Browse Articles

Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial

Identification and validation of biomarkers related to ferroptosis in idiopathic pulmonary fibrosis

Abstract Idiopathic pulmonary fibrosis (IPF) is a kind of interstitial lung disease (ILD). It has a high incidence rate and mortality. Its pathogenesis remains unclear. So far, no effective methods have been found for the early diagnosis of IPF. Ferroptosis has been reported to be critical in the initiation and progression of IPF. Therefore, our aim was to identify the hub gene related to ferroptosis co-expressed in the peripheral blood and pulmonary tissue of patients with IPF. Sequencing data were obtained from the Gene Expression Omnibus database. A comprehensive analysis was conducted on the differentially expressed genes (DEGs) to extract ferroptosis-related differentially expressed genes (FRDEGs). The results showed that ferroptosis-related signal paths were highly enriched in IPF, and 10 FRDEGs were identified.The hub gene was predicted through protein-protein interactions (PPI) and Cytoscape. The diagnostic utility of the hub gene was proven by enzyme-linked immunosorbent assay (ELISA) in serum and by immunohistochemistry (IHC) in pulmonary tissues. The results of ELISA indicated that the levels of ATM in the serum of patients with IPF were significantly lower than the normal levels. In contrast, the results of IHC showed that the expression of ATM in the pulmonary tissues of IPF patients exhibited a notably elevated trend. The immune status was assessed by the CIBERSORT method and so was the relevance between ATM and immune cells. These findings unveiled significant differences in various immune cell types in peripheral blood and pulmonary tissue between the IPF group and the control group. Furthermore, ATM was associated with various immune cells. This study suggests that as a ferroptosis-related gene, ATM assumes a pivotal role in the diagnosis and treatment of IPF. This discovery presents a novel approach for the clinical diagnosis and therapy of IPF.

Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions

Abstract Missense mutations that disrupt protein structural stability are a common pathogenic mechanism in human genetic disease. Here, we quantify potential disruption of protein stability due to amino acid substitution and show that functionally constrained proteins are less susceptible to large mutational changes in stability. Mechanistically, this relates to greater intrinsic disorder among constrained proteins and to increased B-factors in the ordered regions of constrained proteins. This phenomenon means that constrained proteins exhibit smaller stability effects due to missense mutations, and partly explains why overtransmission of pathogenic missense variation is less prevalent in genetic disorders characterised by protein truncations. We show that the most functionally constrained proteins are depleted of both destabilising and overly-stabilising amino acid variation in disease-free populations. Despite this, amino acid substitutions with large stability effects in functionally constrained proteins are still highly prevalent among pathogenic human genetic variation. Importantly, we observe that there are approximately five times more missense variants with large stability effects than there are unambiguous loss-of-function mutations. Missense variants with disruption of stability effects recapitulate the per-gene patterns of functional constraint observed with protein truncating loss-of-function variation, yet their relative abundance abrogates difficulties encountered when estimating functional constraint for the shortest human genes.

Case 8-2025: A 72-Year-Old Woman with Altered Mental Status and Acidemia

A two phase differential evolution algorithm with perturbation and covariance matrix for PEMFC parameter estimation challenges

Programmable mRNA therapeutics for controlled epigenomic modulation of single and multiplexed gene expression in diverse diseases

Disparities in use of physical restraint and chemical sedation in the emergency department by patient housing status

Background A growing body of research has found there to be disproportionate physical restraint and chemical sedation use for historically marginalized populations in the emergency department (ED). This association has been examined with regard to patient race, ethnicity, sex, and age. Preliminary research has highlighted the ways in which unhoused status may also relate to the use of physical restraint and chemical sedation in the ED. Given the adverse health outcomes associated with these methods in the ED, further research is needed to explore the relationship between patient housing status and physical restraint/chemical sedation use in more depth. Methods We conducted a cross-sectional study of all ED visits among patients aged 18 years of age and older presenting to eight hospitals within a regional healthcare network in New England between January 1, 2013, and December 31, 2021. Descriptive statistics and mixed effects logistic regression models nesting by patient were used to characterize the relationship between housing status and likelihood of restraint and/or sedation use. Findings Restraint orders were found in 3,160 (5.7%) visits by unhoused patients, compared to 44,155 (1.5%) for housed patients. Unhoused status was significantly associated with restraint/sedation use (adjusted odds ratio =  1.45, 95% CI 1.36-1.54). Conclusion Our study identified a significant association between housing status and ED restraint and sedation use after adjusting for demographic factors and chief complaints. This finding has important implications pertaining to the care of unhoused patients in the ED and for examination of structural factors like housing status and their impact on psychiatric emergency care.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach

Low serum calcium promotes traumatic intracerebral hematoma expansion by the response of immune cell: A multicenter retrospective cohort study

Plasma exchange and radiation resensitize immunotherapy-refractory melanoma: a phase I trial

Abstract Immune checkpoint inhibitors (ICI) are effective for advanced melanoma. However, most develop ICI resistance. Tumor-derived soluble PD-L1 (sPD-L1) and other immunosuppressive factors drive resistance. We hypothesized that therapeutic plasma exchange (TPE) may remove sPD-L1 from circulation and overcome ICI resistance. Patients with metastatic ICI-resistant melanoma and elevated sPD-L1 received radiotherapy to a minority of metastatic lesions, TPE, and ICI re-challenge. Primary endpoints were adverse events and sPD-L1 reduction. Secondary endpoints included overall survival, response, and progression-free survival. Correlative studies included changes in sPD-L1, other immunosuppressive factors, and immune cell phenotypes. Eighteen patients were included. Treatment was well-tolerated, and levels of sPD-L1 were reduced by TPE (mean 78%, p  < 0.0001). Soluble PD-L1 suppression predicted overall survival. The overall response rate was 61% (16.7% complete, 44.4% partial, 22.2% stable, and 16.7% progressing). Changes in peripheral immune cell populations and immunosuppressive factors predicted overall survival. sPD-L1 and other circulating immunoregulatory molecules mediate ICI resistance. TPE can reduce these factors and resensitize ICI-refractory melanoma. Patients with persistent elevation or rapid rebound of sPD-L1 experienced inferior outcomes, suggesting that multiple courses of TPE may be necessary. These findings may apply to other ICI-resistant cancers. Trial registration: NCT04581382, ReCIPE-M1 (Rescuing Cancer Immunotherapy with Plasma Exchange in Melanoma 1).

Species distribution of Cannabis sativa: Past, present and future

Cannabis sativa L. is an annual flowering herb of Eurasian origin that has long been associated with humans. Domesticated independently at multiple locations at different times for different purposes (food, fiber, and medicine), these long-standing human associations have influenced its distribution. However, changing environmental conditions and climatic fluctuations have also contributed to the distribution of the species and define where it is optimally cultivated. Here we explore the shifts in distribution that C. sativa may have experienced in the past and explore the likely shifts in the future. Modeling under paleoclimatic scenarios shows niche expansion and contraction in Eurasia through the timepoints examined. Temperature and precipitation variables and soil variable data were combined for species distribution modeling in the present day and showed high and improved predictive ability together as opposed to when examined in isolation. The five most important variables explaining ~ 65% of the total variation were soil organic carbon content (ORCDRC), pH index measured in water solution (PHIHOX), annual mean temperature (BIO-1), mean temperature of the coldest quarter (BIO-11) and soil organic carbon density (OCDENS) (AUC =  0.934). Climate model projections where efforts are made to curb emissions (RCP45/SSP245) and the business as usual (RCP85/SSP585) models were evaluated. Under projected future climate scenarios, shifts worldwide are predicted with a loss of ~ 43% in suitability areas with scores above 0.4 observed by 2050 and continued but reduced rates of loss by 2070. Changes in habitat range have large implications for the conservation of wild relatives as well as for the cultivation of Cannabis as the industry moves toward outdoor cultivation practices.

