Targeted protein relocalization via protein transport coupling.

Subcellular protein localization regulates protein function and can be corrupted in cancers and neurodegenerative diseases. The rewiring of localization to address disease-driving phenotypes would be an attractive targeted therapeutic approach. Molecules that harness the trafficking of a shuttle protein to control the subcellular localization of a target protein could enforce targeted protein relocalization and rewire the interactome.

Common maternal health problems and their correlates in early post-partum mothers.

Background: Mothers experience a wide range of maternal health problems after childbirth, which in turn, affect their well-being and ability to care for their newborn. These problems may be influenced by factors such as mode of delivery or socio-economic status.

Objective: This study aims to investigate the prevalence of common maternal health problems and their correlates in a public primary healthcare institution in Singapore.

The Pulse of Singapore: Short-Term HRV Norms.

Short-term heart rate variability (HRV) is increasingly used to assess autonomic nervous system activity and found to be useful for monitoring and providing care due to its quick measurement. With evidence of low HRV associated with chronic diseases, mental disorders, and an increased risk of cardiovascular disease, having normative data of HRV across the age spectrum would be useful for monitoring health and well-being of a population. This study examines HRV of healthy Singapore sample, with ages ranging from 10 to 89 years.

Recent advances in induced proximity modalities.

Challenging disease targets necessitate new approaches for therapeutic intervention. Rewiring protein-biomolecule interactions with proximity-inducing agents extends intervention opportunities beyond target agonism or inhibition. Spanning varied molecular phenotypes and diverse target classes, proximity-inducing agents demonstrate immense potential across target degradation, cleavage, and post-translational editing.

Taming transcription factors with TRAFTACs.

Transcription factors play central roles in numerous diseases yet are notoriously challenging targets for drug development. In this issue of Cell Chemical Biology, Samarasinghe et al. (2021) describe a modular approach to targeting transcription factors for degradation with TRAFTACs, without the need for extensive ligand development campaigns.

Towards personalized induction therapy for esophageal adenocarcinoma: organoids derived from endoscopic biopsy recapitulate the pre-treatment tumor.

Esophageal adenocarcinoma has few known recurrent mutations and therefore robust, reliable and reproducible patient-specific models are needed for personalized treatment. Patient-derived organoid culture is a strategy that may allow for the personalized study of esophageal adenocarcinoma and the development of personalized induction therapy. We therefore developed a protocol to establish EAC organoids from endoscopic biopsies of naïve esophageal adenocarcinomas.

Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy.

Purpose: Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed.

Experimental Design: We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice.

Organoid Cultures as Preclinical Models of Non-Small Cell Lung Cancer.

Purpose: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease.

Experimental Design: Thirty surgically resected NSCLC primary patient tissue and 35 previously established patient-derived xenograft (PDX) models were processed for organoid culture establishment.

Novel combinations of PI3K-mTOR inhibitors with dacomitinib or chemotherapy in PTEN-deficient patient-derived tumor xenografts.

PTEN inactivation occurs commonly in human cancers and putatively activates the PI3K/AKT/ mTOR pathway. Activation of this pathway has been involved in resistance to chemotherapy or anti-EGFR/HER2 therapies. We evaluated the combination of PI3K-mTOR inhibitors with chemotherapy or the pan-HER inhibitor dacomitinib in PTEN-deficient patient-derived tumor xenografts (PDX).

Synergy of WEE1 and mTOR Inhibition in Mutant -Driven Lung Cancers.

-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multitargeted therapy may offer a plausible strategy to effectively treat -driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring mutations.

An Anaplastic Lymphoma Kinase Immunohistochemistry-Negative but Fluorescence In Situ Hybridization-Positive Lung Adenocarcinoma Is Resistant to Crizotinib.

Introduction: Oncogenic fusion of anaplastic lymphoma kinase (ALK) with echinoderm microtubule associated protein like 4 protein or other partner genes occurs in 3% to 6% of lung adenocarcinomas. Although fluorescence in situ hybridization (FISH) is the accepted standard for detecting anaplastic lymphoma receptor tyrosine kinase gene (ALK) gene rearrangement that gives rise to new fusion genes, not all ALK FISH-positive patients respond to ALK inhibitor therapies. We report here an ALK FISH-positive patient-derived xenograft (PDX) that was nonresponsive to crizotinib therapy.

Inhibiting MDM2-p53 Interaction Suppresses Tumor Growth in Patient-Derived Non-Small Cell Lung Cancer Xenograft Models.

Background: The tumor suppressor p53 is frequently inactivated in non-small cell lung cancer (NSCLC). Activation of the p53 pathway by inhibition of its negative regulator MDM2 may offer an attractive approach for NSCLC therapy. We evaluated the antitumor activity of the small-molecule MDM2 inhibitor RG7388 in patient-derived xenograft (PDX) models of NSCLC.

Clinical Utility of Patient-Derived Xenografts to Determine Biomarkers of Prognosis and Map Resistance Pathways in EGFR-Mutant Lung Adenocarcinoma.

Purpose: Although epidermal growth factor receptor (EGFR) -mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies.

Measuring change in health-system pharmacy over 50 years: "reflecting" on the mirror, part I.

The Director's Forum guides pharmacy leaders in establishing patient-centered services in hospitals and health systems. August 2013 marked the 50th anniversary of the publication of the Mirror to Hospital Pharmacy, which was a comprehensive study of hospital pharmacy services in the United States. This iconic textbook was co-authored by Donald Francke, Clifton J.

Therapeutic ultrasound improves strength of achilles tendon repair in rats.

The purpose of this study was to evaluate the effects of therapeutic ultrasound on structural properties and functional performance of Achilles tendon healing. Thirty Sprague-Dawley rats with surgical hemitransected Achilles tendon were studied. Ten were treated daily with 1 MHz continuous ultrasound at 1.

Cdc48p is required for the cell cycle commitment point at Start via degradation of the G1-CDK inhibitor Far1p.

The budding yeast Cdc48p and its mammalian homologue p97 are involved in many important cellular activities. Because previous cdc48 mutants have exclusive G2/M arrest, Cdc48p was thought to play an essential role only during mitosis. We found that Cdc48p is required for the execution of Start (a yeast cell cycle commitment point equivalent to the restriction point in mammalian cells) in both a normal mitotic cell cycle and cell cycle reentry after mating pheromone withdrawal through degradation of the G1-cyclin-dependent kinase inhibitor Far1p.

Cutaneous consequences of photodynamic therapy.

Photodynamic therapy (PDT) has several cutaneous complications: photosensitivity is well known, but the other complications are rarely reported, Since late 1997, we have studied the dermatologic complications of using porfimer sodium PDT to treat either Barrett esophagus with high-grade dysplasia or gastroesophageal cancer in 72 consecutive patients. Cutaneous complications of PDT included serious phototoxicity requiring oral corticosteroid treatment (22 patients; 31%), herpes zoster (HZ) requiring hospitalization and intravenous antiviral treatment (1 patient; 1%), and erythema multiforme drug reaction related to porfimer sodium (1 patient; 1%). PDT-associated dermatologic complications were common and were not related to cutaneous photosensitivity.

Medical management of Cronkhite-Canada syndrome.

We report the case of a patient with Cronkhite-Canada syndrome (CCS) successfully treated with combination medical therapy. This rare, noninherited gastrointestinal polyposis syndrome is associated with characteristic ectodermal abnormalities. The etiology and pathogenesis of CCS are not known.