Support Needs for Return to Work Among Self-employed Workers: A Focus Group Study.

Objective: The aim of this study is to gain insight into the facilitators, barriers, and support needs of Dutch self-employed workers when returning to work (RTW) after sick leave.

Methods: Three focus groups were conducted, involving 15 Dutch self-employed workers who were on sick leave due to health problems. The transcripts were analyzed through thematic content analysis.

Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in -mutant cancers.

The Kirsten rat sarcoma viral oncogene homologue is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies.

A roadmap for sustainable implementation of vocational rehabilitation for people with mental disorders and its outcomes: a qualitative evaluation.

Background: People suffering from mental health disorders have lower work participation compared to people without mental challenges. To increase work participation within this group vocational rehabilitation interventions are often offered. Collaboration between the mental health care and social security sectors is needed to enable professionals to perform optimally when carrying out these interventions.

Barriers and Facilitators to Participation and Key Components of Sleep Health Programs: Perspectives for the Corporate Work Environment.

Objective: The aim of the study is to explore the barriers and facilitators of participation and key components for sleep health programs designed for corporate work environments.

Methods: Semistructured interviews with corporate executives and occupational medicine specialists in the decision making and management of workplace health promotion programs (WHPP) within their companies were held before and during COVID-19. Interviews were transcribed verbatim and analyzed using thematic content analysis to identify themes.

Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma.

Liver cancer is the fourth most common cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed.

Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer.

Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms.

Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.

PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor-positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.

Participatory Approach to Create a Supportive Work Environment for Employees With Chronic Conditions: A Pilot Implementation Study.

Objective: To evaluate a pilot implementation of an organizational-level intervention. The participatory approach (PA) was used to create a supportive work environment for employees with chronic conditions, with a key role for occupational physicians (OPs).

Methods: Twenty-eight semi-structured interviews were conducted with OPs and stakeholders within their organizations.

Workers' views on involving significant others in occupational health care: a focus group study among workers with a chronic disease.

Purpose: To explore workers' views and considerations on involving their significant others (SOs) in occupational health care.

Methods: Four focus group interviews in the Netherlands, with 21 workers who had visited an occupational health physician (OHP) due to work absence caused by a chronic disease. Data was analyzed using thematic analysis.

Trajectories of sickness absence and disability pension days among people with multiple sclerosis by type of occupation.

Background: Multiple sclerosis (MS) can impact working life, sickness absence (SA) and disability pension (DP). Different types of occupations involve different demands, which may be associated with trajectories of SA/DP among people with MS (PwMS).

Objectives: To explore, among PwMS and references, if SA/DP differ according to type of occupation.

EGFR activation limits the response of liver cancer to lenvatinib.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer.

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer.

The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells.

Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in the JAK3 gene.

High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples.

Comparative Network Reconstruction using mixed integer programming.

Motivation: Signal-transduction networks are often aberrated in cancer cells, and new anti-cancer drugs that specifically target oncogenes involved in signaling show great clinical promise. However, the effectiveness of such targeted treatments is often hampered by innate or acquired resistance due to feedbacks, crosstalks or network adaptations in response to drug treatment. A quantitative understanding of these signaling networks and how they differ between cells with different oncogenic mutations or between sensitive and resistant cells can help in addressing this problem.

SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo.

RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs). Inhibition of the RAS oncoproteins has proven difficult, and attempts to target downstream effectors have been hampered by the activation of compensatory resistance mechanisms. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling.

An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.

BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS).

The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting.

Background: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments.

FGFR1, 2 and 3 protein overexpression and molecular aberrations of FGFR3 in early stage non-small cell lung cancer.

This study aimed to determine protein expression levels of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in early stage non-small cell lung cancer (NSCLC). Additionally, a screen to define the frequency of translocation and amplification was performed. Archived tissues from 653 NSCLC samples (adenocarcinoma (AC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)) were analysed with immunohistochemistry (IHC) for expression of FGFR1, 2 and 3.

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.

Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC.

BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential.

Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10-15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination-mediated DNA repair and deficiency results in genomic instability.

PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.

Purpose: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer.

Patients And Methods: Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry-based genotyping.

Current and best practices of genetic testing for maturity onset diabetes of the young: views of professional experts.

Aims: Currently, many patients with maturity onset diabetes of the young (MODY) are undiagnosed or misdiagnosed with type 1 or 2 diabetes. This study aims to assess professional experts' views on factors which may influence the current practice of genetic testing for MODY and to explore next steps toward best practice.

Methods: Twelve semistructured interviews were conducted with professional experts.

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands.

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY.

Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing.

Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the diverse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency.