Effects of prolonged hydroxychloroquine use on the pancreatic tissue and expected ameliorative effect of lactoferrin in rats (biochemical, histological, and morphometric study).

Hydroxychloroquine (HCQ), an antimalarial drug widely used in treating rheumatoid disorders. Many side effects have been reported with HCQ administration indicating its hazardous effects on various organs. No previous studies reported the effect of long-term administration of oral HCQ on pancreatic tissue. Our study assessed pancreatic tissues functional and histopathological alterations following prolonged oral administration of HCQ. We also investigated the possible ameliorative effects of the lactoferrin (LF) coadministration with HCQ in adult male albino rats. Forty adult male Wister albino rats were divided into: negative control, LF positive control (2 g/kg), HCQ-treated (200 mg/kg), and HCQ+LF treated. Biochemical, histological, immunohistochemical, and morphometric analyses of the pancreatic tissues were conducted. Our findings revealed that prolonged oral administration of HCQ induced significant disruption of the pancreatic acinar architecture, enlarged congested islets of Langerhans, and elevated plasma insulin, amylase, and lipase levels. Interestingly, LF administration ameliorated the deleterious effects of prolonged HCQ administration on pancreatic tissue of adult male albino rats. In conclusion, prolonged oral administration of HCQ induced pancreatic tissue damage in rats, while LF attenuates HCQ-induced pancreatic injury. Our results emphasized the necessity of prescribing HCQ with caution, considering both dosage and treatment duration.

Wound Healing Efficacy of Cucurbitaceae Seed Oils in Rats: Comprehensive Phytochemical, Pharmacological, and Histological Studies Tackling AGE/RAGE and Nrf2/Ho-1 Cue.

The Cucurbitaceae family includes several edible species that are consumed globally as fruits and vegetables. These species produce high volumes of seeds that are often discarded as waste. In this study, we investigate the chemical composition and biological activity of three seed oils from Cucurbitaceae plants, namely, cantaloupe, honeydew, and zucchini, in comparison to the widely used pumpkin seed oil for their ability to enhance and accelerate wound healing in rats. Our results showed that honeydew seed oil (HSO) was effective in accelerating wound closure and enhancing tissue repair, as indicated by macroscopic, histological, and biochemical analyses, as compared with pumpkin seed oil (PSO). This effect was mediated by down-regulation of the advanced glycation end products (AGE) and its receptor (RAGE) cue, activating the cytoprotective enzymes nuclear factor erythroid 2 (Nrf2) and heme oxygenase-1 (HO-1), suppressing the inflammatory mediators tumor necrosis factor (TNF)-α, nuclear factor kappa B (NF-κB), and nod-like receptor protein 3 (NLRP3), and reducing the levels of the skin integral signaling protein connexin (CX)-43. Furthermore, immunohistochemical staining for epidermal growth factor (EGF) showed the lowest expression in the skin after treatment with HSO, indicating a well-organized and complete healing process. Other seed oils from cantaloupe and zucchini exhibited favorable activity when compared with untreated rats; however, their efficacy was comparatively lower than that of PSO and HSO. Gas chromatographic analysis of the derivatized oils warranted the superior activity of HSO to its high nutraceutical content of linoleic acid, which represented 65.9% of the fatty acid content. This study's findings validate the use of honeydew seeds as a wound-healing fixed oil and encourage further investigation into the potential of Cucurbitaceae seeds as sources of medicinally valuable plant oils.

Realistic simulation case scenario as a vertical integration teaching tool for medical students: A mixed methods study.

Realistic simulation-based learning has recently become an integral part of medical education and can provide several advantages if applied effectively. This study aimed to develop and validate a realistic simulation case scenario (RSCS) as a novel teaching tool for preclinical medical students. Furthermore, we aimed to evaluate student perception of this tool as a teaching strategy, as well as to acquire an in-depth understanding of student perspectives. We employed the mixed methods approach to explore how clinical reasoning develops through a validated RSCS. This study, which included 50 third-year medical students, was conducted at the College of Medicine, Dar Al Uloom University, KSA between November 2021 and February 2022. Most of the participants (94%) were satisfied with the RSCS method and 92% of the participants reported RSCS as more effective in terms of achieving learning objectives. Many advantages of RSCS have been reported, including the provision of realistic knowledge relating to critical care management, encouraging student participation in the learning process, and enhancing interpersonal and problem-solving skills. In conclusion, RSCS is an effective and dynamic teaching approach that aids in knowledge consolidation with a significant impact on the emotions and cognitive abilities of students.

Lactiplantibacillus plantarum and Saussurea costus as Therapeutic Agents against a Diabetic Rat Model-Approaches to Investigate Pharmacophore Modeling of Human IkB Kinase and Molecular Interaction with Dehydrocostus Lactone of Saussurea costus.

Lactic acid bacteria is well-known as a vital strategy to alleviate or prevent diabetes. Similarly, the plant Saussurea costus (Falc) Lipsch is a preventive power against diabetes. Here, we aimed to determine whether lactic acid bacteria or Saussurea costus is more effective in treating a diabetic rat model in a comparative study manner. An in vivo experiment was conducted to test the therapeutic activity of Lactiplantibacillus plantarum (MW719476.1) and S. costus plants against an alloxan-induced diabetic rat model. Molecular, biochemical, and histological analyses were investigated to evaluate the therapeutic characteristics of different treatments. The high dose of S. costus revealed the best downregulated expression for the IKBKB, IKBKG, NfkB1, IL-17A, IL-6, IL-17F, IL-1ß, TNF-α, TRAF6, and MAPK genes compared to Lactiplantibacillus plantarum and the control groups. The downregulation of IKBKB by S. costus could be attributed to dehydrocostus lactone as an active compound with proposed antidiabetic activity. So, we performed another pharmacophore modeling analysis to test the possible interaction between human IkB kinase beta protein and dehydrocostus lactone as an antidiabetic drug. Molecular docking and MD simulation data confirmed the interaction between human IkB kinase beta protein and dehydrocostus lactone as a possible drug. The target genes are important in regulating type 2 diabetes mellitus signaling, lipid and atherosclerosis signaling, NF-κB signaling, and IL-17 signaling pathways. In conclusion, the S. costus plant could be a promising source of novel therapeutic agents for treating diabetes and its complications. Dehydrocostus lactone caused the ameliorative effect of S. costus by its interaction with human IkB kinase beta protein. Further, future studies could be conducted to find the clinical efficacy of dehydrocostus lactone.

Assessment of Effects of Rosemary Essential Oil on the Kidney Pathology of Diabetic Adult Male Albino Rats.

Background Diabetic nephropathy is a severe condition that causes persistent kidney problems and chronic renal failure. Rosemary (Rosmarinus officinalis L) is widely recognized for its antioxidant, antidiabetic, anti-inflammatory, antithrombotic, hepatoprotective, and anticancer activities. The current study evaluated rosemary essential oil (REO) effects on biochemical, histological, and immunohistochemical kidney alterations in streptozotocin (STZ)-induced diabetic rats and compared these effects with those of insulin and both combined. Methods We randomly distributed 36 adult albino rats into 6 groups: normal control (non-diabetic), diabetic (streptozotocin, 55 mg/kg, intraperitoneal), diabetic insulin-treated (Lantus insulin 2 units/day, SC), diabetic REO-treated (REO, 10 ml, nasogastric gavage), and diabetic insulin & REO-treated groups. Biochemical, histological, and immunohistochemical analyses were conducted. Results The diabetic group revealed a substantial increase in blood glucose, urea, creatinine, and uric acid, as well as malondialdehyde (MDA) and catalase (CAT) concentrations in kidney homogenates, high score of tubular injury, and increased glomerulosclerosis, along with marked reduction of total glutathione (GSH) and superoxide dismutase (SOD) when compared to control. Evident improvement was detected in rats treated with REO as it demonstrated antioxidant, anti-inflammatory, anti-apoptotic, pro-proliferative, and mild anti-hyperglycemic effects on diabetic rats, reducing the kidney damage caused by diabetes. Combined insulin and REO restored normal blood glucose, renal excretory function tests, antioxidant markers, and renal cortex histology. Conclusion The data presented in the current study's in vivo animal model suggests that REO supplementation has beneficial nephroprotective effects on the structural and, to a lesser extent, functional levels of diabetic rats. Furthermore, the detected nephroprotective effects of insulin and REO combined are superior to those of either administered alone. However, further studies are needed to evaluate these conclusions in humans further.

