P53 Overexpression May Represent an Early Marker of Clinicopathologic Progression in Vasculogenic Mesenchymal Lesions of Germ Cell Tumor Origin.

Vasculogenic mesenchymal lesions (VMLs) of germ cell tumor origin are thought to originate in postpubertal-type yolk sac tumor components and include a spectrum of lesions from teratoma with vasculogenic stroma (TVS), to low and high-grade vasculogenic mesenchymal tumors (VMTs). VMLs exhibit rudimentary to well-developed neoplastic vessels within primitive mesenchyme, being considered a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac. They occur in patients with primary mediastinal germ cell tumors after chemotherapy, and a subset progresses to "somatic-type" sarcomas [including angiosarcoma (AS)], with high-grade VMTs likely portending a higher risk. Recently, we encountered a low-grade VMT that progressed to metastatic AS during follow-up. In this case, both the low-grade VMT and the subsequent AS demonstrated p53 overexpression, suggesting that p53 alterations may precede histopathologic transformation. To test this hypothesis, we evaluated neoplasms representing the entire spectrum of VMLs using p53 immunohistochemistry (IHC; clone DO-7, Dako). Overexpression was defined as nuclear positivity in > 80% of neoplastic cells. Because the distinction between high-grade VMT and AS can be subjective in some cases, they were grouped together in a single category. Thirty-nine VMLs were assessed: 16 high-grade VMT/AS, 19 low-grade VMT, and 4 TVS. Patient age ranged from 19 to 46 years (mean, 30 years; male = 97%). Four high-grade VMT/AS and one low-grade VMT showed p53 overexpression (5/39 VMLs, 13%; 4/16 high-grade VMT/AS, 25%). These tumors included 1 unequivocal AS and 1 high-grade VMT/AS with progression to rhabdomyosarcoma. The only low-grade VMT with p53 overexpression demonstrated progression to AS. Another high-grade VMT that progressed to sarcoma demonstrated p53 overexpression in the sarcoma component, but it was excluded because the VMT was not represented in the material available at the time of the study. Lesions with intratumoral grade heterogeneity (classified based the highest grade), demonstrated more pronounced p53 overexpression in the high-grade components. P53 overexpression is associated with disease progression in a subset of VMTs and may precede morphologic transformation to sarcoma. Routine evaluation of VMTs with p53 IHC seems justified, with overexpressors likely requiring an close clinical surveillance.

Genomic characterization, in vitro, and preclinical evaluation of two microencapsulated lytic phages VB_ST_E15 and VB_ST_SPNIS2 against clinical multidrug-resistant Salmonella serovars.

BACKGROUND: Salmonella infections continue to be one of the essential public health issues threatening millions of people. With the increasing occurrence of resistance against conventionally used antibiotics, the search for alternatives has become crucial. In this study, we aimed to isolate, characterize, and evaluate two lytic bacteriophages against clinically isolated multidrug-resistant (MDR) Salmonella serovars. METHODS: Screening for the phage lytic activity was performed using a spot test. Characterization of the isolated phages was done by determining the host range, longevity test, and the effect of temperature, pH, organic solvents, and morphological characterization using a transmission electron microscope. Genomic analysis was performed using Oxford nanopore sequencing. The lytic activities of the free phage lysates and formulated phage as microencapsulated were evaluated both in vitro and in vivo. RESULTS: Two phages (VB_ST_E15 and VB_ST_SPNIS2) were successfully isolated and showed lytic strong activities against MDR Salmonella (S.) Typhimurium ATCC 14,028, S. Paratyphi A, and S. Typhi. The two phages survived at the tested temperatures, maintained their infectivity for 90 days, and retained their activity until 60 °C with thermal inactivation at 65 °C. They were lytic at a pH range from 3 to 11 but lost their activities at extremely acidic or alkaline pH. The phages could withstand the organic solvents but were completely inactivated by 100% ethanol. Both phages were classified under the order Caudoviricetes, and Genus: Uetakevirus. Their genomic sequences were assembled, annotated, and submitted to the NCBI GenBank database (OR757455 and OR757456). The preclinical evaluation using the murine animal model revealed that the two-phage cocktail managed MDR Salmonella infection as evidenced by the reduction in the bacterial burden, increased animal weight, and histopathological examination. CONCLUSION: The two encapsulated phage formulas could be considered promising candidates for the management of MDR Salmonella-associated infections and clinical analysis should be undertaken to evaluate their potential use in humans.

Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response.

Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the "Warburg effect". This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy's impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.

Serotyping and Antimicrobial Resistance Profile of Enteric Nontyphoidal Salmonella Recovered from Febrile Neutropenic Patients and Poultry in Egypt.

