Unveiling potential drug targets for hyperparathyroidism through genetic insights via Mendelian randomization and colocalization analyses.

Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the management of hyperparathyroidism, radical options to halt underlying disease progression remain lacking. Identifying putative genetic drivers and exploring novel drug targets that can impede HPT progression remain critical unmet needs. A Mendelian randomization (MR) analysis was performed to uncover putative therapeutic targets implicated in hyperparathyroidism pathology. Cis-expression quantitative trait loci (cis-eQTL) data serving as genetic instrumental variables were obtained from the eQTLGen Consortium and Genotype-Tissue Expression (GTEx) portal. Hyperparathyroidism summary statistics for single nucleotide polymorphism (SNP) associations were sourced from the FinnGen study (5590 cases; 361,988 controls). Colocalization analysis was performed to determine the probability of shared causal variants underlying SNP-hyperparathyroidism and SNP-eQTL links. Five drug targets (CMKLR1, FSTL1, IGSF11, PIK3C3 and SLC40A1) showed significant causation with hyperparathyroidism in both eQTLGen and GTEx cohorts by MR analysis. Specifically, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and solute carrier family 40 member 1 (SLC40A1) showed strong evidence of colocalization with HPT. Multivariable MR and Phenome-Wide Association Study analyses indicated these two targets were not associated with other traits. Additionally, drug prediction analysis implies the potential of these two targets for future clinical applications. This study identifies PIK3C3 and SLC40A1 as potential genetically proxied druggable genes and promising therapeutic targets for hyperparathyroidism. Targeting PIK3C3 and SLC40A1 may offer effective novel pharmacotherapies for impeding hyperparathyroidism progression and reducing disease risk. These findings provide preliminary genetic insight into underlying drivers amenable to therapeutic manipulation, though further investigation is imperative to validate translational potential from preclinical models through clinical applications.

Combined Assessment of Elevated Plasma Lipoprotein-Associated Phospholipase A2 and Plaque Enhancement Improved Accuracy in the Risk of Acute Ischemic Stroke in Patients with Intracranial Artery Stenosis.

PURPOSE: We evaluated the relationship between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) concentration and plaque characteristics in patients with intracranial artery stenosis and their clinical relevance in acute ischemic stroke. METHODS: Eighty-seven patients with intracranial atherosclerotic stenosis (66 males, 21 females) were retrospectively enrolled. Plasma Lp-PLA2 concentration was measured, and vessel wall magnetic resonance imaging (VW-MRI) was used to determine intracranial vascular stenosis and plaque characteristics, including plaque enhancement, surface morphology, and T1 hyperintensity. Binary logistic regression was used to evaluate the relationship between Lp-PLA2 concentration and plaque characteristics of intracranial artery after adjusting for demographic and confounding factors and to assess their diagnostic efficacy for the risk of acute ischemic stroke. RESULTS: After adjustment for demographic, medication and related lipid factors, Lp-PLA2 elevation was associated with plaque enhancement (odds ratio [OR]=12.7, 95% confidence interval [CI] 2.51-64.82, P=0.002) and surface irregularity (OR=2.9, 95% CI 1.06-7.98, P=0.038). Both Lp-PLA2 elevation (OR=8.8, 95% CI 1.64-47.72, P=0.011) and plaque enhancement (OR=34.3, 95% CI 5.88-200.4, P=0.001) were associated with acute ischemic stroke. Receiver operating characteristic curve analysis showed that the area under the curve for Lp-PLA2 concentration and plaque enhancement combined in the diagnosis of acute ischemic stroke was 0.884, significantly higher than that for Lp-PLA2 concentration (0.724) and plaque enhancement (0.794) alone. CONCLUSION: Elevated Lp-PLA2 is associated with plaque enhancement and plaque surface irregularity. Combined assessment of Lp-PLA2 concentration and plaque enhancement is of greater diagnostic value for the risk of acute ischemic stroke in patients with intracranial artery stenosis.

Low-cost, readily available 3D microscopy imaging system with variable focus spinner.

A large open aperture in an optical system can capture high-resolution images but yields a shallow depth of field. To overcome this issue, we investigated a low-cost, readily available method for retrofitting microscopy imaging systems to achieve 3D focus scanning in this study. Specifically, a procedure for fabricating variable focus spinners with dissimilar plates was introduced, and a sequence of 12 images was captured in different focal planes. The image scale and phase were corrected, and the in-focus pixels were abstracted by employing the Laplacian operator. Finally, an all-in-focus sharp image was generated, and a depth map was obtained.

Assessment of cardiac motion effects on the fiber architecture of the human heart in vivo.

The use of diffusion tensor imaging (DTI) for studying the human heart in vivo is very challenging due to cardiac motion. This paper assesses the effects of cardiac motion on the human myocardial fiber architecture. To this end, a model for analyzing the effects of cardiac motion on signal intensity is presented. A Monte-Carlo simulation based on polarized light imaging data is then performed to calculate the diffusion signals obtained by the displacement of water molecules, which generate diffusion weighted (DW) images. Rician noise and in vivo motion data obtained from DENSE acquisition are added to the simulated cardiac DW images to produce motion-induced datasets. An algorithm based on principal components analysis filtering and temporal maximum intensity projection (PCATMIP) is used to compensate for motion-induced signal loss. Diffusion tensor parameters derived from motion-reduced DW images are compared to those derived from the original simulated DW images. Finally, to assess cardiac motion effects on in vivo fiber architecture, in vivo cardiac DTI data processed by PCATMIP are compared to those obtained from one trigger delay (TD) or one single phase acquisition. The results showed that cardiac motion produced overestimated fractional anisotropy and mean diffusivity as well as a narrower range of fiber angles. The combined use of shifted TD acquisitions and postprocessing based on image registration and PCATMIP effectively improved the quality of in vivo DW images and subsequently, the measurement accuracy of fiber architecture properties. This suggests new solutions to the problems associated with obtaining in vivo human myocardial fiber architecture properties in clinical conditions.

Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.

PURPOSE: We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics. PATIENTS AND METHODS: We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere. RESULTS: Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively). CONCLUSION: A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.