Phosphoenolpyruvate carboxykinase-2 (PCK2) is a therapeutic target in triple-negative breast cancer.

PURPOSE: Metabolic rewiring in malignant transformation is often accompanied by altered expression of metabolic isozymes. Phosphoenolpyruvate carboxykinase-2 (PCK2) catalyzes the rate-limiting step of gluconeogenesis and is the dominant isoform in many cancers including triple-negative breast cancer (TNBC). Our goal was to identify small molecule inhibitors of PCK2 enzyme activity. METHODS: We assessed the impact of PCK2 down regulation with shRNA on TNBC cell growth in vitro and used AtomNet® deep convolutional neural network software to identify potential small molecule inhibitors of PCK2-based structure. We iteratively tested candidate compounds in an in vitro PCK-2 enzyme assay. The impact of the top hit on metabolic flux and cell viability was also assessed. RESULTS: PCK2 downregulation decreased growth of BT-549 and MDA-MB-231 cells and reduced metabolic flux through pyruvate carboxylase. The first AtomNet® in silico structural screen of 7 million compounds yielded 86 structures that were tested in PCK2 enzyme assay in vitro. The top hit (IC50 = 2.4 µM) was used to refine a second round of in silico screen that yielded 82 candidates to be tested in vitro, which resulted in 45 molecules with inhibition > 20%. In the second in vitro screen we also included 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate, previously suggested to be PCK2 inhibitor based on structure, which emerged as the top hit. The specificity of this compound was tested in PCK1 and PCK2 enzymatic assays and showed IC50 of 500 nM and 3.5-27 nM for PCK1 and PCK2, respectively. CONCLUSION: 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate is a high affinity PCK2 enzyme inhibitor that also has significant growth inhibitory activity in breast cell lines in vitro and represents a potential therapeutic lead compound.

BECN1 mRNA expression in breast cancer tissue; significant correlation to tumor grade.

Breast cancer (BC) is a heterogenous disease with multiple pathways implicated in its development, progression, and drug resistance. Autophagy, a cellular process responsible for self-digestion of damaged organelles, had been recognized as eminent player in cancer progression and chemotherapeutic resistance. The haploinsufficiency of Beclin 1 (BECN1), autophagy protein, is believed to contribute to cancer pathogenesis and progression. In our study, we investigated the expression of BECN1 in a BC female Egyptian patient cohort, as well as its prognostic role through evaluating its association with disease free survival (DFS) after 2 years follow up and association of tumor clinicopathological features. Twenty frozen female BC tissue samples and 17 adjacent normal tissue were included and examined for the expression levels of BECN1. Although the tumor tissues showed lower expression 0.73 (0-8.95) than their corresponding normal tissues 1.02 (0.04-19.59), it was not statistically significant, p: 0.463. BECN1 expression was not associated with stage, nodal metastasis or tumor size, p:0.435, 0.541, 0.296, respectively. However, statistically significant negative correlation was found between grade and BECN1 mRNA expression in the studied cases, p:0.028. BECN1 expression had no statistically significant association with DFS, P = 0.944. However, we observed that triple negative (TNBC) cases had significantly lower DFS rate than luminal BC patients, p: 0.022, with mean DFS 19.0 months, while luminal BC patients had mean DFS of 23.41 months. Our study highlights the potential role of BECN1 in BC pathogenesis, showing that BECN1 expression correlates with poorer differentiation of BC, indicating its probable link with disease aggressiveness. DFS two years follow up showed that TNBC subtype remains associated with less favorable prognosis.

Uracil-Selective Cross-Linking in RNA and Inhibition of miRNA Function by 2-Amino-6-vinyl-7-deazapurine Deoxynucleosides.

