A REVIEW TO HONOR THE HISTORICAL CONTRIBUTIONS OF PAULINE GROSS, ALDRED WARTHIN, AND HENRY LYNCH IN THE DESCRIPTION AND RECOGNITION OF INHERITANCE IN COLORECTAL CANCER.

The present manuscript aimed to review the historical development and most important contributions regarding Lynch Syndrome since its first description, more than a century ago. In 1895, a reputed pathologist from Michigan University, Dr. Aldred Scott Warthin, got intrigued by the family history of a local seamstress called Pauline Gross. According to her prevision, she would present an early death due to cancer, which actually happened (from the uterus). Historically, her family was designated "Family G", comprising a group recognized as the longest and most detailed cancer genealogy that has ever been studied. Warthin concluded that its members had genetic susceptibility for cancer, and they are, nowadays, considered the first reported Lynch Syndrome family. At that time, however, the medical cancer community was far less receptive to the association between heredity and cancer, despite the description of other families with similar heredograms. Unfortunately, this historical fact remained somewhat dormant until another investigator inaugurated a new era in the understanding of family cancer clusters. After reports and studies from this family and many others, the condition initially called Cancer Family Syndrome was changed to the eponym Lynch Syndrome. This was a recognition of the extensive and dedicated work developed by Dr. Henry Lynch in describing various characteristics of the disease, and his efforts to establish the correct recommendations for its diagnosis and treatment. Although the future announces there is still far to go for a complete understanding of Lynch Syndrome, the remarkable contributions of Pauline's intuition, Warthin's perseverance, and Lynch's work consistency must never be forgotten by those who already have or will still benefit from this knowledge.

Use of ultrasound for hardware removal.

Introduction Osteosynthesis hardware removal is one of the most frequent practices in Orthopaedic electives surgeries and is usually carried out guided under fluoroscopy. There are other tools such as ultrasound that allow us to visualise the hardware with the advantage of being free of ionizing radiation and with better availability. The objective of our study is to analyse the results obtained in patients undergoing hardware removal in the operating room under ultrasound assistance and local anaesthesia. Material and methods A descriptive study was carried out collecting variables such as demographic data, reason for the removal, pain during the procedure and in subsequent days, as well as the duration and rate of success of the procedure and the degree of satisfaction. Results We obtained a 100% success in ultrasound-guided extraction without the need for conventional radiology, with a mean VAS of 1.91 and need for subsequent analgesia in 36.4% of the cases, with syndesmotic dynamisation being the most frequent reason for intervention. Conclusion Ultrasound is a useful tool in osteosynthesis hardware removal, and that may be sufficient by itself; also saving health personnel and patients from ionizing radiation resulting from the use of conventional fluoroscopy.

Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

Explainable machine learning on baseline MRI predicts multiple sclerosis trajectory descriptors.

Multiple sclerosis (MS) is a multifaceted neurological condition characterized by challenges in timely diagnosis and personalized patient management. The application of Artificial Intelligence (AI) to MS holds promises for early detection, accurate diagnosis, and predictive modeling. The objectives of this study are: 1) to propose new MS trajectory descriptors that could be employed in Machine Learning (ML) regressors and classifiers to predict patient evolution; 2) to explore the contribution of ML models in discerning MS trajectory descriptors using only baseline Magnetic Resonance Imaging (MRI) studies. This study involved 446 MS patients who had a baseline MRI, at least two measurements of Expanded Disability Status Scale (EDSS), and a 1-year follow-up. Patients were divided into two groups: 1) for model development and 2) for evaluation. Three descriptors: ß1, ß2, and EDSS(t), were related to baseline MRI parameters using regression and classification XGBoost models. Shapley Additive Explanations (SHAP) analysis enhanced model transparency by identifying influential features. The results of this study demonstrate the potential of AI in predicting MS progression using the proposed patient trajectories and baseline MRI scans, outperforming classic Multiple Linear Regression (MLR) methods. In conclusion, MS trajectory descriptors are crucial; incorporating AI analysis into MRI assessments presents promising opportunities to advance predictive capabilities. SHAP analysis enhances model interpretation, revealing feature importance for clinical decisions.

Nanotechnology in food packaging materials: role and application of nanoparticles.

