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Carbapenemase-resistant Klebsiella pneumoniae (CRKP) is a genuine burden for physicians and researchers. We aimed at carbapenemase resistance and its relation with capsular serotyping in K. pneumoniae and studied some clinical determinants, which may influence the clinical infections. Initially, 61 K. pneumoniae isolates obtained from various clinical specimens were confirmed at the molecular level and then antimicrobial susceptibility test was performed followed by capsular serotyping performed by multiplex PCR. All isolates were subjected to the detection of carbapenemase genes including blaKPC, blaNDM-1, blaOXA-48, blaVIM, and blaIMP. Clinical and demographic data of all patients were reviewed including age, gender, underlying diseases, and the treatment obtained. Multidrug-resistance was a predominant feature in 77% K. pneumoniae strains. Presence of extended-spectrum beta-lactamase was detected phenotypically in 59% K. pneumoniae strains. Carbapenem resistance was noticed phenotypically in 24.6% isolates. blaOXA-48 and blaNDM-1 were the most frequent carbapenemase genes. blaNDM-1 positive isolates correlated with gentamicin, amikacin, imipenem, and meropenem resistance (p<0.05). The nosocomial isolates mostly harbored blaOXA-48 gene (p<0.02). Amongst all the K. pneumoniae isolates, 59% isolates could be typed and serotype K54 had the highest prevalence followed by K20 and K5. Correlation between the carbapenemase genes, serotype and type of infection showed that blaOXA-48 positive strains had a significant association with K20 serotype and urinary tract infections (p=0.2) while, K20 serotype and blaKPC positive strains were significantly associated with wound infections (K20, p=0.3 and blaKPC, and p=0.4). Mucoid phenotype was not found related to presence of specific carbapenemase genes or serotypes except serotype K20 (p<0.001). Patients with monotherapy had treatment failure in comparison to the combination therapy for blaKPC-associated infections. In conclusion, the present investigation exhibited the significant association between K20 serotype with blaOXA-48. The predominance of K54 reveals the possibility of endemicity in our hospital setting. K. pneumoniae isolated from wound specimens significantly harbors K20 serotype and blaKPC gene. Comprehensive clinical information and the distribution of antibiotic resistance genes, and serotypes may play important roles in the treatment process.

Breast cancer (BC) is a prevalent and highly lethal cancer in females. Like other cancer types, the intricate cellular and molecular heterogeneity leads to the variation of therapeutic outcomes. The development and progression of blood vessels increase the tumor cell expansion and metastasis to remote sites. Based on several pieces of scientific data, different mediators and cells are involved in the promotion of angiogenesis into the tumor parenchyma. Recent data have indicated the critical role of extracellular vesicles, especially exosomes (Exos), in the transfer of angiogenesis molecules between the BC cells. Due to unique physicochemical properties, and the transfer of certain signaling molecules, Exos are at the center of attention in terms of biomarkers and therapeutic bullets in cancer patients. Along with these statements, understanding the modulatory role of Exos in BC angiogenesis seems critical in the clinical setting. Here, the mechanisms by which BC cells can orchestrate the angiogenesis phenomenon via Exos are discussed in detail. The present study can help us to understand the pro-/anti-angiogenesis role of Exos in BC and to design better oncostatic strategies.

Different clones of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are dominating geographically. One of the significant, hypervirulent, CA-MRSA and a significant health concern clones is USA3000, found worldwide regionally with varying frequencies. The clone harbors several mobile genetic elements (MGEs) including, arginine catabolic mobile element (ACME) and copper and mercury resistance genes (COMER), accomplished by horizontal gene transfer from S. epidermidis. Evidence suggests that ACME and COMER have a more prominent role in enhancing biofilm capacity and ultimately persistent infections. This review highlights the comprehensive view on ACME and COMER structure, their distribution, and the mechanism of action along with pathogenetic features of USA3000 encompassing their role in biofilm formation, adhesion, quorum sensing, resistance to antibiotics, chemotaxis, and nutrient uptake. We also provided an insight into the role of ACME and COMER genes in the survival of bacterium. Our results shed light on the emergence of two independent clones possessing ACME (North American) and COMER (South American) elements which later disseminated to other regions. ACME and COMER both are adjacent to staphylococcal cassette chromosome mec type IV (SCCmec IV). The acquisition of mecA, followed by COMER or ACME has been shown as a significant factor in the rise and fall of MRSA strains and their complex ability to adapt to hostile environments. The presence of ACME increases fitness, thereby allowing bacteria to colonize the skin and mucous membrane while COMER contributes to genetic stability by knocking over the copper-mediated killing in macrophages. Evidence suggests that ACME and COMER have a more prominent role in enhancing biofilm capacity and ultimately persistent infections. Interestingly, ACME strains have been shown to possess the ability to counteract skin acidity, thereby allowing increased skin colonization. A profound understanding of MGEs in S. aureus plays an important role in the prevention of epidemic clones.

, one of the clinical superbugs, causes diverse infections because of its variable capsular antigens. This study focused on and aimed to assess any correlation between capsular serotype, capsule-associated virulence genes, and evaluate its resistance to conventional antibiotics in order to gain insight into any regional differences. A total of 61 collected from various clinical specimens were confirmed genotypically. Clinical and demographic data for all patients were reviewed. All isolates were subjected to antimicrobial susceptibility tests. Capsular serotyping and capsule-associated virulence genes were studied using the molecular method. All typeable isolates were typed into K5, K20, and K54 serotypes, and among them, K54 was observed to be predominant. The most common capsule-associated virulence genes comprised (93.4%), (91.8%), and (88.5%), while (29.5%) and (21.3%) were noted at much lower prevalence rates. The gene was significantly associated with K54 positive isolates ( = 0.001), while was associated with K20 positive isolates ( = 0.01). Serotype K54 had a high frequency in isolates collected from patients with pulmonary diseases, while serotype K20 was associated with burn patients. Carbapenems and levofloxacin were the best therapeutic options for the treatment of infections with serotypes K20 and K54.

Purpose The close relationship of the toll-like receptor (TLR) signaling pathway has been indicated with different bioactivates of tumor cells. Here, the impact of TLR4 signaling pathway stimulation/inhibition was assessed on angiogenesis and exosome (Exo) biogenesis in MDA-MB-231 cells. Methods Cells were incubated with lipopolysaccharide (LPS) and simvastatin (SIM) for 48 hours. Cell survival and TLR4 signaling pathway genes were measured using MTT and real-time PCR analysis. The physicochemical properties of Exos were studied using DLS, SEM, and western blotting. The migration capacity and angiogenesis-related genes were assessed using the Transwell insert assay and real-time PCR analysis. Results Data indicated that SIM and LPS can reduce the survival rate in a dose-dependent manner compared to the control cells (p<0.05). The expression of TLR4, NF-κB, IL-1β, MYD88, and TRIF was increased in LPS-treated cells compared to the control group (p<0.05), while these genes were down-regulated or remained unchanged in the SIM group. SEM analysis indicated the reduction of Exo diameter in the LPS groups (p<0.05) with a slight increase of CD63, TSG101, and Rab27 in the presence of LPS. We found an enhanced and reduced migration rate in the LPS and SIM groups compared to the non-treated control cells (p<0.05). The expression of genes related to angiogenesis was down-regulated in both SIM and LPS groups. Conclusion These data indicate that the TLR4 signaling pathway can control the angiogenesis and Exo production in breast cancer cells, which paves the way for the development of de novo therapies in breast cancer patients.

Introduction: Acinetobacter baumannii infections are a growing public-health concern. The bacterium's potentiality to acquire resistance to a number of commonly used antibiotics has turned it into a formidable pathogen. Aims: Molecular characterization of extensive drug resistant (XDR) typing of A. baumannii clinical isolates by polymerase chain reaction. Materials and methods: Thirty XDR A. baumannii were investigated for the presence of genes encoding carbapenemase resistance, biofilm capacity, autoinducer synthase, virulence and surface motility by polymerase chain reaction (PCR). Later, the isolates were typed by plasmid-based replicon (Rep) (PBRT) and trilocus sequence typing. Results: All 30 XDR A. baumannii strains displayed genes related to surface motility, autoinducer synthase, virulence determinant, biofilm related genes except PER, and bap, the frequency of which was 83.3% and 76.6%, respectively. Analysis of rep genes showed highest frequency of rep6 and rep2 genes, with frequency of 75% and 65%, respectively. All XDR A. baumannii strains belonged to SG I (European clone II) group. Conclusions: Our results show the extraordinary plasticity of XDR A. baumannii and suggest that the strains have gained endemicity in our hospital, which could be a great concern in the near future.