MicroRNAs (miRNAs) regulate gene expression through RNA interference. Consequently, miRNA inhibitors, such as anti-miRNA oligonucleotides (AMOs), have attracted attention for treating miRNA overexpression. To achieve efficient inhibition, we developed 2-amino-6-vinylpurine (AVP) nucleosides that form covalent bonds with uridine counterparts in RNA. We demonstrated that mRNA cross-linked with AVP-conjugated antisense oligonucleotides with AVP were protected from gene silencing by exogenous miRNA. However, endogenous miRNA function could not be inhibited in cells, probably because of slow cross-linking kinetics. We recently developed ADpVP, an AVP derivative bearing a 7-propynyl group - which boasts faster reaction rate than the original AVP. Here, we synthesized dADpVP - a deoxy analog of ADpVP - through a simplified synthesis protocol. Evaluation of the cross-linking reaction revealed that the reaction kinetics of dADpVP were comparable to those of ADpVP. In addition, structural analysis of the cross-linked adduct discovered N3 linkage against uridine. Incorporating dADpVP into two types of miRNA inhibitors revealed a marginal impact on AMO efficacy yet improved the performance of target site blockers. These results indicate the potential of cross-linking nucleosides for indirect miRNA function inhibition.

Empowering mind-body wellness: effect of bundling seated exercises and psychoeducational rehabilitation using the teach-back approach on fatigue and coping of women postmastectomy.

BACKGROUND: Being diagnosed with Breast Cancer (BC) is a crisis that throws the patient's life out of balance. Cancer-related fatigue is a debilitating sign experienced by women during and after BC treatment. Regular physical exercise may help mitigate patients' fatigue, enhance coping abilities, improve their quality of life, and overall well-being. In parallel, psychological interventions are geared toward normalizing the lived painful experiences among oncology patients. OBJECTIVE: to examine the effect of bundling seated exercises and psychoeducational rehabilitation using the teach-back approach on fatigue and coping of women postmastectomy. METHODS: A quasi-experimental study was conducted in the Oncology Surgical Department and chemotherapy unit at the Alexandria Main University Hospital, Egypt. A total of 60 women were randomly allocated to either to the study or the control groups. Women in the study group practiced seated exercises and psychological rehabilitation interventions, including mindfulness breathing, problem-solving training, cognitive reframing technique, and thought stopping while the control group received the routine care. RESULTS: The study revealed a significant decline in the fatigue mean scores among participants in the intervention group from 136.10 ± 27.76 to 98.43 ± 25.99 (p < 0.001). Similarly, there was a significant decrease in the patients' mean scores of maladaptive coping, helplessness/ hopelessness (p = 0.014), and anxious preoccupation (p = 0.008). In contrast, there is a noticeable increment in the scores of adaptive coping, such as fighting spirit (p = 0.012), cognitive avoidance (p = 0.002), and fatalism (p = 0.009). CONCLUSION: Bundling seated exercises and psychological rehabilitation interventions using the teach-back approach have been proven to be simple and inexpensive non-pharmacological methods of reducing cancer-related fatigue and improving coping skills among women post-mastectomy. TRIAL REGISTRATION NUMBER: NCT06360276, ClinicalTrails.gov, Retrospectively registered (April 8th, 2024), URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT06360276 .

The Role of Platelet Rich Plasma in Vertebrogenic and Discogenic Pain: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: The present investigation evaluates clinical uses and roles of platelet rich plasma in the management of vetrebrogenic and discogenic mediated pain states. RECENT FINDINGS: Back pain is a common and significant condition that affects millions of people around the world. The cause of back pain is often complex and multifactorial, with discogenic and vertebrogenic pain being two subtypes of back pain. Currently, there are numerous methods and modalities in which back pain is managed and treated such as physical therapy, electrical nerve stimulation, pharmacotherapies, and platelet-rich plasma. To conduct this systematic review, the authors used the keywords "platelet-rich plasma", "vertebrogenic pain", and "discogenic pain", on PubMed, EuroPMC, Who ICTRP, and clinicaltrials.gov to better elucidate the role of this treatment method for combating vertebrogenic and discogenic back pain. In recent decades, there has been a rise in popularity of the use of platelet-rich plasma for the treatment of numerous musculoskeletal conditions. Related to high concentration of platelets, growth factors, cytokines, and chemokines, platelet-rich plasma is effective in reducing pain related symptoms and in the treatment of back pain. Platelet-rich plasma use has evolved and gained popularity for pain related conditions, including vertebrogenic and discogenic back pain. Additional well-designed studies are warranted in the future to better determine best practice strategies to provide future clinicians with a solid foundation of evidence to make advancements with regenerative medical therapies such as platelet-rich plasma.

