Decoding LY6G6D in colorectal cancer: Unraveling biomarker potential and therapeutic insights.

Colorectal cancer (CRC) poses a significant global health challenge with high morbidity and mortality rates. This study investigates the role of LY6G6D, a member of the LY6/uPAR superfamily, in CRC. Employing a bioinformatic approach, we analyzed LY6G6D expression across different cancer types, compared it with known oncogenes in CRC, explored the involved genomic alterations, and assessed associated clinicopathological characteristics. LY6G6D exhibited aberrant expression, particularly elevated in CRC adenocarcinoma and highly specific to tumor tissues when compared with other oncogenes, despite its comparatively low frequency of genomic alteration. Subsequently, tumor immune infiltration analysis revealed distinct associations, primarily indicating a negative correlation, suggesting immune down-regulation. Survival analysis in context of LY6G6D was conducted with Kaplan-Meier (KM) curves, indicating a 10% risk of disease recurrence in the case of elevated expression. Additionally, we constructed a 3D protein model of LY6G6D through ab-inito approach. The protein model was validated, followed by conservation analysis and active site identification. Active site identification of LY6G6D's final predicted model revealed some similar sites that were estimated to be conserved. Target-guided drug molecules were collected and molecular docking was executed, proposing Cardigin (Digitoxin) and Manzamine A as potential therapeutic candidates. In conclusion, LY6G6D emerges as a significant biomarker for diagnostic and therapeutic applications in CRC, highlighting its multifaceted role in tumorigenesis. The proposed drugs present avenues for further investigations.

Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent.

Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI50 values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.

Anticancer genes (NOXA, PAR-4, TRAIL) are de-regulated in breast cancer patients and can be targeted by using a ribosomal inactivating plant protein (riproximin).

BACKGROUND: Anticancer genes are an endogenous defense against transformed cells as they impose antineoplastic effects upon ectopic expression. Profiling the expression of these genes is fundamental for exploring their prognostic and therapeutic relevance in cancers. Natural compounds can upregulate anticancer genes in malignant cells and thus be useful for therapeutic purposes. In this study, we identified the expression levels of anticancer genes in breast cancer clinical isolates. In addition, the purified and sequenced plant protein (riproximin) was evaluated for its potential to induce anticancer genes in two breast cancer cell lines. METHODOLOGY: Expression profiles of three anticancer genes (NOXA, PAR-4, TRAIL) were identified by immunohistochemistry in 45 breast cancer clinical isolates. Breast cancer cells were exposed to riproximin and expression of the anticancer genes was determined by microarray, real-time PCR and western blot methodologies. Lastly, a bioinformatic approach was adopted to highlight the molecular/functional significance of the anticancer genes. RESULTS: NOXA expression was evenly de-regulated among the clinical isolates, while PAR-4 was significantly down-regulated in majority of the breast cancer tissues. In contrast, TRAIL expression was increased in most of the clinical samples. Expression levels of the anticancer genes followed a distinct trend in accordance with the disease severity. Riproximin showed a substantial potential of inducing expression of the anticancer genes in breast cancer cells at transcriptomic and protein levels. The bioinformatic approach revealed involvement of anticancer genes in multiple cellular functions and signaling cascades. CONCLUSION: Anticancer genes were de-regulated and showed discrete expression patterns in breast cancer patient samples. Riproximin effectively induced the expression of selected anticancer genes in breast cancer cells.

The Spectrum of Malignant Neoplasms among Liver Transplant Recipients: Sociodemographic Factors, Mortality, and Hospital Burden.

Objective: To determine the nationwide prevalence of malignant neoplasms (excluding hepatocellular carcinoma-HCC) in hospitalized liver transplant recipients and to study the hospital utilization, and mortality to the incidence of malignancies. To the best of our knowledge, few epidemiological studies addressed outcomes in post-liver transplant patients, such as the annual number of hospitalizations, mortality, patient characteristics regarding malignancies. Methods: NIS database was queried between 2016 and 2018 to retrieve records of patients admitted with a principal or secondary diagnosis of liver transplant following the International Classification of Diseases, tenth Revision (ICD-10). The population was divided into case and control groups according to the presence and absence of malignant neoplasm (MN) except for HCC. We also compared the incidence of MN in LTX patients and non-LTX matched cohort. Results: A total of 7.28% admissions were associated with malignant neoplasms (except HCC) in LTX patients. Lymphomas, respiratory, gastrointestinal (excluding HCC), leukemia, and head/neck were commonest cancers with estimated admission rates of 0.97%, 0.90%, 0.80%, 0.53%, and 0.49%, respectively. Lung cancer was the most frequent malignant neoplasm among White and Black racial/ethnic groups (15.78% and 14.8%), whereas lymphoma was pervasive among Hispanics (20.3%). Lung cancer had the highest in-hospital mortality (10.55%), followed by the cancer of the nervous system (9.09%). The LTX and non-LTX cohort comparison showed that LTX patients are at increased risk of head and neck cancers, skin cancers, lymphomas, tumors, and Myelodysplastic syndrome. According to a multivariate analysis, a statistically significant association existed between malignant neoplasms in LTX patients and the following factors: increasing age (P < .001), higher mortality (P < .001), females with 29% lesser odds than males (P < .001), Black race and Hispanic ethnicity with 20% and 26% lesser odds as compared to White (P < .05). Clinical factors included smoking, Alcoholic cirrhosis, Hepatitis B, and Hepatitis C, were statistically significant risk factors of post-liver transplantation malignancies. Conclusions: Malignancies were frequent among elderly patients and predominantly in males. Lymphoproliferative diseases were the most prevalent malignancy types, followed by respiratory/lung cancer- which showed the highest mortality risk of all cancers. LTX patients are at increased risk of head and neck cancers, skin cancers, lymphoma, tumors, and Myelodysplastic syndrome compared to non-LTX patients.

Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate.

Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.

Methemoglobin is an endogenous toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage.

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NFκB) in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from erythrocyte breakdown have been postulated to be endogenous TLR4 ligands: methemoglobin (metHgb), heme and hemin. However, poor water solubility of heme and hemin, and lipopolysaccharide (LPS) contamination have confounded our understanding of these molecules as endogenous TLR4 ligands. We used a 5-step process to obtain highly purified LPS-free metHgb, as confirmed by Fourier Transform Ion Cyclotron Resonance mass spectrometry and by the Limulus amebocyte lysate assay. Using this preparation, we show that metHgb is a TLR4 ligand at physiologically relevant concentrations. metHgb caused time- and dose-dependent secretion of the proinflammatory cytokine, tumor necrosis factor α (TNFα), from microglial and macrophage cell lines, with secretion inhibited by siRNA directed against TLR4, by the TLR4-specific inhibitors, Rs-LPS and TAK-242, and by anti-CD14 antibodies. Injection of purified LPS-free metHgb into the rat subarachnoid space induced microglial activation and TNFα upregulation. Together, our findings support the hypothesis that, following SAH, metHgb in the subarachnoid space can promote widespread TLR4-mediated neuroinflammation.

PLL-g-PEG Polymer Inhibits Antibody-Drug Conjugate Uptake into Human Corneal Epithelial Cells In Vitro.

