An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of aldosterone in human serum and plasma.

OBJECTIVES: An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedure (RMP) for aldosterone quantification in human serum and plasma is presented. METHODS: The material used in this RMP was characterized by quantitative nuclear magnetic resonance (qNMR) to assure traceability to SI Units. For liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis a two-dimensional heart cut LC approach, in combination with an optimal supported liquid extraction protocol, was established for the accurate analysis of aldosterone in human serum and plasma in order to minimize matrix effects and avoid the co-elution of interferences. Assay validation was performed according to current guidelines. Selectivity and specificity were assessed using spiked serum; potential matrix effects were examined by a post column infusion experiment and the comparison of standard line slopes. An extensive protocol over 5 days was applied to determine precision, accuracy and trueness. Measurement uncertainty was evaluated according to the Guide to the Expression of Uncertainty in Measurement (GUM), for which three individual sample preparations were performed on at least two different days. RESULTS: The RMP allowed aldosterone quantification within the range of 20-1,200 pg/mL without interference from structurally-related compounds and no evidence of matrix effects. Intermediate precision was ≤4.7% and repeatability was 2.8-3.7% for all analyte concentrations. The bias ranged between -2.2 and 0.5% for all levels and matrices. Total measurement uncertainties for target value assignment (n=6) were found to be ≤2.3%; expanded uncertainties were ≤4.6% (k=2) for all levels. CONCLUSIONS: The RMP showed high analytical performance for aldosterone quantification in human serum and plasma. The traceability to SI units was established by qNMR content determination of aldosterone, which was utilized for direct calibration of the RMP. Thus, this candidate RMP is suitable for routine assay standardization and evaluation of clinical samples.

Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun.

Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.

Sexual Harassment: Knowledge, Prevalence, Pattern, and Impacts Among Egyptian Female College Students.

Sexual harassment (SH) is an uprising problem worldwide, especially in Egypt. This study aims to determine the magnitude, patterns, and circumstances of SH among female students at Suez Canal University. A cross-sectional study was conducted on a representative female student sample (N = 644) from all the faculties using a self-administered anonymous questionnaire. The high prevalence of SH among college students in this study could be a consequence of the absence of knowledge about the legal framework. It mostly happened at all times of the day and night in the streets, and the least amount happened on the campus. Most of the harassers were younger than 20 years old and strangers. The majority of harassed females and surrounding people displayed negative reactions. None of the harassed females notified the authorities. The majority blamed men, and half claimed the SH act was due to the absence of religious principles. Moreover, the ignorance of the majority is with Egyptian law against SH. Both psychological and social impacts are significantly experienced by the harassed females. Thus, it is urgent to establish an institutional program (e.g., psycho-educative sessions during classes and peer training) or national awareness campaigns. Such programs and trainings aim to increase the awareness of students about the SH legal framework and how to deal with such acts, either as a victim or a witness, and how to provide the needed psychological assistance.

Managing acute presentations of atheromatous renal artery stenosis.

BACKGROUND: Atherosclerotic renovascular disease (ARVD) often follows an asymptomatic chronic course which may be undetected for many years. However, there are certain critical acute presentations associated with ARVD and these require a high index of suspicion for underlying high-grade RAS (renal artery stenosis) to improve patient outcomes. These acute presentations, which include decompensated heart failure syndromes, accelerated hypertension, rapidly declining renal function, and acute kidney injury (AKI), are usually associated with bilateral high-grade RAS (> 70% stenosis), or high-grade RAS in a solitary functioning kidney in which case the contralateral kidney is supplied by a vessel demonstrating renal artery occlusion (RAO). These presentations are typically underrepresented in large, randomized control trials which to date have been largely negative in terms of the conferred benefit of revascularization. CASE PRESENTATION: Here we describe 9 individual patients with 3 classical presentations including accelerated phase hypertension, heart failure syndromes, AKI and a fourth category of patients who suffered recurrent presentations. We describe their response to renal revascularization. The predominant presentation was that consistent with ischaemic nephropathy all of whom had a positive outcome with revascularization. CONCLUSION: A high index of suspicion is required for the diagnosis of RAS in these instances so that timely revascularization can be undertaken to restore or preserve renal function and reduce the incidence of hospital admissions for heart failure syndromes.

Effects of Prosody Rehabilitation on Acoustic Analysis of Prosodic Features in Hearing-Impaired Children: A Randomized Controlled Trial.

BACKGROUND: The role of prosody in language acquisition and effective communication is documented in research. Nevertheless, rehabilitation of prosodic skills in children with hearing impairment using hearing aids or cochlear implants is relatively neglected compared to other speech and language areas. OBJECTIVE: To detect the effect of prosodic rehabilitation using the adapted translated version of the "Prosody Treatment Program" on expression of prosodic features in Egyptian Arabic-speaking hearing-impaired school-age children fitted with hearing aids or cochlear implant devices in comparison to conventional auditory and language rehabilitation. METHODS: This study was conducted on 34 children with sensorineural hearing loss in a randomized controlled trial design. Children were randomly divided into 2 groups, group A (cases) and group B (control), by block randomization. Both groups were initially evaluated for their prosodic skills using objective measures. Group A received rehabilitation for prosody using the Prosody Treatment Program for 1 h, once per week for 3 months, while group B received conventional auditory and language training and served as their control. Both groups were re-evaluated using the same protocol after 3 months of therapy. RESULTS: A statistically significant improvement of most of the assessed prosodic parameters in group A was shown when comparing the pretherapy and posttherapy scores, as well as comparing between both studied groups after therapy. CONCLUSIONS: Prosody is amenable to motor learning. The Prosody Treatment Program seems to be an effective rehabilitation tool in improving some prosodic skills of hearing-impaired children. Prosodic rehabilitation showed superiority to conventional auditory and language training in improving the expression of some prosodic features and pragmatic language skills.

Augmenter of Liver Regeneration (ALR) regulates bile acid synthesis and attenuates bile acid-induced apoptosis via glycogen synthase kinase-3ß (GSK-3ß) inhibition.

Bile acid synthesis is restricted to hepatocytes and is rate-limited by CYP7A1 (cholesterol 7α hydroxylase). CYP7A1 expression undergoes tight regulation and is repressed after partial hepatectomy to prevent the accumulation of toxic bile acids. Augmenter of Liver Regeneration (ALR) is a hepatotrophic factor shown to support liver regeneration by augmenting cell proliferation and reducing apoptosis. Nevertheless, less is known about ALR's role in protecting hepatocytes from bile acid accumulation and bile acid-induced apoptosis. Therefore, HepG2 and Huh-7 cells were incubated with recombinant human ALR (rALR) and the expression of CYP7A1, bile acid-induced apoptosis as well as potential molecular mechanisms were analyzed. We found that rALR reduces CYP7A1 expression by increasing nuclear NFκB levels. Moreover, rALR reduced glycochenodeoxycholate (GCDC)-induced-apoptosis by decreased expression of pro-apoptotic Bax and enhanced expression of anti-apoptotic Mcl-1, which is regulated by phosphatidylinositol-3-kinase (PI3K)/Akt activation and glycogen synthase kinase-3ß (GSK3ß) phosphorylation. Inhibitors for PI3K/Akt (GSK690693) and GSK3ß (SB415286) confirmed the specificity of rALR treatment for this pathway. In addition, rALR reduces pro-death signaling by decreasing GCDC-induced JNK phosphorylation. Taken all together, rALR might contribute to protecting hepatocytes from toxic concentrations of bile acids by down-regulating their denovo synthesis, attenuating apoptosis by activation of PI3K/Akt - GSK3ß pathway and inhibition of JNK signaling. Thereby this suggests a new role of ALR in augmenting the process of liver regeneration.

Adverse outcomes associated with rapid linear and non-linear patterns of chronic kidney disease progression.