Apigenin Attenuates Hippocampal Microglial Activation and Restores Cognitive Function in Methotrexate-Treated Rats: Targeting the miR-15a/ROCK-1/ERK1/2 Pathway.

Microglial activation underpins the methotrexate (MTX)-induced neurotoxicity; however, the precise mechanism remains unclear. This study appraised the potential impact of apigenin (Api), a neuroprotective flavonoid, in MTX-induced neurotoxicity in rats in terms of microglial activation through targeting the miR-15a/Rho-associated protein kinase-1 (ROCK-1)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Male Sprague Dawley rats were randomly divided into 4 groups: Normal control (saline i.p. daily and i.v. on days 8 and 15); Api control (20 mg/kg, p.o.) daily for 30 days; MTX-alone (75 mg/kg, i.v.) on days 8 and 15, then four i.p. injections of leucovorin (LCV): 6 mg/kg after 18 h, then three doses (3 mg/kg) every 8 h post-MTX; and Api co-treated (20 mg/kg/day, p.o.) throughout the model for 30 days, with administration of MTX and LCV as in group 3. MTX administration elevated hippocampal ionized calcium-binding adaptor protein-1 (Iba-1) immunostaining, indicating microglial activation. This was accompanied by neuroinflammation, oxidative stress, and enhanced apoptosis manifested by elevated hippocampal interleukin-1ß, malondialdehyde, and caspase-3, and decreased reduced glutathione levels. Concurrently, abated miR-15a expression, overexpression of its target ROCK-1, diminished downstream ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation, and decreased hippocampal brain-derived neurotrophic factor (BDNF) levels were observed. Api mitigated the MTX-induced neurotoxicity by reversing the biochemical, histopathological, and behavioral derangements tested by novel object recognition and Morris water maze tests. Conclusively, Api lessens MTX-induced neuroinflammation, oxidative stress, and apoptosis and boosts cognitive function through inhibiting microglial activation via modulating the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway. Graphical abstract showing the effects of methotrexate and apigenin co-treatment in MTX-induced neurotoxicity model. On the left, methotrexate (MTX) administration to rats resulted in hippocampal miR-15a downregulation, which triggered an enhanced expression of its target ROCK-1, consequently inhibiting the downstream ERK1/2/CREB/BDNF pathway, instigating a state of microglial activation, neuroinflammation, oxidative stress, and apoptosis. On the other hand, apigenin (Api) co-treatment restored miR-15a, inhibited ROCK-1 expression, and activated the ERK1/2/CREB/BDNF pathway, leading to diminished hippocampal microglial activation, neuroinflammation, and apoptosis, and restoration of the redox balance, along with improvement in memory and cognitive function of the MTX-treated rats.

Enhanced Wound Healing Potential of Spirulina platensis Nanophytosomes: Metabolomic Profiling, Molecular Networking, and Modulation of HMGB-1 in an Excisional Wound Rat Model.

Excisional wounds are considered one of the most common physical injuries. This study aims to test the effect of a nanophytosomal formulation loaded with a dried hydroalcoholic extract of S. platensis on promoting excisional wound healing. The Spirulina platensis nanophytosomal formulation (SPNP) containing 100 mg PC and 50 mg CH exhibited optimum physicochemical characteristics regarding particle size (598.40 ± 9.68 nm), zeta potential (-19.8 ± 0.49 mV), entrapment efficiency (62.76 ± 1.75%), and Q6h (74.00 ± 1.90%). It was selected to prepare an HPMC gel (SPNP-gel). Through metabolomic profiling of the algal extract, thirteen compounds were identified. Molecular docking of the identified compounds on the active site of the HMGB-1 protein revealed that 12,13-DiHome had the highest docking score of -7.130 kcal/mol. SPNP-gel showed higher wound closure potential and enhanced histopathological alterations as compared to standard (MEBO® ointment) and S. platensis gel in wounded Sprague-Dawley rats. Collectively, NPS promoted the wound healing process by enhancing the autophagy process (LC3B/Beclin-1) and the NRF-2/HO-1antioxidant pathway and halting the inflammatory (TNF-, NF-κB, TlR-4 and VEGF), apoptotic processes (AIF, Caspase-3), and the downregulation of HGMB-1 protein expression. The present study's findings suggest that the topical application of SPNP-gel possesses a potential therapeutic effect in excisional wound healing, chiefly by downregulating HGMB-1 protein expression.

