A selective S-acyltransferase inhibitor suppresses tumor growth.

S-acyltransferases play integral roles in essential physiological processes including regulation of oncogenic signaling pathways. While discovered over 40 years ago the field still lacks specific S-acylation inhibitors thus the potential benefit of pharmacologically targeting S-acyltransferases for human disease is still unknown. Here we report the identification of an orally bioavailable acyltransferase inhibitor SD-066-4 that inhibits the acyltransferase ZDHHC20.

Spatial omics techniques and data analysis for cancer immunotherapy applications.

In-depth profiling of cancer cells/tissues is expanding our understanding of the genomic, epigenomic, transcriptomic, and proteomic landscape of cancer. However, the complexity of the cancer microenvironment, particularly its immune regulation, has made it difficult to exploit the potential of cancer immunotherapy. High-throughput spatial omics technologies and analysis pipelines have emerged as powerful tools for tackling this challenge.

Chemical probe mediated visualization of protein S-palmitoylation in patient tissue samples.

While protein palmitoylation has been studied for decades, our understanding of its clinical importance is minimal compared to other post translational modifications. As a result of the inherent challenges preventing the production of antibodies to palmitoylated epitopes we are unable to correlate levels of protein palmitoylation in biopsied tissues at a meaningful resolution. The most common method for detecting palmitoylated proteins without metabolic labelling is through chemical labeling of palmitoylated cysteines with the acyl-biotinyl exchange (ABE) assay.

Hallux valgus with second metatarsalgia: Is second metatarsal Weil osteotomy necessary?

Background: The role of concomitant Weil osteotomy to address second toe metatarsalgia during hallux valgus correction is unclear. We aimed to critically analyse outcomes of an additional Weil osteotomy versus isolated Scarf osteotomy.in the management of hallux valgus and second metatarsalgia.

Healthcare professionals' perspectives on facilitators of and barriers to CKD management in primary care: a qualitative study in Singapore clinics.

Introduction: The burden of chronic kidney disease (CKD) is rising globally including in Singapore. Primary care is the first point of contact for most patients with early stages of CKD. However, several barriers to optimal CKD management exist.

MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer.

Unlabelled: MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein-coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC).

Normative FJS-12 scores for the knee in an Asian population: a cross-sectional study.

Background: The Forgotten Joint Score is a patient-reported outcome measure validated in assessing patients post knee arthroplasty, anterior cruciate ligament (ACL) reconstruction surgery and patellar dislocation. A previous study had established the normative scores of a population in the USA but included knees with pathology. The aim of our study is to obtain normative Forgotten Joint Scores in young Asian adults without any pre-existing knee pathologies to increase the interpretability of the Forgotten Joint Score-12 (FJS-12) score.

Polymetatarsia of the Foot without Polydactyly: A Case Report.

Case: We report a rare case of polymetatarsia without polydactyly. Our patient presented with pain and difficulty with shoewear. Radiographs showed an accessory metatarsal arising from the lateral aspect of the fourth metatarsal proximal metaphysis, fusing distally with the medial aspect of the fifth metatarsal head to form a single metatarsophalangeal joint.

Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis.

The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resistance that develops. Overcoming resistance mechanisms requires a deeper understanding of EGFR regulation in cancer cells.

Leveraging advances in immunopathology and artificial intelligence to analyze in vitro tumor models in composition and space.

Cancer is the leading cause of death worldwide. Unfortunately, efforts to understand this disease are confounded by the complex, heterogenous tumor microenvironment (TME). Better understanding of the TME could lead to novel diagnostic, prognostic, and therapeutic discoveries.

Perceived barriers and facilitators to chronic kidney disease care among patients in Singapore: a qualitative study.

Objective: To outline the facilitators and barriers to patients' self-management of predialysis chronic kidney disease (CKD).

Design: Qualitative.

Setting: Three polyclinics in a public primary care institution in Singapore.

