Voltage Gated Calcium Channel Dysregulation May Contribute to Neurological Symptoms in Calmodulinopathies.

Calmodulinopathies are caused by mutations in calmodulin (CaM), and result in debilitating cardiac arrythmias such as long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). In addition, many patients exhibit neurological comorbidities, including developmental delay and autism spectrum disorder. Until now, most work into these mutations has focused on cardiac effects, identifying impairment of Ca /CaM-dependent inactivation (CDI) of Ca 1.

Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.

Background: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8 T cells include less differentiated stem-like exhausted T (Tex) cells and terminally exhausted T (Tex) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients.

A Natural History Study of Timothy Syndrome.

Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene . Timothy syndrome patients were first identified as having a cardiac presentation of Long QT and syndactyly of the fingers and/or toes, and an identical variant in , Gly406Arg. However, since this original identification, more individuals harboring diverse variants in have been identified and have presented with various cardiac and extra-cardiac symptoms.

Rapid modeling of an ultra-rare epilepsy variant in wild-type mice by in utero prime editing.

Generating animal models for individual patients within clinically-useful timeframes holds great potential toward enabling personalized medicine approaches for genetic epilepsies. The ability to rapidly incorporate patient-specific genomic variants into model animals recapitulating elements of the patient's clinical manifestations would enable applications ranging from validation and characterization of pathogenic variants to personalized models for tailoring pharmacotherapy to individual patients. Here, we demonstrate generation of an animal model of an individual epilepsy patient with an ultra-rare variant of the NMDA receptor subunit GRIN2A, without the need for germline transmission and breeding.

Calmodulin Mutations in Human Disease.

Calcium ions (Ca) are the basis of a unique and potent array of cellular responses. Calmodulin (CaM) is a small but vital protein that is able to rapidly transmit information about changes in Ca concentrations to its regulatory targets. CaM plays a critical role in cellular Ca signaling, and interacts with a myriad of target proteins.

CACNA1C-Related Channelopathies.

The CACNA1C gene encodes the pore-forming subunit of the Ca1.2 L-type Ca channel, a critical component of membrane physiology in multiple tissues, including the heart, brain, and immune system. As such, mutations altering the function of these channels have the potential to impact a wide array of cellular functions.

Impaired Ca1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8.

Mutations in the Ca1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as long-QT type 8 (LQT8), which results in cardiac arrhythmias that are often fatal in early childhood. A growing number of such pathogenic mutations in Ca1.

CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms.

The first pathogenic mutation in CaV1.2 was identified in 2004 and was shown to cause a severe multisystem disorder known as Timothy syndrome (TS). The mutation was localized to the distal S6 region of the channel, a region known to play a major role in channel activation.

Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.

Voltage-gated sodium (Nav1.5) channels support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of Na1.

Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials.

Methods: We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study.

Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations.

Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB).

BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study.

Introduction: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy.

Methods: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays.

What's next in cancer immunotherapy? - The promise and challenges of neoantigen vaccination.

The process of tumorigenesis leaves a series of indelible genetic changes in tumor cells, that when expressed, have the potential to be tumor-specific immune targets. Neoantigen vaccines that capitalize on this potential immunogenicity have shown efficacy in preclinical models and have now entered clinical trials. Here we discuss the status of personalized neoantigen vaccines and the current major challenges to this nascent field.

Profile of soluble factors in pleural effusions predict prognosis in mesothelioma.

Background: Pleural mesothelioma is a deadly asbestos induced cancer. Less than 10% of mesothelioma patients survive 5 years post diagnosis. However survival can range from a few months to a number of years.

Neutrophil-to-lymphocyte ratio in malignant pleural fluid: Prognostic significance.

Predicting survival of patients with malignant pleural effusions (MPEs) is notoriously difficult. A robust prognostic marker can guide clinical decision making. The neutrophil-to-lymphocyte ratio (NLR) in blood has been shown to predict survival in many cancers.

The molecular basis of the inhibition of Ca1 calcium-dependent inactivation by the distal carboxy tail.

Ca/calmodulin-dependent inactivation (CDI) of Ca channels is a critical regulatory process that tunes the kinetics of Ca entry for different cell types and physiologic responses. CDI is mediated by calmodulin (CaM), which is bound to the IQ domain of the Ca carboxy tail. This modulatory process is tailored by alternative splicing such that select splice variants of Ca1.

Tumor Infiltrating Effector Memory Antigen-Specific CD8 T Cells Predict Response to Immune Checkpoint Therapy.

Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8 cytotoxic T lymphocyte (CTL) function, but changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT.

Infanticide vs. inherited cardiac arrhythmias.

Aims: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children's deaths as part of an inquiry into the mother's convictions.

Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome.

Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.

Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma.

Neoantigens present unique and specific targets for personalized cancer immunotherapy strategies. Given the low mutational burden yet immunotherapy responsiveness of malignant mesothelioma (MM) when compared to other carcinogen-induced malignancies, identifying candidate neoantigens and T cells that recognize them has been a challenge. We used pleural effusions to gain access to MM tumor cells as well as immune cells in order to characterize the tumor-immune interface in MM.

Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment.

Dexamethasone is a synthetic glucocorticoid commonly used for the prevention and management of side effects in cancer patients undergoing chemotherapy. While it is effective as an anti-emetic and in preventing hypersensitivity reactions, dexamethasone depletes peripheral blood lymphocytes and impacts immune responses. The effect of dexamethasone on the number and quality of tumour-infiltrating leukocytes has not been reported.

Neo-antigen specific T cell responses indicate the presence of metastases before imaging.

Non-small cell lung cancer (NSCLC) causes 19% of all Australian cancer deaths, with a 5-year survival post-resection of around 60%. Post-operative recurrence is due to metastases that were undetectable pre-operatively, or growth of microscopic locoregional residual disease. However, post-operative imaging modalities typically only detect more advanced tumours; where PET-CT has a detection limit of 6-7 mm.

A bilobal model of Ca-dependent inactivation to probe the physiology of L-type Ca channels.

L-type calcium channels (LTCCs) are critical elements of normal cardiac function, playing a major role in orchestrating cardiac electrical activity and initiating downstream signaling processes. LTCCs thus use feedback mechanisms to precisely control calcium (Ca) entry into cells. Of these, Ca-dependent inactivation (CDI) is significant because it shapes cardiac action potential duration and is essential for normal cardiac rhythm.

Combination immune checkpoint blockade as an effective therapy for mesothelioma.

Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the best therapeutic option for mesothelioma have yet to be fully elucidated.