The role of adjuvant treatment for early-stage uterine clear cell carcinomas.

BACKGROUND: Uterine clear cell carcinoma is a rare and aggressive subtype of endometrial carcinoma. Prospective clinical trials have not been feasible for this rare tumor, and data regarding the optimal adjuvant treatment regimen for early-stage uterine clear cell carcinomas is limited. Our study's objective was to determine if adjuvant chemotherapy or radiation therapy improves patients' outcomes in stage I and II uterine clear cell carcinoma. METHODS: Patients with stage I and II uterine clear cell carcinoma were identified at a single institution. All cases were reviewed by a gynecologic pathologist. Both pure and mixed non-serous uterine clear cell carcinomas were included. Primary outcomes were recurrence free survival and overall survival. RESULTS: A total of 71 patients were identified including 39 (55%) pure and 32 (45%) mixed clear cell carcinoma. Most patients were FIGO stage IA (77.5%). Most patients (n = 58, 82%) received adjuvant therapy, including 43 (61%) receiving chemotherapy, 50 (70%) receiving radiation therapy, and 35 (49%) receiving both. Recurrence free survival was not significantly different among patients receiving no or <6 cycles of chemotherapy versus patients receiving 6 cycles of chemotherapy (p = 0.39). However, median OS was significantly different among patients receiving no or <6 cycles of chemotherapy versus 6 cycles of chemotherapy (p = 0.004). On univariable analysis, 6 cycles of chemotherapy was significantly associated with improved OS (HR 0.1, 95% CI 0.01-0.07). Presence of LVSI, mutated p53, number of pelvic and para-aortic lymph nodes assessed, adjuvant chemotherapy (any number of cycles), and >2 medical co-morbidities were not significant predictors of OS on univariable analysis. On multivariable analysis, 6 cycles of adjuvant chemotherapy remained a significant predictor of improved OS (HR 0.1, 95% CI 0.01-0.8). CONCLUSIONS: In this study, administration of 6 cycles of chemotherapy appears to significantly improve OS. This finding suggests consideration of 6 cycles of adjuvant chemotherapy in patients with early-stage uterine clear cell carcinoma, however clinical trials are needed to confirm these findings.

Ranuncoside's attenuation of scopolamine-induced memory impairment in mice via Nrf2 and NF-ĸB signaling.

Scopolamine is a well-known pharmacological agent responsible for causing memory impairment in animals, as well as oxidative stress and neuroinflammation inducer which lead to the development of Alzheimer disease. Although a cure for Alzheimer's disease is unavailable. Ranuncoside, a metabolite obtained from a medicinal plant has demonstrated antioxidant and anti-inflammatory properties in vitro, making it a promising treatment with potential anti-Alzheimer disease properties. However, as ranuncoside has not been evaluated for its antioxidant and anti-neuroinflammatory properties in any in vivo model, our study aimed to evaluate its neurotherapeutic efficacy against scopolamine-induced memory impairment in adult male albino mice. Mice were randomly divided into four experimental groups. Mice of group I was injected with saline, group II was injected with scopolamine (1 mg/kg/day) for 3 weeks. After receiving a daily injection of scopolamine for 1 week, the mice of group III were injected with ranuncoside (10 mg/kg) every other day for 2 weeks along with scopolamine daily and group IV were injected with ranuncoside on 5th alternate days. Behavioral tests (i.e., Morris water maze and Y-maze) were performed to determine the memory-enhancing effect of ranuncoside against scopolamine's memory deleterious effect. Western blot analysis was also performed to further elucidate the anti-neuroinflammatory and antioxidant effects of ranuncoside against scopolamine-induced neuroinflammation and oxidative stress. Our results showed memory-enhancing, anti-neuroinflammatory effect, and antioxidant effects of ranuncoside against scopolamine by increasing the expression of the endogenous antioxidant system (i.e., Nrf2 and HO-1), followed by blocking neuroinflammatory markers such as NF-κB, COX-2, and TNF-α. The results also revealed that ranuncoside possesses hypoglycemic and hypolipidemic effects against scopolamine-induced hyperglycemia and hyperlipidemia in mice as well as scopolamine's hyperglycemic effect. In conclusion, our findings suggest that ranuncoside could be a potential agent for the management of Alzheimer's disease, hyperglycemia, and hyperlipidemia.