Distal oblique osteotomy versus cheilectomy for moderate-advanced hallux rigidus: A 2-year propensity-score-matched study.

Background: The surgical treatment of moderate-advanced hallux rigidus is controversial. Cheilectomy is widely used but has recurrence rates of up to 30%. Dorsal oblique metatarsal osteotomy (DOO) has also shown good results, however, there is no study comparing outcomes of the DOO against cheilectomy.

A Review of the Gillquist Maneuver: Modifications for a Safer and Easily Reproducible Approach for Knee Transintercondylar Notch Posterior Compartment Arthroscopy.

The original Gillquist maneuver is done by passing the arthroscope through a portal in the patella tendon between the medial femoral condyle and posterior cruciate ligament to enter the posterior compartment. This is done blind and has been documented to result in broken cameras and damaged equipment. It is also necessary to do a notchplasty to aid the advancement of the camera in patients.

The Forgotten Joint Score-12 in Anterior Cruciate Ligament injuries.

Purpose: The Forgotten Joint Score (FJS-12) is a scoring system initially created to assess post arthroplasty outcomes. It has since been used to evaluate Anterior Cruciate Ligament surgery outcomes. Our study aims to evaluate the applicability and validity of the FJS-12 in post Anterior Cruciate Ligament reconstructed patients, and to assess correlation with established Patient Reported Outcome Measure Scores in the same population.

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization.

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses.

PI3K Catalytic Subunits α and β Modulate Cell Death and IL-6 Secretion Induced by Talc Particles in Human Lung Carcinoma Cells.

Hydrated magnesium silicate (or "talc" particles) is a sclerosis agent commonly used in the management of malignant pleural effusions, a common symptom of metastatic diseases, including lung cancers. However, the direct effects of talc particles to lung carcinoma cells, which can be found in the malignant pleural effusion fluids from patients with lung cancer, are not fully understood. Here, we report a study of the signaling pathways that can modulate the cell death and IL-6 secretion induced by talc particles in human lung carcinoma cells.

MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types.

Protease-activated receptor 1 (PAR1), a thrombin-responsive G protein-coupled receptor (GPCR), is implicated in promoting metastasis in multiple tumor types, including both sarcomas and carcinomas, but the molecular mechanisms responsible remain largely unknown. We previously discovered that PAR1 stimulation in endothelial cells leads to activation of NF-κB, mediated by a protein complex comprised of CARMA3, Bcl10, and the MALT1 effector protein (CBM complex). Given the strong association between NF-κB and metastasis, we hypothesized that this CBM complex could play a critical role in the PAR1-driven metastatic progression of specific solid tumors.

Retained foreign objects in casts in children.

Cast immobilization is a noninvasive and effective option in the treatment of fractures in children. However, its use can be associated with complications, such as pressure sores, skin infections, thermal injuries, and joint stiffness. In clinical practice, retained foreign objects in casts are not uncommon.

The unstable slipped capital femoral epiphysis: does the rate of osteonecrosis really depend on the timing of surgery and surgical technique?

The aim of this study was to investigate whether the timing of surgery and surgical technique affect the rate of osteonecrosis in unstable slipped capital femoral epiphysis (SCFE). This is a retrospective review of all unstable slips that were treated at our institution over 8.5 years with a minimum follow-up period of 12 months.

Building predictive in vitro pulmonary toxicity assays using high-throughput imaging and artificial intelligence.

Human lungs are susceptible to the toxicity induced by soluble xenobiotics. However, the direct cellular effects of many pulmonotoxic chemicals are not always clear, and thus, a general in vitro assay for testing pulmonotoxicity applicable to a wide variety of chemicals is not currently available. Here, we report a study that uses high-throughput imaging and artificial intelligence to build an in vitro pulmonotoxicity assay by automatically comparing and selecting human lung-cell lines and their associated quantitative phenotypic features most predictive of in vivo pulmonotoxicity.

The CARMA3-Bcl10-MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer.

The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NFκB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival.

Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.

The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients.