Metaplastic thymoma in the middle mediastinum: a rare case report and surgical treatment analysis of a 32-year-old female patient.

Background: Metaplastic thymoma (MT), an exceedingly rare variant of primary thymic epithelial neoplasms, is distinguished by its indolent progression and unique histopathological profile. It presents a biphasic pattern characterized by solid epithelial and spindle cell components, potentially leading to diagnostic confusion with type A thymomas or the type A component of type AB thymomas. Accurate diagnosis is pivotal for optimal therapeutic strategies and prognostication. Case Description: We document an exceptional case of a 32-year-old woman, incidentally discovered to have a mediastinal nodule in the middle compartment on chest computed tomography (CT). The lesion was excised via video-assisted thoracoscopic surgery. Histological evaluation revealed a biphasic cellular architecture comprising epithelioid and spindle cells. Immunohistochemical analysis demonstrated significant positivity for CK5/6 and P40 in epithelial cells, and vimentin and epithelial membrane antigen in spindle cells, with a low proliferation index marked by Ki-67. Noteworthy, fluorescence in situ hybridization (FISH) analysis identified a YAP1::MAML2 gene fusion, with a predominant pattern suggestive of fusion gene presence, thus corroborating the diagnosis of MT. Conclusions: This report underscores the critical role of a multifaceted diagnostic approach, including histopathological, immunohistochemical, and genetic analyses, in the identification of MT. The detection of the YAP1::MAML2 gene fusion through FISH analysis provides a robust diagnostic marker, highlighting the necessity for clinical and pathological vigilance for this rare tumor.

Combined transcriptomics and metabolomics analysis reveals salinity stress specific signaling and tolerance responses in the seagrass Zostera japonica.

KEY MESSAGE: Multiple regulatory pathways of Zostera japonica to salt stress were identified through growth, physiological, transcriptomic and metabolomic analyses. Seagrasses are marine higher submerged plants that evolved from terrestrial monocotyledons and have fully adapted to the high saline seawater environment during the long evolutionary process. As one of the seagrasses growing in the intertidal zone, Zostera japonica not only has the ability to quickly adapt to short-term salt stress but can also survive at salinities ranging from the lower salinity of the Yellow River estuary to the higher salinity of the bay, making it a good natural model for studying the mechanism underlying the adaptation of plants to salt stress. In this work, we screened the growth, physiological, metabolomic, and transcriptomic changes of Z. japonica after a 5-day exposure to different salinities. We found that high salinity treatment impeded the growth of Z. japonica, hindered its photosynthesis, and elicited oxidative damage, while Z. japonica increased antioxidant enzyme activity. At the transcriptomic level, hypersaline stress greatly reduced the expression levels of photosynthesis-related genes while increasing the expression of genes associated with flavonoid biosynthesis. Meanwhile, the expression of candidate genes involved in ion transport and cell wall remodeling was dramatically changed under hypersaline stress. Moreover, transcription factors signaling pathways such as mitogen-activated protein kinase (MAPK) were also significantly influenced by salt stress. At the metabolomic level, Z. japonica displayed an accumulation of osmolytes and TCA mediators under hypersaline stress. In conclusion, our results revealed a complex regulatory mechanism in Z. japonica under salt stress, and the findings will provide important guidance for improving salt resistance in crops.

Analysis of Drug Resistance Characteristics of Mycobacterium Tuberculosis in Anhui Province, 2016-2022.