Global concerns about food security, driven by rising demand, have prompted the exploration of nanotechnology as a solution to enhance food supply. This shift comes in response to the limitations of conventional technologies in meeting the ever-increasing demand for food products. Consequently, nanoparticles play a crucial role in enhancing food production, preservation, and extending shelf life by imparting exceptional properties to materials. Nanoparticles and nanostructures with attributes like expansive surface area and antimicrobial efficacy, are versatile in both traditional packaging and integration into biopolymer matrices. These distinctive qualities contribute to their extensive use in various food sector applications. Hence, this review explores the physicochemical properties, functions, and biological aspects of nanoparticles in the context of food packaging. Furthermore, the synergistic effect of nanoparticles with different biopolymers, alongside its different potential applications such as food shelf-life extenders, antimicrobial agents and as nanomaterials for developing smart packaging systems were summarily explored. While the ongoing exploration of this research area is evident, our review highlights the substantial potential of nanomaterials to emerge as a viable choice for food packaging if the challenges regarding toxicity are carefully and effectively modulated.

Systematic Review and Meta-Analysis of the Diagnostic Accuracy of a Graded Gait and Truncal Instability Rating in Acutely Dizzy and Ataxic Patients.

BACKGROUND: In patients presenting with acute prolonged vertigo and/or gait imbalance, the HINTS [Head-Impulse, Nystagmus, Test-of-Skew] are very valuable. However, their application may be limited by lack of training and absence of vertigo/nystagmus. Alternatively, a graded gait/truncal-instability (GTI, grade 0-3) rating may be applied. METHODS: We performed a systematic search (MEDLINE/Embase) to identify studies reporting on the diagnostic accuracy of bedside examinations in adults with acute vestibular syndrome. Diagnostic test properties were calculated for findings using a random-effects model. Results were stratified by GTI-rating used. RESULTS: We identified 6515 articles and included 18 studies (n = 1025 patients). Ischemic strokes (n = 665) and acute unilateral vestibulopathy (n = 306) were most frequent. Grade 2/3 GTI had moderate sensitivity (70.8% [95% confidence-interval (CI) = 59.3-82.3%]) and specificity (82.7 [71.6-93.8%]) for predicting a central cause, whereas grade 3 GTI had a lower sensitivity (44.0% [34.3-53.7%] and higher specificity (99.1% [98.0-100.0%]). In comparison, diagnostic accuracy of HINTS (sensitivity = 96.8% [94.8-98.8%]; specificity = 97.6% [95.3-99.9%]) was higher. When combining central nystagmus-patterns and grade 2/3 GTI, sensitivity was increased to 76.4% [71.3-81.6%] and specificity to 90.3% [84.3-96.3%], however, no random effects model could be used. Sensitivity was higher in studies using the GTI rating (grade 2/3) by Lee (2006) compared to the approach by Moon (2009) (73.8% [69.0-78.0%] vs. 57.4% [49.5-64.9%], p = 0.001). CONCLUSIONS: In comparison to HINTS, the diagnostic accuracy of GTI is inferior. When combined with central nystagmus-patterns, diagnostic accuracy could be improved based on preliminary findings. GTI can be readily applied in the ED-setting and also in patients with acute imbalance syndrome.

A Novel Foodstuff Mixture Improves the Gut-Liver Axis in MASLD Mice and the Gut Microbiota in Overweight/Obese Patients.

Microbial community control is crucial for maintaining homeostasis of the gut-liver axis in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that supplementation with a mixture of Mexican foodstuffs (MexMix)-Opuntia ficus indica (nopal), Theobroma cacao (cocoa) and Acheta domesticus (crickets)-enriches several beneficial taxa in MASLD mice and overweight/obese humans. Thus, MexMix induces an important prebiotic effect. In mice, a restoration of intestinal health was observed due to the increased short-chain fatty acids (SCFAs) and intestinal crypt depth, Ocln and Cldn1 expression, and decreased Il6 and Tnfa expression. MexMix significantly reduced steatosis in the mice's liver and modified the expression of 1668 genes. By PCR, we corroborated a Tnfa and Pparg decrease, and a Cat and Sod increase. In addition, MexMix increased the hepatic NRF2 nuclear translocation and miRNA-34a, miRNA-103, and miRNA-33 decline. In overweight/obese humans, MexMix improved the body image satisfaction and reduced the fat intake. These findings indicate that this new food formulation has potential as a therapeutic approach to treat conditions associated with excessive consumption of fats and sugars.

Preoperative brachytherapy of early-stage cervical cancer: A multicenter study by the SFRO brachytherapy group.

