-
The Journal of Pharmacology and... Jun 2024Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor...
Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the -carborane series, its poor pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. This study investigates - and -substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.
PubMed: 38936980
DOI: 10.1124/jpet.123.001874 -
The Journal of Pharmacology and... Jun 2024Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease...
Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, well-tolerated, and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and, ultimately, apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment for ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. , VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models and has potent anti-tumor and anti-metastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.
PubMed: 38936977
DOI: 10.1124/jpet.124.002298 -
International Journal of Surgery Case... Jun 2024Pierre Robin Sequence (PRS) is a rare and complex condition that often necessitates the collaboration of a full medical team from various disciplines to save the lives...
INTRODUCTION AND IMPORTANCE
Pierre Robin Sequence (PRS) is a rare and complex condition that often necessitates the collaboration of a full medical team from various disciplines to save the lives of babies with this genetic mutation, characterized by three clinical manifestations: glossoptosis, micrognathia, and cleft palate. Treatment primarily involves freeing upper airway obstructions and enhancing nutrition to allow the babies to lead a normal life. The lip-tongue adhesion procedure has been identified in medical literature as the recommended approach to addressing the issues associated with Pierre Robin sequence, and this method was successfully adopted in this case.
CASE PRESENTATION
2.5 kg, a newborn male baby with an abnormal position of the tongue and the inability to breastfeed and feed normally, without any medical, family, or social history. Following an examination, it was discovered that the baby had a posterior position of the tongue, micrognathia, and a cleft palate, leading to a diagnosis of Pierre Robin Sequence (Figs. 1, 2). Preparations for the baby's surgery have commenced. The baby was solely fed intravenously and provided with an oxygen mask for 25 days until all necessary consultations were completed and the baby's readiness for surgery and general anesthesia was confirmed. The surgical plan involved attaching the tongue to the lower lip to enhance the tongue's muscular strength, addressing the posterior position issue, and delaying the palate repair until the age of 1.5 years.
CLINICAL DISCUSSION
PRS is a clinical entity characterized by the triad of mandibular hypoplasia (small jaw), glossoptosis (hypotonic, retracted tongue) and respiratory obstruction that require a multidisciplinary team for initial evaluation and management and maintenance care. TLA is a simple and effective procedure for increasing the cross-sectional area of oropharyngeal port.
CONCLUSION
Handling airway obstruction in Pierre Robin Sequence involves various factors, and there is no universal treatment that can address all cases. Appropriate airway management strategies and feeding programs are essential for each individual with PRS. Our review highlights that TLA is a straightforward surgical procedure with minimal or no short-term complications. TLA should be considered as the primary surgical intervention when relief is needed.
PubMed: 38936141
DOI: 10.1016/j.ijscr.2024.109932 -
PloS One 2024[This corrects the article DOI: 10.1371/journal.pone.0283604.].
Correction: Medico-economic comparison of two anticoagulant treatment strategies: Vitamin K antagonists vs. direct oral anticoagulants in older adults in nursing homes in France. The "MIKADO" study.
[This corrects the article DOI: 10.1371/journal.pone.0283604.].
PubMed: 38935740
DOI: 10.1371/journal.pone.0306377 -
PloS One 2024Research on gender inequality is crucial as it unveils the pervasive disparities that persist across various domains, shedding light on societal imbalances and providing...
BACKGROUND
Research on gender inequality is crucial as it unveils the pervasive disparities that persist across various domains, shedding light on societal imbalances and providing a foundation for informed policy-making.
AIM
To investigate gender differences in scientometric indices among faculty members in dental schools across Iran. This included overall data and speciality-specific data.
METHODS
The publication profiles of academic staff in all dental schools were examined using the Iranian Scientometric Information Database (ISID, http://isid.research.ac.ir). Variables analyzed were working field, academic degree, the total number of papers, papers per year, total number of citations, percentage of self-citation, h-index, g-index, citations per paper, gender, university type, number of years publishing, proportion of international papers, first-author papers, and corresponding-author papers. Mann-Whitney and Kruskal-Wallis nonparametric tests were used to analyze the relationship between background characteristics and scientometric indicators. The extracted data were analyzed using R v4.0.1.
RESULTS
The database included 1850 faculty members, of which about 60% (1104 of 1850) were women. Men (n = 746) had a higher number of papers (6583 vs. 6255) and citations (60410 vs. 39559) compared with women; 234 of the 376 faculty members with no papers were women. Almost half of the women (N = 517 of 1104) were in Type 2 universities, and nearly half of the men (N = 361 of the 746) were faculty members at Type 1 universities (Type 1 universities ranking higher than Type 2 and 3 universities). The medians of scientometric indices were higher in men, except for self-citation percentage (0 (IQR = 2) vs. 0 (IQR = 3), P = 0.083), international papers percentage (0 (IQR = 7.5) vs. 0 (IQR = 16.7), P<0.001). The proportion of corresponding-author papers was more than 62% higher in women (25 (IQR = 50) vs. 15.4 (IQR = 40), P<0.001). Men had a two-fold higher median h-index (2 (IQR = 4) vs. 1 (IQR = 3), P<0.001). Restorative dentistry and pediatric dentistry had the highest men-to-women ratios (1.5 for both). Dental materials and oral and maxillofacial surgery showed the lowest men-to-women ratios (0.42 and 0.5, respectively).
CONCLUSIONS
Women made up the majority of dental faculty members in Iran. Nevertheless, men showed better scientometric results in several significant indices. Having identified scientometric information reflecting differences across faculty members, further research is now needed to better understand the drivers of these differences.
Topics: Iran; Humans; Male; Female; Faculty, Dental; Publications; Bibliometrics; Sex Distribution; Schools, Dental; Publishing
PubMed: 38935641
DOI: 10.1371/journal.pone.0300698 -
PloS One 2024The patterning cascade model of crown morphogenesis has been studied extensively in a variety of organisms to elucidate the evolutionary history surrounding postcanine...
OBJECTIVE
The patterning cascade model of crown morphogenesis has been studied extensively in a variety of organisms to elucidate the evolutionary history surrounding postcanine tooth form. The current research is the first to use a large modern human sample to examine whether the crown configuration of lower deciduous and permanent molars aligns with expectations derived from the model. This study has two main goals: 1) to determine if metameric and antimeric pairs significantly differ in size, accessory trait expression, and relative intercusp spacing, and 2) assess whether the relative distance among early-forming cusps accounts for observed variation in accessory cusp expression.
METHODS
Tooth size, intercusp distance, and morphological trait expression data were collected from 3D scans of mandibular dental casts representing participants of the Harvard Solomon Islands Project. Paired tests were utilized to compare tooth size, accessory trait expression, and relative intercusp distance between diphyodont metameres and permanent antimeres. Proportional odds logistic regression was implemented to investigate how the odds of greater accessory cusp expression vary as a function of the distance between early-developing cusps.
RESULTS/SIGNIFICANCE
Comparing paired molars, significant differences were identified for tooth size and cusp 5 expression. Several relative intercusp distances emerged as important predictors of cusp 6 expression, however, results for cusp 5 and cusp 7 did not match expected patterns. These findings support previous quantitative genetic results and suggest the development of neighboring crown structures represents a zero-sum partitioning of cellular territory and resources. As such, this study contributes to a better understanding of the foundations of deciduous and permanent molar crown variation in humans.
Topics: Humans; Tooth Crown; Molar; Dentition, Permanent; Morphogenesis; Tooth, Deciduous; Odontogenesis; Male; Child; Female
PubMed: 38935640
DOI: 10.1371/journal.pone.0304455 -
MMWR. Morbidity and Mortality Weekly... Jun 2024Since the launch of the Global Polio Eradication Initiative in 1988, substantial progress has been made in the interruption of wild poliovirus (WPV) transmission...
Since the launch of the Global Polio Eradication Initiative in 1988, substantial progress has been made in the interruption of wild poliovirus (WPV) transmission worldwide: global eradication of WPV types 2 and 3 were certified in 2015 and 2019, respectively, and endemic transmission of WPV type 1 continues only in Afghanistan and Pakistan. After the synchronized global withdrawal of all serotype 2 oral poliovirus vaccines (OPVs) in 2016, widespread outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2) have occurred, which are linked to areas with low population immunity to poliovirus. Officials in Somalia have detected ongoing cVDPV2 transmission since 2017. Polio vaccination coverage and surveillance data for Somalia were reviewed to assess this persistent transmission. During January 2017-March 2024, officials in Somalia detected 39 cVDPV2 cases in 14 of 20 regions, and transmission has spread to neighboring Ethiopia and Kenya. Since January 2021, 28 supplementary immunization activities (SIAs) targeting cVDPV2 were conducted in Somalia. Some parts of the country are security-compromised and inaccessible for vaccination campaigns. Among 1,921 children with nonpolio acute flaccid paralysis, 231 (12%) had not received OPV doses through routine immunization or SIAs, 95% of whom were from the South-Central region, and 60% of whom lived in inaccessible districts. Enhancing humanitarian negotiation measures in Somalia to enable vaccination of children in security-compromised areas and strengthening campaign quality in accessible areas will help interrupt cVDPV2 transmission.
