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The apolipoprotein E (APOE) ɛ4 allele is a recognized genetic risk factor for Alzheimer’s Disease (AD). Studies have shown that APOE ɛ4 mediates the modulation of intrinsic functional brain networks in cognitively normal individuals and significantly disrupts the whole-brain topological structure in AD patients. However, how APOE ɛ4 regulates brain functional connectivity (FC) and consequently affects the levels of cognitive impairment in AD patients remains unknown. In this study, we systematically analyzed functional magnetic resonance imaging (fMRI) data from two distinct cohorts: an In-house dataset includes 59 AD patients (73.37 ± 6.42 years), and the ADNI dataset includes 117 AD patients (74.91 ± 7.91 years). Experimental comparisons were conducted by grouping AD patients based on both APOE ɛ4 status and cognitive impairment levels of AD. Network-Based Statistic (NBS) method and the Graph Neural Network Explainer (GNN-Explainer) were combined to identify significant FC changes across different comparisons. Importantly, the GNN-Explainer method was introduced as an enhancement over the NBS method to better model complex high-order nonlinear characteristics for discovering FC features that significantly contribute to classification tasks. The results showed that APOE ɛ4 primarily influenced temporal lobe FCs, while it influenced different cognitive impairment levels of AD by adjusting prefrontal-parietal FCs. These findings were validated by p-values < 0.05 from NBS method, and 5-fold cross-validation along with ablation studies from the GNN-Explainer method. In conclusion, our findings provide new insights into the role of APOE ɛ4 in altering FC dynamics during the progression of AD, highlighting potential targets for early intervention.

A new theoretical-based constitutive model has been proposed in this study to concurrently predict the ageing and coupled creep-ageing behavior in both micro and macro ways of aluminum alloys under complex thermal and mechanical loading histories. The nucleation, growth and coarsening theories for age strengthening of aluminum alloys have been modified with the integration of dislocation-based theories raised by plastic or creep deformation to form the new theoretical-based creep-ageing modelling framework. Both the key microstructures (precipitates, solid solutes and dislocations) and macro properties (creep/stress-relaxation, yield strength and strengthening components) under various thermal and loading histories (e.g., single-step/multi-step isothermal and non-isothermal, pre-strain loaded) of a typical Al–Zn–Mg alloy have been effectively predicted and validated by the same set model. Furthermore, the capability of the developed model to reveal the detailed deformation and strengthening mechanisms with complex thermal and loading histories, and to assist the design of complex non-isothermal creep-ageing processes with optimization objectives of accurate shape and high strength in the formed alloys has been discussed and demonstrated.

Background: Lung adenocarcinoma (LUAD) stands as the foremost histological subtype of non-small-cell lung cancer, accounting for approximately 40% of all lung cancer diagnoses. However, there remains a critical unmet need to enhance the prediction of clinical outcomes and therapy responses in LUAD patients. Keratins (KRTs), serving as the structural components of the intermediate filament cytoskeleton in epithelial cells, play a crucial role in the advancement of tumor progression. This study investigated the prognostic significance of the KRT family gene and developed a KRT gene signature (KGS) for prognostic assessment and treatment guidance in LUAD. Methods: Transcriptome profiles and associated clinical details of LUAD patients were meticulously gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The KGS score was developed based on the expression of five prognostic KRT genes (KRT7, KRT8, KRT17, KRT18, and KRT80), and the upper quartile of the KGS score was chosen as the cutoff. The Kaplan-Meier method was evaluated to compare survival outcomes between KGS-high and KGS-low groups. The underlying mechanism was further investigated by GSEA, GSVA, and other bioinformatic algorithms. Results: High expression of the KGS signature exhibited a robust association with poorer overall survival (OS) in the TCGA-LUAD dataset (HR: 1.81; 95% CI: 1.35–2.42, P = 0.00011). The association was further corroborated in three external GEO cohorts, including GSE31210 (HR: 3.31; 95% CI: 1.7–6.47, P = 0.00017), GSE72094 (HR: 1.95; 95% CI: 1.34–2.85, P = 0.00057) and GSE26939 (HR: 3.19; 95% CI: 1.74–5.84, P