Purpose: In this study the effectiveness of encapsulating of 5-azacytidine into the lipid nanoparticles was investigated and in vitro effect of encapsulated 5-azacytidine studied on MCF-7 cell lines Methods: 5-azacytidine -loaded solid lipid nanoparticles were produced by double emulsification (w/o/w) method by using stearic acid as lipid matrix, soy lecithin and poloxamer 407 as surfactant and co-surfactant respectively. Particle size, zeta potential, surface morphology, entrapment efficiency and kinetic of drug release were studied. In vitro effect of 5-azacytidine on MCF-7 cell line studied by MTT assay, DAPI staining, Rhodamine B relative uptake, and also Real time RT-PCR was performed for studying difference effect of free and encapsulated drug on expression of RARß2 gene. Results: The formulation F5 with 55.84±0.46 % of entrapment efficiency shows zero order kinetic of drug release and selected for in vitro studies; the cytotoxicity of free drug and encapsulated drug in 48 h of incubation have significant difference. DAPI staining shows morphology of apoptotic nucleus in both free and encapsulated drug, Rhodamine B labeled SLNs show time dependency and accumulation of SLNs in cytoplasm. Real time qRT-PCR doesn’t show any significant difference (p>0.05) in expression of RARß2 gene in both cells treated with free or encapsulated drug. Conclusion: The results of the present study indicated that the entrapment of 5-azacytidine into SLNs enhanced its cytotoxicity performance and may pave a way for the future design of a desired dosage form for 5-azacytidine.

In this paper, a comprehensive model is proposed to design a network for a multi-period, multi-echelon, and multi-product inventory controlled supply chain. Various marketing strategies and guerrilla marketing approaches are considered in the design process under the static competition condition. The goal of the proposed model is to efficiently respond to the customers' demands in the presence of the pre-existing competitors and the price inelasticity of demands. The proposed optimization model considers multiple objectives that incorporate both market share and total profit of the considered supply chain network, simultaneously. To tackle the proposed multi-objective mixed-integer nonlinear programming model, an efficient hybrid meta-heuristic algorithm is developed that incorporates a Taguchi-based non-dominated sorting genetic algorithm-II and a particle swarm optimization. A variable neighborhood decomposition search is applied to enhance a local search process of the proposed hybrid solution algorithm. Computational results illustrate that the proposed model and solution algorithm are notably efficient in dealing with the competitive pressure by adopting the proper marketing strategies

Uropathogenic Escherichia coli (UPEC) are the strains diverted from the intestinal status and account mainly for uropathogenicity. This pathotype has gained specifications in structure and virulence to turn into a competent uropathogenic organism. Biofilm formation and antibiotic resistance play an important role in the organism’s persistence in the urinary tract. Increased consumption of carbapenem prescribed for multidrug-resistant (MDR) and Extended-spectrum-beta lactamase (ESBL)-producing UPECs, has added to the expansion of resistance. The World Health Organization (WHO) and Centre for Disease Control (CDC) placed the Carbapenem-resistant Enterobacteriaceae (CRE) on their treatment priority lists. Understanding both patterns of pathogenicity, and multiple drug resistance may provide guidance for the rational use of anti-bacterial agents in the clinic. Developing an effective vaccine, adherence-inhibiting compounds, cranberry juice, and probiotics are non-antibiotical approaches proposed for the treatment of drug-resistant UTIs. We aimed to review the distinguishing characteristics, current therapeutic options and promising non-antibiotical approaches against ESBL-producing and CRE UPECs.

Urinary tract infection is the most common infection in almost half of the renal transplant patients. The development of UTI in these patients may progress to bacteremia, acute T cell-mediated rejection, impaired allograft function, or allograft loss, along with the increased risk of hospitalization and death. Among various pathogens implicated, Uropathogenic E. coli (UPEC), especially sequence type 131 (ST131), is the most virulent and multidrug-resistant pathogen. High antimicrobial resistance to most β-lactam antibiotics, mediated by extended spectrum β-lactamases (ESBLs) produced by UPEC, is a challenge in the clinical management of UTIs in kidney transplant recipients. Indeed, multidrug resistance to β-lactam antibiotics is a direct consequence of ESBL production. Resistance to other antibiotics such as aminoglycosides, fluoroquinolones, and trimethoprim-sulphamethoxazole has also been reported in ESBLs-producing UPEC, which reduces the therapeutic options, rising healthcare-associated costs and subsequently leads to renal failure or even graft loss. In this review, we aimed to discuss the post-transplant risk factors of UTI, UPEC virulence factors (VF), and the related factors including quorum sensing, and stress resistance genes. Furthermore, we searched for the current treatment strategies and some of the alternate approaches proposed as therapeutic options that may affirm the treatment of ESBL-producing UPEC.