MUC1 is a transmembrane glycoprotein that is overexpressed and aberrantly glycosylated in epithelial cancers. The cytoplasmic tail of MUC1 (MUC1 CT) aids in tumorigenesis by upregulating the ...expression of multiple oncogenes. Signal transducer and activator of transcription 3 (STAT3) plays a crucial role in several cellular processes and is aberrantly activated in many cancers. In this study, we focus on recent evidence suggesting that STAT3 and MUC1 regulate each other's expression in cancer cells in an auto-inductive loop and found that their interaction plays a prominent role in mediating epithelial-to-mesenchymal transition (EMT) and drug resistance. The STAT3 inhibitor Napabucasin was in clinical trials but was discontinued due to futility. We found that higher expression of MUC1 increased the sensitivity of cancer cells to Napabucasin. Therefore, high-MUC1 tumors may have a better outcome to Napabucasin therapy. We report how MUC1 regulates STAT3 activity and provide a new perspective on repurposing the STAT3-inhibitor Napabucasin to improve clinical outcome of epithelial cancer treatment.
Summary Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor ...degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov , number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio HR 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 17% in the fulvestrant group vs 24 10% in the anastrozole group) and hot flushes (26 11% in the fulvestrant group vs 24 10% in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. Funding AstraZeneca.
Aim
Many species experienced population turnover and local extinction during the Late Pleistocene. In the case of megafauna, it remains challenging to disentangle climate change and the activities of ...Palaeolithic hunter‐gatherers as the main cause. In contrast, the impact of humans on rodent populations is likely to be negligible. This study investigated which climatic and/or environmental factors affect the population dynamics of the common vole. This temperate rodent is widespread across Europe and was one of the most abundant small mammal species throughout the Late Pleistocene.
Location
Europe.
Taxon
Common vole (Microtus arvalis).
Methods
We generated a dataset comprised of 4.2 kb long fragment of mitochondrial DNA (mtDNA) from 148 ancient and 51 modern specimens sampled from multiple localities across Europe and covering the last 60 thousand years (ka). We used Bayesian inference to reconstruct their phylogenetic relationships and to estimate the age of the specimens that were not directly dated.
Results
We estimated the time to the most recent common ancestor of all last glacial and extant common vole lineages to be 90 ka ago and the divergence of the main mtDNA lineages present in extant populations to between 55 and 40 ka ago, which is earlier than most previous estimates. We detected several lineage turnovers in Europe during the period of high climate variability at the end of Marine Isotope Stage 3 (MIS 3; 57–29 ka ago) in addition to those found previously around the Pleistocene/Holocene transition. In contrast, data from the Western Carpathians suggest continuity throughout the Last Glacial Maximum (LGM) even at high latitudes.
Main Conclusions
The main factor affecting the common vole populations during the last glacial period was the decrease in open habitat during the interstadials, whereas climate deterioration during the LGM had little impact on population dynamics. This suggests that the rapid environmental change rather than other factors was the major force shaping the histories of the Late Pleistocene faunas.
The harsh climatic conditions during the Last Glacial Maximum (LGM) period have been considered the cause of local extinctions and major faunal reorganizations that took place at the end of the ...Pleistocene. Recent studies have shown, however, that in addition many of these ecological events were associated with abrupt climate changes during the so-called Late Glacial and the Pleistocene/Holocene transition. Here we used ancient DNA to investigate the impact of those changes on European populations of temperate vole species (Microtus arvalis). The genetic diversity of modern populations and the fossil record suggests that the species may have survived cold episodes, like LGM, not only in the traditional Mediterranean glacial refugia but also at higher latitudes in cryptic northern refugia located in Central France, the northern Alps as well as the Carpathians. However, the details of the post-glacial recolonization and the impact of the Late Glacial and Early Holocene climate changes on the evolutionary history of the common vole remains unclear. To address this issue, we analysed mtDNA cytochrome b sequences from more than one hundred common vole specimens from 36 paleontological and archaeological sites scattered across Europe. Our data suggest that populations from the European mid- and high latitudes suffered a local population extinction and contraction as a result of Late Glacial and Early Holocene climate and environmental changes. The recolonization of earlier abandoned areas took place in the Mid- to Late Holocene. In contrast, at low latitudes, in Northern Spain there was a continuity of common vole populations. This indicates different responses of common vole populations to climate and environmental changes across Europe and corroborates the hypothesis that abrupt changes, like those associated with Younger Dryas and the Pleistocene/Holocene transition, had a significant impact on populations at the mid- and high latitudes of Europe.
•Post-glacial history of the European common vole reconstructed using ancient DNA.•Population turnovers at mid- and high latitudes at Pleistocene/Holocene transition.•Continuity of common vole populations at low latitudes.
Summary
Background
The long‐term outcome of patients after antitumour necrosis factor alpha (anti‐TNF) discontinuation is not well known.
Aims
To assess the risk of relapse in the long‐term after ...anti‐TNF discontinuation.
Methods
This was an extension of the evolution after anti‐TNF discontinuation in patients with inflammatory bowel disease (EVODIS) study (Crohn's disease or ulcerative colitis patients treated with anti‐TNFs in whom these drugs were withdrawn after achieving clinical remission) based in the same cohort of patients whose outcome was updated. Clinical remission was defined as a Harvey–Bradshaw index ≤4 points in Crohn's disease, a partial Mayo score ≤2 in ulcerative colitis and the absence of fistula drainage despite gentle finger compression in perianal disease.
