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Progress of antibody–drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies
No full textThe cell-surface receptor tyrosine kinase c-mesenchymal-epithelial transition factor (c-Met) is overexpressed in a wide range of solid tumors, making it an appropriate target antigen for the development of anticancer therapeutics. Various antitumor c-Met-targeting therapies (including monoclonal antibodies [mAbs] and tyrosine kinases) have been developed for the treatment of c-Met-overexpressing tumors, most of which have so far failed to enter the clinic because of their efficacy and complications. Antibody–drug conjugates (ADCs), a new emerging class of cancer therapeutic agents that harness the target specificity of mAbs to deliver highly potent small molecules to the tumor with the minimal damage to normal cells, could be an attractive therapeutic approach to circumvent these limitations in patients with c-Met-overexpressing tumors. Of great note, there are currently nine c-Met-targeting ADCs being examined in different phases of clinical studies as well as eight preclinical studies for treating various solid tumors. The purpose of this study is to present a broad overview of clinical- and preclinical-stage c-Met-targeting ADCs. Graphical Abstract: (Figure presented.
Investigating the relationship between insulin use and all-cause mortality, breast cancer mortality, and recurrence risk in diabetic patients with breast cancer: A comprehensive systematic review and meta-analysis
No full textBackground The co-occurrence of breast cancer and diabetes presents complex clinical challenges, as each condition may influence the progression and management of the other, potentially worsening patient outcomes. This study aims to examine the association between insulin use and the risks of all-cause mortality, breast cancer-specific mortality, and recurrence in diabetic patients with breast cancer. Methods A systematic review and meta-analysis were conducted using studies identified from multiple databases, including Web of Science, Scopus, PubMed, Cochrane, Google Scholar, and Embase. The meta-analysis approach was used to estimate the relative risk (RR) of the relationship between insulin use and the risks of all-cause mortality, breast cancer-specific mortality, and recurrence in diabetic patients with breast cancer. Heterogeneity among studies was assessed using statistical tests such as the Chi-square test, I2, and forest plots. Meta-regression and sensitivity analyses were performed to explore sources of heterogeneity. The quality of the included studies was assessed using the Newcastle-Ottawa Scale checklist. Data were analyzed using Stata version 17 (Stata Corp, College Station, Texas). Results Data from 22 studies conducted between 2002 and 2023, with a total of 159,674 participants, were analyzed. Nineteen studies were rated as high quality, and three as moderate quality. Diabetic patients with breast cancer who received insulin had a 1.65 (95% CI: 1.36–2.02; P < 0.001; I2 = 89.7%) times higher risk of overall mortality compared to those who did not use insulin. Meta-regression revealed that sample size and study quality were significant contributors to heterogeneity (P ≤ 0.10). Furthermore, insulin use was associated with a 1.22 (95% CI: 1.05–1.42; P = 0.009; I2 = 37.9%) times higher risk of breast cancer-specific mortality. For breast cancer recurrence, insulin use was associated with a 1.45 (95% CI: 1.19–1.77; P < 0.001; I2 = 3.4%) times higher risk. Sensitivity analysis confirmed the stability of the results across all outcomes. Conclusion This meta-analysis provides strong evidence that insulin use in diabetic patients with breast cancer is associated with increased risks of overall mortality, breast cancer-specific mortality, and recurrence. These findings underscore the need for careful consideration of insulin therapy in this patient population
Global, regional, and national stillbirths at 20 weeks' gestation or longer in 204 countries and territories, 1990–2021: findings from the Global Burden of Disease Study 2021
No full textBackground: Stillbirth is a devastating and often avoidable adverse pregnancy outcome. Monitoring stillbirth levels and trends—in a comprehensive manner that leaves no one uncounted—is imperative for continuing progress in pregnancy loss reduction. This analysis, completed as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, methodically accounted for different stillbirth definitions with the aim of comprehensively estimating all stillbirths at 20 weeks or longer for 204 countries and territories from 1990 to 2021. Methods: We extracted data on stillbirths from 11 412 sources across 185 of 204 countries and territories, including 234 surveys, 231 published studies, 1633 vital statistics reports, and 10 585 unique location-year