The aim of this study was to update the information on internationally acceptable standards and clinical practice recommendations for the management of patients with primary aldosteronism (PA). The ...Taiwan Society of Aldosteronism (TSA) Task Force acknowledged the novel issues of PA and reached a group consensus on PA in Taiwan by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. Unilateral adrenalectomy is the preferred treatment for patients with aldosterone-producing adenoma (APA). For medical treatment with mineralocorticoid receptor antagonists (MRAs), spironolactone is the first-line treatment, and eplerenone is a reasonable alternative in PA patients intolerant or contraindicated to spironolactone. The dose of MRAs can be titrated according to plasma renin activity (PRA). For screening PA-related comorbidities, we suggest albuminuria to predict a post-treatment decline in renal function, echocardiography as cardiac evaluation, bone mineral density scan for osteoporosis, and obstructive sleep apnea. In tissue and genetic surveys, we suggest immunohistochemical staining and somatic mutation screening for post-operative adrenal specimens in APA patients. With this consensus, we hope to update the information on PA for clinical physicians to facilitate better identification, management and treatment of patients with PA.
Surgery for obstructive sleep apnea (OSA) has changed in concept and technique that transformed from radical excision to functional reconstruction. The aim of this study was to investigate the safety ...and effectiveness of palatal hybrid surgery in OSA patients.
Palatal hybrid surgery is a tissue-specific technique (mucosa-preservation, tonsil-excision, fat-ablation, muscle-relocation/suspension) used in treating OSA patients with velopharyngeal obstruction. The study included 46 consecutive adults OSA patients. The palatal hybrid surgery annotates uvulopalatopharyngoplasty in stereoscopic reconstruction of tonsillar fossa (pharyngoplasty), omni-suspension of the soft palate (palatoplasty) and advancement of uvula (uvuloplasty).
No patient experienced airway compromise, voice change or persistent nasal regurgitation following palatal hybrid surgery. One patient existed postoperative tonsillar fossa bleeding received conservative treatment. Postoperative pain in visual analogue scale (VAS) showed average score of 3, 3, 2, 0 at the 1st, 3rd, 7th, 14th day, respectively. Perioperative snoring severity (VAS) (8.7 vs 2.6) and daytime sleepiness (Epworth Sleepiness Scale) (11.3 vs 5.5) all improved significantly (p < 0.001). Posterior air space in retropalatal area increased from 8.4 to 11.1 mm (p < 0.001). Home sleep test showed that apnea–hypopnea index significantly reduced from 41.8 to 18.2 event/h and minimal oxygen saturation increased from 72.4 to 81.5% (p < 0.001). The success rate in individual Friedman stage was 100% (stage I), 63% (stage II) and 58% (stage III) with a total success rate of 63%.
Palatal hybrid surgery using tissue-specific maneuver annotates UPPP in concept and technique. The results show that palatal hybrid surgery is mini-invasive with low morbid and is effective in improving subjective clinic symptoms, objective sleep parameters and success rate of OSA.
BackgroundImmunological checkpoint blockade is effective in treating various malignancies. Identifying predictive biomarkers to assist patient selection for immunotherapy has become a priority in ...both clinical and research settings.MethodsMutations in patients who responded to immunotherapy were identified through next-generation sequencing. Relationships among protein kinase, DNA-activated, catalytic polypeptide (PRKDC) mutations, mutation load and microsatellite instability (MSI) were analyzed using datasets from The Cancer Genome Atlas. These relationships were validated by conducting an in vitro study and by using tissue samples from 34 patients with gastric cancer. The CT26 animal model was used to evaluate the role of PRKDC as a predictive biomarker and the efficacy of the DNA-PK inhibitor.ResultsFrom the published literature, we found that among patients whose tumors harbored PRKDC mutations, 75%, 53.8%, and 50% of those with lung cancer, melanoma, and renal cell carcinoma, respectively, responded to immunotherapy. Most of these mutations were truncating and located in functional domains or in a destabilizing PRKDC protein structure. Additional analysis showed that a PRKDC mutation was significantly associated with a high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer. Patients with gastric cancer or colon cancer harboring PRKDC mutations were also highly associated with MSI-high status. Finally, we found that knockout PRKDC or DNA-PK inhibitor (PRKDC encodes the catalytic subunit of DNA-dependent protein kinase) enhanced the efficacy of the anti-programmed cell death protein one pathway monoclonal antibody in the CT26 animal model.ConclusionsPRKDC is not only a predictive biomarker but also a drug target for immune checkpoint inhibitors.
Current research on the epigenetic repercussions of exposure to a combination of pollutants is limited. This study aims to discern DNA methylation probes associated with exposure to multiple ...pollutants, serving as early effect markers, and single-nucleotide polymorphisms (SNPs) as surrogate indicators for population susceptibility. The investigation involved the analysis of urine exposure biomarkers for 11 heavy metals (vanadium, arsenic, mercury, cadmium, chromium, nickel, lead, manganese, copper, strontium, thallium), polycyclic aromatic hydrocarbon (PAHs) (1-hydroxypyrene), genome-wide DNA methylation sequencing, and SNPs array on all study participants. The data were integrated with metabolomics information and analyzed both at a community level based on proximity to home addresses relative to the complex and at an individual level based on exposure biomarker concentrations.BACKGROUNDCurrent research on the epigenetic repercussions of exposure to a combination of pollutants is limited. This study aims to discern DNA methylation probes associated with exposure to multiple pollutants, serving as early effect markers, and single-nucleotide polymorphisms (SNPs) as surrogate indicators for population susceptibility. The investigation involved the analysis of urine exposure biomarkers for 11 heavy metals (vanadium, arsenic, mercury, cadmium, chromium, nickel, lead, manganese, copper, strontium, thallium), polycyclic aromatic hydrocarbon (PAHs) (1-hydroxypyrene), genome-wide DNA methylation sequencing, and SNPs array on all study participants. The data were integrated with metabolomics information and analyzed both at a community level based on proximity to home addresses relative to the complex and at an individual level based on exposure biomarker concentrations.On a community level, 67 exposure-related CpG probes were identified, while 70 CpG probes were associated with urine arsenic concentration, 2 with mercury, and 46 with vanadium on an individual level. These probes were annotated to genes implicated in cancers and chronic kidney disease. Weighted quantile sum regression analysis revealed that vanadium, mercury, and 1-hydroxypyrene contributed the most to cg08238319 hypomethylation. cg08238319 is annotated to the aryl hydrocarbon receptor repressor (AHRR) gene, and AHRR hypomethylation was correlated with an elevated risk of lung cancer. AHRR was further linked to deregulations in phenylalanine metabolism, alanine, aspartate, and glutamate metabolism, along with heightened oxidative stress. Additionally, three SNPs (rs11085020, rs199442, and rs10947050) corresponding to exposure-related CpG probes exhibited significant interaction effects with multiple heavy metals and PAHs exposure, and have been implicated in cancer progression and respiratory diseases.RESULTSOn a community level, 67 exposure-related CpG probes were identified, while 70 CpG probes were associated with urine arsenic concentration, 2 with mercury, and 46 with vanadium on an individual level. These probes were annotated to genes implicated in cancers and chronic kidney disease. Weighted quantile sum regression analysis revealed that vanadium, mercury, and 1-hydroxypyrene contributed the most to cg08238319 hypomethylation. cg08238319 is annotated to the aryl hydrocarbon receptor repressor (AHRR) gene, and AHRR hypomethylation was correlated with an elevated risk of lung cancer. AHRR was further linked to deregulations in phenylalanine metabolism, alanine, aspartate, and glutamate metabolism, along with heightened oxidative stress. Additionally, three SNPs (rs11085020, rs199442, and rs10947050) corresponding to exposure-related CpG probes exhibited significant interaction effects with multiple heavy metals and PAHs exposure, and have been implicated in cancer progression and respiratory diseases.Our findings underscore the pivotal role of AHRR methylation in gene-environment interactions and highlight SNPs that could potentially serve as indicators of population susceptibility in regions exposed to multiple heavy metals and PAHs.CONCLUSIONOur findings underscore the pivotal role of AHRR methylation in gene-environment interactions and highlight SNPs that could potentially serve as indicators of population susceptibility in regions exposed to multiple heavy metals and PAHs.
