Visfatin Promotes the Metastatic Potential of Chondrosarcoma Cells by Stimulating AP-1-Dependent MMP-2 Production in the MAPK Pathway

Chondrosarcoma is a malignant bone tumor that is characterized by high metastatic potential and marked resistance to radiation and chemotherapy. The knowledge that adipokines facilitate the initiation, progression, metastasis, and treatment resistance of various tumors has driven several in vitro and in vivo investigations into the effects of adipokines resistin, leptin, and adiponectin upon the development and progression of chondrosarcomas. Another adipokine, visfatin, is known to regulate tumor progression and metastasis, although how this molecule may affect chondrosarcoma metastasis is unclear. Here, we found that visfatin facilitated cellular migration via matrix metalloproteinase-2 (MMP-2) production in human chondrosarcoma cells and overexpression of visfatin enhanced lung metastasis in a mouse model of chondrosarcoma. Visfatin-induced stimulation of MMP-2 synthesis and activation of the AP-1 transcription factor facilitated chondrosarcoma cell migration via the ERK, p38, and JNK signaling pathways. This evidence suggests that visfatin is worth targeting in the treatment of metastatic chondrosarcoma.

SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells

Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.

A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry

SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identified small molecules that can reduce surface expression of TMPRSS2 using a 2,700 FDA-approved or current clinical trial compounds. Among these, homoharringtonine and halofuginone appear the most potent agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrated marked resistance to SARS-CoV-2 pseudoviral infection. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat COVID-19 infection.

Autophagy as a Potential Therapy for Malignant Glioma

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.

Hepsin enhances liver metabolism and inhibits adipocyte browning in mice

Hepsin is a transmembrane serine protease primarily expressed in the liver. To date, the physiological function of hepsin remains poorly defined. Here we report that hepsin-deficient mice have low levels of blood glucose and lipids and liver glycogen, but increased adipose tissue browning and basal metabolic rates. The phenotype is caused by reduced hepatocyte growth factor activation and impaired Met signaling, resulting in decreased liver glucose and lipid metabolism and enhanced adipocyte browning. Hepsin-deficient mice exhibit marked resistance to high-fat diet-induced obesity, hyperglycemia, and hyperlipidemia. Indb/dbmice, hepsin deficiency ameliorates obesity and diabetes. These data indicate that hepsin is a key regulator in liver metabolism and energy homeostasis, suggesting that hepsin could be a therapeutic target for treating obesity and diabetes.

Clinical and molecular characterization of both methicillin-resistant andsensitive staphylococcus aureus mastitis

This study targeted bovine mastitis as a possible source of livestock-associated methicillin-resistant Staphylococcus aureus (MRSA), to identify clinical signs associated with MRSA- and non-MRSA-associated mastitis. Thirty-eight mastitis cases (68 infected quarters) were investigated. Gram-positive cocci-shaped isolates were selected based on Baird Parker agar growth as well as Gram-stained bacterial smears. Molecular screening for Staphylococcus aureus (S. aureus) yielded 17 isolates, of which five (29.41%) were methicillin resistant. The five isolates were mecA positive, but mecC negative. Multilocus sequence typing (MLST) indicated that sequence type 1 (ST1) was the identified type of all isolates of MRSA. S. aureus-associated cases showed different clinical forms of mastitis, including subclinical, acute, chronic, and gangrenous. Additionally, subclinical mastitis was the only detected condition associated with MRSA, which may represent a potential hidden risk for humans. Phenotypically, isolates of MRSA showed resistance to all of the tested β-lactam antimicrobials, with marked resistance to tetracycline and gentamycin. Based on our knowledge, this is the first report to identify MRSA ST1 in Egypt. Bovine mastitis could be a source for the dissemination of MRSA to humans and other animals. Additionally, while methicillin-resistance may have no effect on the clinical outcome of mastitis, it does affect therapeutic success, particularly when β-lactam antimicrobials are used.

Oxidative Thermal Sintering and Redispersion of Rh Nanoparticles on Supports with High Oxygen Ion Lability

The thermal sintering under oxidative conditions of Rh nanoparticles supported on oxides characterized by very different oxygen storage capacities (OSC) and labilities was studied at 750 and 850 °C. Under sintering conditions, significant particle growth occurred for Rh/γ-Al2O3 (up to 120% at 850 °C). In striking contrast, Rh/ACZ (alumina–ceria–zirconia) and Rh/CZ (ceria–zirconia) exhibited marked resistance to sintering, and even moderate (ca. −10% at 850 °C) to pronounced (ca. −60% at 850 °C) redispersion of the Rh. A model is proposed based on a double-layer description of metal–support interactions assigned to back-spillover of labile oxygen ions onto the Rh particles, accompanied by trapping of atomic Rh by the resulting surface oxygen vacancies. This model accounts for the observed resistance to sintering and actual redispersion of Rh, consistent with both alternative sintering mechanisms, namely Ostwald ripening (OR) or particle migration and coalescence (PMC).