OBJECTIVE: To report the results of a multicenter cohort of preoperative brachytherapy (PBT) for treatment of early-stage cervical cancer (ESCC). METHODS: A retrospective analysis was conducted among five French comprehensive cancer centers on behalf of the SFRO Brachytherapy Group to examine the outcome of patients with ESCC who received PBT between 2001 and 2019 because of adverse prognostic factors (tumor size >2 cm, presence of lymphovascular invasion, adenocarcinoma).Brachytherapy was followed 4-8 weeks later by surgery. Local relapse free, distant metastasis-free survival, disease-free, and overall survival and adverse effects were examined. Uni- and multivariate analyses were conducted looking for oncological prognostic factors. RESULTS: A total of 451 patients were identified, with a mean tumor size of 24.7 mm. Adenocarcinoma accounted for 43.5% of cases, and lympho-vascular space invasion (LVSI) was present in 15.7%. A complete histological response was observed in 69.6%. With a mean follow-up of 75.4 months, DFS, LRFS, and OS rates at five years were 88% [95% CI (84-91), 98% [95% CI (96-99), and 92% [95% CI (87-95)], respectively. At the last follow-up, 8.2% of patients had died, including 31 (6.8%) from cervical cancer. Severe side effects range from 1.1% to 2%. At multivariate analysis, adenocarcinoma histological type, tumor size ≥2 cm, and the presence of residual tumors were prognosticators for DFS and DMFS. CONCLUSION: PBT shows excellent oncological outcomes in this cohort of patients with adverse histoprognostic factors. Favorable survival rates and low complications rates were observed, supporting this strategy in the management of ESCC.

Basketball technique action recognition using 3D convolutional neural networks.

This research investigates the recognition of basketball techniques actions through the implementation of three-dimensional (3D) Convolutional Neural Networks (CNNs), aiming to enhance the accurate and automated identification of various actions in basketball games. Initially, basketball action sequences are extracted from publicly available basketball action datasets, followed by data preprocessing, including image sampling, data augmentation, and label processing. Subsequently, a novel action recognition model is proposed, combining 3D convolutions and Long Short-Term Memory (LSTM) networks to model temporal features and capture the spatiotemporal relationships and temporal information of actions. This facilitates the facilitating automatic learning of the spatiotemporal features associated with basketball actions. The model's performance and robustness are further improved through the adoption of optimization algorithms, such as adaptive learning rate adjustment and regularization. The efficacy of the proposed method is verified through experiments conducted on three publicly available basketball action datasets: NTURGB + D, Basketball-Action-Dataset, and B3D Dataset. The results indicate that this approach achieves outstanding performance in basketball technique action recognition tasks across different datasets compared to two common traditional methods. Specifically, when compared to the frame difference-based method, this model exhibits a significant accuracy improvement of 15.1%. When compared to the optical flow-based method, this model demonstrates a substantial accuracy improvement of 12.4%. Moreover, this method showcases strong robustness, accurately recognizing actions under diverse lighting conditions and scenes, achieving an average accuracy of 93.1%. The research demonstrates that the method reported here effectively captures the spatiotemporal relationships of basketball actions, thereby providing reliable technical assessment tools for basketball coaches and players.

Ultrasound Therapy With High-Pressure Pulses Is Effective to Reduce the Effects of Collagenase-Induced Tendinopathy in Rat's Achilles Tendon.

OBJECTIVE: We propose an ultrasonic treatment for collagenase-induced tendinopathy in rat's Achilles tendon using pulses with a low number of cycles, high acoustic pressure and very low duty cycle. METHODS: Twenty rats were used to perform the experiment. Four experimental groups of calcaneal tendons were studied: control (n = 6), sham (n = 4), collagenase-induced tendinopathy (n = 8) and ultrasound-treated collagenase-induced tendinopathy (n = 8). Surgical intervention was performed to expose the tendons prior to collagenase injection. A 1 MHz ultrasonic tansducer with a focusing lens was used. Ultrasonic treatments were used with an average total treatment time of 2.5 min, 20-cycle pulses, pressure amplitude p = 7 MPa, and 0.02% duty cycle. Histopathology of the samples was performed to evaluate nuclear density, acute inflammation, and signs of neovascularization. Collagen (types I and III), elastic fibers, and glycosaminoglycans were also analyzed. RESULTS: No tendon involvement was found by the surgical process. Ultrasonic treatment is safe, as it does not affect healthy tendons. When collagenase infiltrated animals were treated with US, a clear predominance of type I collagen fibers and a similar collagen ratio profile to that observed in the control and sham groups was observed, with a higher density of elastic fibers compared to the control and sham groups and a significant increase in the density of glycosaminoglycans. CONCLUSION: The ultrasound treatment proposed reduces the effects of the artificial collagenase lesion to reach the basal level after 45 d.