Objective: To preliminarily assess the prevalence and control effect of tuberculosis and drug-resistant tuberculosis (TB) in Anhui province, and analyze the trends in the changing drug resistance spectrum of Mycobacterium tuberculosis (Mtb) isolated in Anhui province from 2016 to 2022. Methods: From 2016 to 2022, a total of 2336 culture-positive tuberculosis strains were collected from four drug resistance monitoring sites. Patient demographic information was collected and drug susceptibility testing was conducted. Results: Among the 2336 Mycobacterium tuberculosis complex strains, 1788 (76.54%) were from male patients and 548 (23.46%) were from female patients. The majority were of Han ethnicity, from rural areas, and employed in agriculture, with 12.54% (285/2273) having diabetes. A total of 1893 (81.04%) strains were sensitive to all six anti-TB drugs tested, and 443 (18.96%) strains were resistant to at least one or more anti-TB drugs. The drug resistance rate for patients undergoing initial treatment was 16.80% (348/2071), and 35.85% (95/265) for those receiving retreatment. Among the six anti-TB drugs, the resistance rates from highest to lowest were: INH (10.55%, 236/2336), SM (8.18%, 183/2336), OFX (6.53%, 146/2336), RFP (5.95%, 133/2336), EMB (2.37%, 53/2336), KM (1.97%, 44/2336). Significant differences were observed in MDR strains across different ages, types, with or without diabetes, and geographical sources (χ2=14.895,76.534,6.032,5.109, all P<0.05). Conclusion: The tuberculosis prevention and control measures have controlled the drug resistance rate of Mycobacterium tuberculosis to a certain extent. However, there are still statistical differences in drug resistance rates among TB patients with different categories, age groups, regions, and diabetic diseases. Early detection and prompt treatment of patients with drug-resistant TB remain critical to controlling the spread of this disease.

Liquid-based cytology specimens for next-generation sequencing in lung adenocarcinoma: challenges and evaluation of targeted therapy.

BACKGROUND: To explore challenges of liquid-based cytology (LBC) specimens for next-generation sequencing (NGS) in lung adenocarcinoma and evaluate the efficacy of targeted therapy. METHODS: A retrospective analysis was conducted on the NGS test of 357 cases of advanced lung adenocarcinoma LBC specimens and compared with results of histological specimens to assess the consistency. The impact of tumor cellularity on NGS test results was evaluated. The utility of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) was collected. Clinical efficacy evaluation was performed and survival curve analysis was conducted using the Kaplan-Meier method. RESULTS: There were 275 TKI-naive and 82 TKI-treated specimens, the mutation rates of cancer-related genes detected in both groups were similar (86.2% vs. 86.6%). The EGFR mutation rate in the TKI treated group was higher than that in the TKI-naive group (69.5% > 54.9%, P = 0.019). There was no significant difference in the EGFR mutation frequency among different tumor cellularity in the TKI-naive group. However, in the TKI treated group, the frequency of EGFR sensitizing mutation and T790M resistance mutation in specimens with < 20% tumor cellularity was significantly lower than that in specimens with ≥ 20% tumor cellularity. Among 22 cases with matched histological specimens, 72.7% (16/22) of LBC specimens were completely consistent with results of histological specimens. Among 92 patients with EGFR-mutant lung adenocarcinoma treated with EGFR-TKIs in the two cohorts, 88 cases experienced progression, and the median progression-free survival (PFS) was 12.1 months. CONCLUSIONS: Cytological specimens are important sources for gene detection of advanced lung adenocarcinoma. When using LBC specimens for molecular testing, it is recommended to fully evaluate the tumor cellularity of the specimens.

Perioperative remedial antiviral therapy in hepatitis B virus-related hepatocellular carcinoma resection: How to achieve a better outcome.

BACKGROUND: Although the benefits of antiviral therapy for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) have been proven, researchers have not confirmed the differences in patient outcomes between patients who received preoperative antiviral therapy for a period of time (at least 24 wk) and patients who received remedial antiviral therapy just before radical resection for HBV-related HCC. AIM: To investigate the efficacy of perioperative remedial antiviral therapy in patients with HBV-related HCC. METHODS: A retrospective study of patients who underwent radical resection for HBV-related HCC at the First Affiliated Hospital of Xi'an Jiaotong University from January 2016 to June 2019 was conducted. Considering the history of antiviral therapy, patients were assigned to remedial antiviral therapy and preoperative antiviral therapy groups. RESULTS: Kaplan-Meier analysis revealed significant differences in overall survival (P < 0.0001) and disease-free survival (P = 0.035) between the two groups. Multivariate analysis demonstrated that a history of preoperative antiviral treatment was independently related to improved survival (hazard ratio = 0.27; 95% confidence interval: 0.08-0.88; P = 0.030). CONCLUSION: In patients with HBV-related HCC, it is ideal to receive preoperative long-term antiviral therapy, which helps patients tolerate more extensive hepatectomy; however, remedial antiviral therapy, which reduces preoperative HBV-DNA levels to less than 4 Log10 copies DNA/mL, can also result in improved outcomes.