Cost-effectiveness analysis of tumor molecular classification in high-risk early-stage endometrial cancer.

PURPOSE: Tumor molecular analyses in endometrial cancer (EC) includes 4 distinct subtypes: (1) POLE-mutated, (2) mismatch repair protein (MMR) deficient, (3) p53 mutant, and (4) no specific molecular profile. Recently, a sub-analysis of PORTEC-3 demonstrated notable differences in treatment response between molecular classification (MC) groups. Cost of testing is one barrier to widespread adoption of MC. Therefore, we sought to determine the cost-effectiveness of MC in patients with stage I and II high-risk EC. METHODS: A Markov decision model was developed to compare tumor molecular classification (TMC) vs. no testing (NT). A healthcare payor's perspective and 5-year time horizon were used. Base case data were abstracted from PORTEC-3 and the molecular sub-analysis. Cost and utility data were derived from public databases, peer-reviewed literature, and expert input. Strategies were compared using the incremental cost-effectiveness ratio (ICER) with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness-to-pay threshold of $100,000 per QALY gained. Sensitivity analyses were performed to test model robustness. RESULTS: When compared to NT, TMC was cost effective with an ICER of $25,578 per QALY gained; incremental cost was $1780 and incremental effectiveness was 0.070 QALYs. In one-way sensitivity analyses, results were most sensitive to the cost of POLE testing, but TMC remained cost-effective over all parameter ranges. CONCLUSIONS: TMC in early-stage high-risk EC is cost-effective, and the model results were robust over a range of parameters. Given that MC can be used to guide adjuvant treatment decisions, these findings support adoption of TMC into routine practice.

Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis.

Garlic's main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of -4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.

Bearing Stake 1977 revisited: An understanding of ambient sound sources in the Indian Ocean.

A previous analysis of 1977 passive acoustic recordings in the Indian Ocean focused on sound pressure levels (SPLs) and showed that SPLs were slightly depth dependent and highly influenced by shipping activities [Wagstaff and Aitkenhead, IEEE J. Ocean. Eng. 30(2), 295-302 (2005)]. Consequently, SPL alone does not provide a consistent comprehensive metric to compare among sites or with contemporary recordings in the same region. Therefore, a source separation analysis was devised and applied to identify the major sound source contributions at three Indian Ocean locations. Shipping noise was a major sound contributor in all sites, while the site with the most diverse number of sources was in the central Arabian Sea.

An Empirical Mode Decomposition-based detection and classification approach for marine mammal vocal signals.

Detecting marine mammal vocalizations in underwater acoustic environments and classifying them to species level is typically an arduous manual analysis task for skilled bioacousticians. In recent years, machine learning and other automated algorithms have been explored for quickly detecting and classifying all sound sources in an ambient acoustic environment, but many of these still require a large training dataset compiled through time-intensive manual pre-processing. Here, an application of the signal decomposition technique Empirical Mode Decomposition (EMD) is presented, which does not require a priori knowledge and quickly detects all sound sources in a given recording. The EMD detection process extracts the possible signals in a dataset for minimal quality control post-processing before moving onto the second phase: the EMD classification process. The EMD classification process uniquely identifies and labels most sound sources in a given environment. Thirty-five recordings containing different marine mammal species and mooring hardware noises were tested with the new EMD detection and classification processes. Ultimately, these processes can be applied to acoustic index development and refinement.

Intraoperative Archive of Right Colonic Vascular Variability Aids Central Vascular Ligation and Redefines Gastrocolic Trunk of Henle Variants.