Diatoms are ecologically important phytoplankton as they contribute 40% of the marine primary production and play an essential role in the biogeochemical cycles of many elements. Ocean warming, as a pressing environmental stressor, can profoundly affect the population structure and ecological services of diatoms. However, the molecular mechanisms underpinning cellular and physiological changes of diatoms under heat wave and heat selection conditions remain underexplored. This study revealed the transcriptomic and physiological responses of a model diatom species P. tricornutum to ocean warming at an elevated temperature (25 °C in comparison with 20 °C) under scenarios of heat shock (∼7 days; ∼7 generations) and heat selection (∼175 days; ∼165 generations). While unchanged cell growth and reduced Fv/Fm were recorded in the heat shock treatment, significant reductions in the cell growth rate and Fv/Fm were evident in the heat selection treatment. Contents of Chl-a, carotenoid, total soluble protein, carbon (C), and nitrogen (N) increased significantly in both treatments. Transcriptomics analysis showed that elevated temperature suppressed signaling pathways related to photosynthesis but activated signaling pathways involving in fatty acid metabolism and nitrogen metabolism following the heat selection, associated with elevated substance storage and enlarged cell size. As a result, the increase of both C and N suggest that more energy was likely allocated to growth than division under ocean warming. Notably, P. tricornutum showed a higher resistance to nitrogen limitation condition after acclimating to ocean warming possibly by activation of nitrogen metabolism and uptake. P. tricornutum responded to the projected ocean warming through readjusting energy metabolism.

Pharmacologic inhibition of PARP is the primary therapeutic strategy for BRCA mutant ovarian cancer. However, most of patients carry wild-type BRCA1/2 with no significant clinical benefits from PARP inhibitors, calling for the needs to further understanding and developing new strategy when employing PARP inhibitors to treat ovarian cancer. Here, we show that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of PARP inhibitor olaparib. Mechanistically, pharmacological inhibition or genetic deletion of PARP downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Furthermore, ferroptosis perturbation results in significant resistance to olaparib without affecting DNA damage response, while boosting ferroptosis by ferroptosis inducers (FINs) synergistically sensitizes BRCA-proficient ovarian cancer cells and xenografts to PARP inhibitor. Together, our results reveal a previously unappreciated mechanism coupling ferroptosis to PARP inhibition and suggest the combination of PARP inhibitor and FINs in the treatment of BRCA-proficient ovarian cancer.

Summary: We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

To investigate the changes of physiological and biochemical indexes, male mice were fed a regular diet or short time high fat diet (HFD) for 10 days with oral administration of saline, metformin, resveratrol, or injected intraperitoneally (ip) with digoxin respectively every day. Food intake and body weight were recorded simultaneously. Blood was collected after mice were sacrificed and then tested with commercial kits. The data manifested that metformin and resveratrol only ameliorate free fatty acids and glycerol in HFD-fed mice. Data interpretation of this part can be found in the research article “Metformin and resveratrol ameliorate muscle insulin resistance through preventing lipolysis and inflammation in hypoxic adipose tissue” (Zhao et al.,) [1]. Keywords: Metformin, Resveratrol, High fat diet, Free fatty acids, Glycerol

Objective: In patients with atrial fibrillation (AF) and end-stage renal disease (ESRD), oral anticoagulants are contraindicated, and left atrial appendage occlusion (LAAO) is an alternative treatment. However, the efficacy of thromboembolic prevention using LAAO in these patients has rarely been reported in Asian populations. To our knowledge, this is the first long-term LAAO study in patients with AF undergoing dialysis in Asia. Methods: In this study, 310 patients (179 men) with a mean age of 71.3 ± 9.6 years and mean CHA2DS2-VASc 4.2 ± 1.8 were consecutively enrolled at multiple centers in Taiwan. The outcomes of 29 patients with AF and ESRD undergoing dialysis who underwent LAAO were compared to those without ESRD. The primary composite outcomes were stroke, systemic embolization, or death. Results: No difference in mean CHADS-VASc score was noted between patients with versus without ESRD (4.1 ± 1.8 vs. 4.6 ± 1.9, p = 0.453). After a mean follow-up of 38 ± 16 months, the composite endpoint was significantly higher in patients with ESRD (hazard ratio, 5.12 [1.4–18.6]; p = 0.013) than in those without ESRD after LAAO therapy. Mortality was also higher in patients with ESRD (hazard ratio, 6.6 [1.1–39.7]; p = 0.038). The stroke rate was numerically higher in patients with versus without ESRD, but the difference was not statistically significant (hazard ratio, 3.2 [0.6–17.7]; p = 0.183). Additionally, ESRD was associated with device-related thrombosis (odds ratio, 6.15; p = 0.047). Conclusion: Long-term outcomes of LAAO therapy may be less favorable in patients with AF undergoing dialysis, possibly because of the poor condition of patients with ESRD.