In this study, a novel yet general strategy is proposed and demonstrated to enhance the energy storage density (ESD) of dielectric capacitors by introducing a built-in electric field in the ...dielectric layer, which increases the applied electric field required to polarize the dielectric. By using the top and bottom electrodes of different work functions, a built-in electric field is created in the antiferroelectric layer, which leads to an increase in the critical fields for the antiferroelectric-ferroelectric phase transition and thus the enhancement of ESD. Accordingly, the TiO2/ZrO2/TiO2 antiferroelectric capacitor with asymmetric electrodes demonstrates an ultra-high ESD of 114.5 J cm−3, which is improved by ~21% compared to the antiferroelectric capacitor without a built-in field, along with high efficiency of 76%. The achieved ESD is record-high among the HfO2/ZrO2-based lead-free antiferroelectric thin-film capacitors. The result indicates that engineering the built-in electric field can be an effective and promising approach to increasing the ESD for electrostatic supercapacitors.
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•A novel yet general strategy to enhance energy storage density (ESD) in dielectrics by built-in field engineering is proposed and theoretically derived.•Built-in field of opposite direction causes increase of applied electric field and thus increment of ESD.•The strategy is demonstrated on an antiferroelectric supercapacitor by asymmetric electrodes and work functions, revealing 21% improvement in ESD.•A record-high ESD of 114.5 J cm− 3 among Hf/ZrO2-based antiferroelectrics is achieved, along with outstanding efficiency and endurance.
A major pharmacological assumption is that lowering disease-promoting protein levels is generally beneficial. For example, inhibiting metastasis activator BACH1 is proposed to decrease cancer ...metastases. Testing such assumptions requires approaches to measure disease phenotypes while precisely adjusting disease-promoting protein levels. Here we developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic safe harbor locus. Unexpectedly, engineered MDA-MB-231 metastatic human breast cancer cells become more, then less and then more invasive as we tune BACH1 levels up, irrespective of the native BACH1. BACH1 expression shifts in invading cells, and expression of BACH1's transcriptional targets confirm BACH1's nonmonotone phenotypic and regulatory effects. Thus, chemical inhibition of BACH1 could have unwanted effects on invasion. Additionally, BACH1's expression variability aids invasion at high BACH1 expression. Overall, precisely engineered, noise-aware protein-level control is necessary and important to unravel disease effects of genes to improve clinical drug efficacy.
With capital-skill complementarity, the secular decline in the price of capital equipment due to equipment-specific technological progress (ESTP) keeps pushing up the demand for skilled relative to ...unskilled labor and raising the skill premium. This paper quantitatively characterizes the dynamics of optimal taxation in response. Two main results emerge, regardless of whether the Ramsey (1927) or the Mirrlees (1971) approach is adopted. First, a tax on capital equipment corrects the 'pecuniary externalities' caused by ESTP. The correction prescribes a downward or an upward adjustment of tax rates over time, depending on whether ESTP takes place at an accelerated or a decelerated pace. Second, both Ramsey and Mirrlees approaches prescribe an increasing marginal tax rate on labor income over time. Interestingly, we find that the prescribed pattern of optimal taxation resembles the empirical decline in capital taxes and the increase in labor taxes observed in the United States. In particular, despite the significant rise in the skill premium, the welfare gains of tax reform toward optimal Ramsey taxes are modest and small.