BACKGROUND: Vascular supply to the right colon has become an issue because of high variability and subsequent impact on minimally invasive surgery. Past cadaveric or radiologic anatomic assessments are noncomprehensive. OBJECTIVE: Intraoperative charting of right colonic arteriovenous anatomy was undertaken to determine the incidence and scope of vascular variations. DESIGN: Vascular anatomy variations were documented in snapshot images, captured during laparoscopic video recordings or through open surgical digital photography. SETTINGS: Data were drawn from consecutive right hemicolectomies, routinely entailing complete mesocolic excision with central vascular ligation. PATIENTS: Seventy patients (mean age, 62.7 years; 37 women (52.8%); 33 men (47.2%)), each with surgically treatable right-sided colon cancer, were prospectively studied. RESULTS: Both ileocolic and middle colic arteries were regularly identified (100%), with right colic artery present in 41.4% of patients. Ileocolic and middle colic veins consistently drained into the right colon. Although the ileocolic vein always emptied into the superior mesenteric vein, drainage of the middle colic vein was split (superior mesenteric vein, 94.3%; gastrocolic trunk of Henle, 5.3%), as was drainage of the right colic (superior mesenteric vein, 43.3%; gastrocolic trunk of Henle, 56.7%) and accessory middle colic veins (superior mesenteric vein, 54.5%; gastrocolic trunk of Henle, 45.5%), present in 42.9% and 15.7% of patients. Gastrocolic trunk of Henle was found in 88.6% of patients, usually draining into the superior mesenteric vein. No significant sex-related differences were present regarding the incidence and scope of variability displayed by the right colic artery, right colic vein, accessory middle colic vein, or gastrocolic trunk of Henle classification (p > 0.05). LIMITATIONS: The inconsistency between cadaver and live surgery anatomy and the low BMI of the Asian population might be drawbacks of our study. CONCLUSIONS: Variations in right colonic arteriovenous channels, assessed intraoperatively, corroborate those established by cadaveric and radiologic means, prompting a new gastrocolic trunk of Henle classification.

NORMALIZATION OF SERUM VITAMIN D IMPROVES SEMEN MOTILITY PARAMETERS IN PATIENTS WITH IDIOPATHIC MALE INFERTILITY.

CONTEXT: Idiopathic male infertility is evident in half of infertile males. Vitamin D receptors are expressed throughout male reproductive tract, including spermatozoa, promoting motility. Epidemiological studies revealed the positive association between serum vitamin D and semen quality. However, there are no clinical studies examining the differential role of vitamin D in idiopathic male infertility. OBJECTIVES: 1) To investigate the association between vitamin D deficiency and idiopathic male infertility, and 2) To determine whether vitamin D deficient males would show restoration of semen quality parameters upon supplementation with vitamin D. DESIGN: This was a year-long case-control study from November 2015 to November 2016. A therapeutic intervention cohort for 2 months was also performed. SUBJECTS AND METHODS: 117 Jordanian males were enrolled. Following a clinical evaluation by a urologist, baseline serum vitamin D and semen fluid analyses were collected. Participants were stratified into 3 groups: controls (n=30), idiopathic infertility (n=67), and secondary infertility (n=20). Idiopathic infertility patients with low vitamin D (n= 45) were supplemented with oral vitamin D, 5000 IU, once daily for two months. Thereafter, serum vitamin D and semen fluid analyses were reassessed (n= 34; 11 patients were lost to follow up). RESULTS: Vitamin D was significantly lower in patients with idiopathic infertility than in both controls and men with secondary infertility. Significant improvement of progressive and total sperm motility was observed after vitamin D treatment. Vitamin D correlated significantly with semen quality in the study population. However, no correlation was found between vitamin D and any of the semen quality parameters in the idiopathic infertility group. CONCLUSIONS: Vitamin D supplementation improves sperm motility in idiopathic male infertility patients with low vitamin D. Larger and longer clinical trials are warranted to validate the use of vitamin D in these cases.