Background/purpose: Amiodarone increases exposure of direct oral anticoagulants (DOACs). We aimed to analyze the effects of concurrent amiodarone use on DOAC concentrations and clinical outcomes. Methods: Patients who were ≥20 years of age, had atrial fibrillation, and took DOAC were enrolled to provide trough and peak samples for DOAC concentration measurements using ultra-high-performance liquid chromatography-tandem mass spectrometry. The results were compared with concentrations reported in clinical trials to define above, within, or under the expected range. The outcomes of interest were major bleeding and any gastrointestinal bleeding. Multivariate logistic regression and Cox proportional hazards model were used to determine the impact of amiodarone on above-range concentration and clinical outcomes, respectively. Results: A total of 722 participants (420 men, 58.2%) were enrolled to provide 691 trough samples and 689 peak samples. Among them, 21.3% concurrently used amiodarone. The proportion of patients with above-range trough and peak concentrations was 16.4% and 30.2%, respectively, for amiodarone users, in contrast to 9.4% and 19.8% for amiodarone non-users. The use of amiodarone was associated with above-range trough and peak concentrations (odds ratio [OR] = 2.00 [1.16, 3.47] and 1.82 [1.19, 2.79], respectively). However, amiodarone was not a significant predictor of major bleeding or any gastrointestinal bleeding. Conclusion: Concurrent amiodarone use led to increased DOAC concentration but was not associated with a higher risk of major bleeding or any gastrointestinal bleeding. Therapeutic monitoring of DOAC users concurrently taking amiodarone may be recommended for patients with an additional risk of increased DOAC exposure.

Background: Obstructive sleep apnea (OSA) is a risk factor for atrial fibrillation (AF); however, it is unclear whether AF increases the risk of OSA. Furthermore, sex differences among patients with both AF and OSA remain unclear. We aimed to determine the association between an increased AF burden and OSA and investigate the differences in clinical characteristics between women and men with AF and OSA. Methods: This was a descriptive, cross-sectional analysis from a prospective cohort study. Patients with non-valvular AF were recruited from the cardiac electrophysiology clinic of a tertiary center; they underwent a home sleep apnea test and 14-day ambulatory electrocardiography. Moderate-to-severe OSA was defined as an apnea-hypopnea index of ≥15. Results: Of 320 patients with AF, 53.4% had moderate-to-severe OSA, and the mean body mass index (BMI) was 25.6 kg/m2. Less women (38.2%) had moderate-to-severe OSA than men (59.3%) (p

Objective: In vitro fertilization (IVF) treatment has gradually adopted the practice of culturing embryos until the blastocyst stage on the D5 or D6 as the standard approach. PGT-A is commonly used in vitro fertilization (IVF). This study aimed to evaluate the clinical outcomes of frozen embryo transfers (FETs) using single blastocyst transfers (SBTs) on the fifth (D5) or sixth (D6) day of development in cycles that underwent preimplantation genetic testing for aneuploidy (PGT-A). Materials and methods: The patients who had at least one euploid or mosaic blastocyst of good quality determined by PGT-A results and received single embryo transfer (SET) cycles were included in the study. In this study, the live birth rate (LBR) and neonatal outcomes were compared after the transfer of single biopsied D5 and D6 blastocysts in frozen embryo transfer (FET) cycles. Results: A total of 527 frozen-thawed blastocyst transfer (FET) cycles (8449 biopsied embryos were analyzed). No significant difference in the implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR) between the transfers of D5 and D6 blastocysts. Birth weight was the only perinatal outcome that showed a significant difference between the D5 and D6 groups. Conclusion: The study confirmed that the transfer of a single euploid or mosaic blastocyst, regardless of whether it was on the fifth (D5) or sixth (D6) day of development, can lead to promising clinical results.

