagnosis of cancer and in some cases harbor prognostic implications. The biology of cancer is dictated not only by cancer cells but also by the surrounding tumor microenvironment. In particular, the role of miRNAs within the tumor microenvironment is emerging as of paramount importance. This review will focus on the current knowledge of the role of miRNAs and both cellular and stromal components of the tumor microenvironment. We will also discuss more recent findings, showing that miRNAs can be found inside of exosomes and mediate the cross-talk between cancer cells and surrounding cells, leading to the discovery of new fascinating molecular mechanisms leading to a better understanding of the cancer 'niche' and how these noncoding RNAs can become very promising diagnostic molecules.

Objective: To determine the molecular epidemiology of extended-spectrum β-lactamase (ESBL) by testing a cohort of clinical ESBL-producing bacterial isolates that were isolated in the Kingdom of Bahrain., Methods: ESBL producing Enterobacteriaceae isolates (based on phenotypic tests) were collected from Microbiology Laboratory of the Salmaniya Medical Complex, Bahrain between January-June 2006. Antibiotic susceptibility to a panel of antibiotics was performed and bla(CTX-M) genes were detected by multiplex PCR., Results: A total of 230 isolates (Escherichia coli, n=180; Klebsiella pneumoniae, n=50) were studied, 98% were CTX-M type. For Escherichia coli isolates, 65 (36.1%) harbored CTXM+TEM combination and 68 (37.8%) had CTX-M alone. In contrast, for Klebsiella pneumoniae isolates only 5 (10.0%) harbored the CTX-M combination, and none had CTX-M only. The bla(CTX-M) gene was found predominantly in urine isolates (n=145/230; 63.0%). Sensitivity to imipenem and nitrofurantoin was 100% and 60%, respectively. CTX-M carriage was associated with the resistance to fluoroquinolones, trimethoprim-sulfamethoxazole and aminoglycosides., Conclusions: Our study documentes high prevalence of CTX-M ESBL type among Escherichia coli and Klebsiella from the Kingdom of Bahrain. The apparent dissemination of CTX-M producers could represent a substantial barrier in the treatment of community-acquired infections. The use of extended-spectrum cephalosporins, quinolones, and aminoglycosides is compromised, leaving carbapenems as the therapeutic option for severe infections caused by ESBL producers., (Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.)

One approach for a safer smallpox vaccine is to utilize recombinant subunits rather than live vaccinia virus (VACV). The products of the VACV envelope genes A27L, L1R, B5R, and A33R induce protective antibodies in animal models. We propose that proteins that elicit T-cell responses, as well as neutralizing antibodies, will be important to include in a molecular vaccine. To evaluate VACV-specific memory T-cell responses, peripheral blood mononuclear cells (PBMC) from four VACV vaccinees were tested against whole VACV and the individual envelope proteins A27, B5, L1, and A33, using gamma interferon enzyme-linked immunospot and cytokine flow cytometry assays. PBMC were stimulated with autologous dendritic cells infected with VACV or electroporated with individual VACV protein mRNAs. T-cell lines from all donors, vaccinated from 1 month to over 20 years ago, recognized all four VACV envelope proteins. Both CD4(+) and CD8(+) T-cell responses to each protein were detected. Further analysis focused on representative proteins B5 and A27. PBMC from a recent vaccinee exhibited high frequencies of CD4(+) and CD8(+) T-cell precursors to both B5 (19.8 and 20%, respectively) and A27 (6.8 and 3.7%). In comparison, B5- and A27-specific T-cell frequencies ranged from 0.4 to 1.3% in a donor vaccinated 3 years ago. Multiple CD4(+) and CD8(+) T-cell epitopes were identified from both A27 and B5, using overlapping 15-mer peptides. These data suggest that all four VACV envelope proteins may contribute to protective immunity, not only by inducing antibody responses, but also by eliciting T-cell responses.

Some reports indicate that amyloidosis is a rare occurrence in persons with periodic peritonitis (familial Mediterranean fever), while others seem to show it occurs relatively frequently. Two cases were seen among 80 patients in Iraq. Twenty-one consecutive rectal biopsies were negative for amyloidosis. The variation in reported incidence is partly real and partly apparent. Amyloidosis occurs frequently in certain ethnic groups, and it is possible that there are two traits, one for periodic peritonitis and the other for amyloidosis.

Fatty acid synthesis by subcellular fractions of human aorta was studied by measuring the incorporation of either radioactive acetyl-CoA or malonyl-CoA into long chain fatty acids. The high speed supernatant fraction contained fatty acid synthetase and was capable of de novo fatty acid synthesis. The fatty acid synthetase from chicken aorta was purified 800-fold from the high speed supernatant and was judged to be 10% pure at this level. Its molecular weight was estimated to be 450,000 on the basis of agarose gel filtration chromatography, while under dissociating conditions a molecular weight of 220,000 was obtained on sodium dodecyl sulphate disc gel electrophoresis. Fatty acid synthesis was dependent on acetyl-CoA, malonyl-CoA and NADPH. The major product was free palmitic acid. In enzymatic and physical characteristics the chicken aorta fatty acid synthetase strongly resembles the synthetase isolated from chicken liver. The two enzymes cross-react immuno-chemically and this homology provides the possibility of studying the synthesis and degradation of the aorta synthetase during the development of atherosclerosis.

The incidence of chronic cor pulmonale in Iraq has been studied for the first time. Of the total 1,102 cardiac cases admitted to the Medical City Hospital in a 1-year period, 168 patients belonged to this group (15.25%). The most frequent cause is chronic obstructive airway disease. Smoking is thought to be an important factor in the occurrence of obstruction. Chronic and repeated infections during different phases of life are thought to play a major role in the pathogenesis. Occupation and dust probably have no significant effect. Schistosomiasis and tuberculosis are rare causes.