Mona R. El‐ Ansary

Globally, colorectal cancer ranks second in terms of mortality and is the third most frequent cancer. This study was designed to evaluate empagliflozin ability to suppress the progression of 1,2‐dimethylhydrazine (DMH)‐induced colorectal cancer. An 8‐week regimen of 40 mg/kg/twice a week of DMH to generate colorectal cancer. Three groups of eight male Wistar rats were created as follows: normal control, DMH group and DMH + empagliflozin (30 mg/kg; p.o.). The colonic levels of the antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were restored, empagliflozin adjusted the redox imbalance provoked by DMH. Immunohistochemical study proved the impact of empagliflozin in downregulating nuclear factor kappa B (NF‐κB) that was elevated by DMH. Empagliflozin counteracted the DMH‐triggered inflammation by reducing vascular endothelial growth factor (VEGF), interlukin‐6 (IL‐6) and cyclooxygenase‐2 (COX‐2) levels. Empagliflozin hindered tumor cell proliferation which has supported by the decline in proliferating cell nuclear antigen (PCNA) mRNA expression. Empagliflozin halted the DMH‐activated oncogenic phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/the mammalian target of rapamycin (mTOR) signaling pathway, demonstrated by western blot analysis. Histopathological assessment verified that empagliflozin suppressed the formation of dysplastic aberrant crypt foci (ACF). Empagliflozin has been suggested to suppress the progression of colorectal carcinogenesis.

Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer‐related deaths globally. Linagliptin is a dipeptidyl peptidase‐4 (DPP‐4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti‐inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2‐dimethylhydrazine (DMH)‐induced CRC via modulation of NFAT‐mediated IL‐6 and JAK2/STAT3/NF‐κB signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8‐week duration. Twenty‐four Wistar rats were segregated into three groups of eight rats each; normal control, DMH‐induced CRC and DMH + linagliptin (10 mg/kg; p.o). Linagliptin attenuated DMH‐induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF‐κB) induced by DMH which is highlighted using immunohistochemistry analysis. The anti‐inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T‐cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin‐6 (IL‐6) and cyclooxygenase‐2 (COX‐2) levels. Linagliptin mitigate the protein expression of DMH‐activated oncogenic janus‐activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B‐cell lymphoma 2 (Bcl‐2) and a significant elevation in Bcl‐2‐associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT‐mediated IL‐6 with JAK2/STAT3/NF‐κB signaling cascades.

Central line-associated bloodstream infection (CLABSI) is among the most serious hospital acquired infections. Therefore, the rapid detection of the causative microorganism is of crucial importance to allow for the appropriate antimicrobial therapy. In the present study, we analyzed the clinical performance of the BioFire FilmArray Blood Culture Identification 2 (BCID2) panel in the identification of 33 microbial species and 10 antibiotic resistance genes in comparison to the VITEK-2 system. A total of 104 blood specimens were included. The FilmArray BCID2 results were concordant with the VITEK-2 system in 69/97 specimens (71.1%). Non-concordance was either due to the detection of more pathogens by the FilmArray BCID2 23/28 (82%) or microbial species were misidentified 5/28 (18%). Hence, in comparison to the VITEK-2 system, the FilmArray BCID2 panel showed an overall sensitivity of 75.8% (95% CI, 66–83%) and an overall specificity of 98% (95% CI, 97–98.8%) in detecting microbial species. For the resistance genes, the FilmArray BCID was able to detect the presence of blaCTX-M gene in 23 Gram-negative isolates, blaNDM and blaOXA-48- like genes in 14 and 13 isolates, respectively. The mecA and mecC genes were found in 23 Staphylococcus species, while mecA, mecC and MREJ genes were found in 4 Staphylococcus aureus isolates. The sensitivity and specificity for detecting resistance genes by the FilmArray BCID2 was 90% (95% CI, 81.4–95%) and 99.6% (95% CI, 99–100%), respectively. As concluded, the present study emphasizes the high sensitivity and specificity of the FilmArray BCID2 in the rapid and reliable detection of different bacteria and fungi from positive blood culture bottles, as well as the accurate detection of various antibiotic resistance markers.