Increased protein aggregation in Zucker diabetic fatty rat brain: identification of key mechanistic targets and the therapeutic application of hydrogen sulfide.

BACKGROUND: Diabetes and particularly high blood glucose levels are implicated in neurodegeneration. One of the hallmarks of neurodegeneration is protein aggregation. We investigated the presence of protein aggregation in the frontal brain of Zucker diabetic fatty (ZDF) rats, an animal model for diabetes. Further, the effect of NaHS in suppressing protein aggregation in cultured brain slices from ZDF was assessed. RESULTS: The levels of protein synthesis, protein/gene expression, autophagy and anti-oxidant defense were evaluated in ZDF and control (Lean) brains.Compared to Lean, ZDF brains displayed a significant increase in protein aggregates, p-tau, fibronectin expression and protein glycosylation. Increased phosphorylation of mTOR and S6 ribosomal protein in ZDF indicated higher protein synthesis, while the increase in ubiquitinated proteins and LC3-I in ZDF brains accompanied by lower LC3-II expression and LC3-II/LC3-I levels indicated the blockage of proteolytic pathways. CBS (cystathionine beta synthase) protein and mRNA expression and thiol group levels in ZDF brains were lower compared to Lean. ZDF brains show a higher level of reactive oxygen species. In vitro NaHS treatment normalized proteostasis while counteracting oxidative stress. CONCLUSION: Our data demonstrate increased protein synthesis and aggregation in the diabetic ZDF rat brain, which was reversible by NaHS treatment.This is the first report on the potential use of NaHS as a novel strategy against protein aggregation in diabetic brain.

Apigenin: A Bioflavonoid with a Promising Role in Disease Prevention and Treatment.

Apigenin is a powerful flavone compound found in numerous fruits and vegetables, and it offers numerous health-promoting benefits. Many studies have evidenced that this compound has a potential role as an anti-inflammatory and antioxidant compound, making it a promising candidate for reducing the risk of pathogenesis. It has also been found to positively affect various systems in the body, such as the respiratory, digestive, immune, and reproductive systems. Apigenin is effective in treating liver, lung, heart, kidney, neurological diseases, diabetes, and maintaining good oral and skin health. Multiple studies have reported that this compound is capable of suppressing various types of cancer through the induction of apoptosis and cell-cycle arrest, suppressing cell migration and invasion, reduction of inflammation, and inhibiting angiogenesis. When used in combination with other drugs, apigenin increases their efficacy, reduces the risk of side effects, and improves the response to chemotherapy. This review broadly analyzes apigenin's potential in disease management by modulating various biological activities. In addition, this review also described apigenin's interaction with other compounds or drugs and the potential role of nanoformulation in different pathogeneses. Further extensive research is needed to explore the mechanism of action, safety, and efficacy of this compound in disease prevention and treatment.

Correlation of tumor size with other prognostic factors in uterine serous carcinoma: a large multi-institutional study.

OBJECTIVE: Uterine serous carcinoma (USC) constitutes 10% of uterine cancers but ~40% of deaths. Tumor size is a known prognostic factor in other solid tumors. In endometriod cancers it is one element used to identify the need for complete staging, while its significance in USC is debated. Therefore tumor size was examined as an independent prognostic factor. METHODS: Clinical and pathologic variables were recorded for 236 institutional patients, and those patients in the SEER database with USC. Chi-square and Fisher exact t-tests were utilized and survival data generated via Kaplan-Meier method; multivariate analysis was performed via cox-regression. RESULTS: The patients' mean age was 67.2 years (range 40-91). Survival ranged from 0 to 184 months (mean 42.8). We used a tumor size cut-off of 1cm and noted significant associations with myometrial invasion (p<0.0001), angiolymphatic invasion (p<0.0001), peritoneal washings (p=0.03), stage (p=0.015) and positive lymph nodes (p=0.05). Furthermore, recurrence was associated with larger tumors (p=0.03). In multivariate analysis, extra-uterine disease was the only factor associated with both recurrence and survival. Review of the SEER database noted association of larger tumors with lymph node involvement and a significant survival advantage with tumors <1cm in both univariate and multivariate analysis. CONCLUSIONS: Treatment options for USC are often predicated on the surgical stage and therefore components of the staging are vitally important. The 1cm tumor-size cut-off should be studied prospectively as a prognostic indicator of survival and recurrence in USC and considered for inclusion in USC staging.