BACKGROUND: Patients with rapidly declining renal function face the dual threat of end-stage renal disease (ESRD) and mortality prior to ESRD. What is less well characterised is whether the pattern of the renal trajectory, linear or non-linear, unmasks subgroups of rapidly progressing patients that face adverse outcomes in a differential manner. METHODS: An individual eGFR slope was applied to all outpatient estimated glomerular filtration rate (eGFR) values for each patient in the Salford Kidney Study from 2002 to 2018 who had at least 2 years follow-up, ≥4 eGFR values and baseline eGFR 15 to < 60 ml/min/1.73m2. Rapid progression was defined as an annual eGFR slope of ≤ - 3 ml/min/1.73m2/yr and patients were categorised as linear or non-linear progressors based on the nature of their eGFR-time graphs. A Fine-Gray competing risk hazard model was used to determine factors associated with progression to ESRD and with mortality prior to ESRD. Cumulative incidence function curves highlighted differences in outcomes between linear and non-linear patients. RESULTS: There were 211 rapidly deteriorating patients with linear eGFR trajectories and 61 rapid non-linear patients in the study cohort. Factors associated with ESRD included younger age, male gender, lower baseline eGFR and higher serum phosphate, whilst older age, history of myocardial infarction and anaemia predicted mortality prior to ESRD. Over a median follow-up of 3.7 years, linear progressors reached ESRD sooner whilst those with non-linear progression faced significantly higher rates of mortality prior to ESRD. CONCLUSIONS: Patients with rapid eGFR decline have high rates of adverse outcomes that are differentially expressed in those progressing linearly and non-linearly as a result of differing phenotypic profiles. Consequently, addressing individual risk factor profiles is important to deliver optimal personalised patient care.

A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control. METHODS: This is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months. RESULTS: There was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses. CONCLUSIONS: With a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.

Longitudinal change in c-terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease.

BACKGROUND: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes. METHODS: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis. RESULTS: Across our population, median baseline eGFR was 32.3mls/min/1.73m2, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events. CONCLUSION: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.

Bile acid-induced apoptosis and bile acid synthesis are reduced by over-expression of Augmenter of Liver Regeneration (ALR) in a STAT3-dependent mechanism.

Cholestasis represents pathophysiologic syndromes defined as an impaired bile flow from the liver. As an outcome, bile acids accumulate and promote hepatocytes injury followed by liver cirrhosis and liver failure. Bile acids induce apoptosis, ER stress and mitochondrial membrane instability. In this study we aimed to investigate the role of cytosolic short form of ALR (Augmenter of Liver Regeneration) in the synthesis of bile acids and bile acid-induced apoptosis. Human hepatoma cells over-expressing the short form of ALR (sfALR, 15 kDa) were incubated with glycochenodeoxycholic acid (GCDCA), and then primary bile acids' production and apoptosis were analyzed. High levels of cytosolic sfALR reduced CYP7A1 mRNA expression and bile acids levels, the rate-limiting enzyme in the classic pathway of bile acid synthesis. This reduction was attributed to STAT3 (signal transducer and activator of transcription 3) activation and reduction of HNF4α (Hepatocyte nuclear factor 4α). Furthermore, apoptosis induction by GCDCA and TRAIL was reduced in cells over-expressing sfALR which was attributed to reduced expression of death receptor 5 (DR5). We found decreased hepatic mRNA levels of ALR and FOXA2 (Forkhead Box A2), an inducer of ALR expression, in human cholestatic liver samples which might explain the increased accumulation of bile acids and bile acid-induced apoptosis in cholestasis patients.

Predictive factors of rapid linear renal progression and mortality in patients with chronic kidney disease.

BACKGROUND: Risk factors predictive of rapid linear chronic kidney disease (CKD) progression and its associations with end-stage renal disease (ESRD) and mortality requires further exploration, particularly as patients with linear estimated glomerular filtration rate (eGFR) trajectory represent a clear paradigm for understanding true CKD progression. METHODS: A linear regression slope was applied to all outpatient eGFR values for patients in the Salford Kidney Study who had ≥2 years follow-up, ≥4 eGFR values and baseline CKD stages 3a-4. An eGFR slope (ΔeGFR) of ≤ - 4 ml/min/1.73m2/yr defined rapid progressors, whereas - 0.5 to + 0.5 ml/min/1.73m2/yr defined stable patients. Binary logistic regression was utilised to explore variables associated with rapid progression and Cox proportional hazards model to determine predictors for mortality prior to ESRD. RESULTS: There were 157 rapid progressors (median ΔeGFR - 5.93 ml/min/1.73m2/yr) and 179 stable patients (median ΔeGFR - 0.03 ml/min/1.73m2/yr). Over 5 years, rapid progressors had an annual rate of mortality or ESRD of 47 per 100 patients compared with 6 per 100 stable patients. Factors associated with rapid progression included younger age, female gender, higher diastolic pressure, higher total cholesterol:high density lipoprotein ratio, lower albumin, lower haemoglobin and a urine protein:creatinine ratio of > 50 g/mol. The latter three factors were also predictive of mortality prior to ESRD, along with older age, smoking, peripheral vascular disease and heart failure. CONCLUSIONS: There is a heterogenous interplay of risk factors associated with rapid linear CKD progression and mortality in patients with CKD. Furthermore, rapid progressors have high rates of adverse outcomes and require close specialist monitoring.