Topics: Humans; Poliomyelitis; Somalia; Poliovirus; Poliovirus Vaccine, Oral; Disease Outbreaks; Child, Preschool; Infant; Population Surveillance; Immunization Programs; Vaccination Coverage; Child
PubMed: 38935565
DOI: 10.15585/mmwr.mm7325a2 -
STAR Protocols Jun 2024Periodontal ligament cells (PDLCs) and macrophages in bone marrow cells have been widely used to investigate novel therapeutic agents to treat periodontitis. Here, we...
Periodontal ligament cells (PDLCs) and macrophages in bone marrow cells have been widely used to investigate novel therapeutic agents to treat periodontitis. Here, we present a protocol for collecting primary mouse PDLCs and bone marrow cells. We detail steps for culturing and differentiation for both cell types and review data analysis for in vitro experiments using primary PDLCs and bone marrow cells. This protocol can be used to explore the impact of novel therapeutic agents using in vitro experiments. For complete details on the use and execution of this protocol, please refer to Sirisereephap et al..
PubMed: 38935507
DOI: 10.1016/j.xpro.2024.103162 -
International Journal of Implant... Jun 2024This propensity score matching, multicenter, cross-sectional study was performed to examine the effects of various prosthetic methods for dental clinic outpatients with...
Effects of various prosthetic methods for patients with Kennedy Class I partial edentulism on oral hypofunction, subjective symptoms, and oral health-related quality of life.
PURPOSE
This propensity score matching, multicenter, cross-sectional study was performed to examine the effects of various prosthetic methods for dental clinic outpatients with Kennedy Class I partial edentulism (KCIPE) on oral hypofunction, subjective frailty symptoms, and oral health-related quality of life (QOL).
METHODS
Patients (n = 348) were classified into the following three groups for analysis: NT, patients with natural dentition providing intermaxillary contact in four occlusal supporting zones; RPD, patients with KCIPE who received removable partial dentures; and ISFP, patients with KCIPE who received implant-supported fixed prostheses. Participants' basic characteristics were recorded, and oral function tests were conducted. Subjective symptoms of physical and oral frailty were investigated via questionnaire. Oral health-related QOL was assessed using the Japanese short version of the Oral Health Impact Profile (OHIP-JP16). Propensity score matching was performed to adjust for patient background factors that could influence oral hypofunction in each group.
RESULTS
Compared with the ISFP group, the RPD group had significantly higher rates of poor oral hygiene, reduced occlusal force, decreased masticatory function, and declines in swallowing function and oral hypofunction; the odds ratio for oral hypofunction was 4.67. Compared with the ISFP group, the RPD group had significantly greater subjective symptoms of physical frailty and oral frailty, as well as higher OHIP scores.
CONCLUSIONS
Prosthetic treatment of KCIPE affected oral hypofunction, subjective frailty symptoms, and oral health-related QOL in dental clinic outpatients.
Topics: Humans; Quality of Life; Cross-Sectional Studies; Male; Female; Middle Aged; Oral Health; Jaw, Edentulous, Partially; Denture, Partial, Removable; Aged; Surveys and Questionnaires; Propensity Score; Dental Prosthesis, Implant-Supported; Denture, Partial, Fixed; Adult
PubMed: 38935335
DOI: 10.1186/s40729-024-00555-w -
Journal of Comparative Effectiveness... Jun 2024This is a summary of findings from two research studies (known as clinical trials). The studies looked at how well a medicine called relugolix combination therapy worked... (Review)
Review
WHAT IS THIS SUMMARY ABOUT?
This is a summary of findings from two research studies (known as clinical trials). The studies looked at how well a medicine called relugolix combination therapy worked in women with heavy menstrual bleeding (heavy bleeding during a period) with uterine fibroids (noncancerous or benign growths in the uterus). In this analysis of the studies, researchers looked at how patients self-reported their uterine fibroid symptoms before and after taking relugolix combination therapy. Researchers also looked at how patients self-reported the impact of uterine fibroids on their health-related quality of life before and after taking relugolix combination therapy.
WHAT WERE THE RESULTS?
Women took either relugolix combination therapy or placebo (a pill that contains no medicine) by mouth once daily for 24 weeks. Women completed the Uterine Fibroid Symptom and Quality of Life questionnaire (where "quality of life" refers to the women's health-related quality of life related to uterine fibroids) before, during, and after treatment. The questionnaire let researchers see if the women felt that relugolix combination therapy decreased the burden of uterine fibroid symptoms and improved the women's health-related quality of life related to uterine fibroids. More women said that they felt less distress due to their uterine fibroid symptoms and that their health-related quality of life related to uterine fibroids was better after taking relugolix combination therapy compared with women who took placebo.
WHAT DO THE RESULTS MEAN?
Relugolix combination therapy may lessen distress associated with uterine fibroid symptoms and improve health-related quality of life related to uterine fibroids.
PubMed: 38934918
DOI: 10.57264/cer-2023-0194