Prognostic impact of lymphadenectomy in uterine serous cancer.

OBJECTIVE: To estimate the survival impact of lymphadenectomy in women diagnosed with uterine serous cancer. DESIGN: Women with a diagnosis of uterine serous cancer were identified from the Surveillance, Epidemiology and End Results Program (SEER) from 1988 to 2007. Only surgically treated women were included. SETTING: The Surveillance, Epidemiology and End Results Program database provided data from 17 registries. POPULATION: The study population comprised 4178 women. METHODS: Statistical analyses using Student's t-test, Kaplan-Meier survival methods and Cox proportional hazards regression were performed. MAIN OUTCOME MEASURE: Overall survival. RESULTS: Three thousand, one hundred and ninety-four (67.7%) women underwent lymphadenectomy. Older women (≥65 years) and Caucasian women (relative to Asian) were less likely to have lymphadenectomy (P < 0.001). The prevalence of nodal metastasis in women having lymphadenectomy was 32%. Of the 1997 women who had disease grossly confined to the uterus and underwent lymphadenectomy, 387 (19%) were found to have nodal metastasis. Lymphadenectomy was associated with improved survival; women who underwent lymphadenectomy were 41% (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.54-0.64; P < 0.001) less likely to die than women who did not have the procedure. Moreover, more extensive lymphadenectomy correlated positively with survival. Compared with women with 1-10 nodes removed, those with more extensive lymphadenectomy (>10 nodes removed) were 26% (HR, 0.74; 95% CI, 0.67-0.83; P < 0.001) less likely to die. The impact of the extent of lymphadenectomy on survival was significant in both node-negative and node-positive women. CONCLUSION: Age and race influenced the prevalence of lymphadenectomy in our cohort. This study suggests that the extent of lymphadenectomy is associated with significant improvement in survival of women with uterine serous cancer.

Public perspective toward extended community pharmacy services in sub-national Saudi Arabia: An online cross-sectional study.

BACKGROUND: In many developed countries, the scope of community pharmacy services has extended to include advanced applications. Unlike traditional practices that focus on pharmaceutical sales, extended community pharmacy services (ECPSs) are patient-centred and typically offered by specialised healthcare centres, which improve public health, reduce pressure imposed on healthcare professionals, and rationalise health system expenditures. However, based on the findings of several studies, community pharmacies (CPs) only provide marginalised services. Public reviews are thus crucial to effectively utilise such services. This study explored CPs use among the Saudi public in terms of knowledge, attitudes, and barriers to ECPSs. MATERIALS AND METHODS: We conducted a cross-sectional web-based survey of a non-probability sample between October and December 2021. Numerical and graphical descriptive statistics were employed with an additional analytical assessment using binary logistic regression to determine the association between participant characteristics and the barriers to ECPSs use. RESULTS: A total of 563 individuals participated in this study, approximately 33% of which revealed CPs as the first place they visit for medication concerns. Most individuals were not aware of medication therapy management and health screening services (77% and 68%, respectively). Pharmacy clinics offering private counselling and receiving patient electronic medical records were unknown to the participants (78% and 63%, respectively). A substantial proportion of the cohort considered lack of privacy (58%) and inadequate communication with community pharmacists (56%) as key barriers to the use of ECPSs. Logistic regression analysis revealed that the underdeveloped infrastructure of CPs was significantly associated with almost all factors. CONCLUSION: Most services and facilities were found to be underutilised. Positive public attitudes were associated with concerns regarding privacy and cost of services. Consistent with Saudi Vision 2030, supporting CPs and increasing the public awareness of ECPSs have significant implications on public health.