The Impact of Salinity on Crop Yields and the Confrontational Behavior of Transcriptional Regulators, Nanoparticles, and Antioxidant Defensive Mechanisms under Stressful Conditions: A Review.

One of the most significant environmental challenges to crop growth and yield worldwide is soil salinization. Salinity lowers soil solution water potential, causes ionic disequilibrium and specific ion effects, and increases reactive oxygen species (ROS) buildup, causing several physiological and biochemical issues in plants. Plants have developed biological and molecular methods to combat salt stress. Salt-signaling mechanisms regulated by phytohormones may provide additional defense in salty conditions. That discovery helped identify the molecular pathways that underlie zinc-oxide nanoparticle (ZnO-NP)-based salt tolerance in certain plants. It emphasized the need to study processes like transcriptional regulation that govern plants' many physiological responses to such harsh conditions. ZnO-NPs have shown the capability to reduce salinity stress by working with transcription factors (TFs) like AP2/EREBP, WRKYs, NACs, and bZIPs that are released or triggered to stimulate plant cell osmotic pressure-regulating hormones and chemicals. In addition, ZnO-NPs have been shown to reduce the expression of stress markers such as malondialdehyde (MDA) and hydrogen peroxide (H2O2) while also affecting transcriptional factors. Those systems helped maintain protein integrity, selective permeability, photosynthesis, and other physiological processes in salt-stressed plants. This review examined how salt stress affects crop yield and suggested that ZnO-NPs could reduce plant salinity stress instead of osmolytes and plant hormones.

Emerging Trends in Non-Protein Amino Acids as Potential Priming Agents: Implications for Stress Management Strategies and Unveiling Their Regulatory Functions.

Plants endure the repercussions of environmental stress. As the advancement of global climate change continues, it is increasingly crucial to protect against abiotic and biotic stress effects. Some naturally occurring plant compounds can be used effectively to protect the plants. By externally applying priming compounds, plants can be prompted to trigger their defensive mechanisms, resulting in improved immune system effectiveness. This review article examines the possibilities of utilizing exogenous alpha-, beta-, and gamma-aminobutyric acid (AABA, BABA, and GABA), which are non-protein amino acids (NPAAs) that are produced naturally in plants during instances of stress. The article additionally presents a concise overview of the studies' discoveries on this topic, assesses the particular fields in which they might be implemented, and proposes new avenues for future investigation.

Blockage of Autophagy for Cancer Therapy: A Comprehensive Review.

The incidence and mortality of cancer are increasing, making it a leading cause of death worldwide. Conventional treatments such as surgery, radiotherapy, and chemotherapy face significant limitations due to therapeutic resistance. Autophagy, a cellular self-degradation mechanism, plays a crucial role in cancer development, drug resistance, and treatment. This review investigates the potential of autophagy inhibition as a therapeutic strategy for cancer. A systematic search was conducted on Embase, PubMed, and Google Scholar databases from 1967 to 2024 to identify studies on autophagy inhibitors and their mechanisms in cancer therapy. The review includes original articles utilizing in vitro and in vivo experimental methods, literature reviews, and clinical trials. Key terms used were "Autophagy", "Inhibitors", "Molecular mechanism", "Cancer therapy", and "Clinical trials". Autophagy inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) have shown promise in preclinical studies by inhibiting lysosomal acidification and preventing autophagosome degradation. Other inhibitors like wortmannin and SAR405 target specific components of the autophagy pathway. Combining these inhibitors with chemotherapy has demonstrated enhanced efficacy, making cancer cells more susceptible to cytotoxic agents. Clinical trials involving CQ and HCQ have shown encouraging results, although further investigation is needed to optimize their use in cancer therapy. Autophagy exhibits a dual role in cancer, functioning as both a survival mechanism and a cell death pathway. Targeting autophagy presents a viable strategy for cancer therapy, particularly when integrated with existing treatments. However, the complexity of autophagy regulation and the potential side effects necessitate further research to develop precise and context-specific therapeutic approaches.

