Alexion Pharma (Switzerland)

Experimental evolution has been a useful tool for investigating long-term temporal evolutionary dynamics and molecular mechanisms underlying adaptation. However, extracting fundamental principles and predictive features of evolutionary outcomes from these datasets remains challenging. Here we sought to circumvent these challenges by comparing distant yeast species that share several evolutionary features but differ in evolutionary history and genome architecture, that is Saccharomyces cerevisiae and Schizosaccharomyces pombe. We evolved ten populations of the fission yeast for 10,000 generations in the same conditions as a pre-existing budding yeast dataset, allowing us to observe repeatable evolutionary outcomes within species but diverse molecular targets of adaptation across species. The most frequent route of adaptation was through changes in carbon flux metabolism, which was previously unseen in S. cerevisiae evolved populations, but similar evolutionary paths have been observed in wild populations. This suggests that parallelism is pervasive and that mechanisms of adaptation can be shared among closely related or distant species. Despite similar gene content and identical environments, recurrent adaptation across S. pombe populations involved different genes than in S. cerevisiae and was detectable mostly at the transcriptomic level. This indicates that trans-regulatory effects and contingency may contribute to differences in evolutionary outcomes between these species.

Patients with transfusion-dependent thalassemia (TDT) require lifelong blood transfusions; data on the psychosocial and economic impact on patients and their caregivers remain limited. The study aims to address this gap by describing the burden of TDT on pediatric, young, and adult patients, as well as their caregivers, within real-world settings in Italy. This is a cross-sectional, descriptive study conducted between May and December 2021. TDT patients and their caregivers from Italian sites were invited to complete an online survey with the Ratip and Modell questionnaire (1996) and another bespoke questionnaire. All subjects signed an online informed consent before responding to the questionnaires. Seventy-nine subjects completed the survey: 59 patients (43 adults and 16 children) and 20 caregivers (the majority of adult patients were aged 41-50 years). The age at diagnosis differed between adults and pediatric patients, being earlier in the latter (0-2 months in 43.8%). Nearly half of patients received more than one transfusion/month. More than half of the patients experienced blood shortages, particularly during the summer. School absenteeism was reported as a major issue. TDT continues to impose a significant burden, negatively impacting daily life, work, education, and social interactions. The availability of blood resources remains a critical issue, particularly in high-prevalence regions. The study highlights the need for ongoing research, innovative approaches, and enhanced support to ensure improved well-being for TDT patients and their caregivers.

Patients with neuromyelitis optica spectrum disorder (NMOSD) may experience increased signs and symptoms of their underlying disease when vaccinated against meningococcal disease before receiving complement component 5 inhibitor therapies. This retrospective analysis indicated an overall low relapse incidence (mean [range], 3.3% [0.7%-10.6%]) of physician-reported relapses occurring within 4 weeks of meningococcal vaccination in those screened in CHAMPION-NMOSD (NCT04201262), randomized to eculizumab or placebo in PREVENT (NCT01892345), and from the Japanese postmarketing surveillance of eculizumab in patients with anti-aquaporin-4 antibody-positive NMOSD. Further studies are needed to determine if postvaccination relapses are attributable to vaccination or inherent relapse risk among these patients.

Because a disease-modifying therapy is now available, bone scintigraphy plays a crucial role in diagnosing transthyretin cardiac amyloidosis (ATTR-CM). We retrospectively analyzed 24 patients with ATTR-CM to determine the amyloid accumulation volume (AAV: mean standardized uptake value×volume) of the left ventricular wall. AAV showed a significant decrease (591.1±426.0 vs. 213.8±201.9, P<0.0001) after tafamidis treatment, and correlated with troponin T (R=0.49, P=0.022). AAV provided a precise quantitative evaluation of the amyloid burden in ATTR-CM.

The calcium-sensing receptor (CaSR) plays a crucial role in cellular signaling and has been implicated in cancer progression. However, its specific role in breast cancer remains unclear. This study aimed to investigate CaSR gene expression levels, its correlation with oncogenic pathways, and its protein localization in human breast cancer tissues. Quantitative real-time PCR (qRT-PCR) was used to analyze the relative expression of CaSR and associated genes in malignant and adjacent non-malignant breast cancer tissue samples. Pearson correlation analysis was performed to assess relationships between CaSR and other oncogenic markers. Immunohistochemistry (IHC) was conducted to evaluate CaSR protein localization and intensity in different breast cancer grades and fibroadenoma tissues. Our findings revealed that 56% of patients exhibited elevated CaSR expression, with significant positive correlations between CaSR and oncogenic genes such as HOTAIR, SNOR78, BC200, DSG1, DSC1, HER2, BRCA1, p38 MAPK, and Akt (p = 0.001 for most correlations). Additionally, CaSR expression negatively correlated with menopausal status (p = 0.001), suggesting hormonal influences on its regulation. IHC analysis showed strong membranous and cytoplasmic staining in grade II tumors without metastasis (+ 3) but weak or undetectable CaSR expression in advanced metastatic cases. These findings indicate a potential role for CaSR in tumor progression, adhesion, and metastasis. Importantly, this study provides novel evidence linking CaSR expression to non-coding RNAs, desmosomal adhesion molecules, and MAPK/AKT signaling pathways, highlighting previously unexplored mechanisms through which CaSR may influence breast cancer progression and metastatic behavior. Further research is needed to determine its potential as a biomarker or therapeutic target in breast cancer treatment.

The authors have disclosed no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Obesity is a complex, multifactorial disease influenced by genetic, hormonal, and metabolic factors. The fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes have been implicated in body weight regulation through gut–brain signaling and their interactions with adipokines and enteroendocrine hormones. This study investigated the association between gastric expression of FTO and MC4R genes and circulating levels of leptin, adiponectin, and ghrelin in individuals with and without obesity. We conducted a case–control study including 50 patients with obesity undergoing sleeve gastrectomy and 50 controls undergoing diagnostic endoscopy. Gastric tissue gene expression was assessed by qRT-PCR, and serum hormone levels were quantified using ELISA. Inverse propensity score weighting was used to adjust for age and sex. FTO expression was significantly upregulated in patients with obesity (fold-change: 5.8 vs. 1.0, p < 0.001), showing a parallel elevation with adiponectin and BMI at the group level. In contrast, MC4R expression was significantly downregulated (fold-change: 0.1 vs. 1.0, p < 0.001), and positively associated with HOMA-IR and showed a borderline positive trend with fasting blood glucose (p = 0.074). Adiponectin levels were paradoxically elevated in the obesity group and correlated with both BMI and HDL. Leptin and ghrelin levels showed no significant group differences. These findings suggest that altered gastric expression of FTO and MC4R may contribute to obesity-related metabolic disturbances through peripheral adipokine pathways. Further investigation into tissue-specific gene–hormone interactions may inform novel therapeutic strategies for obesity.