Folicitin abrogates scopolamine induced oxidative stress, hyperlipidemia mediated neuronal synapse and memory dysfunction in mice.

No effective drug treatment is available for Alzheimer disease, thus the need arise to develop efficient drugs for its treatment. Natural products have pronounced capability in treating Alzheimer disease therefore current study aimed to evaluate the neuro-protective capability of folicitin against scopolamine-induced Alzheimer disease neuropathology in mice. Experimental mice were divided into four groups i.e. control (single dose of 250 µL saline), scopolamine-administered group (1 mg/kg administered for three weeks), scopolamine plus folicitin-administered group (scopolamine 1 mg/kg administration for three weeks followed by folicitin administration for last two weeks) and folicitin-administered group (20 mg/kg administered for 5 alternate days). Results of behavioral tests and Western blot indicated that folicitin has the capability of recovering the memory against scopolamine-induced memory impairment by reducing the oxidative stress through up-regulating the endogenous antioxidant system like nuclear factor erythroid 2-related factor and Heme oxygenase-1 while prohibiting phosphorylated c-Jun N-terminal kinase. Similarly, folicitin also improved the synaptic dysfunction by up-regulating SYP and PSD95. Scopolamine-induced hyperglycemia and hyperlipidemia were abolished by folicitin as evidenced through random blood glucose test, glucose tolerance test and lipid profile test. All these results revealed that folicitin being a potent anti-oxidant is capable of improving synaptic dysfunction and reducing oxidative stress through Nrf-2/HO-1 pathway, thus plays a key role in treating Alzheimer disease as well as possess hyperglycemic and hyperlipidemic effect. Furthermore, a detailed study is suggested.

Community pharmacists' perspectives towards automated pharmacy systems and extended community pharmacy services: An online cross-sectional study.

Background: Private sector partnerships through community pharmacies are essential for effective healthcare integration to achieve the United Nations 2030 Agenda for Sustainable Development Goals. This partnership can provide significant clinical outcomes and reduce health system expenditures by delivering services focused on patient-centred care, such as public health screening and medication therapy management. Objectives: To assess the understanding of the proposed strategic and health system reform in Saudi Arabia by exploring community pharmacists' perspectives towards the capacity and readiness of community pharmacies to use automated pharmacy systems, provide extended community pharmacy services, and identify perceived barriers. Materials and methods: This multicentre, cross-sectional, web-based survey was conducted in Saudi Arabia (October-December 2021). Graphical and numerical statistics were used to describe key dimensions by the background and characteristics of the respondents, and multiple ordinal logistic regression analyses were sought to assess their associations. Results: Of the 403 consenting and participating community pharmacists, most were male (94%), belonged to chain pharmacies (77%), and worked >48 h per week (72%). Automated pharmacy systems, such as electronic prescriptions, were never utilised (50%), and health screening services, such as blood glucose (76%) and blood pressure measurement (74%), were never provided. Services for medication therapy management were somewhat limited. Age groups ≤40 years, chain pharmacies, >10 years of experience and ≥ 3 pharmacists in place with <100 daily medication prescriptions and Jazan province were significantly more likely to provide all medication therapy management services than others. Operational factors were the barriers most significantly associated with the independent variables. Conclusion: The results showed that most services and automated pharmacy systems remained limited and well-needed. When attempting to implement these services to drive change, community pharmacies face numerous challenges, and urgent efforts by private and government sectors are essential to improve pharmaceutical care in community pharmacy settings.

Structural Dynamics of P-Rex1 Complexed with Natural Leads Establishes the Protein as an Attractive Target for Therapeutics to Suppress Cancer Metastasis.