Comprehensive assessment of cow manure hydrothermal treatment products for land application and energy recovery.

In this study, cow manure was hydrothermally treated in a 2-litre reactor for 1 h at temperatures between 100 °C and 260 °C. Both the raw manure and the solid and liquid products of the hydrothermal treatment were characterized to understand the fate of the inorganic elements and to assess the suitability of the products for land applications and energy recovery. Satisfactory elemental balances were obtained for the organic and most inorganic elements and indicated that most inorganic elements were incorporated into the solids with lower solubility, with the exception of potassium and sodium, which were mostly solubilized in the process water; calcium and chlorine were also solubilized to a lesser extent in the process water. Elemental composition and surface functional groups showed that hydrochar produced within the hydrothermal carbonization range (180-260 °C) seemed better suited for utilization as a soil amendment than raw cow manure. The potential for energy recovery lies in the anaerobic digestion of the process water, from which higher methane yields can be obtained than from raw cow manure. Lower temperatures in hydrothermal carbonization are considered a compromise for the safe land applications of cow manure, energy recovery from the process water, and enhanced dewaterability. These findings can help to eliminate bottlenecks in the upscaling of cow manure hydrothermal treatment and promote the circular bio-economy.

Effect of two esthetic digitally produced materials used in fabrication of extracoronal attachments on the stresses Induced in removable partial dentures.

BACKGROUND: Preservation of the remaining structures while maintaining an esthetic appearance is a major objective in removable partial prosthodontics. So, the aim of the current study was to compare the stresses induced on the supporting structures by two digitally produced esthetic core materials; Zirconia and Polyetheretherketone when used as an extracoronal attachment in distal extension removable partial dentures using strain gauge analysis. METHODS: A mandibular Kennedy class II stone cast with the necessary abutments' preparations was scanned. The mandibular left canine and first premolar teeth were virtually removed. An acrylic mandibular left canine and first premolar teeth were prepared with heavy chamfer finish line and scanned. Virtual superimposition of the acrylic teeth in their corresponding positions was done. Two strain gauge slots were designed: distal to the terminal abutment and in the residual ridge. Two models and two sets of scanned teeth were digitally printed. The printed teeth were then placed in their corresponding sockets in each model and scanned. The attachment design was selected from the software library and milled out of Zirconia in the model ZR and Polyetheretherketone in the model PE. Five removable partial dentures were constructed for each model. The strain gauges were installed in their grooves. A Universal testing machine was used for unilateral load application of 100 N (N). For each removable partial denture, five measurements were made. The data followed normal distribution and were statistically analyzed by using unpaired t test. P value < 0.05 was considered to be statistically significant. RESULTS: During unilateral loading unpaired t test showed statistically significant difference (p = 0.0001) in the microstrain values recorded distal to the abutment between the models ZR (-1001.6 µÎµ ± 24.56) and PE (-682.6 µÎµ ± 22.18). However, non statistically significant difference (p = 0.3122) was observed in the residual ridge between them; ZR (16.2 µÎµ ± 4.53) and PE (15 µÎµ ± 3.74). CONCLUSIONS: In removable partial dentures, Polyetheretherketone extracoronal attachment induces less stress on the supporting abutments compared to the zirconia one with no difference in the stresses induced by them on the residual ridge.