Redistribution of defective mitochondria-mediated dihydroorotate dehydrogenase imparts 5-fluorouracil resistance in colorectal cancer.

Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant cancer cells; however, potential therapeutic targets remain elusive. This study investigated ferroptosis vulnerability and dihydroorotate dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU.

The challenge of survivors of gynecological carcinomas: a retrospective study on occurrence of second tumors.

OBJECTIVE: To clarify the epidemiologic characteristics and risk of other tumors in survivors of gynecological tumors. MATERIALS AND METHODS: This is a retrospective study based on the Surveillance, Epidemiology, and End Results database (SEER). RESULTS: The morbidity of other malignant tumors in patients with gynecological cancer was 8.07%. The most common subsequent tumors are breast, lung, colorectal, thyroid, and bladder cancers. Taking the incidence rate of the general population as reference, the second tumor with the highest relative risk in patients with cervical cancer is vulvar cancer. Bladder cancer is the second tumor with the highest relative risk value both in patients with corpus and ovarian cancer. The median period from the diagnosis of the initial tumor to the diagnosis of the second tumor was 5 years. Most patients with other tumors following gynecological cancer showed worse prognosis than patients with gynecological tumors only. However, thyroid cancer following ovarian cancer is a protective factor in survival. CONCLUSION: Patients with gynecological tumors have a significantly higher risk of malignant tumors in other systems compared to ordinary population. It is necessary to be vigilant against subsequent high-risk tumors and tumors with poor prognosis within 5 years of initial diagnosis.

Consistency Analysis of Programmed Death Ligand 1 Expression in Non-Small Cell Lung Cancer Between Pleural Effusion and Matched Primary Lung Cancer Tissues by Immunohistochemical Double Staining.

In clinical practice, programmed death ligand 1 (PD-L1) detection is prone to nonspecific staining due to the complex cellular composition of pleural effusion smears. In this study, diaminobenzidine (DAB) and 3-amino-9-ethylcarbazole (AEC) immunohistochemistry double staining was performed to investigate PD-L1 expression in tumor cells from malignant pleural effusion (MPE). MPE was considered as a metastasis in non-small cell lung cancer patients; thus, the heterogeneity between metastatic and primary lung cancer was revealed as well. Ninety paired specimens of MPE cell blocks and matched primary lung cancer tissues from non-small cell lung cancer patients were subjected to PD-L1 and thyroid transcription factor-1(TTF-1)/p63 immunohistochemistry double staining. Two experienced pathologists independently evaluated PD-L1 expression using 3 cutoffs (1%, 10%, and 50%). PD-L1 expression in MPE was strongly correlated with that in matched primary lung cancer tissues (R = 0.813; P < .001). Using a 4-tier scale (cutoffs: 1%, 10%, and 50%), the concordance was 71.1% (Cohen's κ = .534). Using a 2-tier scale, the concordance was 75.6% (1%, Cohen's κ = 0.53), 78.9% (10%, Cohen's κ = 0.574), and 95.6% (50%, Cohen's κ = 0.754). The rates of PD-L1 positivity in MPE (56.7%) were higher than that in lung tissues (32.2%). All 27 discordant cases had higher scores in MPE. The double-staining method provided superior identification of PD-L1-positive tumor cells on a background with nonspecific staining. In conclusion, PD-L1 expression was moderately concordant between metastatic MPE cell blocks and matched primary lung carcinoma tissues, with variability related to tumor heterogeneity. MPE should be considered to detect PD-L1 when histological specimens are unattainable, especially when PD-L1 expression is >50%. PD-L1 positivity rates were higher in MPE. Double staining can improve PD-L1 detection by reducing false-negative/positive results.

The detection of PD-L1 expression on liquid-based cytology in pleural effusion of lung adenocarcinoma and its prognostic evaluation: Between paired liquid-based cytology and cell block samples.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression levels measured by immunohistochemistry have been proven to predict the outcome of immunotherapy in lung adenocarcinoma (LUAD). However, data on PD-L1 expression on liquid-based cytology (LBC) in malignant pleural effusion (MPE) is scarce. METHODS: This study cohort included 60 cases with MPE suffering from LUAD. PD-L1 SP263 assay was used for immunocytochemistry (ICC) on LBC and matched cell block (CB) to validate ICC protocols on LBC slides. Clinical outcomes were analyzed based on immunotherapy and PD-L1 tumor proportion scores (TPS) on LBC slides and CBs. RESULTS: PD-L1 expression with TPS ≥1% was lower in LBCs than in CBs (33 of 60 [55.0%] vs. 35 of 60 [58.3%]; p = .687). Even with the TPS ≥50% threshold, PD-L1 expression was lower in LBCs (10 of 60 [16.7%] vs. 15 of 60 [25%]; p = .125). Epidermal growth factor receptor (EGFR) exon 20 mutation, tumor cell proportion, and pleural fluid neutrophil-to-lymphocyte ratio were related to PD-L1 expression on CBs (p = .013, p = 0.022, and p = .011), respectively. Patients with subsequent immune checkpoint inhibitor therapy remained a better prognostic in subgroups of PD-L1 positive expression on LBC slides (TPS ≥1%, p = .041). CONCLUSIONS: LBC specimens had comparable performance to CBs in PD-L1 assessment and predicting treatment response to PD-L1-defined therapy.

Ratio of waist circumference to body mass index: A novel predictor of clinical outcome in hypertension patients.

We aim to investigate the influence of waist circumference and body mass index (BMI) on all-cause death and cardiovascular-specific death in patients with hypertension. This prospective cohort study, based on waist circumference and body mass index measurements in patients with hypertension, provided risk estimates of all-cause mortality and cardiovascular events. The waist circumference-to-BMI ratio (WtBR) is an anthropometric measure integrating waist circumference and BMI. We utilized multivariable Cox regression analysis, restricted cubic spline model, Kaplan-Meier plot, random forest analysis, and sensitivity analysis to assess the relationship of WtBR with all-cause mortality. Subsequently, Fine-Gray competing risk regression models were applied to precisely evaluate the probability of cardiovascular-specific death attributed to high WtBR. The results indicate that thea deceased group showed significantly higher WtBR and lower BMI compared with the alive groups (P < .05), while no significant difference was observed in waist circumference (P = .373). When analyzed as continuous, the risk of all-cause death elevated with increasing WtBR in the adjusted model with an HR of 2.42 (95% CI, 2.06-2.85). The restricted cubic spline illustrated an elevated risk of all-cause mortality as WtBR increased (J-shaped curve). Nevertheless, WtBR showed no significant association with cardiovascular-specific death and the prediction model exhibited a reliable performance in the testing set. This study supported that WtBR, an anthropometric measure, is independently associated with all-cause death in hypertensive patients. It's advisable to routinely assess waist circumference in hypertensive patients regardless of BMI, in order to more effectively manage the risk of obesity-related health.

Quality-of-Life Bronchiectasis Respiratory Symptom Scale Predicts the Risk of Exacerbations in Adults with Bronchiectasis: A Prospective Observational Study.

