Death-associated protein kinase 1 promotes growth of p53-mutant cancers

Estrogen receptor–negative (ER-negative) breast cancers are extremely aggressive and associated with poor prognosis. In particular, effective treatment strategies are limited for patients diagnosed with triple receptor–negative breast cancer (TNBC), which also carries the worst prognosis of all forms of breast cancer; therefore, extensive studies have focused on the identification of molecularly targeted therapies for this tumor subtype. Here, we sought to identify molecular targets that are capable of suppressing tumorigenesis in TNBCs. Specifically, we found that death-associated protein kinase 1 (DAPK1) is essential for growth of p53-mutant cancers, which account for over 80% of TNBCs. Depletion or inhibition of DAPK1 suppressed growth of p53-mutant but not p53-WT breast cancer cells. Moreover, DAPK1 inhibition limited growth of other p53-mutant cancers, including pancreatic and ovarian cancers. DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR pathway. Our studies demonstrated that high DAPK1 expression causes increased cancer cell growth and enhanced signaling through the mTOR/S6K pathway; evaluation of multiple breast cancer patient data sets revealed that high DAPK1 expression associates with worse outcomes in individuals with p53-mutant cancers. Together, our data support targeting DAPK1 as a potential therapeutic strategy for p53-mutant cancers.     

Isolation and Antibiogram of Clostridium tetani from Clinically Diagnosed Tetanus Patients

Clostridium tetani, the etiologic agent of tetanus, produces a toxin that causes spastic paralysis in humans and other vertebrates. This study was aimed for isolation, identification, and determination of antimicrobial susceptibility of C. tetani from clinically diagnosed tetanus patients. Isolation was done from deep-punctured tissues of the foot and arm injuries of 80 clinically diagnosed tetanus patients from the Pakistan Institute of Medical Sciences hospital. We successfully screened out five C. tetani isolates out of 80 samples based on the strain-specific characteristics confirmed through biochemical testing and toxin production. A disc diffusion method was used for antimicrobial susceptibilities and C. tetani isolates showed susceptibility to cefoperazone, chloramphenicol, metronidazole, penicillin G, and tetracycline, but were found to be resistant to erythromycin and ofloxacin. During animal testing, all the infected mice developed symptoms of tetanus. The results showed that identification of C. tetani is possible using biochemical and molecular tools and that the strains of C. tetani isolated had not developed resistance against the antibiotics most often used for the treatment of tetanus.     

Exploiting immunology and molecular genetics for rational vaccine design against tuberculosis.

One hundred years after the Nobel Prize was awarded to Robert Koch for his work on tuberculosis (TB) and 85 years after the development of the attenuated vaccine strain, Mycobacterium bovis bacille Calmette-Guérin (BCG), by Albert Calmette and Camille Guérin, effective prevention measures against TB are still not available. However, the first decade of the 21st century will witness the implementation of clinical trials with several novel vaccine candidates. These candidates fall into two groups: (1) subunit vaccines aimed at boosting the immune response induced by a BCG prime, and (2) recombinant (r)BCG improved to replace the current BCG vaccine strain. For boosting, protein and DNA vaccines in suitable adjuvant or delivery systems, respectively, as well as recombinant viral carriers, such as recombinant modified vaccinia virus Ankara, are being tested. For rBCG prime, a vaccine strain with higher immunogenicity and a strain overexpressing a dominant antigen have been developed. These vaccine candidates will have passed phase I clinical trials before the end of 2006. The goal for the future would be to have these novel vaccine candidates tested in different combinations to facilitate the design of the most efficacious vaccination protocol.     

Staged versus one-step approach for multivessel percutaneous coronary interventions

Background Percutaneous coronary interventions (PCIs) in patients with multivessel coronary artery disease (CAD) may be staged or performed in a single session. No data exist about the relative safety and efficacy of these 2 strategies. Our aim was to compare short-term and long-term outcomes of patients with multivessel CAD who underwent PCI in 1 versus 2 sessions. Methods and Results The study included 264 consecutive patients who underwent treatment in our center during 1997 and 1998. PCI was conducted in a single session in 129 patients and was staged in 135 patients. The mean interval between the sessions in the staged group was 45.6 ± 22.3 days. The rates of major adverse cardiac events (MACEs) during in-hospital stay did not differ significantly between the staged (combined for both stages) and nonstaged groups (2.2% vs 4.6%; P = .28). A trend for lower event rates at 30-day (2.9% vs 6.9%; P = .13) and 1-year follow-up (26.1 vs 35.9; P = .08) favored the staged arm. Diameter stenosis ≥50% was found in 17% of patients in the staged group in the second session and was successfully retreated in most of them. No MACE occurred between the sessions. Multivariate analysis identified staging of the procedure as a single independent predictor of MACE at 1-year follow-up (P = .05). Conclusion Our results suggest that a practical staging strategy within 4 to 8 weeks is safe and allows for identification and treatment of potential excessive proliferative response in the previously intervened lesions during the second procedure. (Am Heart J 2002;143:1017-26.)     

