The Increased Frequency of Carbapenem Resistant Non Fermenting Gram Negative Pathogens as Causes of Health Care Associated Infections in Adult Cancer Patients

Background and Aim: Multi drug resistant Non fermenting gram negative bacilli (NFGNB) have emerged as a major cause of health-care associated infections especially in immunocompromised hosts. The aim of the study was to investigate the prevalence of NFGNB as a cause of health-care associated infections (HAI) in cancer patients and determine their resistance pattern. Patients and Methods: During the study period, 158 NFGNB isolates were collected. Microscan Walk Away 9 was used for identification and testing for the metallo-β-lactamases (MBLs) was done by Imipenem-EDTA combined disk synergy test (CDST-IPM). Results: NFGNB represented 29.0% of infections caused by gram negative organisms. Carbapenem resistance, the multi-drug resistant (MDR) phenotype, and MBL production were documented in 70%, 63%, and 59% of NFGNB isolates, respectively. MDR-NFGNB rates were significantly higher among hospitalized patients, medical department and those with longer duration of hospital stay (p = 0.034, 0.026, 0.019;respectively) than non MDR-NFGNB. Conclusion: A high level of carbapenem and multi-drug resistance were detected among the non-fermenter pathogens isolated from hospitalized cases and were more frequently encountered in high risk adult cancer patients requiring longer duration of hospitalization. The MDR-NFGNB are constituting important causes of health-care associated infections in cancer patients.

Association of KRAS Gene and microRNA-124-3p in Sporadic Colorectal Tumours

Aim: To reveal the exonic and 3’UTR sequences of KRAS, TP53, APC, BRAF, PIK3CA genes in sporadic colorectal tumors and to investigate the clinical relevance of 3’UTR variations in miRNA profiles. Methods: In the study, the exonic and 3’UTR sequences of five genes in 12 sporadic colorectal tumors were extracted by next generation sequencing. In tumors with variation in the 3’UTR region, the changes caused by the variation in the miRNA binding profile were detected. The expression profile of these miRNAs in colorectal and other solid tumors compared to normal tissue was determined. Pathway analysis was performed to determine which signaling pathways miRNAs affect. Results: Case-10 in our study was wild type KRAS and received cetuximab treatment and developed drug resistance. In this case, it was concluded that the expression of KRAS increased and tumorigenesis progressed due to miRNAs that do not bind to this region due to variations in the 3’UTR region. Among these miRNAs, hsa-miR-124-3p was found to have decreased expression in colorectal tumors and to be associated with the ECM-receptor interaction pathway. Conclusion: Variations in the 3’UTR regions of genes critical in the process of carsinogenesis are associated with drug resistance and the process of tumorigenesis.

Effect of Nano - Titanium Dioxide with Different Antibiotics against Methicillin-Resistant Staphylococcus Aureus

The different investigation has been carried out on the biological activities of titanium dioxide nanoparticle but the effect of this nano product on the antibacterial activity of different antibiotics has not been yet demonstrated. In this study the nano size TiO2 is synthesized using citric acid and alpha dextrose and the enhancement effect of TiO2 nanoparticle on the antibacterial activity of different antibiotics was evaluated against Methicillin-resistant Staphylococcus aureus (MRSA). During the present study, different concentrations of nano-scale TiO2 were tested to find out the best concentration that can have the most effective antibacterial property against the MRSA culture. Disk diffusion method was used to determine the antibacterial activity of these antibiotics in the absence and presence of sub inhibitory concentration of TiO2 nano particle. A clinical isolate of MRSA, isolated from Intensive Care Unit (ICU) was used as test strain. In the presence of sub-inhibitory concentration of TiO2 nanoparticle (20 μg/disc) the antibacterial activities of all antibiotics have been increased against test strain with minimum 2 mm to maximum 10mm. The highest increase in inhibitory zone for MRSA was observed against pencillin G and amikacin (each 10 mm). Conversely, in case of nalidixic acid, TiO2 nanoparticle showed a Synergic effect on the antibacterial activity of this antibiotic against test strain. These results signify that the TiO2 nanoparticle potentate the antimicrobial action of beta lactums, cephalosporins, aminoglycosides, glycopeptides, macrolids and lincosamides, tetracycline a possible utilization of nano compound in combination effect against MRSA.

Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart

The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.

