Interdependency of estradiol-mediated ERα activation and subsequent PR and GREB1 induction to control cell cycle progression.

Various groups of chemicals that we encounter in every-day life are known to disrupt the endocrine system, such as estrogen mimics that can disturb normal cellular development and homeostasis. To understand the effect of estrogen on intracellular protein dynamics and how this relates to cell proliferation, we aimed to develop a quantitative description of transcription factor complexes and their regulation of cell cycle progression in response to estrogenic stimulation. We designed a mathematical model that describes the dynamics of three proteins, GREB1, PR and TFF1, that are transcriptionally activated upon binding of 17β-estradiol (E2) to estrogen receptor alpha (ERα).

Are Repeat-Dose Toxicity Studies Informative for Safety Assessment of Vaccine Candidates? A Survey of Vaccine Developers.

A BioSafe-sponsored survey investigated how vaccine companies (n = 12) perceive the value of the repeat-dose toxicity studies for safety assessment of vaccine candidates. As all major vaccine developers were part of the survey, it was considered representative for the industry practices up to 2022. Vaccine developers indicated that they see scientific value in performing repeat-dose toxicity studies with vaccines, especially when novel components (e.

Microbes put drugs in(action).

Interactions between the gut microbiome, nutrients, drugs, and host physiology are inherently complex. Gut microbes contribute significantly towards host homeostasis and can modulate host-targeted drugs, affecting therapeutic outcomes. Finding ways to harness the gut microbiome to improve drug efficacy can be a promising strategy to advance precision medicine.

The Link Between Childhood Abuse Experiences and Homeless People's Quality of Life: A Longitudinal Study.

Studies report a relatively high prevalence of childhood abuse experiences (CAE) among adult homeless people. Within homeless populations, people with CAE appear to be worse off than homeless people without such experiences. This study compares a broad set of factors influencing the quality of the daily lives of Dutch homeless people with and without CAE.

C16ORF70/MYTHO promotes healthy aging in C.elegans and prevents cellular senescence in mammals.

The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people.

ICH S1 prospective evaluation study: weight of evidence approach to predict outcome and value of 2-year rat carcinogenicity studies. A report from the regulatory authorities subgroup.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiated a process in 2012 to revise the S1B Guideline "Testing for Carcinogenicity of Pharmaceuticals". Previous retrospective analysis indicated the importance of histopathological risk factors in chronic toxicity studies, evidence of endocrine perturbation, and positive genetic toxicology results as potentially predictive indicators of carcinogenic risk. In addition, a relationship between pharmacodynamic activity and carcinogenicity outcome in long-term rodent studies has been reported.

[F]FDG-PET/CT-based risk stratification in women with locally advanced uterine cervical cancer.

Background: [F]FDG-PET/CT is used for staging and treatment planning in patients with locally advanced cervical cancer (LACC). We studied if a PET-based prediction model could provide additional risk stratification beyond International Federation of Gynaecology and Obstetrics (FIGO) staging in our population with LACC to aid treatment decision making.

Methods: In total, 183 patients with LACC treated with chemoradiation between 2013 and 2018 were included.

Hyperbaric Oxygen Therapy and Late Local Toxic Effects in Patients With Irradiated Breast Cancer: A Randomized Clinical Trial.

Importance: Hyperbaric oxygen therapy (HBOT) is proposed as treatment for late local toxic effects after breast irradiation. Strong evidence of effectiveness is lacking.

Objective: To assess effectiveness of HBOT for late local toxic effects in women who received adjuvant radiotherapy for breast cancer.

Malnutrition is associated with poor survival in women receiving radiotherapy for cervical cancer.

Objective: Cancer patients are at risk of malnutrition, which is associated with poor oncological outcomes. The aim of this study was to assess the incidence of malnutrition before, during, and after radiotherapy in locally advanced cervical cancer patients. In addition, we evaluated the impact of malnutrition on survival, and whether and when malnourished patients were referred to a dietitian.

Precision assessment of bowel motion quantification using 3D cine-MRI for radiotherapy.

. The bowel is an important organ at risk for toxicity during pelvic and abdominal radiotherapy. Identifying regions of high and low bowel motion with MRI during radiotherapy may help to understand the development of bowel toxicity, but the acquisition time of MRI is rather long.

Improving referral rates for smoking cessation: A multifaceted intervention aimed at radiation oncologists.

Objective: Continuation of smoking after a cancer diagnosis increases the burdensome side effects from cancer treatment, and decreases the chances of cure. Smoking cessation may improve oncological outcomes in cancer patients. This study aims to evaluate if radiation oncologists can be motivated by a smoking cessation awareness intervention to discuss smoking status more frequently and increase the referral rate for smoking cessation-support.

Long-term postoperative opioid use in orthopaedic patients.

Background: The prevalence of long-term opioid use after orthopaedic surgery varies from 1.4% to 24% and has mostly been studied with prescription data, making it difficult to estimate the size and impact of the problem. This study aims to assess the prevalence and predictors of long-term postoperative opioid use in a high volume and tertiary orthopaedic centre by using online patient reported measures.

Structural and time-resolved mechanistic investigations of protein hydrolysis by the acidic proline-specific endoprotease from Aspergillus niger.