Post-process finishing of the additively manufactured (AMed) surfaces is still a critical issue, especially for the AMed surfaces with complex surface geometry, which largely limits the application of additive manufacturing. Hence, this paper presents a multi-jet polishing (MJP) method for post processing of AMed surfaces, utilizing a number of pressurized micro/nanometer abrasive water jets. A group of systematic polishing tests are conducted on 316L stainless steel (SS) prepared by powder bed fusion, to test the polishing performance, as well as the effect of key parameters. Moreover, surface integrity characterization and analysis are also carried out to make full evaluation of the MJP process on AMed 316L SS. The results indicate that MJP is effective for the post processing of AMed 316L SS, to obtain nanometric surface roughness on AMed surfaces, shedding the light on wide application of MJP for AMed complex surfaces.

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Early control of LDL-C to prevent ASCVD later in life is important. The Taiwan Society of Lipids and Atherosclerosis in association with the other seven societies developed this new lipid guideline focusing on subjects without clinically significant ASCVD. In this guideline for primary prevention, the recommended LDL-C target is based on risk stratification. A healthy lifestyle with recommendations for foods, dietary supplements and alcohol drinking are described. The pharmacological therapies for LDL-C reduction are recommended. The aim of this guideline is to decrease the risk of ASCVD through adequate control of dyslipidemia in Taiwan.

The antioxidant activity of curcumin has been extensively investigated for years. However, its molecular function mechanism remained unclear. Our preliminary study showed that curcumin downregulated miR-22-3p expression. This study aimed to address whether miR-22-3p mediated the antioxidant activity of curcumin and the possible action mechanism. The results showed that miR-22-3p repression increased the total cellular antioxidant capacity and enhanced the endogenous antioxidant enzyme system of LO2 cells. In addition, miR-22-3p-deteriorated cellular antioxidant capacity was prevented by curcumin pretreatment. Moreover, miR-22-3p inhibition significantly improved mitochondrial function and biogenesis. Further investigation demonstrated that a mitochondrial key regulator, the cardiolipin synthase gene (CRLS1), was targeted and downregulated by miR-22-3p. CRLS1 overexpression also significantly improved cellular antioxidant capacity and enhanced mitochondrial function and biogenesis in LO2 cells. Taken together, all these data suggested that miR-22-3p modulated the antioxidant effect of curcumin via targeting CRLS1, which may provide novel insights into miRNA-mediated antioxidant mechanism of curcumin.

Background/purpose: Studies have reported the advantages of digital imaging-assisted orthognathic surgery planning, but there is scarce information about a full digital planning modality. This study evaluated the 3D cephalometric-based and patient-reported outcomes of a full digital workflow for orthognathic surgery planning in the treatment of asymmetric maxillomandibular disharmony. Methods: A postoperative 3D image dataset of 30 Taiwanese Chinese patients with asymmetric skeletal Class III deformities who underwent full digital planning for two-jaw surgery were retrieved from the authors’ database. The 3D cephalometric data (dental, skeletal, and soft tissue evaluations) were compared to the ethnicity-matched 3D cephalometric normative values. Patient-reported outcome measure tools regarding postoperative overall appearance and satisfaction with facial areas (ranging from 0 to 100 and 0 to 10, respectively) were administered. The number of needed or requested revisionary surgery was collected. Results: No difference (all p > 0.05) was observed between the orthognathic-surgery-treated patients and the normative value for most of the tested 3D cephalometric parameters, with the exception (p