Effect of different fabrication workflows on the passive fit of screw-retained bar splinting two interforaminal implants: a parallel blinded randomised clinical trial.

BACKGROUND: To clinically compare the effect of the conventional and the digital workflows on the passive fit of a screw retained bar splinting two inter-foraminal implants. METHODS: The current study was designed to be a parallel triple blinded randomised clinical trial. Thirty six completely edentulous patients were selected and simply randomized into two groups; conventional group (CG) and digital group (DG). The participants, investigator and outcome assessor were blinded. In the group (CG), the bar was constructed following a conventional workflow in which an open top splinted impression and a lost wax casting technology were used. However, in group (DG), a digital workflow including a digital impression and a digital bar milling technology was adopted. Passive fit of each bar was then evaluated clinically by applying the screw resistance test using the "flag" technique in the passive and non passive situations. The screw resistance test parameter was also calculated. Unpaired t-test was used for intergroup comparison. P-value < 0.05 was the statistical significance level. The study protocol was reviewed by the Research Ethics Committee in the author's university (Rec IM051811). Registration of the clinical trial was made on clinical trials.gov ID NCT05770011. An informed consent was obtained from all participants. RESULTS: Non statistically significant difference was denoted between both groups in all situations. In the passive situation, the mean ± standard deviation values were 1789.8° ± 20.7 and1786.1° ± 30.7 for the groups (CG) and (DG) respectively. In the non passive situation, they were 1572.8° ± 54.2 and 1609.2° ± 96.9. Regarding the screw resistance test parameter, they were 217° ± 55.3 and 176° ± 98.8. CONCLUSION: Conventional and digital fabrication workflows had clinically comparable effect on the passive fit of screw retained bar attachments supported by two dental implants.

Effect of different framework materials on stresses induced in distal extension removable partial dentures: A strain gauge analysis.

PURPOSE: Evaluation of the strain transmitted to the abutments and residual ridge by polyetherketoneketone material compared to the cobalt-chromium one in distal extension removable partial dentures (RPDs) to fulfill the objective of preservation of the supporting structures. MATERIALS AND METHODS: A virtual model simulating a Kennedy class I partially edentulous mandibular arch was designed. Two models, one for each group, were printed. Five RPDs were made in each group. In group CR, the framework was milled from a cobalt-chromium alloy. While in group PK, it was milled from a polyetherketoneketone blank. Strain gauge rosettes were bonded distal to the last abutment and posteriorly in the distal end of the residual ridge. Unilateral vertical and oblique loadings were applied. Mann-Whitney U test was used for inter-group comparisons while the Friedman test was used for intra-group comparisons and corrected by Wilcoxon Signed-Rank Sum. The significance level was set at p ≤ 0.05. RESULTS: During unilateral vertical load application, a statistically significant difference was found between both groups distal to the abutment in the loaded and unloaded sides as well as the residual ridge on the unloaded side. During oblique load application, a statistically significant difference was found between both groups in all slots. CONCLUSION: Polyetherketoneketone material induces less stress on the abutments and more stress on the residual ridges compared to the cobalt-chromium ones. Therefore, it may be recommended for weak abutments supporting RPDs.

Combining Sunitinib and Bevacizumab for the Management of Advanced Renal Cell Carcinoma: A Phase I/II Trial.