Rationale: The relationship between symptoms, measured using a validated disease-specific questionnaire, and longitudinal exacerbation risk has not been demonstrated in bronchiectasis. Objectives: The aim of this study is to investigate whether baseline symptoms, assessed using the Quality-of-Life Bronchiectasis Respiratory Symptom Scale (QoL-B-RSS) and its individual component scores, could predict future exacerbation risk in patients with bronchiectasis. Methods: The study included 436 adults with bronchiectasis from three tertiary hospitals. Symptoms were measured using the QoL-B-RSS, with scores ranging from 0 to 100, where lower scores indicated more severe symptoms. We examined whether symptoms as continuous measures were associated with the risk of exacerbation over 12 months. The analysis was also repeated for individual components of the QoL-B-RSS score. Results: The baseline QoL-B-RSS score was associated with an increased risk of exacerbations (rate ratio, 1.25 for each 10-point decrease; 95% confidence interval [CI], 1.15-1.35; P < 0.001), hospitalizations (rate ratio, 1.24; 95% CI, 1.05-1.43; P = 0.02), and reduced time to the first exacerbation (hazard ratio, 1.12; 95% CI, 1.03-1.21; P = 0.01) over 12 months, even after adjusting for relevant confounders, including exacerbation history. The QoL-B-RSS score was comparable to exacerbation history in its association with future frequent exacerbations (defined as three or more exacerbations per year) and hospitalization (area under the curve, 0.86 vs. 0.84; P = 0.46; and area under the curve, 0.81 vs. 0.83; P = 0.41, respectively). Moreover, patients with more severe symptoms in the majority of individual components of the QoL-B-RSS were more likely to experience exacerbations. Conclusions: Symptoms can serve as useful indicators for identifying patients at increased risk of exacerbation in bronchiectasis. Beyond relying solely on exacerbation history, a comprehensive assessment of symptoms could facilitate timely and cost-effective implementation of interventions for exacerbation prevention.

Comparative safety of different sodium-glucose transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials.

Backgrounds: The safety of different sodium-glucose transporter 2 (SGLT-2) inhibitors remains uncertain due to the lack of head-to-head comparisons. Methods: This network meta-analysis (NMA) was performed to compare the safety of nine SGLT-2 inhibitors in patients with type 2 diabetes (T2DM). PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for studies published in English before August 30, 2022. Published and unpublished randomized controlled trials (RCTs) comparing the safety of individual SGLT-2 inhibitors in patients with T2DM were included. A Bayesian NMA with random effects model was applied. Subgroup and sensitivity analyses were performed. The quality of the evidence was evaluated using the Confidence in Network Meta-Analysis framework. Results: Nine SGLT-2 inhibitors were evaluated in 113 RCTs (12 registries) involving 105,293 adult patients. Reproductive tract infections (RTIs) were reported in 1,967 (4.51%) and 276 (1.01%) patients in the SGLT-2 inhibitor and placebo groups, respectively. Furthermore, pollakiuria was reported in 233 (2.66%) and 45 (0.84%) patients, respectively. Compared to placebo, a significantly higher risk of RTIs was observed with canagliflozin, ertugliflozin, empagliflozin, remogliflozin, dapagliflozin, and sotagliflozin, but not with luseogliflozin and ipragliflozin, regardless of gender. An increased risk of pollakiuria was observed with dapagliflozin [odds ratio (OR) 10.40, 95% confidence interval (CI) 1.60-157.94) and empagliflozin (OR 5.81, 95%CI 1.79-32.97). Remogliflozin (OR 6.45, 95%CI 2.18-27.79) and dapagliflozin (OR 1.33, 95%CI 1.10-1.62) were associated with an increased risk of urinary tract infections (UTIs). Instead, the included SGLT-2 inhibitors had a protective effect against acute kidney injury (AKI). No significant differences were found for hypovolemia, renal impairment or failure, fracture, diabetic ketoacidosis (DKA), amputation, and severe hypoglycemia between the SGLT-2 inhibitor and the placebo groups. Conclusion: In patients with T2DM, dapagliflozin was associated with an increased risk of RTIs, pollakiuria, and UTIs. Empagliflozin increased the risk of RTIs and pollakiuria. Remogliflozin increased the risk of UTIs. None of the SGLT-2 inhibitors showed a significant difference from the placebo for hypovolemia, renal impairment or failure, fracture, DKA, amputation, and severe hypoglycemia. The findings guide the selection of SGLT-2 inhibitors for patients with T2DM based on the patient's profiles to maximize safety. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022334644.