The continuous development of multidrug resistance pathogens with limited therapeutic options has become a great problem globally that impose sever health hazards. Accordingly, searching for of new antimicrobials became an urgent demand and great challenge. Soil significantly have been associated with several species that are antibiotic producers. In this study, combination of conventional screening methods with Liquid chromatography- Mass spectroscopy (LC/MS) and metagenomic nanopore sequence analysis have been conducted for the deciphering the active metabolites produced by soil isolate(s). Preliminary soil screening resulted in a Gram-negative isolate identified via 16S ribosomal RNA as Alcaligenes faecalis isolate MZ921504 with promising antimicrobial activities against wide range of MDR gram-positive and gram-negative pathogens. The LC/MS analysis of the metabolites of A. faecalis isolate MZ921504 confirmed the presence of ectoine, bacillibactin, quinolobactin and burkholderic acid. Metagenomics sequence analysis of the soil sample (NCBI GenBank accession PRJNA771993) revealed the presence of conserved biosynthetic gene clusters of ectoine, bacteriocin, bacillibactin, quinolobactin, terpene and burkholderic acid of A. faecalis. In conclusion, A. faecalis isolate MZ921504 is a promising source for antimicrobial metabolites. LC/MS spectral analysis and third generation sequencing tools followed by secondary metabolite gene clusters analysis are useful methods to predict the nature of the antimicrobial metabolites.

Purpose: We aimed to optimize the factors affecting the production of the allylamine antifungal, terbinafine, by Lysinibacillus isolate MK212927, a natural producer of this broad-spectrum fungicidal compound. Methods: We employed a central composite design to optimize the five most important variables influencing the production of terbinafine which were carbon source, nitrogen source, temperature, pH and agitation. Results: The optimum conditions were found to be starch 5 g/L, ammonium chloride 5 g/L, temperature 32°C, agitation 150 rpm and pH 7. The actual response (inhibition zone diameter) was highly comparable to the value predicted by the model, indicating a valid model. Using the standard calibration curve of terbinafine, the optimized conditions resulted in an increase in the antifungal metabolite production (terbinafine) by about 1.6-fold (1814.662 μg/mL compared to 1165.550 μg/mL under standardized conditions). Conclusion: This is the first report, to the best of our knowledge, on optimized production of terbinafine by Lysinibacillus species. Hence, these findings may be useful as baseline data for scaling up the production of terbinafine from a natural microbial source.

Purpose: This study aimed to detect the prevalence of carbapenemase producers (CPs) among extensive drug-resistant (XDR)-carbapenemase producing Gram-negative bacteria (GNB) recovered from various clinical specimens of hospitalized neutrophilic febrile patients in two major tertiary care hospitals in Egypt. Methods: Standard methods were used to evaluate the antimicrobial susceptibility of clinical isolates according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Phenotypic and genotypic analysis of CPs were carried out and statistically analyzed using standard methods. Results: Three hundred and forty-two GNB were obtained from 342 clinical specimens during the period of the study, where 162 (47%) were enterobacterial isolates, including, 63 (18.4%) Escherichia coli, 87 (25.4%) Klebsiella spp., 5 (1.46%) Enterobacter cloacae, 5 (1.46%) Salmonella spp. and 2 (0.6%) Proteus and 180 (53%) were non-fermentative bacilli including, 129 (37.7%), Acinetobacter baumannii, and 51 (14.9%), Pseudomonas spp. Out of the 342 GNB, 188 (54.9%) isolates were multi-drug resistant (MDR). Of these, 52 (27.6%) were XDR as well as CPs as confirmed phenotypically. The MIC of imipenem against the XDR GNB against showed either low (11 isolates; 21.1%; MIC range =4– 32 μg/mL) or high levels of resistance (41 isolates; 78.8%; MIC range = 64-≥ 1024). The most prevalent carbapenem resistance (CR) genes were blaKPC (63.5%) followed by blaOXA-48 (55.7%) and blaVIM (28.8%). No significant association could be observed between the MIC level and the presence of CR genes (P value > 0.05). Conclusion: High prevalence of MDR (54.9%) and XDR (27.6%) GNB pathogens associated with high levels of resistance to carbapenems were observed. All XDR GNB were CPs and tested positive for at least one of the CR genes. However, most of them (78.8%) showed a high level of CR (MIC range = 64-≥ 1024) with no significant association with the CR genes.

The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5 weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p)), and SAR-treated group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p.) + SAR(4 mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.