Purpose: Antibody-drug conjugates (ADCs) are a relatively recent advance in the delivery of chemotherapeutics that improve targeting of cytotoxic agents. However, despite their antitumor activity, severe ocular adverse effects, including vision loss, have been reported for several ADCs. The nonspecific uptake of ADCs into human corneal epithelial cells (HCECs) and their precursors via macropinocytosis has been proposed to be the primary mechanism of ocular toxicity. In this study, we evaluated the ability of a novel polymer, poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG), to decrease the ADC rituximab-mc monomethylauristatin F (MMAF) (RIX) uptake into human corneal epithelial (HCE-T) cells. Methods: HCE-T cells were exposed to increasing concentrations of RIX to determine inhibition of cell proliferation. HCE-T cells were treated with PLL-g-PEG, the macropinocytosis inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA), or vehicle. After 30 min of incubation, RIX was added. ADC was detected by fluorescent anti-human immunoglobulin G and fluorescently conjugated dextran as viewed by microscopy. Results: RIX caused dose-dependent inhibition of HCE-T cell proliferation. EIPA significantly reduced RIX uptake and decreased macropinocytosis as assessed by direct quantification of RIX using a fluorescently conjugated anti-human antibody as well as quantification of macropinocytosis using fluorescently conjugated dextran. PLL-g-PEG resulted in a dose-dependent inhibition of RIX uptake with half-maximal inhibitory concentrations of 0.022%-0.023% PLL-g-PEG. Conclusion: The data show PLL-g-PEG to be a potent inhibitor of RIX uptake by corneal epithelial cells and support its use as a novel therapeutic approach for the prevention of ocular adverse events associated with ADC therapy.

Predicting Success: A Comprehensive Analysis of High School and Admission Test Scores on Future Academic Performance of Dental Students.

Introduction Dental school admissions in Pakistan traditionally rely on Higher Secondary School Certificate (HSSC), University of Health Sciences (UHS), and National Testing Service (NTS) scores, with limited research available on their predictive validity for dental school performance. This study aims to investigate the correlation between a student's first-year dental school performance and their HSSC, UHS, and NTS scores. Methods A total of 282 records, spanning the years 2016 to 2020, were obtained from a single private dental institution. The data included HSSC, UHS, and/or NTS scores, with the first professional examination results as the dependent variable. Statistical analysis was conducted using the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 25.0, Armonk, NY), encompassing descriptive statistics, Pearson's correlation coefficients, and multiple regression analysis. Results Pearson's coefficients revealed weak to moderate positive correlations between the first professional examination and HSSC (r=0.209, p<.01), UHS (r=0.344, p<.01), and NTS (r=0.350, p<.01), all statistically significant at p < 0.01. Multiple regression analysis indicated that UHS scores contributed the highest explanatory power (R² = 0.146) in predicting first professional examination results. Conclusion A positive correlation between HSSC, UHS, and NTS scores with dental students' performance in the first professional examination is observed. However, the correlations are moderate, highlighting the importance of incorporating assessments that consider cognitive, behavioral, and skill-related aspects in admissions processes. Given the evolving landscape of dental education, these findings underscore the need for a holistic approach to identify candidates better equipped to serve the healthcare sector.

What inhibits the progress of early-career women in Karachi? Studying the effects of socio-spatial mobility barriers on women's employment.

BACKGROUND: There is a widespread acceptance and shift towards sustainable, inclusive and smart mobility solutions around the world. However, in Karachi, poorly coordinated urban planning, lack of effective governance structure and investment in transport, has allowed the growth of an almost unregulated and ungovernable informal transport sector. Women are more severely affected by the poor service since men not only have more space allocated to them on public transport but also have the freedom to use alternative and cheaper private vehicles such as motorbikes and cycles. Poor representation of women in the transport sector further aggravates the situation. OBJECTIVE: The paper aims to highlight the gender-disaggregated effects of poor transport design, provision and lack of personal agency on mobility, for emphasising the social and cultural attitudes faced by female employees. It argues that not integrating the gender-based disadvantages faced by women into planning, reinforces their disadvantaged position and force them to take complex trips. METHODS: Scenario-based questions were designed for focus group discussion which covered not only the everyday mobility challenges but also their reactions to the potential solutions. For a gender-based comparative analysis, two separate focus group discussions were organised. RESULTS: Adopting a sector-based mapping approach of the issues discussed in the groups helped understand the complexity of female user experience at various levels, starting from planning or discussing the trips with families, to making modal choices. It also helped to tease out the impact of these issues on their employment opportunities as early-career women. CONCLUSION: The model proposed in this paper can help illustrate where changes can be made in the system considering the social aspects of transport.