Background/Purpose: To investigate the characteristics of subjective symptoms and objective parameters among young patients with dry eye disease (DED) and compare them with those of older patients. Methods: We retrospectively enrolled 675 patients with DED who were divided into three age groups (20–41 years [younger], 41–60 years [middle], and >60 years [older]) (n = 143, 304, and 228, respectively). Subjective symptoms were evaluated using Standardized Patient Evaluation of Eye Dryness (SPEED) and Ocular Surface Disease Index (OSDI) questionnaires. Aqueous tear secretion was evaluated with the Schirmer test II. The number of expressible meibomian glands was evaluated with a slit-lamp-aided standardized evaluator. Lipid layer thickness (LLT), blink/incomplete blink rates and meibography were measured with the LipiView® II interferometer. The extent of the meibomian gland dropout was graded using a meiboscale. Results: The younger age group had higher subjective symptom severity, as reflected by higher SPEED (p

Background & Aims: Proper resolution of inflammation is essential to maintaining homeostasis, which is important as a dysregulated inflammatory response has adverse consequences, even being regarded as a hallmark of cancer. However, our picture of dynamic changes during inflammation remains far from comprehensive. Methods: Here we used single-cell transcriptomics to elucidate changes in distinct cell types and their interactions in a mouse model of chemically induced colitis. Results: Our analysis highlights the stromal cell population of the colon functions as a hub with dynamically changing roles over time. Importantly, we found that Serpina3n, a serine protease inhibitor, is specifically expressed in stromal cell clusters as inflammation resolves, interacting with a potential target, elastase. Indeed, genetic ablation of the Serpina3n gene delays resolution of induced inflammation. Furthermore, systemic Serpina3n administration promoted the resolution of inflammation, ameliorating colitis symptoms. Conclusions: This study provides a comprehensive, single-cell understanding of cell-cell interactions during colorectal inflammation and reveals a potential therapeutic target that leverages inflammation resolution.

Background/Purpose: The objective of this study was to create a normative database of 3D cephalometric measurements for adult Chinese in Taiwan to understand the specific features, as well as to provide information for 3-dimensional (3D) orthognathic surgery planning for patients with maxillofacial deformity. Methods: A cross-sectional study was conducted on 30 male and 30 female adults with normal and balanced facial appearance, skeletal Class I pattern, and proper interincisal relationship with normal occlusion. Cone-beam computed tomography was performed. After standard orientation of the 3D image models, 51 landmarks were digitized and 3D cephalometric measurements of overall facial features, midface, maxilla, mandible, dentoalveolus, and soft tissue were performed and analyzed. Results: Reliability and reproducibility of the 3D measurement were achieved. The data showed significant differences between males and females in facial height ratio, midface prominence, midface and maxilla width, mandible width and length for the skeleton, lower incisal inclination and interincisal angle for the dentoalveolus, and lip height, facial height and chin throat angle for the soft tissue. These dataset presented specific facial characteristics of the Chinese face as compared with other populations. Conclusion: The normative data helps to serve as a guide for maxillofacial treatment for globally ethnic Chinese, particularly useful for orthodontic treatment, 3D planning of orthognathic surgery and outcome assessment. Gender and ethnic differences need to be taken into consideration. Keywords: 3D cephalometry, Cone-beam computed tomography, Normative data, 3D planning, Orthognathic surgery

Background: Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications. Methods: We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant. Findings: A copy number deletion of GSTM3 (chr1:109737011-109737301, hg38) containing the eighth exon and the transcription stop codon was observed in 23.9% of BrS patients versus 0.8% of 15,829 controls in Taiwan Biobank (P < 0.001), and 0% in gnomAD. Co-segregation analysis showed that the co-segregation rate was 20%. Patch clamp experiments showed that in an oxidative stress environment, GSTM3 down-regulation leads to a significant decrease of cardiac sodium channel current amplitude. Ventricular arrhythmia incidence was significantly greater in gstm3 knockout zebrafish at baseline and after flecainide, but was reduced after quinidine, consistent with clinical observations. BrS patients carrying the GSTM3 deletion had higher rates of sudden cardiac arrest and syncope compared to those without (OR: 3.18 (1.77–5.74), P