Splenic abscess due to Salmonella enterica infection successfully treated with percutaneous drainage.

A 66-year-old female presented to our hospital with diffuse abdominal pain and diarrhea. An abdominal CT showed a splenic abscess of 9.9 x 6.1 x 6.5 cm. A conservative approach with US-guided percutaneous drainage and antibiotic treatment was performed successfully. Splenic abscess is a rare complication of Salmonella spp infection. In selected cases, percutaneous drainage can be performed safely with good efficacy.

Medicinal chemistry curriculum and pedagogical practices at Canadian pharmacy schools: Towards standardization of practice.

INTRODUCTION: Medicinal chemistry instruction in PharmD programs at Canadian universities is considered an important foundational science. However, with few guidelines for the required content most programs have observed a decrease in hours of medicinal chemistry instruction. A Medicinal Chemistry Special Interest Group (SIG) was formed to address these issues nationally and initiated a pan-Canadian environmental scan to better understand the depth and breadth of medicinal chemistry instruction. METHODS: The SIG carried out an environmental scan to identify medicinal chemistry content, delivery and assessments in PharmD programs in Canada. RESULTS: Core medicinal chemistry concepts across the PharmD programs are in general agreement with those listed by the Accreditation Council for Pharmacy Education. Medicinal chemistry was typically taught as didactic lectures either as a standalone course or within a pharmacology course, although one program integrated some medicinal chemistry within therapeutics focused problem-based learning. There was no consistent time in program where medicinal chemistry occurred. CONCLUSIONS: The SIG found that similar medicinal chemistry content is taught across all Canadian PharmD programs, but incorporation of medicinal chemistry in therapeutics courses was minimal. Core concepts within six high-level overarching themes that guide our collective instruction were identified. The core concepts require developing high-level cognitive processes such as knowledge application and synthesis that practicing pharmacists are expected to possess for entry to practice. We the authors posit that in addition to providing a unique tool for pharmacists to employ in therapeutic decision-making, medicinal chemistry also provides early practice of important problem-solving and critical thinking skills.

Health-Related Quality of Life Long-Term Study in Lung Transplant Patients: A Single-Center Experience.

INTRODUCTION: Health-related quality of life (HRQL) assessment plays a crucial role in the follow-up care of lung transplanted (LTx) patients. Previous reports have indicated that the HRQL achieved by these patients is often poorer compared to that of healthy individuals. However, the factors contributing to this lower HRQL remain unclear. This prospective study aimed to assess the effectiveness of using both a generic and a disease-specific HRQL instrument in evaluating the outcomes of patients who have undergone LTx. METHODS: A total of 111 LTx patients were enrolled in the study, with 88 survivors completing the 5-year follow-up and 23 nonsurvivors identified within the first 3 y. Among the participants, 84 underwent double LTx, while 27 received a single LTx. Patients were interviewed before LTx, at 6 mo post-transplantation, and annually thereafter. Two validated instruments were utilized: the Euro quality of life five dimensions, a generic measure, and the St. George's Respiratory Questionnaire (SGRQ), a disease-specific questionnaire. RESULTS: The study showed significant improvements in Euro Quality of Life five Dimensions scores from 6 mo after LTx. Specifically, the percentage of patients without Mobility problems increased from 23% before LTx to 71% at 5 y (P = <0.001), while the ability to self-care improved from 48% to 100% (P = <0.001). The ability to carry out usual activities improved from 13% to 86% (P = <0.001), and the proportion of patients without anxiety and depression increased from 50% to 86% (P > 0.004). However, there was no significant improvement observed in Pain, with only a slight reduction from 57% to 42.8% (P = 0.22). The SGRQ also showed improvements in all dimensions (symptoms, impact, activities) (P < 0.001). However, by the fifth year, the HRQL scores remained below normal reference values. Chronic graft dysfunction was associated with a decline in SGRQ scores. Bilateral LTx patients exhibited better SGRQ scores compared to unilateral LTx patients from the first year post-transplantation. Notably, there were no differences in scores between nonsurvivors and survivors. CONCLUSIONS: The study highlights the long-term improvement in HRQL among LTx patients, with greater improvements observed in physical dimensions compared to psychological dimensions. Bilateral LTx was associated with better SGRQ scores than unilateral LTx, and chronic graft dysfunction primarily affected SGRQ scores. These findings underscore the importance of utilizing both generic and specific HRQL instruments in assessing LTx outcomes.