Phosphatidylinositol 3,4,5-trisphosphate- (PIP3-) dependent Rac exchanger 1 (P-Rex1) functions as Rho guanine nucleotide exchange factor and is activated by synergistic activity of Gßγ and PIP3 of the heterotrimeric G protein. P-Rex1 activates Rac GTPases for regulating cell invasion and migration and promotes metastasis in several human cancers including breast, prostate, and skin cancer. The protein is a promising therapeutic target because of its multifunction roles in human cancers. Herein, the present study attempts to identify selective P-Rex1 natural inhibitors by targeting PIP3-binding pocket using large-size multiple natural molecule libraries. Each library was filtered subsequently in FAF-Drugs4 based on Lipinski's rule of five (RO5), toxicity, and filter pan assay interference compounds (PAINS). The output hits were virtually screened at the PIP3-binding pocket through PyRx AutoDock Vina and cross-checked by GOLD. The best binders at the PIP3-binding pocket were prioritized using a comparative analysis of the docking scores. Top-ranked two compounds with high GOLD fitness score (>80) and lowest AutoDock binding energy (< -12.7 kcal/mol) were complexed and deciphered for molecular dynamics along with control-P-Rex1 complex to validate compound binding conformation and disclosed binding interaction pattern. Both the systems were seen in good equilibrium, and along the simulation time, the compounds are in strong contact with the P-Rex1 PIP3-binding site. Hydrogen bonding analysis towards simulation end identified the formation of 16 and 22 short- and long-distance hydrogen bonds with different percent of occupancy to the PIP3 residues for compound I and compound 2, respectively. Radial distribution function (RDF) analysis of the key hydrogen bonds between the compound and the PIP3 residues demonstrated a strong affinity of the compounds to the mentioned PIP3 pocket. Additionally, MMGB/PBSA energies were performed that confirmed the dominance of Van der Waals energy in complex formation along with favorable contribution from hydrogen bonding. These findings were also cross-validated by a more robust WaterSwap binding energy predictor, and the results are in good agreement with a strong binding affinity of the compounds for the protein. Lastly, the key contribution of residues in interaction with the compounds was understood by binding free energy decomposition and alanine scanning methods. In short, the results of this study suggest that P-Rex1 is a good druggable target to suppress cancer metastasis; therefore, the screened druglike molecules of this study need in vitro and in vivo anti-P-Rex1 validation and may serve as potent leads to fight cancer.

Availability of Antidotes for Management of Acute Toxicity Cases at Emergency Departments in Qassim Hospitals: A Retrospective Study.

BACKGROUND: Drug overdose is a medico-social issue worldwide that may occur intentionally or unintentionally. It is one of the most common reasons for emergency department visits, and it is also a frequent cause of morbidity and mortality globally. This study aims to determine the occurrence of acute toxicity cases and their management outcomes at the emergency departments in Qassim Province hospitals in Saudi Arabia. In addition, the study aims to investigate the antidote availabilities at those medical centers. METHODS: A retrospective hospital record-based study of acute toxicity cases admitted to the emergency department in hospitals in Qassim during the period from January 1, 2020, to December 31, 2020, was conducted. Data were collected based on hospital resources such as gastrointestinal decontamination, stabilization, elimination enhancement resources, and antidotes from Qassim hospitals, and the availability of antidotes as well as the clinical data of the patients with the management outcome. RESULTS: A total of 264 patients with acute toxicity were admitted to the emergency departments of 14 hospitals in Qassim Province in 2020. Of the 264 cases, 179 (68%) were males, and 85 (32%) cases were females. Ninety-five percent of the cases were admitted to public hospitals, whereas 5% were admitted to private hospitals. The largest group by age of admitted cases were aged 11-20 years (19.3%). This study showed that 99% received appropriate treatment for their cause of toxicity, whereas 1% did not. The most common causes of toxicity in Qassim were found to be food poisoning (20.5%), followed by intentional suicide attempts with warfarin/enoxaparin/aspirin overdoses (15.9%) and acetaminophen (paracetamol) overdosage seen in 15.5% of admitted cases. Flagyl, in addition to fluids, was used in the management of 16.7% of cases, N-acetyl cysteine was used for 16.3%, and vitamins K and B6 were used for 14.0% of cases. Activated charcoal, atropine, calcium chloride, calcium gluconate, flumazenil, insulin, magnesium, sodium bicarbonate, and vitamin K were available at all the studied hospitals. However, all the hospitals lacked both ethylenediaminetetraacetic acid (EDTA) and a cyanide kit. Methylene blue and leucovorin were available in only one of the studied hospitals.