combinations from vital registration systems. Our final dataset comprised 11 different definitions, which were adjusted to match two gestational age thresholds: 20 weeks or longer (reference) and 28 weeks or longer (for comparisons). We modelled the ratio of stillbirth rate to neonatal mortality rate with spatiotemporal Gaussian process regression for each location and year, and then used final GBD 2021 assessments of fertility and all-cause neonatal mortality to calculate total stillbirths. Secondary analyses evaluated the number of stillbirths missed with the more restrictive gestational age definition, trends in stillbirths as a function of Socio-demographic Index, and progress in reducing stillbirths relative to neonatal deaths. Findings: In 2021, the global stillbirth rate was 23·0 (95% uncertainty interval [UI] 19·7–27·2) per 1000 births (stillbirths plus livebirths) at 20 weeks' gestation or longer, compared to 16·1 (13·9–19·0) per 1000 births at 28 weeks' gestation or longer. The global neonatal mortality rate in 2021 was 17·1 (14·8–19·9) per 1000 livebirths, corresponding to 2·19 million (1·90–2·55) neonatal deaths. The estimated number of stillbirths occurring at 20 weeks' gestation or longer decreased from 5·08 million (95% UI 4·07–6·35) in 1990 to 3·04 million (2·61–3·62) in 2021, corresponding to a 39·8% (31·8–48·0) reduction, which lagged behind a global improvement in neonatal deaths of 45·6% (36·3–53·1) for the same period (down from 4·03 million [3·86–4·22] neonatal deaths in 1990). Stillbirths in south Asia and sub-Saharan Africa comprised 77·4% (2·35 million of 3·04 million) of the global total, an increase from 60·3% (3·07 million of 5·08 million) in 1990. In 2021, 0·926 million (0·792–1·10) stillbirths, corresponding to 30·5% of the global total (3·04 million), occurred between 20 weeks' gestation and 28 weeks' gestation, with substantial variation at the country level. Interpretation: Despite the gradual global decline in stillbirths between 1990 and 2021, the overall number of stillbirths remains substantially high. Counting all stillbirths is paramount to progress, as nearly a third—close to 1 million in total—are left uncounted at the 28 weeks or longer threshold. Our findings draw attention to the differential progress in reducing stillbirths, with a high burden concentrated in countries with low development status. Scarce data availability and poor data quality constrain our capacity to precisely account for stillbirths in many locations. Addressing inequities in universal maternal health coverage, strengthening the quality of maternal health care, and improving the robustness of data systems are urgently needed to reduce the global burden of stillbirths. Funding: Bill & Melinda Gates Foundation
Secretome of human amniotic membrane stem cells promote recovery and testicular functions through modulating SIRT1/NRF2/TNF-α pathway in mice testicular torsion: An experimental study
No full textBackground: Testicular ischemia/reperfusion injury, a significant result of testicular torsion, can lead to the risk of male infertility. Objective: The current study aimed to evaluate the effect of human amniotic membrane-derived mesenchymal stem cells (hAMSCs) secretome on testicular torsion/detorsion (T/D) in mice. Materials and Methods: All the experiments were performed in the Anatomy Department of Tehran University of Medical Sciences, Tehran, Iran, during the period of March 2023 to December 2023. 40 male NMRI mice (5–7 wk, 25–30 gr) were randomized into: 1) the sham group: mice received sham operations with no other interventions, 2) T/D group, 3) negative control group; torsion detorsion + intratesticular injection of Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12, and 4) the T/D group + hAMSCs secreted factors. Serum testosterone levels, hematoxylin and eosin staining, and sperm quality parameters were used to evaluate the therapeutic effects of hAMSCs secreted factors on the testicular structure and function. Tissue oxidative stress was measured by determining malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase-1. Nuclear factor erythroid 2-related factor 2, Kelch-like ECH-associated protein 1, NAD-dependent deacetylase sirtuin-1, tumor necrosis factor-alpha and tumor protein P53 mRNA expressions were assessed in testis via real-time polymerase chain reaction. Results: The results showed that hAMSCs secreted factors alleviated testicular T/D injury by attenuating oxidative stress, inflammatory response, and apoptosis via modulating the sirtuin-1/ nuclear factor erythroid 2-related factor 2/tumor necrosis factor-alpha signaling pathway. Conclusion: hAMSCs secreted factors increased antioxidative, anti-inflammatory, and antiapoptotic properties which consequently increased testosterone levels, spermatogenesis, and sperm quality parameter