Triple‐negative breast cancer (TNBC) is the most lethal subtype of breast cancer owing to its aggressive nature and the lack of targeted therapy for most patients. MYC, an oncogenic transcription ...factor, is elevated in TNBC and causes accelerated tumor growth through metabolic reprogramming. However, there is currently no drug available in clinics to inhibit MYC. Ring Finger Protein 8 (RNF8), an E3 ubiquitin ligase, is highly expressed in TNBC and essential for tumor progression. To comprehensively understand the role of RNF8 in TNBC, we conducted RNA‐sequencing and found that the downregulation of RNF8 attenuates the activity of the MYC network in human TNBC cell lines. Moreover, we observed the reduced glucose uptake and utilization in TNBC cells with RNF8 knockdown as a result of the decreased expression of MYC and its target genes such as glucose transporter GLUT1 and key glycolytic enzyme HK2. Knockdown of RNF8 also decreased the metabolic influx in the glycolysis pathway as revealed in the isotope tracer studies coupled with mass spectrometry analysis. Importantly, the treatment of proteasome inhibitor MG132 was able to restore MYC protein expression, while cycloheximide chase assay showed that MYC protein has a shorter half‐life in TNBC cells with RNF8 deficiency. In vivo ubiquitination assay further demonstrated that RNF8 mediates Lysine (K)63‐linked ubiquitination over MYC, suggesting that RNF8 mediates K63‐linked ubiquitination to stabilize MYC against proteasomal degradation. Taken together, these results suggest that RNF8 enhances MYC signaling, thereby promoting metabolic reprogramming and tumor progression in TNBC. Targeting RNF8 may be a reasonable alternative to inhibit MYC‐driven cancers such as TNBC.
This study investigated the effect of a combination of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and basal insulin (BI) in poorly controlled type 2 diabetes mellitus previously treated with ...premixed insulin. The possible therapeutic benefit of the subject is mainly hoped to provide a direction for optimizing treatment options to reduce the risk of hypoglycemia and weight gain. A single-arm, open-label study was conducted. The antidiabetic regimen was switched to GLP-1 RA plus BI to replace previous treatment with premixed insulin in type 2 diabetes mellitus subjects. After 3 months of treatment modification, GLP-1 RA plus BI was compared for superior outcomes by continuous glucose monitoring system. There were 34 subjects at the beginning, 4 withdrew due to gastrointestinal discomfort, and finally 30 subjects completed the trial, of which 43% were male; the average age was 58 ± 9 years old, and the average duration of diabetes was 12 ± 6 years, the baseline glycated hemoglobin level was 8.6 ± 0.9 %. The initial insulin dose of premixed insulin was 61 ± 18 units, and the final insulin dose of GLP-1 RA + BI was 32 ± 12 units (P < .001). Time out of range (from 59%-42%), time-in-range (from 39%-56%) as well as glucose variability index including standard deviation also improved, mean magnitude of glycemic excursions, mean daily difference and continuous population in continuous glucose monitoring system, continuous overall net glycemic action (CONGA). Also noted was a decrease in body weight (from 70.9 kg-68.6 kg) and body mass index (all P values < .05). It provided important information for physicians to decide to modify therapeutic strategy as individualized needs.
This letter reports of the fabrication of high-performance p-channel polycrystalline germanium (poly-Ge) thin-film transistors (TFTs) using continuous-wave laser crystallization (CLC). During the CLC ...process, the direction of crystallization matches the direction of laser scanning due to a strong temperature gradient in the melting region. This makes it possible to fabricate high-quality poly-Ge thin films with 1-D longitudinal grains as large as <inline-formula> <tex-math notation="LaTeX">2\,\,\mu \text{m}\,\,\times 20\,\,\mu \text{m} </tex-math> </inline-formula>. We fabricated the proposed p-channel CLC Ge TFTs with channel width of <inline-formula> <tex-math notation="LaTeX">0.7~\mu \text{m} </tex-math> </inline-formula> and a channel length each of <inline-formula> <tex-math notation="LaTeX">0.7~\mu \text{m} </tex-math> </inline-formula>. Consequently, the proposed p-channel CLC Ge TFTs with single-crystal-like channel fabricated on a longitudinal grain with biaxial tensile strain achieved a superior field-effect mobility of 1014.9 cm 2 /V-s.
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