Bile acids down-regulate the expression of Augmenter of Liver Regeneration (ALR) via SHP/HNF4α1 and independent of Egr-1.

Bile acids (BA) are signaling molecules that activate nuclear factors and g-protein coupled receptors signaling to maintain metabolic homeostasis. However, accumulation of toxic BA promotes liver injury by initiating inflammation, inducing apoptosis and causing oxidative stress leading to cirrhosis and liver failure. Augmenter of Liver Regeneration (ALR) is a hepatotrophic growth factor with anti-apoptotic and anti-oxidative properties that has been shown to improve mitochondrial and hepatic functions in rats after bile duct ligation. In the current study we aimed to analyze the regulation of the pro-survival protein, ALR, under conditions of cytotoxic concentrations of BA. Promoter studies of ALR (-733/+527 bp) revealed potential binding sites for various transcription factors like Egr-1, HNF4α and two bile acid response elements (BARE). Using a full-length and several truncated promoter constructs for ALR we analyzed promoter activity and showed that BA reduce ALR promoter activity whereas Egr-1 transfection induces it. EMSA and supershift analysis confirmed the specific binding of Egr-1 to its response element within ALR promoter and this binding was reduced upon simultaneous stimulation with BA. We also showed that ALR promoter activity and protein expression are induced by HNF4α1 and repressed by SHP. In conclusion, these results indicate that BA negatively regulate ALR expression by SHP activation.

Augmenter of liver regeneration (ALR) exhibits a dual signaling impact on hepatic acute-phase response.

The acute-phase response (APR) is an inflammatory process triggered mainly by IL-6 in response to neoplasm, tissue injury, infection or inflammation. Signaling of IL-6 is transduced by activating STAT3 which rapidly results in production of acute-phase proteins (APPs) such as fibrinogen ß (FGB) and haptoglobin (HP). Augmenter of liver regeneration (ALR), a hepatotrophic factor supporting liver regeneration, was reported to be upregulated after liver damage. In this study we analyzed the role of ALR for IL-6 signaling and APR. Thus, we investigated the expression and release of APPs in human liver cells under conditions of increased exogenous or endogenous ALR. HepG2 cells and ALR-reexpressing HepG2 cells were treated with IL-6 in the presence or absence of exogenous ALR for different time points. The mRNA expression and release of both FGB and HP were measured by RT-PCR and ELISA. We found that exogenously applied ALR attenuated the IL-6-induced mRNA expression and protein secretion of both FGB and HP. In contrast, IL-6 stimulation in HepG2 cells which re-express ALR, revealed elevated APR shown by increased mRNA expression and secretion of FGB and HP. Furthermore, we found that ALR-mediated regulation of IL-6-induced APP production is accompanied by altered STAT3 activity. While exogenous ALR reduced the IL-6-induced phosphorylation of STAT3, endogenous ALR enhanced STAT3 activity in liver cells. In conclusion, ALR, dependent on its localization, changes APR at least in part, by modifying STAT3 activation. This study shows a dual signaling of ALR and suggests that ALR is pivotal for the regulation of APR, a crucial event in liver injury and regeneration.

DMAP: a connectivity map database to enable identification of novel drug repositioning candidates.

BACKGROUND: Drug repositioning is a cost-efficient and time-saving process to drug development compared to traditional techniques. A systematic method to drug repositioning is to identify candidate drug's gene expression profiles on target disease models and determine how similar these profiles are to approved drugs. Databases such as the CMAP have been developed recently to help with systematic drug repositioning. METHODS: To overcome the limitation of connectivity maps on data coverage, we constructed a comprehensive in silico drug-protein connectivity map called DMAP, which contains directed drug-to-protein effects and effect scores. The drug-to-protein effect scores are compiled from all database entries between the drug and protein have been previously observed and provide a confidence measure on the quality of such drug-to-protein effects. RESULTS: In DMAP, we have compiled the direct effects between 24,121 PubChem Compound ID (CID), which were mapped from 289,571 chemical entities recognized from public literature, and 5,196 reviewed Uniprot proteins. DMAP compiles a total of 438,004 chemical-to-protein effect relationships. Compared to CMAP, DMAP shows an increase of 221 folds in the number of chemicals and 1.92 fold in the number of ATC codes. Furthermore, by overlapping DMAP chemicals with the approved drugs with known indications from the TTD database and literature, we obtained 982 drugs and 622 diseases; meanwhile, we only obtained 394 drugs with known indication from CMAP. To validate the feasibility of applying new DMAP for systematic drug repositioning, we compared the performance of DMAP and the well-known CMAP database on two popular computational techniques: drug-drug-similarity-based method with leave-one-out validation and Kolmogorov-Smirnov scoring based method. In drug-drug-similarity-based method, the drug repositioning prediction using DMAP achieved an Area-Under-Curve (AUC) score of 0.82, compared with that using CMAP, AUC = 0.64. For Kolmogorov-Smirnov scoring based method, with DMAP, we were able to retrieve several drug indications which could not be retrieved using CMAP. DMAP data can be queried using the existing C2MAP server or downloaded freely at: http://bio.informatics.iupui.edu/cmaps CONCLUSIONS: Reliable measurements of how drug affect disease-related proteins are critical to ongoing drug development in the genome medicine era. We demonstrated that DMAP can help drug development professionals assess drug-to-protein relationship data and improve chances of success for systematic drug repositioning efforts.

"Mastectomy for individuals with gender dysphoria below 26 years of age: A systematic review and meta-analysis".

BACKGROUND: Gender dysphoria (GD) refers to psychological distress associated with the incongruence between one's sex and one's gender. In response to GD, birth-registered females may choose to undergo mastectomy. In this systematic review, we summarize and assess the certainty of the evidence on the effects of mastectomy. METHODS: We searched MEDLINE, Embase, PsycINFO, Social Sciences Abstracts, LGBTQ+ Source, and Sociological Abstracts through June 20, 2023. We included studies comparing mastectomy to no mastectomy in birth-registered females under 26 years of age with GD. Outcomes of interest included psychological and psychiatric outcomes, and physical complications. Pairs of reviewers independently screened articles, abstracted data, and assessed risk of bias of the included studies. We performed meta-analysis and assessed the certainty of the evidence using the GRADE approach. RESULTS: We included 39 studies. Observational studies (n=2) comparing mastectomy to chest binding provided very low certainty evidence for the outcome of GD. One observational study comparing mastectomy to no mastectomy provided very low certainty evidence for the outcomes global functioning and suicide attempts, and low certainty evidence for the outcome non-suicidal self-injury (aOR 0.47 [95% CI 0.22 to 0.97]). Before-after (n=2) studies provided very low certainty evidence for all outcomes. Evidence from case series (n=34) studies ranged from high to very low certainty. CONCLUSION: Case series studies demonstrated high certainty evidence for the outcomes of death, necrosis, and excessive scarring; however, these are limited in methodological quality. In comparative and before-after studies the evidence ranged from low to very low certainty.

Unveiling the therapeutic potential of Taxifolin in Cancer: From molecular mechanisms to immune modulation and synergistic combinations.

BACKGROUND: Taxifolin (TAX), a flavonoid abundant in various medicinal plants, has gained attention for its multifaceted role in cancer therapy and cytoprotection against chemotherapy-induced toxicities. TAX modulates key signaling pathways to regulate several processes within tumors, thus potentially playing an important role in tumor suppression. PURPOSE: This review aims to explore the current understanding of TAX's role in cancer therapy including its antitumor mechanisms, synergistic combinations, and cytoprotective effects. The review also addresses the safety profile of TAX, highlights its pharmacokinetic (PK) properties limiting its use, and summarizes the suggested pharmaceutical and chemical solutions to overcome these limitations. METHODOLOGY: A literature review was conducted through searching online databases such as PubMed and Google Scholar using several combinations of relevant keywords related to TAX's potential in anticancer therapy. A total of 84 articles published within the last 15 years were included in this review and analyzed following the PRISMA guidelines. RESULTS: TAX inhibits tumor proliferation, migration, and invasion via the cGMP-PKG pathway, inducing G1-phase arrest and apoptosis. TAX's anti-angiogenic and pro-apoptotic effects are mediated by downregulating Hif1-α, VEGF, and AKT. Additionally, it can synergize the conventional chemotherapeutic agents, enhancing their efficacy and mitigating drug resistance by inhibiting P-glycoprotein expression. Additionally, TAX demonstrates cytoprotective effects against cisplatin-induced nephrotoxicity and neurotoxicity, cyclophosphamide/pazopanib-induced hepatotoxicity, methotrexate-induced oral mucositis, and doxorubicin-induced cardiotoxicity by inhibiting ferroptosis. TAX further has immunomodulatory effects in the tumor microenvironment, enhancing immune responses and sensitizing tumors to immune checkpoint inhibitors. Advancements in TAX's anticancer effects include introducing novel drug delivery systems and chemical modifications to generate derivatives with improved pharmacological effects. CONCLUSION: Clinical trials are needed to confirm TAX's safety and effectiveness in cancer therapy, optimize formulations, and investigate synergistic combinations. Overall, TAX holds promise as a versatile anticancer agent, offering direct anticancer effects and protective benefits against chemotherapy-induced toxicities.

Exploring antiproliferative activities and kinase profile of ortho-substituted N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)benzamides.

Designing kinase inhibitors that bind to the substrate site of oncogenic kinases in a promising, albeit less explored, approach to kinase inhibition as it was sought to avoid the issue of untoward off-target modulations. Our previously identified compound KAC-12 with a meta-chlorophenyl substitution was an example of this approach. While it showed confirmed inhibitory activity against cancer cells, this substitution shifted the profile of affected targets away from Src/tubulin which were seen with the parent KX-01. In this paper, we synthesized compounds with ortho-substitutions, and we investigated the effect of such substitutions on their cellular and subcellular activities. The compound N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-2-(morpholine-4-carbonyl)benzamide (4) exhibited substantial activities against cell lines such HCT116 (IC50 of 0.97 µM) and IC50 HL60 (2.84 µM). Kinase profiling showed that compound 4 trended consistently with KAC-12 as it did not affect Src, but it had more impact on members of the Src family of kinases (SFK) such as Yes, Hck, Fyn, Lck, and Lyn. Both compounds exhibited profound downregulation effects on Erk1/2 but differed on others such as GSK3α/ß and C-Jun. Collectively, this study further support to the hypothesis that small structural changes might bring higher changes in their kinome profile.

Differences in management approaches for lupus nephritis within the UK.

Objectives: Outcomes of therapy for LN are often suboptimal. Guidelines offer varied options for treatment of LN and treatment strategies may differ between clinicians and regions. We aimed to assess variations in the usual practice of UK physicians who treat LN. Methods: We conducted an online survey of simulated LN cases for UK rheumatologists and nephrologists to identify treatment preferences for class IV and class V LN. Results: Of 77 respondents, 48 (62.3%) were rheumatologists and 29 (37.7%) were nephrologists. A total of 37 (48.0%) reported having a joint clinic between nephrologists and rheumatologists, 54 (70.0%) reported having a multidisciplinary team meeting for LN and 26 (33.7%) reported having a specialized lupus nurse. Of the respondents, 58 (75%) reported arranging a renal biopsy before starting the treatment. A total of 20 (69%) of the nephrologists, but only 13 (27%) rheumatologists, reported having a formal departmental protocol for treating patients with LN (P < 0.001). The first-choice treatment of class IV LN in pre-menopausal patients was MMF [41 (53.2%)], followed by CYC [15 (19.6%)], rituximab [RTX; 12 (12.5%)] or a combination of immunosuppressive drugs [9 (11.7%)] with differences between nephrologists' and rheumatologists' choices (P = 0.026). For class V LN, MMF was the preferred initial treatment, irrespective of whether proteinuria was in the nephrotic range or not. RTX was the preferred second-line therapy for non-responders. Conclusion: There was variation in the use of protocols, specialist clinic service provision, biopsies and primary and secondary treatment choices for LN reported by nephrologists and rheumatologists in the UK.

Antibiotic prophylaxis for the prevention of surgical site infections following colorectal surgery: protocol for network meta-analysis of randomized trials.

BACKGROUND: Surgical site infections continue to be a significant challenge following colorectal surgery. These can result in extended hospital stays, hospital readmissions, increased treatment costs, and negative effects on patients' quality of life. Antibiotic prophylaxis plays a crucial role in preventing infection during surgery, specifically in preventing surgical site infections after colorectal surgery in adult patients. However, the optimal antibiotic regimen is still unclear based on current evidence. Considering the limitations of existing reviews, our goal is to conduct a comprehensive systematic review and network meta-analysis of randomized controlled trials to evaluate the comparative benefits and harms of available antibiotic prophylaxis regimens for preventing surgical site infections following colorectal surgery in adult patients. METHODS: We will search the Medline, EMBASE, CINAHL, Scopus, and Cochrane Central Register of Controlled Trials databases to identify relevant randomized controlled trials. We will include trials that (1) enrolled adults who underwent colorectal surgeries and (2) randomized them to any systemic administration of antibiotic (single or combined) prophylaxis before surgery compared to an alternative systemic antibiotic (single or combined antibiotic), placebo, control, or no prophylactic treatment. Pairs of reviewers will independently assess the risk of bias among eligible trials using a modified Cochrane risk of bias instrument for randomized trials. Our outcomes of interest include the rate of surgical site infection within 30 days of surgery, hospital length of stay, 30-day mortality, and treatment-related adverse effects. We will perform a contrast-based network meta-analysis using a frequentist random-effects model assuming a common heterogeneity parameter. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be utilized to assess the certainty of evidence for treatment effects. DISCUSSION: By synthesizing evidence from available RCTs, this study will provide valuable insight for clinicians, patients, and health policymakers on the most effective antibiotics for preventing surgical site infection. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023434544.

Assessment of chemokines MIP-1α and MIP-1 ßin Iraqi women with polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is reproductive, endocrine, and metabolic disorder affecting females. The pathology of PCOS is complicated and associated to chronic low-grade inflammation, this includes a disruption in pro-inflammatory factor production, leukocytosis, and endothelial cell dysfunction, also associated with high level of pro-inflammatory cytokines, chemokines and leukocyte count. In addition, PCOS is characterized by hormonal and immunological dysfunction. Inflammation of the ovary affects ovulation and induces or aggravates systemic inflammation. Macrophage inflammatory protein-1 (MIP-1), a pro-inflammatory chemokine, is crucial in the recruitment of inflammatory and immunological cells to the place of inflammation or infection, T- and B-lymphocytes, neutrophils, macrophages, mast cells, dendritic cells and natural killer cells are all capable of producing large amounts of MIP-1. The current study aimed to investigate the role of MIP-1α and MIP-1ß in Iraqi patients with PCOS and their correlation with obesity and other demographic parameters. This study included two groups, 60 women with PCOS and 30 control women, conducted during the period from October 2022 to January 2023. The diagnosis of PCOS women was based on two out of three of the following diagnostic criteria (hyperandrogenism - oligo or anovulation - polycystic ovaries). MIP-1 alpha and Beta levels were determined by ELISA. The outcomes revealed that the group with PCOS showed significant increase in the level of MIP-1α (635.28 ±20.58) than in the control women, (571.20 ±25.92), (p<0.05). Although there was an increase the level of MIP-1ß in women with PCOS (191.85 ±17.54) than in the control group (165.31 ±11.01), the difference did not reach statistical significance. In conclusion, based on our findings, that MIP-1α and MIP-1ß increased in PCOS cases, this may indicate that PCOS is low grade chronic inflammation.