A Field Experiment on Puberty Education among Iranian Female Adolescents: A Comparison of School-based and Family-based Interventions
No full textBackground: It is necessary to enhance understanding and attitudes towards puberty and reproductive health within the framework of the culture and beliefs of the community. The aim of this study was to investigate the effect of school-based education compared with family-based education on puberty health behaviors in teenage girls. Methods: In 2018, an experimental field study was conducted on 272 high school girl students who were selected through multi-stage sampling method. A questionnaire was used for collecting the data. Face and content validity of the questionnaire was determined by nine health and fertility education experts. Content validity ratio and index were calculated by Lawshe and Walts and Basel methods. The test-retest method and Cronbach’s alpha coefficient were used for checking the reliability of the questionnaire. The Cronbach’s alpha for knowledge, attitude and behavior was 0.81, 0.92, and 0.73, respectively; also, ICC for all questions was 0.81. The students completed the questionnaire in two stages. Interventions were conducted for mothers, teachers and students through lecture and group discussion. The collected data were analyzed using SPSS version 16. Chi-Square, Paired T-test, ANOVA and ANCOVA were used for data analysis. Results: The results showed that after the intervention, knowledge, attitude and behavior scores were significantly higher, and the increase in the school-centered group was more than the family-centered group. Also, there was no significant difference in the mean scores in the control group. Conclusions: School engagement allows for the implementation of effective interventions to enhance menstrual management, ultimately leading to a decrease in negative psychosocial outcomes through improved interactions in the classroom
Presumed Partial Third Nerve Palsy after COVID-19 Vaccination: A Case Report
No full textBackground: COVID-19 vaccination has been crucial in controlling the pandemic, yet it has been associated with various complications. Common mild adverse reactions include discomfort and swelling at the injection site, urticaria, rashes, fever, and headaches. Severe adverse events of special interest (AESI) have also been reported, such as facial nerve palsy, myelitis, ischemia, and cranial nerve palsies.Methods: We report a 76-year-old patient with right partial third nerve palsy 20 days after receiving the second dose of COVID-19 vaccine. Laboratory tests and neuroimaging found no explanation for the patient's problem. The patient was followed up without medications and, over time, the patient's symptoms improved.Conclusion: A notable case involved third nerve palsy following COVID-19 vaccination, highlighting the potential for neurological complications. While these severe reactions are rare, their occurrence emphasizes the need for continuous monitoring and research to ensure vaccine safety. Overall, the benefits of vaccination outweigh the risks, but awareness of potential complications is essential for effective healthcare management
Vaccine enhancement and improved immunogenicity using erythrocytes as carriers
No full textAchieving optimal immunogenicity and efficacy in vaccination presents significant challenges, including the need for multiple doses and the limited immunogenicity observed with certain vaccine formulations. To overcome these obstacles, researchers are exploring supplementary components and innovative delivery strategies. The development of an effective vaccine delivery technology is crucial for achieving sufficient protective immunity and disease prevention. This article focuses on the potential of erythrocytes as vaccine carriers to enhance vaccine effectiveness, particularly in the context of whole particle vaccines. The extended lifespan of erythrocytes enables sustained antigen exposure, resulting in continuous antigen presentation to immune cells. Moreover, erythrocytes exhibit biocompatibility, a well-established safety profile, and the capacity to modulate immune responses through interactions with complement receptors. These characteristics position erythrocytes as an appealing platform for targeted vaccine delivery. The hypothesis suggests utilizing bispecific monoclonal antibodies to complement receptor 1 and specific pathogen proteins to hitchhike inactivated pathogens onto erythrocytes. These modified erythrocytes can then serve as carriers to deliver the whole particle vaccine to antigen-presenting cells (APCs) or function as APCs themselves in the spleen. This article puts forward treatment protocols aimed at improving accessibility of vaccinations at the appropriate location, reducing the frequency of vaccine doses, and stimulating sufficient protective immunit