Low Efficiency of the Commonly Prescribed Drugs against Klebsiella pneumonia, Escherichia coli and Acinetobacter Species as the Causative Agents of Blood Stream Infection in Malabo, Equatorial Guinea

The prevalence of multi drug resistant gram-negative bacteria to commonly first line drugs in blood is a serious problem in Equatorial Guinea and other world. This is the first study describing antibiotic resistance analysis of blood stream infection in Equatorial Guinea. Our study presents alarming rate of inefficiency of the most commonly prescribed drugs to treatment Klebsiella pneumoniae, Escherichia coli and Acinetobacter species isolates as the most frequency etiologic agents in blood stream infection. Out of 1849 blood culture the bacterial etiological agents were isolated from 196 (10.6%) samples. E. coli (n = 22), K. pneumonia (n = 39) and Acinetobacter (n = 17) represent 71.6% of all gram negative bacterial isolates. Almost all isolates of K. pneumonia and Acinetobacter sp. (92.1% and 100%, respectively) and about 50% of E. coli strains possessed extended-spectrum β-lactamase activity. Alarming level of multi drug resistant gram negative strains was observed. E. coli and K. pneumonia and Acinetobacter isolates demonstrated low sensitivity to all commonly prescribed drugs such as Ampicillin, Trimethoprim/Sulfamethoxazole, Doxycycline, Gentamycin Amoxicicline/Clavulanic Acid, Cefuroxime, Ciprofloxacine. It is especially worth noting the low efficiency of third generation cephalosporins (Cefrtiaxon) against Acinetobacter and Klebsiella with their resistance rate of 94.7% and 100% respectively. Moreover, the alarming level of low sensitivity to Piperacilin/Tazobactam of K. pneumonia (22%) and Acinetobacter (29.4%) was been found. The 17.6% of Acinetobacter isolated was carbomenem resistant. Just Imipenem and Amikacin were the most sensitive drug against these bacterial strains.

MiR-142-3p enhances chemosensitivity of breast cancer cells and inhibits autophagy by targeting HMGB1

MiR-142-3p has been reported to act as a tumor suppressor in breast cancer.However,the regulatory effect of miR-142-3p on drug resistance of breast cancer cells and its underlying mechanism remain unknown.Here,we found that miR-142-3p was significantly downregulated in the doxorubicin(DOX)-resistant MCF-7 cell line(MCF-7/DOX).MiR-142-3p overexpression increased DOX sensitivity and enhanced DOXinduced apoptosis in breast cancer cells.High-mobility group box 1(HMGB1)is a direct functional target of miR-142-3p in breast cancer cells and miR-142-3p negatively regulated HMGB1 expression.Moreover,overexpres sion of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by miR-142-3p up-regulation.In conclusion,miR-142-3p overexpression may inhibit autophagy and promote the drug sensitivity of breast cancer cells to DOX by targeting HMGB 1.The miR-142-3 p/HMGB1 axis might be a novel target to regulate the drug resistance of breast cancer patients.

The epigallocatechin gallate derivative Y_6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo

Previously, we reported that Y_6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin(DOX)–mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y_6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter(ABCB1 or P-glycoprotein, P-gp). Our results showed that Y_6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y_6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y_6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mousetumor xenograft model, Y_6(110 mg/kg, intragastric administration), in combination with doxorubicin(2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y_6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

The urgent need for more potent antiretroviral therapy in low-income countries to achieve UNAIDS 90-90-90 and complete eradication of AIDS by 2030

Background:Over 90%of Human Immunodeficiency Virus(HIV)infected individuals will be on treatment by 2020under UNAIDS 90-90-90 global targets.Under World Health Organisation(WHO)"Treat All"approach,this number will be approximately 36.4 million people with over 98%in low-income countries(LICs).Main body:Pretreatment drug resistance(PDR)largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors(NNRTIs),efavirenz and nevirapine,has been increasing with roll-out of combined antiretroviral therapy(cART)with 29%annual increase in some LICs countries.PDR has exceeded 10%in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations.If no change in regimens is enforced in LICs,it’s estimated that over 16%of total deaths,9%of new infections,and 8%of total cART costs will be contributed by HIV drug resistance by 2030.Less than optimal adherence,and adverse side effects associated with currently available drug regimens,all pose a great threat to achievement of 90%viral suppression and elimination of AIDS as a public health threat by 2030.This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide.Conclusions:The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance,better safety,and tolerability profiles.It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment,support for adherence to cART,patient follow up and adequate drug stocks to help achieve a free AIDS generation.