Antifungal resistance in cnlac1 possessing Cryptococcus neoformans isolated from domestic and feral pigeons in West Bengal, India

Cryptococcus neoformans acts as a major etiology of human infections in immunocompromised, cancer and transplant patients. The present study was conducted to detect the occurrence and antifungal resistance of C. neoformans in domestic and feral pigeons in and around Kolkata, a metropolitan city in India with considerable size of pigeon population. Weathered droppings of domestic and feral pigeons (n=917) were collected from different pet bird shelters, different buildings and other places. Isolation and identification of C. neoformans was performed based on cultural, biochemical properties. Antifungal sensitivity of the confirmed isolates were performed according to standard CLSI protocols with seven antifungals and caspofungin. A total of 153(16.68%) samples were found positive for Cryptococcus neoformans var. neoformans. All the isolates possessed CNLAC1 outer gene in PCR. Antifungal sensitivity revealed marked resistance to amphotericin-B (33.33%), fluconazole (20.91%), flucytosine (11.11%), and ketoconazole (8.49%). This is of great concern as the study area (Kolkata) is a densely populated city and the birds are in close proximity to the people.

Recent Antibiotic Sensitivity Pattern of Escherichia Coli in Urinary Tract Infection

The objective of the study is to assess the recent sensitivity pattern of Escherichia coli in Urinary tract infection (UTI). Widespread use of antibiotics has led to the emergence of resistant microorganisms. As the antibiotic sensitivity patterns of the microorganisms are frequently changing, this retrospective analysis was designed to assess the recent antibiotic sensitivity pattern of Escherichia coli (E. coli) in urinary tract infection among the human population. Details of 358 urine culture positive reports for E. coli and their antibiotic sensitivity pattern pertaining to the study period of 6 months from Jan 2017 to June 2017 were collected from Microbiology Laboratory of Diagnostic Centers at Rajshahi and the results were statistically analyzed. The antibiotics tested for sensitivity were amikacin, gentamycin, ciprofloxacin, levofloxacin, cotrimoxazole, nitrofurantoin, ceftazidime, ceftriaxone and cefixime. The sensitivity pattern of E.coli to antibiotics in UTI was amikacin (82.68 gentamycin (75.97%), nitrofurantoin (70.67), levofloxacin (44.13%), ceftazidime (42.17%), co-trimoxazole (40.78%), ceftriaxone (38.54%), ciprofloxacin (35.75%), and cefixime (24.02%). The study highlighted the marked resistance of E. coli to quinolones and third generation cephalosporins.TAJ 2017; 30(1): 61-65

Contamination sources, biofilm-forming ability and biocide resistance of Staphylococcus aureus in tilapia-processing facilities

The major contamination sources, biofilm-forming ability and biocide resistance of Staphylococcus aureus in tilapia-processing plants were evaluated. Twenty-five processing control points were analysed twice in two factories, including whole tilapias, frozen fillets, water and food-contact surfaces. No final product was contaminated with S. aureus. However, high concentrations of S. aureus carrying enterotoxin ( se) genes were found in several processing points of both factories due to the application of inadequate hygienic and handling procedures, which generate a high risk of cross-contamination of the tilapia fillets with staphylococcal enterotoxins. Nine S. aureus strains were characterized by RAPD-PCR using primers AP-7, ERIC-2 and S. A wide diversity of se gene profiles was detected, most strains being multi- se-carriers. All S. aureus strains showed high biofilm-forming ability on stainless steel and polystyrene. Biofilm-forming ability was correlated with the presence of fliC H7 and the type of origin surface (metallic or plastic). A marked resistance of S. aureus to peracetic acid and sodium hypochlorite was also observed, required doses being higher than those recommended by manufacturers to be eradicated. Case-by-case approaches are thus recommended to determine the sources and degree of contamination present in each factory, which would allow applying precise responses that avoid, or at least reduce, the presence of bacterial pathogens and the emergence of antimicrobial resistance.