BACKGROUND: Tyrosine kinase inhibitors remain a cornerstone in managing metastatic clear cell renal cell carcinoma (RCC). The 4 weeks on/2 weeks off intermittent sunitinib schedule could result in rebound angiogenesis and tumor progression in the 2-week rest period. We propose using bevacizumab during this period for continuous antiangiogenic effects. METHOD: This was a phase I/II study of patients with advanced clear cell RCC. Sunitinib was given 50 mg daily on a 4-week on/2-week off schedule. Bevacizumab was given on day 29 of each sunitinib cycle. The bevacizumab starting dose was 5 mg/kg, and the dose was escalated to 10 mg if there was no dose-limiting toxicity. The primary endpoints were response rate and progression-free survival (PFS). RESULTS: Twenty-five patients were recruited. The study was closed prematurely because of poor accrual. No dose-limiting toxicity was observed with 5 mg bevacizumab. One patient achieved a complete response, and 12 achieved a partial response (52% response rate). At a median follow-up of 42.2 months (95%, confidence interval (CI) 32.9 to 51.4), the median PFS duration was 16.5 months (95% CI 4.1-28.8), and the median overall survival time was 33.3 months (95% CI 19.4-47.3). Twenty-two patients (88%) had at least one grade 3 or 4 toxicity; the most common were thrombocytopenia (32%), lymphopenia (32%), hypertension (28%), and fatigue (24%). CONCLUSION: Continuous angiogenesis blockade by adding bevacizumab to the sunitinib on/off regimen for advanced RCC yields significant antitumor activity with manageable increased toxicity.

Combined Prophylactic Hyperthermic Intraperitoneal Chemotherapy and Intraoperative Radiotherapy for Localized Gastroesophageal Junction and Gastric Cancer: A Comparative Nonrandomized Study.

BACKGROUND: The peritoneum frequently is the only recurrence site after radical resection of gastric cancer. Data suggest that hyperthermic intraperitoneal chemotherapy (HIPEC) and intraoperative radiotherapy (IORT) reduce peritoneal recurrence and possibly improve survival for patients with resected gastric and serosal involvement. This study aimed to evaluate the efficacy of combining prophylactic HIPEC and IORT after radical resection of localized gastric cancer. METHODS: In this retrospective study, the medical records of adult patients with histologically proven gastric/gastroesophageal adenocarcinoma who underwent radical resection with curative intent were evaluated for recurrence and survival according to whether they received prophylactic HIPEC and IORT. RESULTS: The eligibility criteria were met by 58 patients, 33 of whom underwent prophylactic HIPEC and IORT after radical surgery. Overall, 91% the HIPEC/IORT group and 72% of the surgery-only group had ≤pT3 disease. The median follow-up period was 26.6 months for the HIPEC/IORT group and 50.6 months for the surgery group. Locoregional recurrence occurred for six patients (18.1%) in the HIPEC/IORT group and five patients (20%) in the surgery-only group, with peritoneal metastasis (PM) occurring in respectively three (9%) and six (24%) patients. The median recurrence-free survival (RFS) duration was 23.2 months (95% confidence interval [CI] 6.5-39.9 months) for the HIPEC/IORT group versus 24.8 months (95% CI 0.0-51.1 months) for the surgery-only group (p = 0.88), and the corresponding 5-year overall survival (OS) estimates were 69% and 58%. CONCLUSION: Prophylactic HIPEC and IORT after radical surgery for localized gastric or gastroesophageal cancer did not improve RFS or OS for an unselected group of patients at risk for peritoneal recurrence.

Early right ventricular dysfunction after primary percutaneous coronary intervention in anterior versus isolated inferior myocardial infarction assessed by tissue Doppler imaging and speckle tracking echocardiography.