Infections with carbapenem-resistant Gram-negative bacteria (GNB) are among the most frequent complications in the immunocompromised cancer patients because of their considerable morbidity and mortality. Therefore, the aim of the current study was to characterize the prevalence of carbapenemase-producing GNB recovered from febrile neutropenic pediatric cancer patients in Egypt. Standard methods were used for identification, sensitivity testing (Kirby-Bauer and broth microdilution method according to CLSI guidelines). Standard methods were applied for both phenotypic and genotypic detection of the carbapenemase-producing GNB. A total of 185 GNB were recovered from different clinical specimens, Escherichia (E.) coli (86; 46.48%), followed by Klebsiella spp. (71; 38.37%), Acinetobacter (A.) baumannii (7; 3.78%) and others including Pseudomonas spp., Enterobacter (Ent.) cloacae and Proteus spp. (21; 11.35%). It is a matter of concern that 116 out of 171 enterobacterial isolates (94.15%) showed resistance to three or more antimicrobial classes and were considered multidrug resistant. Additionally, the rate of carbapenem-resistance displayed a worrisome trend as 113 out of 171 enterobacterial isolates (66.08%) and 12 out of 14 non fermenting bacilli (85.71%) showed resistance pattern to at least one of the tested carbapenems. After performing a series of phenotypic tests for initial screening of potential carbapenemase producers, molecular characterization to the 29 extracted plasmids were subjected to PCR (using 5 common carbapenemase primers). The results revealed that bla_OXA-48 was the most prevalent 17 (58.62%), followed by bla_NDM 8(27.58%), then bla_VIM 3 (10.3%) and bla_KPC 2 (6.89%). These results are an alarming threat to public health that calls for urgent application of antimicrobial stewardship programs along with routine surveillance for controlling outbreaks.

Prevalence of multidrug-resistant Gram-negative pathogens isolated from febrile neutropenic cancer patients with bloodstream infections in Egypt and new synergistic antibiotic combinations Sally Tohamy Tohamy,1 Khaled Mohamed Aboshanab,2 Hadir Ahmed El-Mahallawy,3 Mona R El-Ansary,4 Salwa Selim Afifi1 1Department of Microbiology and Immunology, Faculty of Pharmacy For Girls, Al-Azhar University, Cairo, Egypt; 2Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 3Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 4Department of Biochemistry, Modern University for Technology and Information, Cairo, Egypt Introduction: Bloodstream infections with multidrug-resistant (MDR) Gram-negative bacteria (GNB) are among the most frequent complications in immunocompromised cancer patients because of their considerable morbidity and mortality. Several guidelines on antimicrobial therapy have addressed empirical treatment for such serious infections; however, the emergence of microbial resistance has become a significant problem worldwide. Materials and methods: In this study, starting from November 2015 to October 2016, a total of 529 blood specimens were collected from febrile neutropenic cancer patients at a tertiary care cancer hospital in Egypt. Results: On examination for positive bacterial growth, it was found that 334 specimens showed no growth, while 195 were positive. Out of the 195 positive culture specimens, 102 (102/195, 52.3%) were Gram-negative and 93 (93/195, 47.7%) were Gram-positive. Out of the 102 GNB, 70 (70/102, 68.6%) were MDR, including Escherichia coli (27/70, 38.6%), Klebsiella pneumoniae (24/70, 34.3%), Acinetobacter baumannii (9/70, 12.8%), Enterobacter cloacae (4/70, 5.7%), Pseudomonas aeruginosa (2/70, 2.8%), Klebsiella oxytoca (2/70, 2.8%), and Klebsiella ornithinolytica (2/70, 2.8%). All MDR GNB showed high resistance to ampicillin, cefepime, ceftriaxone, and cephradine (minimum inhibitory concentration at which 50% of the isolates were inhibited [MIC50] >512 μg/mL for each). However, they showed good susceptibility to colistin (MIC50 <1 μg/mL). The most common extended-spectrum β-lactamases (ESBLs) genes detected were ctx-m (39/70, 55.7%), shv (31/70, 44.3%), and tem (22/70, 31.4%). The most common aminoglycoside-resistant gene detected was aac(6’)-Ib (42/70, 60%) followed by the plasmid-mediated quinolone resistance determinants; qnrA (2/70, 2.8%), qnrB (9/70, 12.8%), and qnrS (19/70, 27.1%). ESBL determinants were significantly associated with resistance to ciprofloxacin, levofloxacin, amikacin, and carbapenems (P-value <0.005). The fractional inhibitory concentration index for ampicillin/sulbactam plus ceftriaxone, ampicillin/sulbactam plus amikacin, and amikacin plus levofloxacin showed synergism against 29 (29/70, 41.4%), 19 (19/70, 27.1%), and 11 (11/70, 15.7%) isolates of the tested MDR GNB isolates, respectively. Conclusion: Accordingly, new empirical antibiotics should be administered including the use of colistin or meropenem alone or both against the MDR GNB in neutropenic cancer patients. Keywords: ESBLs, plasmid-mediated quinolone resistance, PMQR, fractional inhibitory concentration, FICI