Selection of disease modifying therapies in multiple sclerosis based on patient's age and disease activity: Data from a nationwide registry.

BACKGROUND: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting. METHODS: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET). RESULTS: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01). CONCLUSION: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue.

Influence of Preterm Birth and Low Birthweight on Physical Fitness: A Systematic Review, Meta-Analysis, and Meta-Regression.

BACKGROUND: Preterm birth and low birthweight (LBW) might be associated with reduced physical fitness, although evidence remains inconclusive. OBJECTIVE: To examine the influence of preterm birth and LBW on physical fitness, as well as to assess whether variables such as gestational age, birthweight, or age at assessment moderate these effects. METHODS: PubMed, Scopus, and PsycINFO were systematically searched from inception to 7 December 2023 for case-control and cohort studies analyzing the association between preterm birth or LBW (or gestational age or birthweight as continuous variables) with at least one physical fitness-related outcome (i.e., cardiorespiratory fitness (CRF), muscle strength, flexibility, speed, agility). Random-effects meta-analysis and meta-regression models were used to estimate the pooled effect size, as well as to examine potential associations between the magnitude of the effect and gestational age, birthweight, or age at assessment. RESULTS: Fifty-two studies (n = 920,603 participants, average age ranging from 4.7 to 34.4 years) were included. Preterm birth was associated with reduced CRF (standardized mean difference (SMD) = -0.38, 95% confidence interval (CI) = -0.51 to -0.25) and muscle strength (SMD = -0.44, 95% CI = -0.79 to -0.08). LBW was associated with reduced CRF (SMD = -0.40, 95% CI = -0.64 to -0.17), muscle strength (SMD = -0.18, 95% CI = -0.24 to -0.13), flexibility (SMD = -0.11, 95% CI = -0.22 to -0.01), and agility (SMD = -0.99, 95% CI = -1.91 to -0.07). Meta-regression analyses showed that a lower gestational age or birthweight were associated with larger reductions in physical fitness, whereas no consistent association was found for the age at assessment. CONCLUSION: Both preterm birth and LBW seem associated with reduced physical fitness regardless of age, with larger reductions overall observed in individuals with lower gestational age or birthweight. These findings might support the implementation of preventive strategies (e.g., fitness monitoring and physical exercise interventions) in these populations through the life course. PROSPERO registration: CRD42021231845.

Validation of the Spanish version of the Pediatric Asthma Severity Score (PASS) in a population of Hispanic children.

BACKGROUND: The Pediatric Asthma Severity Score (PASS) is one of the most-used clinical scoring systems for assessing the severity of asthma exacerbations in children. The aim of the present study was to validate a Spanish version of the PASS in a population of Hispanic children with asthma exacerbations living in urban Bogota, Colombia. METHODS: In a prospective cohort and a validation study, parents/caregivers of children between 2 and 18 years old attended in the emergency department (ED) with asthma exacerbations who were admitted to the inpatient unit were invited to participate in the study. During the hospitalization period, we gathered the necessary data for assessing the criterion validity (comparing its score with the Pediatric Respiratory Assessment Measure [PRAM]), construct validity, interrater reliability, responsiveness, and internal consistency of the Col-PASS, the Colombian version of the PASS. RESULTS: At baseline, the scores of the Col-PASS correlated positively with the scores of the PRAM score (ρ = 0.588, p < .001). The baseline Col-PASS scores in patients who required admission to a more complex service were significantly higher than those in patients who presented clinical improvement (1.0 (0.0-2.0) vs. 0.0 (0.0-0.0), p < .001). The interrater reliability was found to be κ = 0.897, 95% CI 0.699-1.000, p < .001. Cronbach's α was .701 for the questionnaire as a whole. CONCLUSION: The Col-PASS has excellent construct validity, adequate criterion validity, interrater reliability, responsiveness; and acceptable internal consistency when used in children between 2 and 18 years old with asthma exacerbations.

Prediabetes as a risk factor for all-cause and cause-specific mortality: a prospective analysis of 115,919 adults without diabetes in Mexico City.