Sex differences in clinical profile and risk factors of cerebral venous sinus thrombosis at a high-altitude area: A 10-year retrospective cross-sectional study
No full textCerebral venous sinus thrombosis (CVST) is an uncommon disorder with an increased mortality risk. Data on the sex-specific clinical profile and related factors can be practical in clinical diagnosis and management. Thus, we aimed to assess CVST characteristics in Shahrekord, the most elevated city among the centers of the provinces of Iran, referred to as the Roof of Iran. In this retrospective cross-sectional study, we reviewed the hospital records of 127 CVST patients between April 2013 and June 2023 to analyze the demographic characteristics, clinical profile, disease outcomes, and risk factors. STROBE guidelines were used to report this study. Females comprised 65.3% of the study. Females' age was almost equal to male patients (37.51 ± 13.95 years vs 38.09 ± 16.18 years, P=.832), and more than half of the patients (59.1%) were married. Clinical characteristics showed no significant difference between the sexes. In contrast to males, females had multifarious risk factors. However, the main risk factors for both sexes were CVST and hypertension. Most patients had 1 sinus affected (55.9%), and the location of thrombosis was mainly in the right transverse sinus in males (38.63%) and superior sagittal sinus in females (33.73%). However, those with more than 2 affected sinuses were mostly women. Regarding radiological findings, sinusitis was significantly seen in men (18.18% vs 3.61%). Among laboratory data, females significantly had higher erythrocyte sedimentation rate levels than males (21.66 ± 24.39 vs 9.60 ± 8.55). This study indicates that among CVST patients, men have significantly higher occurrences of sinusitis, and higher levels of erythrocyte sedimentation rate were observed in women. However, no other significant differences were found. More extensive studies are essential to fully comprehend the sex-specific aspects of CVST
Pheochromocytoma/Paraganglioma Syndrome Type 1 Presenting with Atypical Symptoms and a Novel Pathogenic Variant in the SDHD Gene: A Case Report
No full textThis case report presents a 10-year-old patient diagnosed with pheochromocytoma/paraganglioma syndrome type 1 (PPGL1), underlined by a novel heterozygous pathogenic variant (c.154_161del, p.ser52Profster14) in the SDHD gene. Initially, the patient manifested symptoms unusual for pheochromocytoma, including polyuria and polydipsia; however, further diagnostic investigations revealed a pheochromocytoma (PCC) tumor in the adrenal gland. Subsequently, whole exome sequencing (WES) test identified a pathogenic frameshift variant in the SDHD gene, strongly suggestive of PPGL1. This study highlights the importance of considering atypical symptoms in diagnosing rare pediatric pheochromocytoma/paraganglioma tumors and underscores the value of genetic testing in identifying underlying genetic causes, thereby facilitating personalized management of the condition
Global estimates on the number of people blind or visually impaired by Uncorrected Refractive Error: a meta-analysis from 2000 to 2020
No full textBackground: Uncorrected refractive error (URE) is a readily treatable cause of visual impairment (VI). This study provides updated estimates of global and regional vision loss due to URE, presenting temporal change for VISION 2020 Methods: Data from population-based eye disease surveys from 1980–2018 were collected. Hierarchical models estimated prevalence (95% uncertainty intervals [UI]) of blindness (presenting visual acuity (VA) < 3/60) and moderate-to-severe vision impairment (MSVI; 3/60 ≤ presenting VA < 6/18) caused by URE, stratified by age, sex, region, and year. Near VI prevalence from uncorrected presbyopia was defined as presenting near VA < N6/N8 at 40 cm when best-corrected distance (VA ≥ 6/12). Results: In 2020, 3.7 million people (95%UI 3.10–4.29) were blind and 157 million (140–176) had MSVI due to URE, a 21.8% increase in blindness and 72.0% increase in MSVI since 2000. Age-standardised prevalence of URE blindness and MSVI decreased by 30.5% (30.7–30.3) and 2.4% (2.6–2.2) respectively during this time. In 2020, South Asia GBD super-region had the highest 50+ years age-standardised URE blindness (0.33% (0.26–0.40%)) and MSVI (10.3% (8.82–12.10%)) rates. The age-standardized ratio of women to men for URE blindness was 1.05:1.00 in 2020 and 1.03:1.00 in 2000. An estimated 419 million (295–562) people 50+ had near VI from uncorrected presbyopia, a +75.3% (74.6–76.0) increase from 2000 Conclusions: The number of cases of VI from URE substantively grew, even as age-standardised prevalence fell, since 2000, with a continued disproportionate burden by region and sex. Global population ageing will increase this burden, highlighting urgent need for novel approaches to refractive service delivery