Results
This was an observational, retrospective, multicenter study. A total of 1055 patients were included. The median follow‐up time was 34 months. The incidence rate of relapse was 12% per patient‐year (95% confidence interval CI = 11‐14). The cumulative incidence of relapse was 50% (95% CI = 47‐53): 19% at one year, 31% at 2 years, 38% at 3 years, 44% at 4 years and 48% at 5 years of follow‐up. Of the 60% patients retreated with the same anti‐TNF after relapse, 73% regained remission. Of the 75 patients who did not respond, 48% achieved remission with other therapies. Of the 190 patients who started other therapies after relapse, 62% achieved remission with the new treatment.
Conclusions
A significant proportion of patients who discontinued the anti‐TNF remained in remission. In case of relapse, retreatment with the same anti‐TNF was usually effective. Approximately half of the patients who did not respond after retreatment achieved remission with other therapies.
More than 1000 patients discontinued the anti‐TNF therapy after having achieved clinical remission. Half of them relapsed during follow‐up. After relapse, 60% of the patients restarted the same anti‐TNF, 36% received other therapeutic options, and 4% were operated on. Of the patients who restarted the same anti‐TNF, 73% achieved remission. Of the patients who received other therapeutic options, two‐thirds achieved remission.
Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains ...like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second‐level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long‐term therapeutic strategy. Endotype‐driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment.
Arterial hypertension is a significant cause of morbidity and mortality in Mexico. However, there is limited data available to understand blood pressure management and cardiometabolic profiles.
To ...assess the prevalence of controlled and uncontrolled blood pressure, as well as the prevalence of cardiometabolic risk factors among patients from the Mexican Registry of Arterial Hypertension (RIHTA).
We conducted a cross-sectional analysis of participants living with arterial hypertension registered on RIHTA between December 2021 and April 2023. We used both the 2017 ACC/AHA and 2018 ESC/ESH thresholds to define controlled and uncontrolled arterial hypertension. We considered eleven cardiometabolic risk factors, which include overweight, obesity, central obesity, insulin resistance, diabetes, hypercholesterolemia, hypertriglyceridemia, low-HDL-C, high-LDL-C, low-eGFR, and high CVD risk.
In a sample of 5,590 participants (female: 61%, n=3,393; median age: 64 IQR: 56-72 years), the prevalence of uncontrolled hypertension varied significantly, depending on the definition (2017 ACC/AHA: 59.9%, 95% CI: 58.6-61.2 and 2018 ESC/ESH: 20.1%, 95% CI: 19.0-21.2). In the sample, 40.43% exhibited at least 5-6 risk factors, and 32.4% had 3-4 risk factors, chiefly abdominal obesity (83.4%, 95% CI: 82.4-84.4), high-LDL-C (59.6%, 95% CI: 58.3-60.9), high-CVD risk (57.9%, 95% CI: 56.6-59.2), high triglycerides (56.2%, 95% CI: 54.9-57.5), and low-HDL-C (42.2%, 95% CI: 40.9-43.5).
There is a high prevalence of uncontrolled hypertension interlinked with a high burden of cardiometabolic comorbidities in Mexican adults living with arterial hypertension, underscoring the urgent need for targeted interventions and better healthcare policies to reduce the burden of the disease in our country.
To date, mother‐to‐fetus transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), responsible for the coronavirus disease 2019 (COVID‐19) pandemic, remains controversial. ...Although placental COVID‐19 infection has been documented in some cases during the second‐ and third‐trimesters, no reports are available for the first trimester of pregnancy, and no SARS‐CoV‐2 protein has been found in fetal tissues. We studied the placenta and fetal organs from an early pregnancy miscarriage in a COVID‐19 maternal infection by immunohistochemical, reverse transcription quantitative real‐time polymerase chain reaction, immunofluorescence, and electron microscopy methods. SARS‐CoV‐2 nucleocapsid protein, viral RNA, and particles consistent with coronavirus were found in the placenta and fetal tissues, accompanied by RNA replication revealed by double‐stranded RNA (dsRNA) positive immunostain. Prominent damage of the placenta and fetal organs were associated with a hyperinflammatory process identified by histological examination and immunohistochemistry. The findings provided in this study document that congenital SARS‐CoV‐2 infection is possible during the first trimester of pregnancy and that fetal organs, such as lung and kidney, are targets for coronavirus. The infection and multi‐organic fetal inflammation produced by SARS‐CoV‐2 during early pregnancy should alert clinicians in the assessment and management of pregnant women for possible fetal consequences and adverse perinatal outcomes.
Patients with first-episode psychosis (FEP) report deficits in social support (SS) and diminished and less satisfactory social networks than healthy controls (HC). These SS difficulties are linked ...with symptomatology. The study objectives were to: (a) compare perceived SS between patients with FEP and HC; (b) study sex differences regarding perceived SS in patients with FEP and HC; and (c) explore which sociodemographic, clinical and psychosocial variables are related to perceived SS in the onset of FEP. A total of 146 participants were included: 76 patients with FEP (24 females, 52 males) and 70 HC (20 females, 50 males). Perceived SS was assessed with the DUKE-UNK instrument, which is divided into two subscales: confidant support (CS) and affective support (AS). Significant differences regarding perceived SS were observed between the samples. No sex differences were found concerning perceived SS in each group. For the group with FEP, more years of education, less anxiety/depressive symptoms and better functioning were the most relevant variables for more overall perceived SS and perceived CS. Also, less suicidal risk was the only important indicator for more perceived AS. Interventions in perceived SS could contribute to a good evolution of FEP.
•Significant differences regarding perceived SS were observed between the samples.•No sex differences were found concerning perceived SS in each group.•In FEP, years of education was the most relevant variable for perceived SS and CS.•In FEP, suicidal risk was the only important indicator for perceived AS.
PDF