Liberal or Restrictive Transfusion Strategy in Aneurysmal Subarachnoid Hemorrhage

The development of a bioanalytical method for the simultaneous analysis of gentamicin and tacrolimus in Rat whole blood using UHPLC–MS/MS

Author Correction: The genetic origin of the Indo-Europeans

Author Correction: Coherent coupling between vortex bound states and magnetic impurities in 2D layered superconductors

A multidisciplinary protocol for reducing excessive and maintaining a healthy body weight in the personalized management of chronic diseases in children and adults

Despite regularly used treatment asthma in both children and adults is not fully controlled. This is more prominent in certain disease subtypes, such as obese asthma. The vast complexity of asthma phenotypes and often overlapping endotypes emphasizes the need for implementing the concept of precision medicine in disease management. In order to address these concerns, an innovative and personalized programme for reducing excessive and maintaining a healthy body weight will be developed by experts from pharmaceutical and food industry (Belupo Inc. and Podravka Inc., Croatia) as well as clinical experts (Srebrnjak Children`s Hospital, Croatia). The programme will involve meals replacement (standard and innovative formulas), dietary program and nutritional counseling, physical activity and other individually tailored measures according specific disease phenotypes and underlying pathophysiological mechanisms in each participant. The outcomes of this study should contribute to better control of the underlying condition, reduction of the frequency and severity of symptoms and, consequently, in the improvement of the participant’s overall quality of life.

Sentinel-Lymph-Node Biopsy in Early-Stage Breast Cancer — Is It Obsolete?

Hunting dog behaviour is a key driver impacting harvest quantity and quality of truffles

Abstract Truffles are an iconic food that have long held high regard. Here we explore the seasonality and eco-physiological interactions affecting truffle quality and quantity across time and space. Collaborating with professional truffle hunters working eight different locations, detailed metrics of 3180 recovered truffles from 236 hunt events and spanning a full fruiting period, were recorded. Contrary to expectations, truffle weight showed no correlation with climate variables, suggesting a limited influence of environmental factors such as temperature and precipitation on truffle size. We also found that truffle maturity and damage from mycophagy were strongly linked, with deeper truffles being more mature but also more susceptible to damage. Finally, we observe that scent-dog behaviour significantly impacts the quantity and quality of recovered truffles, and we address the necessity of considering this in truffle ecophysiology studies. Alongside advances in our biological understanding, we make recommendations of how training methods can be improved to lead to greater detection and quality targeting with immediate socioeconomic impact. These findings highlight the complex interplay between truffle physiology, environmental factors, and human and animal behaviours, emphasizing the need for further considered research to enhance our understanding of truffle biology and to improve truffle cultivation practices.

Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation

Oral pain and comorbidities in an edentulous older population: A k-prototypes cluster analysis

Non-odontogenic oral pain is prevalent among the older people and significantly impacts their quality of life. Non-odontogenic oral pain is usually persistent and accompanied by comorbidities such as psychosocial distress and sleep-related problems, which further complicate pain management. The relationship between non-odontogenic oral pain and comorbidities in the older people, however, has not been well documented. This study aimed to identify the factors associated with non-odontogenic oral pain in an edentulous older population and to subgroup this population based on the patterns of oral pain and its associated factors. In this cross-sectional study, data from completely edentulous individuals in the National Health and Nutrition Examination Survey for the period from 2017 to 2020 March (pre-pandemic) were analysed. Associations and correlations between oral pain and 46 other variables, including demographic, questionnaire, examination and laboratory data, were investigated using Pearson’s chi-squared test and Spearman’s rank correlation test. A p value of < 0.05 was considered statistically significant. Clustering of the data was performed using the k-prototypes algorithm, an unsupervised machine learning. Approximately 42% of the edentulous older people experienced oral pain. ‘Having been told to take daily low-dose aspirin’ was significantly associated with oral pain. Oral pain was positively correlated with depressive symptoms and excessive daytime sleepiness (EDS), and negatively correlated with diastolic blood pressure, red blood cell count, haemoglobin level and haematocrit. The k-prototypes algorithm identified a cluster characterised by frequent oral pain, depression and EDS. This study identified distinct patterns of comorbidities among edentulous older people living with oral pain.