A total of 300 human fecal samples were collected from febrile neutropenic patients suffering from severe gastroenteritis, followed by identification and serological characterization of recovered isolates. Fifty nontyphoidal Salmonella (NTS) serovars were recovered. A total of serologically identified 50 NTS serovars recovered from poultry of the same geographical area and during the same period as well as one standard strain S. Poona were supplied by the Bacterial Bank of Animal Health Research Institute of Egypt. Antibiogram analysis revealed that the human and poultry serovars exhibited similar antimicrobial resistance patterns against 28 different antimicrobial agents, particularly against ampicillin, cefotaxime, oxytetracycline, and erythromycin. Plasmids harboring blaCTX-m, blaSHV, blaTEM, and aac(6')-Ib were detected in 11 (22%) and 8 (16%) of human and poultry serovars, respectively. Molecular detection of the most clinically relevant virulence genes and analysis of the associated virulence genotypes proved that the human (n = 11) and poultry serovars (n = 12) shared 11 genotypes. Enterobacterial repetitive intergenic consensus PCR analysis revealed that human and poultry serovars were clustered together in 3 out of the 4 clusters with a similarity index ranged from 0.15 to 1. Since poultry are usually consumed by humans, the presence of resistant bacteria harboring transmissible genetic elements is of great health concern.

Validated analytical study of the effect of Lycopene on the pharmacokinetics of Paracetamol and Chlorzoxazone in rats

Lycopene was reported to influence some cytochrome P450 enzymes activity. The present study investigates the effect of lycopene on the pharmacokinetics of paracetamol and chlorzoxazone. Lycopene (20 mg/kg) was intra-peritoneally administered to two groups of rats for eight consecutive days and two other groups were given vehicle. On the eighth day, chlorzoxazone and paracetamol were separately intravenously administered to a lycopene group and a control group. Blood samples were collected at different time intervals, treated and analyzed using HPLC. The HPLC method used for paracetamol analysis was based on isocratic elution using a mobile phase consisting of water: methanol, (77:23 v/v) at a flow rate 1 mL min−1, Kromasil C18 column, and UV detection at 254 nm using caffeine as internal standard. About chlorzoxazone, separation was carried out using water: acetonitrile (60: 40, v/v) as the mobile phase at a flow rate 1 mL min−1, Inertsil ODS-3 C18 column, UV detection at 283 nm and esomeprazole as internal standard. Statistical analysis of the pharmacokinetic data using student t test showed a significant increase in AUC 0-t , AUC 0-Inf and t1/2 of paracetamol (P<0.05) and of chlorzoxazone (P<0.05) in the groups pretreated with lycopene (20 mg/kg), significant increase in the volume of distribution of paracetamol (P < 0.05), but no significant difference in that of chlorzoxazone. In other words, paracetamol and chlorzoxazone showed significant decrease (P < 0.05), respectively. These results demonstrate that treatment of rats with Lycopene (20mg/kg, ip) has a significant effect on the metabolic clearance and the pharmacokinetics of both drugs

Work-related Musculoskeletal Pain among Different Dental Specialists in United Arab Emirates.

INTRODUCTION: Dentists are at a very high risk of developing work-related musculoskeletal pain. The present study aimed at studying the prevalence of musculoskeletal pain among different dental specialists in the United Arab Emirates (UAE), and correlating the region of pain with the type of clinical work done by the specialists. MATERIALS AND METHODS: A sample of more than 100 dentists was chosen randomly from different emirates in UAE. An interview questionnaire was administered regarding the number of years of experience and the presence, region, duration, and type of musculoskeletal pain they experienced. RESULTS: Musculoskeletal pain is experienced by 83.3% of periodontists, 80% of conservative dentists, 77.8% of endodon-tists, 72.7% of orthodontists, 70% of oral surgeons, 63.6% of prosthodontists, 63% of general dental practitioners, and 50% of pedodontists. The results have also indicated that the region of experienced musculoskeletal pain does vary according to the specialty. From those dentists who experience work-related musculoskeletal pain, 80% of conservative dentists experience pain in neck and shoulders, 66.7% of periodontists, and 54.5% of orthodontists experience pain in the lower back region. More than 50% of endodontists experience pain in the neck and shoulders regions, and 39% of general dental practitioners who experience pain in the neck region. CONCLUSION: Preventive measures need to be taken to decrease the risk of dentists and dental specialists developing work-related musculoskeletal pain. CLINICAL SIGNIFICANCE: The prevalence and distribution of musculoskeletal disorders (MSDs) among registered general dental practitioners and dental specialists in UAE was not clearly documented. The study results indicated that the region that experienced musculoskeletal pain does vary according to the specialty.