This study hypothesized that imaging provides information indicating the right ventricular (RV) involvement after anterior or inferior ST-elevation myocardial infarction (STEMI), beyond standard electrocardiogram (ECG) due to the increasing interest in RV function and assessment techniques. This study aimed to compare RV function between anterior and inferior MI without RV involvement using different echocardiographic modalities. This study included 100 patients with anterior (50 patients) and inferior (50 patients) STEMI, who underwent primary percutaneous coronary intervention (PPCI) and two-dimensional echocardiographic imaging within 24 h after PPCI with RV function analysis by left ventricular (LV) infarct size, LV filling pressure, and RV strain rate. Our primary endpoint was the subclinical RV dysfunction in anterior or inferior MI using tissue Doppler and speckle tracking (STE). The study population included 80 (80%) males and 20 (20%) females. Patients with the anterior STEMI had higher mean creatine kinase-MB (CKMB) and troponin than those with inferior STEMI. This study revealed worse RV dysfunction in patients with anterior than those with inferior STEMI, as reflected by significantly lower RV systolic function, tricuspid annular plane systolic excursion (p ≤ 0.0001), tissue Doppler-derived velocity (p ≤ 0.0001), and STE-derived strain magnitude and rate (p ≤ 0.0001). RV dysfunction occurs in patients without ECG evidence of RV STEMI. RV dysfunction is worse in anterior than inferior MI. Moreover, RV systolic functions were affected by declined LV ejection fraction irrespective of the infarction site, which clinically implies prognostic, treatment, survival rate, and outcome improvement between both conditions. (Trial registration ZU-IRB#:4142/26-12-2017 Registered 26 December 2017, email: IRB_123@medicine.zu.edu.eg).

Discovery of a non-covalent ligand for Rpn-13, a therapeutic target for hematological cancers.

The ubiquitin-proteasome system serves as the major proteolytic degradation pathway in eukaryotic cells. Many inhibitors that covalently bind to the proteasome's active sites have been developed for hematological cancers, but resistance can arise in patients. To overcome limitations of active-site proteasome inhibitors, we and others have focused on developing ligands that target subunits on the 19S regulatory particle (19S RP). One such 19S RP subunit, Rpn-13, is a ubiquitin receptor required for hematological cancers to rapidly degrade proteins to avoid apoptosis. Reported Rpn-13 inhibitors covalently bind to the Rpn-13's Pru domain and have been effective anti-hematological cancer agents. Here, we describe the discovery of TCL-1, a non-covalent binder to the Pru domain. Optimization of TCL-1's carboxylate group to an ester increases its cytotoxicity in hematological cancer cell lines. Altogether, our data provides a new scaffold for future medicinal chemistry optimization to target Rpn-13 therapeutically.

Does dengue and COVID-19 co-infection have worse outcomes? A systematic review of current evidence.

In dengue-endemic regions, the co-infection with SARS-CoV-2 and dengue is a significant health concern. Therefore, we performed a literature search for relevant papers in seven databases on 26 Spetember 2021. Out of 24 articles, the mortality rate and intensive care unit (ICU) admission were 19.1% and 7.8%, respectively. The mean hospital stay was 11.4 days. In addition, we identified two pregnancies with dengue and COVID-19 co-infection; one ended with premature rupture of membrane and intrauterine growth restriction fetus, while the other one ended with maternal mortality and intrauterine fetal death. COVID-19 and dengue co-infection had worse outcomes regarding mortality rates, ICU admission, and prolonged hospital stay. Thus, wise-decision management approaches should be adequately offered to these patients to enhance their outcomes. Establishing an early diagnosis might be the answer to reducing the estimated significant burden of these conditions.

The impact of Parkinson's disease on manifestations and outcomes of Covid-19 patients: A systematic review and meta-analysis.

Parkinson's disease (PD) patients who contracted Coronavirus disease 2019 (Covid-19) had a decline in motor functions; nevertheless, there is limited evidence on whether PD patients have a higher risk for contracting Covid-19 or have worse outcomes. This is the first systematic review and meta-analysis to review the impact of PD on the prognosis of Covid-19 patients. We performed a systematic search through seven electronic databases under the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analyses statement (PRISMA) guidelines. The R software version 4.0.2 was used to calculate pooled sample sizes and their associated confidence intervals (95%CI). Finally, we included 13 papers in this study. The pooled prevalence rate of Covid-19 was 2.12% (95%CI: 0.75-5.98). Fever, cough, fatigue and anorexia were the most common symptoms with a rate of 72.72% (95% CI: 57.3 - 92.29), 66.99% (95% CI: 49.08-91.42), 61.58% (95% CI: 46.69-81.21) and 52.55% (95% CI: 35.09-78.68), respectively. The pooled rates were 39.89% (95% CI: 27.09-58.73) for hospitalisation, 4.7% (95% CI: 1.56-14.16) for ICU admission and 25.1% (95%CI: 16.37-38.49) for mortality. On further comparison of hospitalisation and mortality rates among Covid-19 patients with and without PD, there were no significant differences. In conclusion, the prevalence and prognosis of Covid-19 patients seem comparable in patients with PD and those without it. The increased hospitalisation and mortality may be attributed to old age and co-morbidities.