Expression profiling of anticancer genes in colorectal cancer patients and their in vitro induction by riproximin, a ribosomal inactivating plant protein.

BACKGROUND: Ectopic expression of anticancer genes (ACGs) imposes antineoplastic effects on transformed cells. Clinically, reduced expression of these genes has been linked with poor prognosis, metastasis and chemo/radiotherapy resistance in cancers. Identifying expression pattern of ACGs is crucial to establish their prognostic and therapeutic relevance in colorectal cancer (CRC). In addition to the clinical perspective, naturally occurring compounds can be explored in parallel for inducing ACGs to achieve cancer cell-specific death. METHODOLOGY: Expression profiles of three ACGs (NOXA, PAR-4, TRAIL) were identified via real-time PCR in CRC clinical isolates. Time lapse-based expression modifications in ACGs were studied in a CRC liver metastasis animal model using microarray methodology. Effects of a purified plant protein (riproximin) on selected ACGs were identified in three primary and metastatic CRC cell lines by real-time PCR. Lastly, importance of the ACGs in a cellular environment was highlighted via bioinformatic analysis. RESULTS: ACGs (except NOXA) were persistently downregulated in clinical isolates when comparing the overall mean expression values with normal mucosa levels. In vivo studies showed a prominent inhibition of NOXA and PAR-4 genes in implanted CRC cells during rat liver colonization. TRAIL showed deviation from this theme while showing marked induction during the early period of liver colonization (days 3 and 6 after CRC cell implantation). Riproximin exhibited substantial potential of inducing ACGs at transcriptome levels in selected CRC cell lines. Bioinformatic analysis showed that vital molecular/functional aspects of a cell are associated with the presence of ACGs. CONCLUSION: ACGs are downregulated in primary and metastatic phase of CRC. Riproximin effectively induces ACGs in CRC cells and can be exploited for clinical investigations over time.

Dietary Alcohol Consumption Elicits Corneal Toxicity Through the Generation of Cellular Oxidative Stress.

Purpose: Clinical data suggest that alcohol use is associated with the development of signs and symptoms of dry eye disease. However, preclinical data investigating ocular toxicity after dietary alcohol consumption are lacking. In this study, we investigated the effects of alcohol on the ocular surface, in human corneal epithelial cells (HCE-T) in vitro and in C57BL/6JRj mice in vivo. Methods: HCE-T were exposed to clinically relevant doses of ethanol. To determine the effects of dietary alcohol consumption in vivo, wild-type mice were administered the Lieber-DeCarli liquid diet (5% vol/vol ethanol or isocaloric control) for 10 days ad libitum. Corneal fluorescein staining was performed to assess ocular surface damage. Histopathological and gene expression studies were performed on cornea and lacrimal gland tissue. Results: Sublethal doses of ethanol (0.01%-0.5%) resulted in a dose-dependent increase of cellular oxidative stress in corneal epithelial cells and a significant increase in NFE2L2 and downstream antioxidant gene expression, as well as an increase in NFκB signaling; short-term exposure (0.5%, 4 h) triggered significant corneal epithelial cell barrier breakdown. Exposure to the alcohol-containing diet caused a 3-fold increase in corneal fluorescein staining, with no effect on tear volumes. Corneal thickness was significantly reduced in the alcohol diet group, and corneal tissue revealed dysregulated antioxidant and NFκB signaling. Our data provide the first published evidence that alcohol exposure causes ocular toxicity in mice. Conclusions: Our results are consistent with clinical studies linking past alcohol consumption to signs of ocular surface disease.