Proline-specific endoproteases have been successfully used in, for example, the in-situ degradation of gluten, the hydrolysis of bitter peptides, the reduction of haze during beer production, and the generation of peptides for mass spectroscopy and proteomics applications. Here we present the crystal structure of the extracellular proline-specific endoprotease from Aspergillus niger (AnPEP), a member of the S28 peptidase family with rarely observed true proline-specific endoprotease activity. Family S28 proteases have a conventional Ser-Asp-His catalytic triad, but their oxyanion-stabilizing hole shows a glutamic acid, an amino acid not previously observed in this role.

Nocturnal activity as a useful indicator of adaptability of dogs in an animal shelter and after subsequent adoption.

Dogs in shelters are faced with the challenge of adapting to a kennel after relinquishment and to a novel home after adoption. To measure adaptability of dogs, more feasible behavioural and physiological parameters need to be validated in different contexts. To evaluate nocturnal activity as an indicator of adaptability, we compared nocturnal activity, urinary cortisol:creatinine ratio (UCCR), and body weight changes of sheltered dogs the first period after intake in the shelter and after adoption.

Cohort profile: The Corona Behavioral Unit cohort, a longitudinal mixed-methods study on COVID-19-related behavior, well-being and policy support in the Netherlands.

This 'cohort profile' aims to provide a description of the study design, methodology, and baseline characteristics of the participants in the Corona Behavioral Unit cohort. This cohort was established in response to the COVID-19 pandemic by the Dutch National Institute for Public Health and the Environment (RIVM) and the regional public health services. The aim was to investigate adherence of and support for COVID-19 prevention measures, psychosocial determinants of COVID-19 behaviors, well-being, COVID-19 vaccination, and media use.

Evaluation of non-clinical toxicity studies of COVID-19 vaccines.

In this study we evaluated the outcomes of non-clinical toxicity studies of various SARS-CoV-2 vaccines produced with different manufacturing technologies, with focus on Repeated Dose Toxicity (RDT) and Developmental and Reproductive Toxicity (DART) studies. We found that RDT and DART studies at doses relevant for human treatment showed no adverse effects while remaining observations were expected findings including local reactogenicity, immune response and macroscopic findings at the injection site. We have also reviewed the European Medicines Agency (EMA) nonclinical assessment reports for market authorization.

Sensor-supported measurement of adaptability of dogs (Canis familiaris) to a shelter environment: Nocturnal activity and behavior.

Every shelter dog is faced with the challenge to adapt to a kennel environment. To monitor the welfare of individual shelter dogs, evaluating behavioural and physiological parameters, potentially useful as indicators for adaptability of individual dogs is crucial. Nocturnal activity, i.

Applying genomics in regulatory toxicology: a report of the ECETOC workshop on omics threshold on non-adversity.

In a joint effort involving scientists from academia, industry and regulatory agencies, ECETOC's activities in Omics have led to conceptual proposals for: (1) A framework that assures data quality for reporting and inclusion of Omics data in regulatory assessments; and (2) an approach to robustly quantify these data, prior to interpretation for regulatory use. In continuation of these activities this workshop explored and identified areas of need to facilitate robust interpretation of such data in the context of deriving points of departure (POD) for risk assessment and determining an adverse change from normal variation. ECETOC was amongst the first to systematically explore the application of Omics methods, now incorporated into the group of methods known as New Approach Methodologies (NAMs), to regulatory toxicology.

The Effect of Contemporary Brachytherapy Practices on Prognosis in Women with Locally Advanced Cervical Cancer.

(1) Background: Over the past two decades use of new imaging modalities and the adaptation of applicators have allowed for advances in volumetric (3D) imaging-based brachytherapy practices for patients with locally advanced cervical cancer. The aim of this study was to compare the oncological outcome and toxicity for three consecutively introduced brachytherapy practices in a large single-center cohort; (2) Methods: Patients treated for cervical cancer with primary radiotherapy and curative intent were consecutively included in this retrospective, single-center cohort study from 2006 to 2019. This cohort was divided into three groups (CT, MRI, and MRI+needles) based on the timing of the introduction of a novel brachytherapy practice; 3D brachytherapy planning using CT- and MRI-guided adaptive brachytherapy and the use of parametrial interstitial needles, respectively.

Increased range and contrast in fog with circularly polarized imaging.

Fogs, low lying clouds, and other highly scattering environments pose a challenge for many commercial and national security sensing systems. Current autonomous systems rely on optical sensors for navigation whose performance is degraded by highly scattering environments. In our previous simulation work, we have shown that polarized light can penetrate through a scattering environment such as fog.

Optical Biopsy of Dysplasia in Barrett's Oesophagus Assisted by Artificial Intelligence.

Optical biopsy in Barrett's oesophagus (BE) using endocytoscopy (EC) could optimize endoscopic screening. However, the identification of dysplasia is challenging due to the complex interpretation of the highly detailed images. Therefore, we assessed whether using artificial intelligence (AI) as second assessor could help gastroenterologists in interpreting endocytoscopic BE images.

Linitis plastica of the rectum secondary to prostate carcinoma.

Linitis plastica is an intramural carcinoma that may occur in any hollow organ. Rectal linitis plastica (RLP) is a morphological variant cancer that may occur as a primary form of cancer or secondary as a metastasis of a primary malignancy. We report the case of a man in his 70s with RLP secondary to prostate carcinoma who was initially suspected to have an obstructing rectal adenocarcinoma.