Protective Effects of Crocin Against Methotrexate-Induced Hepatotoxicity in Adult Male Albino Rats: Histological, Immunohistochemical, and Biochemical Study.

BACKGROUND: Among the many known adverse effects of methotrexate (MTX), hepatotoxicity stands out as a major drawback that limits its therapeutic applicability. There is growing evidence that crocin has antioxidant, anti-hyperglycemic, cardioprotective, and anti-inflammatory effects. This study's aim is to evaluate the potential protective effect of crocin against MTX-induced liver damage in rats using biochemical, histological, and immunohistochemical analyses. METHODS: Twenty-four adult male albino rats were split into four groups at random (six rats/group) as follows: normal control (saline, intraperitoneal (i.p.) injections), crocin-treated (100 mg/kg daily for 14 days, i.p.), MTX-treated (20 mg/kg single i.p. injection on day 15), and crocin/MTX-treated groups (crocin 100 mg/kg/day for 14 days, i.p. + MTX 20 mg/kg single i.p. injection on day 15). On day 16 of the experiment, blood and tissue specimens were used to assess the liver functions, oxidative stress markers, transforming growth factor beta 1 (TGF-ß1), caspase-3, BCL-2-associated X protein (BAX), and B-cell lymphoma 2 (BCL-2) expression. RESULTS: The results of the current research revealed the protective actions of crocin against MTX-induced hepatotoxicity. Our results showed that crocin possesses antioxidants (decrease malondialdehyde (MDA), increase glutathione (GSH) levels, and enhance catalase (CAT) and superoxide dismutase (SOD) enzymatic activity), anti-fibrotic (decrease TGF-ß1), and anti-apoptotic (decrease BAX and caspase-3 expression while increase BCL-2) actions in liver. Moreover, crocin administration along with MTX restores the normal histological structure of hepatic tissues. CONCLUSION:  The data presented in the current study using an in vivo animal model support the notion that crocin should be further studied in humans to assess its potential hepatoprotective effects against MTX-induced liver damage.

Dexmedetomidine Attenuates Methotrexate-Induced Neurotoxicity and Memory Deficits in Rats through Improving Hippocampal Neurogenesis: The Role of miR-15a/ROCK-1/ERK1/2/CREB/BDNF Pathway Modulation.

Methotrexate (MTX) is a widely used neurotoxic drug with broad antineoplastic and immunosuppressant spectra. However, the exact molecular mechanisms by which MTX inhibits hippocampal neurogenesis are yet unclear. Dexmedetomidine (Dex), an α2-adrenergic receptor agonist, has recently shown neuroprotective effects; however, its full mechanism is unexplored. This study investigated the potential of Dex to mitigate MTX-induced neurotoxicity and memory impairment in rats and the possible role of the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway. Notably, no former studies have linked this pathway to MTX-induced neurotoxicity. Male Sprague Dawley rats were placed into four groups. Group 1 received saline i.p. daily and i.v. on days 8 and 15. Group 2 received Dex at 10 µg/kg/day i.p. for 30 days. Group 3 received MTX at 75 mg/kg i.v. on days 8 and 15, followed by four i.p. doses of leucovorin at 6 mg/kg after 18 h and 3 mg/kg after 26, 42, and 50 h. Group 4 received MTX and leucovorin as in group 3 and Dex daily dosages as in group 2. Bioinformatic analysis identified the association of miR-15a with ROCK-1/ERK1/2/CREB/BDNF and neurogenesis. MTX lowered hippocampal doublecortin and Ki-67, two markers of neurogenesis. This was associated with the downregulation of miR-15a, upregulation of its target ROCK-1, and reduction in the downstream ERK1/2/CREB/BDNF pathway, along with disturbed hippocampal redox state. Novel object recognition and Morris water maze tests demonstrated the MTX-induced memory deficiencies. Dex co-treatment reversed the MTX-induced behavioral, biochemical, and histological alterations in the rats. These neuroprotective actions could be partly mediated through modulating the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway, which enhances hippocampal neurogenesis.