BACKGROUND: Prediabetes has been associated with increased all-cause and cardiovascular mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations. METHODS: We analyzed data from 115,919 adults without diabetes (diagnosed or undiagnosed) aged 35-84 years who participated in the Mexico City Prospective Study between 1998 and 2004. Participants were followed until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c 5.7% to 6.4%) and the International Expert Committee (IEC, HbA1c 6.0-6.4%) definitions. Cox regression adjusted for confounders was used to estimate all-cause and cause-specific mortality rate ratios (RR) at ages 35-74 years associated with prediabetes. FINDINGS: During 2,085,392 person-years of follow-up (median in survivors 19 years), there were 6,810 deaths at ages 35-74, including 1,742 from cardiovascular disease, 892 from renal disease and 108 from acute diabetic crises. Of 110,405 participants aged 35-74 years at recruitment, 28,852 (26%) had ADA-defined prediabetes and 7,203 (7%) had IEC-defined prediabetes. Compared with those without prediabetes, individuals with prediabetes had higher risk of all-cause mortality at ages 35-74 years (RR 1.13, 95% CI 1.07-1.19 for ADA-defined prediabetes and RR 1.28, 1.18-1.39 for IEC-defined prediabetes), as well as increased risk of cardiovascular mortality (RR 1.22 [1.10-1.35] and 1.42 [1.22-1.65], respectively), renal mortality (RR 1.35 [1.08-1.68] and 1.69 [1.24-2.31], respectively), and death from an acute diabetic crisis (RR 2.63 [1.76-3.94] and 3.43 [2.09-5.62], respectively). RRs were larger at younger than at older ages, and similar for men compared to women. The absolute excess risk associated with ADA and IEC-defined prediabetes at ages 35-74 accounted for6% and 3% of cardiovascular deaths respectively, 10% and 5% of renal deaths respectively, and 31% and 14% of acute diabetic deaths respectively. INTERPRETATION: Prediabetes is a significant risk factor for all-cause, cardiovascular, renal, and acute diabetic deaths in Mexican adults. Identification and timely management of individuals with prediabetes for targeted risk reduction could contribute to reducing premature mortality from cardiometabolic causes in this population. FUNDING: Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, UK Medical Research Council. Instituto Nacional de Geriatría (Mexico City).

Content and tissue expression of Collagen I, Collagen IV, and Laminin in the Extracellular Matrix in Prostate Adenocarcinoma.

Prostate cancer is one of the most common neoplasm in the male population. It is not known why some tumors become more aggressive than others. Although most studies show changes in the expression of cell adhesion molecules and the extracellular matrix correlated with the Gleason score, no study has objectively measured the tissue content of these molecules. This study aims to measure the content and tissue expression of collagen type I and IV and laminin in the extracellular matrix of patients with prostate adenocarcinoma and correlate these findings with the Gleason score and clinical characteristics. Forty-one patients who underwent radical prostate surgery at the Urology Department of a reference Hospital in Brazil between January 2015 and December 2020 were studied. The tissue protein content was estimated under light microscopy at a final magnification of 200 × . The mean collagen I score in prostate adenocarcinoma tissue samples was 7.16 ± 1.03 pixels/field. The mean type IV collagen score was 3.44 ± 0.61 pixels/field. The mean laminin score was 5.19 ± 0.79 pixels/field. The total Gleason score was correlated with both collagen and laminin. All the correlations were negative, which shows that the higher the collagen/laminin expression was, the lower the total Gleason score (p-value < 0,05). According to the Pearson correlation analysis, age has no statistical relationship with collagen and laminin content. PSA, in turn, showed a correlation only with laminin, but r = -0.378 (p = 0.015). Among the associated diseases and lifestyle habits, there is only statistical significance in the comparison of alcoholism for collagen I. For collagen IV and laminin, no statistical significance was obtained with the clinical variables analyzed.

PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives.

Ovarian cancer is the deadliest gynecologic malignancy. The majority of patients diagnosed with advanced ovarian cancer will relapse, at which point additional therapies can be administered but, for the most part, these are not curative. As such, a need exists for the development of novel therapeutic options for ovarian cancer patients. Research in the field of targeted protein degradation (TPD) through the use of proteolysis-targeting chimeras (PROTACs) has significantly increased in recent years. The ability of PROTACs to target proteins of interest (POI) for degradation, overcoming limitations such as the incomplete inhibition of POI function and the development of resistance seen with other inhibitors, is of particular interest in cancer research, including ovarian cancer research. This review provides a synopsis of PROTACs tested in ovarian cancer models and highlights PROTACs characterized in other types of cancers with potential high utility in ovarian cancer. Finally, we discuss methods that will help to enable the selective delivery of PROTACs to ovarian cancer and improve the pharmacodynamic properties of these agents.