Background: The aim of this study is to determine the relationship between the on-treatment lipid profiles and the CV events in CKD and non-CKD population. Method: This study was a multi-center observational registry, the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry. This study follows up patients with CV diseases in Taiwan who have secondary prevention therapies. The primary outcome is the time of first occurrence of a major adverse cardiac events (MACEs). Result: 5388 patients with ASCVD were included and 1478 (27.4%) had CKD without dialysis. CKD patients had higher TG and lower LDL-C levels. The incidence of recurrent MACEs per 1000 person-years in CKD patients was 19.5 (95% CI 15.5–24.9), compared with 9.1 (95% CI 7.4–11.1) in non-CKD patients. In patients with statin therapy, there were no differences in MACE risk between each level of on-treatment LDL-C, TG and HDL-C level. Higher on-treatment non-HDL-C level was a significant predictor for higher MACE risk in patients without CKD, and borderline significant in CKD patients under statin therapy. Heart failure history was also associated with higher MACE risk in both group. Lower body mass index (BMI

To evaluate meibomian gland dysfunction (MGD) by infrared thermography. Methods: An observational study was conducted at the Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan. Participants included 89 MGD patients (30 in Grade 1, 49 in Grade 2, and 10 in Grade 3) and 65 controls. The close-eye thermographic images of the eyelid were obtained noninvasively by infrared thermography. Temperatures at 8 regions of interest (ROIs) of the eyelid margin and a reference temperature at the center of the upper eyelid were measured. The temperature ratio was defined as the temperature of ROI divided by the reference temperature. Results: Eyelid margin temperature measured by infrared thermography increased from temporal side (ROI 1) to the nasal side (ROI 8) of the eye in both MGD patients and control groups. The temperature ratios were significantly higher in MGD participants than in controls, especially at ROI 8. Conclusion: The eyelid margin temperature measured by infrared thermography was higher in MGD participants. Further development of this infrared thermography system may become a rapid and non-invasive tool for MGD screening.

Although triggered arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are often caused by increased levels of circulating catecholamines, the mechanistic link between β-adrenergic receptor (AR) stimulation and the subcellular/molecular arrhythmogenic trigger(s) is unclear. Here, we systematically investigated the subcellular and molecular consequences of β-AR stimulation in the promotion of catecholamine-induced cardiac arrhythmias. Using mouse models of cardiac calsequestrin-associated CPVT, we demonstrate that a subpopulation of Na+ channels, mainly the neuronal Na+ channels (nNav), colocalize with ryanodine receptor 2 (RyR2) and Na+/Ca2+ exchanger (NCX) and are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na+ entry via nNav in the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA)-mediated SR Ca2+ refill is both an essential and a necessary factor for arrhythmogenesis. Furthermore, we show that augmentation of Na+ entry involves β-AR–mediated activation of CAMKII, subsequently leading to nNav augmentation. Importantly, selective pharmacological inhibition as well as silencing of Nav1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo. Taken together, these data suggest that the arrhythmogenic alteration in Na+/Ca2+ handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na+ influx through nNav. Therefore, selective inhibition of these channels and of Nav1.6 in particular can serve as a potential antiarrhythmic therapy.

The calcium-sensing receptor (CaR) is responsible for the regulation of extracellular calcium (Ca2+o) homeostasis. CaR activation has been shown to increase proliferation in several cancer cell lines; however, its presence or function has never been documented in lung cancer. We report that Ca2+o-activated CaR results in MAPK-mediated stimulation of parathyroid hormone-related protein (PTHrP) production in human lung squamous cell carcinoma (SCC) lines and humoral hypercalcemia of malignancy (HHM) in vivo. Furthermore, a single nucleotide polymorphism in CaR identified from a hypercalcemia-inducing lung SCC reduced the receptor's activation threshold leading to increased PTHrP expression and secretion. Increasing the expression of either wild-type CaR or a CaR variant with a single nucleotide polymorphism in the cytoplasmic domain was both necessary and sufficient for lung SCC to induce HHM. Because lung cancer patients who frequently develop HHM and PTHrP expression in lung cancer has been only partially explained, the significance of our findings indicates that CaR variants may provide a positive feedback between PTHrP and calcium and result in the syndrome of HHM.