Evaluation of Short-Term Symptoms Associated With COVID-19 Vaccines Used Among Adolescents in Saudi Arabia.

OBJECTIVES: Several government-sponsored reporting systems have stated mild to moderate side effects of COVID-19 vaccines. However, patient-reported data on COVID-19 vaccine-associated adverse effects in adolescents are lacking. Our objective was to assess the short-term side effects of Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 vaccinations among teenagers in Saudi Arabia. METHODS: A retrospective, cross-sectional study was conducted among individuals aged 12-18 years old who received one of the two mentioned vaccines between July 2021 and March 2022 in Riyadh, Saudi Arabia. RESULTS: The most common short-term side effects reported for COVID-19 vaccines among teenagers in our study were fatigue, pain at the site of injection, fever, chills, headache, nausea, and vomiting. Female participants, individuals who had a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and those who received two doses of the vaccine are at higher risk to develop side effects after getting the vaccine. Importantly, asthmatic participants have a higher incidence of COVID-19 vaccine side effects when compared to those with no history of chronic diseases. CONCLUSION: Our findings might enhance public trust in the COVID-19 vaccine, which could speed up the immunization procedure.

Performance of Children With Donnai-Barrow Syndrome After Cochlear Implantation: A Case Report.

Donnai-Barrow syndrome (DBS) is a rare autosomal recessive hereditary disorder that affects a variety of body systems. One of the most common symptoms in DBS patients is severe bilateral sensorineural hearing loss. The objective of this report is to highlight the performance of such patients after receiving cochlear implants as a management of their hearing loss. We reviewed the medical records of two cousins diagnosed with DBS before and after cochlear implantation, with a particular focus on their auditory and language performance. After receiving the cochlear implant, both patients showed substantial progress in auditory and speech perception, as well as their intelligence quotients, allowing them to join mainstream schools. In conclusion, our findings showed that cochlear implantation can be considered an ideal approach for the management of DBS patients who suffer from bilateral sensorineural hearing loss.

Possible Implication of Nrf2, PPAR-γ and MAPKs Signaling in the Protective Role of Mangiferin against Renal Ischemia/Reperfusion in Rats.

Mangiferin (Mang) is a known glucosylxanthone that has proven its shielding effect against ischemia/reperfusion (Is/R). However, its full underlying mechanistic perspective against renal Is/R induced lesions is not fully revealed. Consequently, the purpose of this study is to track further non-investigated modulatory signals of Mang against the renal Is/R model involving nuclear factor erythroid 2-related factor (Nrf)2/heme oxygenase (HO)-1, peroxisome proliferator-activated receptor (PPAR)-γ/nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling. To ratify our aim, Mang was administrated (20 mg/kg, i.p for seven days) before the induction of bilateral Is/R. Mechanistic maneuver revealed that Mang balanced oxidative state via increasing the expression of the antioxidant Nrf2/HO-1 cue with subsequent enhancement of GSH besides MDA lessening. Additionally, Mang enhanced PPAR-γ mRNA expression and declined p-p38 MAPK and p-JNK expression with concomitant NF-κB downsizing leading to iNOS/NOx and TNF-α rebating. Furthermore, the Mang anti-apoptotic trait was affirmed by enriching Bcl-2 expression as well as decreasing Bax and caspase-3 expression. All these potentials were in the line with the molecular docking results and the improved histopathological findings and renal function biomarkers. Consequently, Mang provided plausible protective mechanisms against renal Is/R-related events, possibly by amending oxidative status, inflammatory mediators, and apoptotic cell death through the involvement of Nrf2, PPAR-γ, MAPK, JNK, and NF-κB signaling.

Performance of Children With Johanson-Blizzard Syndrome After Cochlear Implantation.

Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive hereditary disorder characterized by multi-system involvement and facial dysmorphic features. One of the most common symptoms in JBS patients is bilateral severe to profound sensorineural hearing loss. The objective of this report is to highlight the performance of those patients after receiving cochlear implants (CI) as a management for their hearing loss. In this study, we reviewed the medical records of one female child diagnosed with JBS before and after cochlear implantation, with a particular focus on their auditory and language performance. After receiving the cochlear implant, our patient showed substantial improvement in her hearing threshold and communication abilities when compared to the preoperative condition. In conclusion, although cochlear implantation is considered a good approach for the management of JBS patients, the development of spoken language is not always achieved.

Effects of bee venom and dopamine-loaded nanoparticles on reserpine-induced Parkinson's disease rat model.

Parkinson's disease (PD) is a progressive chronic neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. Current PD therapeutic strategies are mainly symptomatic and can lead to motor complications overtime. As a result, alternative medicine may provide an effective adjuvant treatment for PD as an addition to or as a replacement of the conventional therapies. The aim of this work was to evaluate the effects of Bee Venom (BV) and dopamine (DA)-loaded nanoparticles in a reserpine-induced animal model of PD. After inducing PD with reserpine injection, different groups of male rats were treated with L-Dopa, BV, DA-nanoparticles. Our findings showed that BV and DA-nanoparticles administration restored monoamines, balanced glutamate/GABA levels, halted DNA fragmentation, decreased pro-inflammatory mediators (IL-1ß and TNF-α), and elevated anti-inflammatory mediators (PON1) and neurotropic factor (BDNF) levels in comparison with conventional therapy of PD. Furthermore, in a reserpine-induced PD rat model, the ameliorative effects of BV were significantly superior to that of DA-nanoparticles. These findings imply that BV and DA-nanoparticles could be useful as adjuvant treatments for PD.

Potential Diagnostic and Prognostic Utility of miR-141, miR-181b1, and miR-23b in Breast Cancer.

miRNAs, a group of short noncoding RNAs, are key regulators of fundamental cellular processes and signaling pathways. Dysregulation of miRNA expression with known oncogenic or tumor suppressor functions has been associated with neoplastic transformation. Numerous studies have reported dysregulation of miRNA-141, miR-181b1, and miR-23b in a wide range of malignancies, including breast cancer. To the best of our knowledge, no previous study had demonstrated the expression of miR-141-3p, miR-181b1-5p, and miR-23b-3p in different histological grades and molecular subtypes of breast cancer. Here, we identified differential expression of these three miRNAs in breast cancer tissues compared with benign breast fibroadenomas. In addition, high expression levels of miR-141-3p and miR-181b1-5p are strongly associated with aggressive breast carcinomas. We also confirmed the clinical potential of using the three miRNAs individually or combined as diagnostic and prognostic markers in breast cancer. Using bioinformatics analyses, we identified 23 hub genes of these three miRNAs which are involved in key signaling pathways in breast cancer. Furthermore, the KM plotter online database analysis demonstrates the association between elevated expression of miR-141 and miR-181b and shorter overall survival of breast cancer patients. Together, our data suggest an oncogenic role of the studied miRNAs and highlight their molecular roles and potential clinical applications in breast cancer.

Clinical Significance of Expression Changes and Promoter Methylation of PLA2R1 in Tissues of Breast Cancer Patients.

Phospholipase A2 receptor 1 (PLA2R1) expression and its role in the initiation and progression of breast cancer are an unresolved issue. PLA2R1 was found to endorse several tumor suppressive responses, including cellular senescence and apoptosis. Previous in vitro studies demonstrated that DNA hypermethylation was highly associated with the epigenetic silencing of PLA2R1 in breast cancer cell lines. Our objective was to study the level of PLA2R1 mRNA expression and the methylation of its promoter in different histological grades and molecular subtypes of breast cancer. We performed bioinformatics analyses on available human breast cancer expression datasets to assess the PLA2R1 mRNA expression. We used qRT-PCR to evaluate the PLA2R1 mRNA expression and its promoter's methylation in breast cancer tissue in comparison to breast fibroadenomas. Our results describe, for the first time, the expression of PLA2R1 and the methylation of its promoter in human breast cancer tissues. A significant downregulation of PLA2R1, together with hypermethylation of the promoter was detected in breast cancers of different histological grades and molecular subtypes when compared to benign breast tissues. PLA2R1 promoter hypermethylation was associated with aggressive subtypes of breast cancer. In conclusion, PLA2R1 promoter hypermethylation is a potentially useful diagnostic and prognostic biomarker and could serve as a possible therapeutic target in breast cancer.