Psychological distress,job satisfaction,and work engagement among Palestinian teachers: a cross-sectional study

Background

Work engagement is a positive, fulfilling affective and motivational state of work-related wellbeing and a protective factor for workers' mental health. The aim of the present study was to examine the association between psychological distress (conceptualised as the target variable), job satisfaction, and work engagement in contexts of low-intensity warfare and political violence. According to the salutogenic perspective, the relationship between job satisfaction and psychological distress is influenced by the level of work engagement.

Long-stay patients in pediatric intensive care units: Five-years, 2-points,cross-sectional study

Objectives:To explore the changing patterns of long-stay patients (LSP) to improve the utilization of pediatric intensive care units (PICUs) resources.Methods:This is a 2-points cross-sectional study (5 years apart; 2014-2019) conducted among PICUs and SCICUs in Riyadh, Saudi Arabia. Children who have stayed in PICU for more than 21 days were included.Results:Out of the 11 units approached, 10 (90%) agreed to participate. The prevalence of LSP in all these hospitals decreased from 32% (48/150) in 2014 to 23.4% (35/149) in 2019. The length of stay ranged from 22 days to 13.5 years. The majority of LSP had a neuromuscular or cardiac disease and were admitted with respiratory compromise. Ventilator-associated pneumonia was the most prevalent complication (37.5%). The most commonly used resources were mechanical ventilation (93.8%), antibiotics (60.4%), and blood-products transfusions (35.4%). The most common reason for the extended stay was medical reasons (51.1%), followed by a lack of family resources (26.5%) or lack of referral to long-term care facilities (22.4%).Conclusion:A long-stay is associated with significant critical care bed occupancy, complications, and utilization of resources that could be otherwise utilized as surge capacity for critical care services. Decreasing occupancy in this multicenter study deserves further engagement of the healthcare leaders and families to maximize the utilization of resources.     

A bromine-catalysis-synthesized poly(3,4-ethylenedioxythiophene)/graphitic carbon nitride electrochemical sensor for heavy metal ion determination

In this paper, poly(3,4-ethylenedioxythiophene)/graphitic carbon nitride (PEDOT/g-C₃N₄) composites were prepared by the bromine catalysed polymerization (BCP) method with varying weight ratios of monomer to g-C₃N₄. For comparison, solid-state polymerization (SSP) and metal oxidative polymerization (MOP) methods were also used for the synthesis of PEDOT/g-C₃N₄ composites. Electrochemical determination of heavy metal ions (Cd²⁺ and Pb²⁺) was carried out by differential pulse voltammetry (DPV) on composite-modified glass carbon electrodes (GCEs), which were prepared by different methods. The obtained composites were analysed by Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible absorption spectroscopy (UV-vis), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The results showed that the bromine catalysed polymerization (BCP) method is an effective way to prepare the PEDOT/g-C₃N₄ composite, and the combination of PEDOT with g-C₃N₄ can improve the electrochemical activity of electrode materials. And, the composite from the BCP method modified electrode (PEDOT/10 wt% g-C₃N₄/GCE) exhibited the widest linear responses for Cd²⁺ and Pb²⁺, ranging from 0.06–12 μM and 0.04–11.6 μM with detection limits (S/N = 3) of 0.0014 μM and 0.00421 μM, respectively.

The PEDOT/g-C₃N₄ composite prepared by a Br₂-catalyzed polymerization method exhibited the widest linear electrochemical responses for Cd²⁺ and Pb²⁺.     

Effect of bariatric surgery on circulating FGF‐19: A systematic review and meta‐analysis

Fibroblast growth factor‐19 (FGF‐19) is a gut hormone which interacts with metabolism and is depleted in obesity. There is some indication that the hormone undergoes a resurgence following bariatric surgery (BS), an effect which may contribute to the beneficial outcomes of such procedures. This systematic review and meta‐analysis aims to synthesize the available literature on FGF‐19 levels before and after BS. MEDLINE, Scopus and Web of Science databases were searched, and the effect of different surgical procedures and degrees of body mass index (BMI) reduction on FGF‐19 levels was assessed by DerSimonian and Laird random‐effects model in meta‐analysis and dose–response analyses. This meta‐analysis, which included 474 patients from 25 arms undergoing one of five BS procedures, revealed a significant increase in the levels of circulating FGF‐19 following all‐type BS. Vertical sleeve gastrectomy, duodenal‐jejunal bypass liner and Roux‐en‐Y gastric bypass all significantly increased circulating FGF‐19 levels from baseline. However, gastric banding failed to achieve the same, and in fact, biliopancreatic diversion was associated with decreased circulating FGF‐19. Finally, an inverse association between FGF‐19 and the degree of BMI‐reduction post‐operatively was noted. FGF‐19 is increased by BS and may represent a pharmaceutical target in efforts to reproduce the beneficial effects of BS in a medical setting.