Synchronous Colon and Breast Cancers: A Case Report of Multiple Primary Tumors.

Multiple primary malignant tumors (MPMNs) are not rare entities. We report a case of a 50-year-old female who presented with left upper quadrant abdominal pain and GI bleeding. Initial assessment with CT scan revealed a mass originating from the descending colon. Colonoscopy was performed and a fungating partially obstructed mass at the left splenic flexure was detected. Histopathological examination of biopsy was consistent with mucinous adenocarcinoma. The staging CT scan of the chest and pelvis, followed by a mammogram reported a Synchronous breast mass. Core needle biopsy detected an invasive ducal carcinoma. In the multidisciplinary meeting, it was decided to perform the colon procedure first, followed by adjuvant chemotherapy, and then the breast procedure. The patient had an uneventful recovery after both procedures and was sent to the medical oncology department to continue with the treatment.

Caller ID for Risso's and Pacific White-sided dolphins.

Tracking species with expanding ranges is crucial to conservation efforts and some typically temperate marine species are spreading northward into the Arctic Ocean. Risso's (Gg) and Pacific white-sided (Lo) dolphins have been documented spreading poleward. Further, they make very similar sounds, so it is difficult for both human analysts and classification algorithms to tell them apart. Using automatic detectors and classifiers on large acoustic datasets would improve the efficiency of monitoring these species. variational mode decomposition (VMD) provides both an easier visualization tool for human analysts and exhibited robustness to background noise while extracting features in pulsed signals with very similar spectral properties. The goal of this work was to develop a new visualization tool using VMD and a statistics-based classification algorithm to differentiate similar pulsed signals. The proposed VMD method achieved 81% accuracy, even when using audio files with low SNR that did not have concurrent visual survey data. While many dolphins whistle, pulsed signals are one of the more useful vocalizations to use in detection and classification because of their species-specific acoustic features. Automating the VMD method and expanding it to other dolphin species that have very similar pulsed signals would complement current detection and classification methods and lead to a more complete understanding of ecosystem dynamics under a changing climate.

Recent Advances in Stretchable and Wearable Capacitive Electrophysiological Sensors for Long-Term Health Monitoring.

Over the past several years, wearable electrophysiological sensors with stretchability have received significant research attention because of their capability to continuously monitor electrophysiological signals from the human body with minimal body motion artifacts, long-term tracking, and comfort for real-time health monitoring. Among the four different sensors, i.e., piezoresistive, piezoelectric, iontronic, and capacitive, capacitive sensors are the most advantageous owing to their reusability, high durability, device sterilization ability, and minimum leakage currents between the electrode and the body to reduce the health risk arising from any short circuit. This review focuses on the development of wearable, flexible capacitive sensors for monitoring electrophysiological conditions, including the electrode materials and configuration, the sensing mechanisms, and the fabrication strategies. In addition, several design strategies of flexible/stretchable electrodes, body-to-electrode signal transduction, and measurements have been critically evaluated. We have also highlighted the gaps and opportunities needed for enhancing the suitability and practical applicability of wearable capacitive sensors. Finally, the potential applications, research challenges, and future research directions on stretchable and wearable capacitive sensors are outlined in this review.