Novel biomarker panel predicts prognosis in human papillomavirus-negative oropharyngeal cancer: an analysis of the TAX 324 trial.

BACKGROUND: New treatment strategies for locally advanced head and neck squamous cell carcinoma combine induction chemotherapy and chemoradiation. Identifying the predictors of outcome in sequentially treated patients is critical for focusing therapeutic research. In this analysis, the authors evaluated human papillomavirus type 16 (HPV-16) status and the expression levels of a defined set of biomarkers to identify predictors of response to this treatment modality. METHODS: In total, 114 patients with oropharyngeal cancer (OPC) who were treated on the TAX 324 trial (cisplatin and fluorouracil with or without docetaxel in patients with locally advanced head and neck squamous cell carcinoma) had pretreatment biopsy specimens that were evaluable for HPV-16 DNA and immunohistochemical expression of the following biomarkers: beta-tubulin II (ßT-II), glutathione S-transferase (GST-π), p53, and B-cell lymphoma 2 (Bcl-2). Patients were categorized into risk groups based on their HPV status and biomarker expression levels. RESULTS: Patients with high-risk OPC were defined by HPV-negative status and either elevated expression of ßT-II or levels of at least 2 of the other 3 adverse markers (elevated GST-π, elevated p53, or low Bcl-2). All other HPV-negative patients were categorized as moderate risk. In total, 55 patients were HPV-positive, and 59 patients were HPV-negative, with 34 were categorized as high risk and 25 categorized as moderate risk. The median survival for HPV-positive patients was not reached. The median survival was 44.2 months for moderate-risk patients (95% confidence interval, 20.9 months to not reached) and 12.1 months for high-risk patients (95% confidence interval, 7.5-19.7 months). The 24-month survival rate was 89% for HPV-positive patients, 67% for moderate-risk patients, and 29% for high-risk patients (P < .0001). CONCLUSIONS: The molecular data set in this study readily differentiated between 2 distinct groups of patients with locally advanced, HPV-negative OPC. This risk-stratification strategy may serve as a guide for treatment selection.

Pleomorphic Adenoma of Minor Salivary Gland.

Pleomorphic adenoma is a benign tumor of salivary glands, arising from minor salivary glands, is very rare and presents with a minor female predilection; and the highest occurrence is between the fourth and sixth decades of life. It is of glandular origin, usually presenting as a slowly growing, painless, firm swelling that does not cause ulceration of the overlying mucosa. In this case, a 27-year male presented with swelling on buccal mucosa for three years. The swelling was firm and well circumscribed. Excisional biopsy was done under general anesthesia and the mass was excised. The histopathological evaluation revealed pleomorphic adenoma. This case highlights the need to keep this entity in the differential diagnosis of intra-oral indolent swellings of some duration. Key Words: Pleomorphic adenoma, Buccal mucosa, Minor salivary glands.

Applications of graphene-based electrochemical and optical biosensors in early detection of cancer biomarkers.

Graphene is a one-atom-thick carbon compound, which holds promises for detecting cancer biomarkers along with its derivatives. The atom-wide graphene layer is ideal for cancer biomarker detection due to its unique physicochemical properties like increased electrical and thermal conductivity, optical transparency, and enhanced chemical and mechanical strength. The scientific aim of any biosensor is to create a smaller and portable point of care device for easy and early cancer detection; graphene is able to live up to that. Apart from tumour detection, graphene-based biosensors can diagnose many diseases, their biomarkers, and pathogens. Many existing remarkable pieces of research have proven the candidacy of nanoparticles in most cancer biomarkers detection. This article discusses the effectiveness of graphene-based biosensors in different cancer biomarker detection. This article provides a detailed review of graphene and its derivatives that can be used to detect cancer biomarkers with high specificity, sensitivity, and selectivity. We have highlighted the synthesis procedures of graphene and its products and also discussed their significant properties. Furthermore, we provided a detailed overview of the recent studies on cancer biomarker detection using graphene-based biosensors. The different paths to create and modify graphene surfaces for sensory applications have also been highlighted in each section. Finally, we concluded the review by discussing the existing challenges of these biosensors and also highlighted the steps that can be taken to overcome them.