ATM phosphorylates PP2A subunit A resulting in nuclear export and spatiotemporal regulation of the DNA damage response.

Ataxia telangiectasia mutated (ATM) is a serine-threonine protein kinase and important regulator of the DNA damage response (DDR). One critical ATM target is the structural subunit A (PR65-S401) of protein phosphatase 2A (PP2A), known to regulate diverse cellular processes such as mitosis and cell growth as well as dephosphorylating many proteins during the recovery from the DDR. We generated mouse embryonic fibroblasts expressing PR65-WT, -S401A (cannot be phosphorylated), and -S401D (phospho-mimetic) transgenes. Significantly, S401 mutants exhibited extensive chromosomal aberrations, impaired DNA double-strand break (DSB) repair and underwent increased mitotic catastrophe after radiation. Both S401A and the S401D cells showed impaired DSB repair (nonhomologous end joining and homologous recombination repair) and exhibited delayed DNA damage recovery, which was reflected in reduced radiation survival. Furthermore, S401D cells displayed increased ERK and AKT signaling resulting in enhanced growth rate further underscoring the multiple roles ATM-PP2A signaling plays in regulating prosurvival responses. Time-lapse video and cellular localization experiments showed that PR65 was exported to the cytoplasm after radiation by CRM1, a nuclear export protein, in line with the very rapid pleiotropic effects observed. A putative nuclear export sequence (NES) close to S401 was identified and when mutated resulted in aberrant PR65 shuttling. Our study demonstrates that the phosphorylation of a single, critical PR65 amino acid (S401) by ATM fundamentally controls the DDR, and balances DSB repair quality, cell survival and growth by spatiotemporal PR65 nuclear-cytoplasmic shuttling mediated by the nuclear export receptor CRM1.

Sutureless versus conventional deep sclerectomy for management of open angle glaucoma.

INTRODUCTION: To compare sutureless deep sclerectomy to conventional deep sclerectomy regarding their lowering effect on intraocular pressure (IOP) in cases with open-angle glaucoma. METHODS: This is a prospective interventional randomized comparative study that included 60 eyes of 50 patients with open-angle glaucoma (OAG) who were indicated for surgical intervention. Patients were recruited from the glaucoma subspecialty clinic of the Cairo University teaching hospital and were divided into two groups: group A (underwent sutureless deep sclerectomy) and group B (underwent conventional deep sclerectomy). RESULTS: Both surgeries showed significant reduction of IOP all through the study period: in group A, mean reduction was 71.37%, 53.35%, 50.3%, and 44.33% at 1st day, 1 month, 3 months, and 6 months respectively, and in group B, mean reduction was 57.62%, 40.63%, 37.41%, and 31.68% at 1st day, 1 month, 3 months, and 6 months, respectively. Comparison between percentage of reduction in both groups showed no statistically significant difference. Also, use of anti-glaucoma medications dropped significantly at 6 months postoperatively in both groups with no significant difference between the 2 groups. Regarding reported complications, 12.9% in group A and 10.3% in group B presented with non-serious complications. One month postoperatively, UBM detected non-functioning blebs in 6.4% of group A and 3.4% in group B. Other cases with non-functioning blebs were detected at 3 and 6 months postoperatively, and all cases were managed. CONCLUSION: Sutureless deep sclerectomy seems to be a safe and effective modification, with significant IOP reduction in POAG.