Restoration of intrinsic hand function by superficial radial nerve: an anatomical study.

BACKGROUND: The contralateral seventh cervical (cC7) nerve root transfer represents a cornerstone technique in treating total brachial plexus avulsion injury. Traditional cC7 procedures employ the entire ulnar nerve as a graft, which inevitably compromises its restorative capacity. OBJECTIVE: Our cadaveric study seeks to assess this innovative approach aimed at preserving the motor branch of the ulnar nerve (MBUN). This new method aims to enable future repair stages, using the superficial radial nerve (SRN) as a bridge connecting cC7 and MBUN. METHODS: We undertook a comprehensive dissection of ten adult cadavers, generously provided by the Department of Anatomy, Histology, and Embryology at Fudan University, China. It allowed us to evaluate the feasibility of our proposed technique. For this study, we harvested only the dorsal and superficial branches of the ulnar nerve, as well as the SRN, to establish connections between the cC7 nerve and recipient nerves (both the median nerve and MBUN). We meticulously dissected the SRN and the motor and sensory branches of the ulnar nerve. Measurements were made from the reverse point of the SRN to the wrist flexion crease and the coaptation point of the SRN and MBUN. Additionally, we traced the MBUN from distal to proximal ends, recording its maximum length. We also measured the diameters of the nerve branches and tallied the number of axons. RESULTS: Our modified approach proved technically viable in all examined limbs. The distances from the reverse point of the SRN to the wrist flexion crease were 8.24 ± 1.80 cm and to the coaptation point were 6.60 ± 1.75 cm. The maximum length of the MBUN was 7.62 ± 1.03 cm. The average axon diameters in the MBUN and the anterior and posterior branches of the SRN were 1.88 ± 0.42 mm、1.56 ± 0.38 mm、2.02 ± 0.41 mm,respectively. The corresponding mean numbers of axons were 1426.60 ± 331.39 and 721.50 ± 138.22, and 741.90 ± 171.34, respectively. CONCLUSION: The SRN demonstrated the potential to be transferred to the MBUN without necessitating a nerve graft. A potential advantage of this modification is preserving the MBUN's recovery potential.

Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis.

BACKGROUND: Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. METHODS: A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. RESULTS: The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. CONCLUSION: Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.

Conformational regulation and target-myristoyl switch of calcineurin B homologous protein 3.

Calcineurin B homologous protein 3 (CHP3) is an EF-hand Ca2+-binding protein involved in regulation of cancerogenesis, cardiac hypertrophy, and neuronal development through interactions with sodium/proton exchangers (NHEs) and signalling proteins. While the importance of Ca2+ binding and myristoylation for CHP3 function has been recognized, the underlying molecular mechanism remained elusive. In this study, we demonstrate that Ca2+ binding and myristoylation independently affect the conformation and functions of human CHP3. Ca2+ binding increased local flexibility and hydrophobicity of CHP3 indicative of an open conformation. The Ca2+-bound CHP3 exhibited a higher affinity for NHE1 and associated stronger with lipid membranes compared to the Mg2+-bound CHP3, which adopted a closed conformation. Myristoylation enhanced the local flexibility of CHP3 and decreased its affinity to NHE1 independently of the bound ion, but did not affect its binding to lipid membranes. The data exclude the proposed Ca2+-myristoyl switch for CHP3. Instead, a Ca2+-independent exposure of the myristoyl moiety is induced by binding of the target peptide to CHP3 enhancing its association to lipid membranes. We name this novel regulatory mechanism 'target-myristoyl switch'. Collectively, the interplay of Ca2+ binding, myristoylation, and target binding allows for a context-specific regulation of CHP3 functions.

Association between Coronary Artery Disease Reporting and Data System-recommended Post-Coronary CT Angiography Management and Clinical Outcomes in Patients with Stable Chest Pain from a Chinese Registry.

Background Coronary Artery Disease Reporting and Data System (CAD-RADS) was developed to standardize and optimize disease management in patients after coronary CT angiography (CCTA), but the impact of CAD-RADS management recommendations on clinical outcomes remains unclear. Purpose To retrospectively assess the association between the appropriateness of post-CCTA management according to CAD-RADS version 2.0 and clinical outcomes. Materials and Methods From January 2016 to January 2018, consecutive participants with stable chest pain referred for CCTA were prospectively included in a Chinese registry and followed for 4 years. Retrospectively, CAD-RADS 2.0 classification and the appropriateness of post-CCTA management were determined. Propensity score matching (PSM) was used to adjust for confounding variables. Hazard ratios (HRs) for a major adverse cardiovascular event (MACE), relative risks for invasive coronary angiography (ICA), and the corresponding number needed to treat were estimated. Results Of the 14 232 included participants (mean age, 61 years ± 13 [SD]; 8852 male), 2330, 2756, and 2614 were retrospectively categorized in CAD-RADS 1, 2, and 3, respectively. Only 26% of participants with CAD-RADS 1-2 disease and 20% with CAD-RADS 3 received appropriate post-CCTA management. After PSM, appropriate post-CCTA management was associated with lower risk of MACEs (HR, 0.34; 95% CI: 0.22, 0.51; P < .001), corresponding to a number needed to treat of 21 in CAD-RADS 1-2 but not CAD-RADS 3 (HR, 0.86; 95% CI: 0.49, 1.85; P = .42). Appropriate post-CCTA management was associated with decreased use of ICA in CAD-RADS 1-2 (relative risk, 0.40; 95% CI: 0.29, 0.55; P < .001) and 3 (relative risk, 0.33; 95% CI: 0.28, 0.39; P < .001), resulting in a number needed to treat of 14 and 2, respectively. Conclusion In this retrospective secondary analysis, appropriate disease management after CCTA according to CAD-RADS 2.0 was associated with lower risk of MACEs and more prudent use of ICA. ClinicalTrials.gov registration no. NCT04691037 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Leipsic and Tzimas in this issue.

Diagnostic Performance of Machine Learning-Derived Radiomics Signature of Pericoronary Adipose Tissue in Coronary Computed Tomography Angiography for Coronary Artery In-Stent Restenosis.

RATIONALE AND OBJECTIVES: Coronary inflammation can alter the perivascular fat phenotype. Hence, we aimed to assess the diagnostic performance of radiomics features of pericoronary adipose tissue (PCAT) in coronary computed tomography angiography (CCTA) for in-stent restenosis (ISR) after percutaneous coronary intervention. MATERIALS AND METHODS: In this study, 165 patients with 214 eligible vessels were included, and ISR was found in 79 vessels. After evaluating clinical and stent characteristics, peri-stent fat attenuation index, and PCAT volume, 1688 radiomics features were extracted from each peri-stent PCAT segmentation. The eligible vessels were randomly categorized into training and validation groups in a ratio of 7:3. After performing feature selection using Pearson's correlation, F test, and least absolute shrinkage and selection operator analysis, radiomics models and integrated models that combined selected clinical features and Radscore were established using five different machine learning algorithms (logistic regression, support vector machine, random forest, stochastic gradient descent, and XGBoost). Subgroup analysis was performed using the same method for patients with stent diameters of ≤ 3 mm. RESULTS: Nine significant radiomics features were selected, and the areas under the curves (AUCs) for the radiomics model and the integrated model were 0.69 and 0.79, respectively, for the validation group. The AUCs of the subgroup radiomics model based on 15 selected radiomics features and the subgroup integrated model were 0.82 and 0.85, respectively, for the validation group, which showed better diagnostic performance. CONCLUSION: CCTA-based radiomics signature of PCAT has the potential to identify coronary artery ISR without additional costs or radiation exposure.