Prevalence of C-shaped canal and related variations in maxillary and mandibular second molars in the Indian Subpopulation: A cone-beam computed tomography analysis.

Aim: The aim of this study was to evaluate the prevalence and anatomical configuration of the C-shaped canal in permanent maxillary and mandibular second molars in the Greater Noida population by compiling the results of data that used cone-beam computed tomography (CBCT) analysis. Subjects and Methods: CBCT images were taken from the archive in the department of oral medicine and radiology taken for diagnostic purposes referred by other departments in the dental college. Five hundred CBCT records of patients, between the age group of 15-40 years, containing maxillary second molars and mandibular second molars were selected and reviewed. Statistical Analysis: Statistical analysis was done using the Chi-square test to find out the most common configuration of the C-shaped canal between maxillary and mandibular second molars. Results: Hundred and ten out of 500 patients had C-shaped canals (22%). Among them, 58 teeth (52.7%) were continuous C-shaped canals, 41 teeth (37.3%) were semicolon-shaped canals and 11 teeth (10%) had separated canals. (Chi-square test value = 8.26, P = 0.024). Statistically significant difference was found in configuration types. Among the jaw type, 62 maxillary second molar presented with C-shaped canal (25.1%) and 48 mandibular second molar presented with C-shaped canal (18.9%) (Chi-square test value = 3.87, P = 0.276). However, the difference was statistically insignificant in relation to the jaw type. Conclusions: Within the limitation of the study, we can conclude that the overall prevalence of C-shaped canals was 22% and the most common C-shaped canal configuration type was continuous (52.7%). However, no statistically significant difference was found in relation to jaw type.

A Rare Case of Recurrent Arterial Thrombosis Secondary to Iron Deficiency Anemia.

Iron deficiency anemia is the leading cause of anemia all over the world. Iron deficiency is known to cause reactive thrombocytosis. However, arterial thrombosis secondary to reactive thrombocytosis is a rare entity. In this article, we present a case of a 37-year-old female with recurrent arterial thrombosis due to severe thrombocytosis caused by iron deficiency anemia. The patient developed spleen and kidney infractions, as well as abdominal aortic thrombosis. She was subsequently treated with iron and aspirin with an improvement of the anemia and thrombocytosis, with no further thrombotic complications. Arterial thrombosis is a very serious condition as the thrombus can embolize to carotid arteries leading to stroke or to peripheral blood vessels causing peripheral ischemia and gangrene. Iron deficiency anemia is a reversible cause of thrombocytosis that can be treated very easily to avoid thrombotic complications.

Topical Porphyrin Antioxidant Protects Against Ocular Surface Pathology in a Novel Rabbit Model for Particulate Matter-Induced Dry Eye Disease.

Purpose: Particulate matter (PM) is a primary cause for the development of acute and chronic dry eye disease, especially irritant-induced conjunctivitis. The purpose of the present study was to determine the effects of fine atmospheric PM on the rabbit ocular surface, and determine the protective effects of a synthetic antioxidant, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (Mn-TM-2-PyP), in vitro and in vivo. Methods: Rabbit corneal epithelial cells (SIRC) were exposed to increasing concentrations of PM to determine the effects on cell motility and viability. The in vivo effects of topically instilled PM were tested in New Zealand White rabbits. Comprehensive ophthalmic exams and corneal fluorescein staining were performed. Results: Exposure to PM resulted in dose-dependent cell death and impaired cellular motility; Mn-TM-2-PyP protected against PM-induced cytotoxicity and significantly increased SIRC cell motility. In vivo, exposure to PM (5 mg/ml, topical, 3 times daily for 7 days) resulted in signs of dry eye, notably hyperemia, increased corneal fluorescein staining, and decreased tear volumes. Mn-TM-2-PyP significantly improved hyperemia and corneal fluorescein readouts but had no effect on tear production. Lifitegrast (Xiidra®) showed similar pharmacologic efficacy to Mn-TM-2-PyP. Conclusion: Overall, these data provide evidence that PM induces phenotypes of ocular surface disease responsive to antioxidant and immunosuppressant therapy. To our knowledge this is the first report of a large animal model to study PM-induced ocular surface disease. The present work provides standardized experimental paradigms for the comprehensive in vitro and in vivo testing of novel therapeutic approaches targeting PM-induced conjunctivitis and dry-eye.