Shift work and risk of skin cancer: A systematic review and meta-analysis.

Shift work with circadian disruption has been considered as a carcinogenic risk factor for skin cancer. The few prior studies that investigated the association between shift work and skin cancer have inconclusive results. Our main objective was to evaluate the associations between shift work and the risks of different types of skin cancer. We systematically searched PubMed, Web of Science, Cochrane Library, EMBASE and Science Direct until October 2018 for studies that included a relationship between shift work and skin cancer. Our search yielded 193 articles and 9 studies met the criteria for our review. The included studies involved 3,579,147 participants and 17,308 skin cancer cases. Overall, ever shift work, was associated with increased risk of melanoma (RR = 1.10, 95% CI = 1.05-1.16) and a significant decrease in the risk of BCC (RR = 0.90, 95% CI = 0.88-0.93). No association between shift work and the risk of SCC was detected. Interestingly, our dose response analysis demonstrated that the risk of melanoma cumulatively increases by 2% for every year of shift work (RR = 1.02; 95% CI = 1.00-1.03). In conclusion, shift work is associated with increased risk of melanoma and deceased risk of BCC. Further studies are needed to confirm our findings and to elucidate the related potential biological mechanisms.

MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis.

Breast cancer is a heterogeneous disease comprising the estrogen receptor (ER)-positive luminal subtype which is subdivided into luminal A and luminal B and ER-negative breast cancer which includes the triple-negative subtype. This study has four aims: 1) to examine whether Minichromosome Maintenance (MCM)2, MCM4, and MCM6 can be used as markers to differentiate between luminal A and luminal B subtypes; 2) to study whether MCM2, MCM4, and MCM6 are highly expressed in triple-negative breast cancer, as there is an urgent need to search for surrogate markers in this aggressive subtype, for drug development purposes; 3) to compare the prognostic values of these markers in predicting relapse-free survival; and 4) to compare the three approaches used for scoring the protein expression of these markers by immunohistochemistry (IHC). MCM2, MCM4, MCM6, and MKI67 mRNA expression was first studied using in silico analysis of available breast cancer datasets. We next used IHC to evaluate their protein expression on tissue microarrays using three scoring methods. MCM2, MCM4, and MCM6 can help in distinction between luminal A and luminal B whose therapeutic management and clinical outcomes are different. MCM2, MCM4, MCM6, and Ki-67 are highly expressed in breast cancer of high histological grades that comprise clinically aggressive tumors such as luminal B, HER2-positive, and triple-negative subtypes. Low transcript expression of these markers is associated with increased probability of relapse-free survival. A positive relationship exists among the three scoring methods of each of the four markers. An independent validation cohort is needed to confirm their clinical utility.

PPARγ Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers.

Metastatic breast cancer is still incurable so far; new specifically targeted and more effective therapies for triple-negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPARγ. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPARγ both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPARγ ligands. Mechanistically, we show for the first time PPARγ-induced ANXA1 protein directly interacts with receptor interacting protein-1 (RIP1), promoting its deubiquitination and thereby activating the caspase-8-dependent death pathway. We further identified this underlying mechanism also involved a PPARγ-induced ANXA1-dependent autoubiquitination of cIAP1, the direct E3 ligase of RIP1, shifting cIAP1 toward proteosomal degradation. Collectively, our study provides first insight for the suitability of using drug-induced expression of ANXA1 as a new player in RIP1-induced death machinery in TNBCs, presenting itself both as an inclusion criterion for patient selection and surrogate marker for drug response in future PPARγ chemotherapy trials. Mol Cancer Ther; 16(11); 2528-42. ©2017 AACR.