The impact of a sacroiliac joint belt on function and pain using the active straight leg raise in pregnancy-related pelvic girdle pain.

INTRODUCTION: Pelvic girdle pain (PGP) is the most common musculoskeletal concern in pregnancy. The Active Straight Leg Raise (ASLR) test is diagnostic. Sacroiliac joint (SIJ) belts are included in multimodal therapy, but there is no established predictive measure to determine which pregnant women will benefit. OBJECTIVE: To determine if the ASLR score is immediately reduced by SIJ belt application and whether PGP pain and function improves after 4 weeks of belt use. DESIGN: Prospective observational cohort study. SETTING: Academic medical center. PARTICIPANTS: Pregnant women at least 18 years of age in the second or third trimester of pregnancy with posterior PGP and ASLR score of 2 to 10. INTERVENTIONS: Four-week SIJ belt use. MAIN OUTCOME MEASURES: ASLR, Numerical Rating Scale (NRS), Pelvic Girdle Questionnaire (PGQ), Perceived Global Impression of Improvement (PGII). RESULTS: Sixty-three women enrolled. On multivariable analysis, immediate belted ASLR score was -2.70 points lower than the non-belted ASLR score (P < .001). Four weeks later there was significant improvement in the ASLR score with a belt (Mdiff = -0.99; P = .001) and without a belt (Mdiff = -1.94; P < .001); the decline was more precipitous for the non-belted response (Mdiff = -0.96; P = .02). Current NRS pain scores declined from baseline by approximately -0.94 points (P < .001). This decline did not depend on ASLR scores (interaction P = .43) or wearing a belt at the time of testing (interaction P = .51). Similar conclusions held for participants' usual NRS score and average PGQ score. After 4 weeks, 82% reported improvement based on the PGII. CONCLUSIONS: SIJ belts are a safe, well-tolerated, and effective therapeutic option for pregnancy-related PGP. The ASLR score is immediately reduced following SIJ belt application but does not predict pain score 4 weeks later. SIJ belt leads to significant improvements in pain and function over time.

In silico screening, SAR and kinetic studies of naturally occurring flavonoids against SARS CoV-2 main protease.

The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) pandemic has become a global challenge based on its replication within the host cells that relies on non-structural proteins, protease (Mpro). Flavonoids, an important class of naturally occurring compounds with medicinal importance, are frequently available within fruits and vegetables. Herein, we report the in silico studies on naturally occurring flavonoids consisting of molecular docking studies and evaluation of theoretical kinetics. In this study, we prepared a library of nine different classes of naturally occurring flavonoids and screened them on Autodock and Autodockvina. The pharmacokinetic properties of most promising compounds have been predicted through ADMET SAR, inhibition constants, ligand efficiency and ligand fit quality have been worked out theoretically. The results revealed that naturally occurring flavonoids could fit well in the receptor's catalytic pocket, interact with essential amino acid residues and could be useful for future drug candidates through in vitro and in vivo studies. Moreover, MD simulation studies were conducted for two most promising flavonoids and the protein-ligand complexes were found quite stable. The selected natural flavonoids are free from any toxic effects and can be consumed as a preventive measure against SARS CoV-2.