Diabetes and aortic dissection: unraveling the role of 3-hydroxybutyrate through mendelian randomization.

BACKGROUND: In observational and experimental studies, diabetes has been reported as a protective factor for aortic dissection. 3-Hydroxybutyrate, a key constituent of ketone bodies, has been found to favor improvements in cardiovascular disease. However, whether the protective effect of diabetes on aortic dissection is mediated by 3-hydroxybutyrate is unclear. We aimed to investigate the causal effects of diabetes on the risk of aortic dissection and the mediating role of 3-hydroxybutyrate in them through two-step Mendelian randomization. MATERIALS AND METHODS: We performed a two-step Mendelian randomization to investigate the causal connections between diabetes, 3-hydroxybutyrate, and aortic dissection and calculate the mediating effect of 3-hydroxybutyrate. Publicly accessible data for Type 1 diabetes, Type 2 diabetes, dissection of aorta and 3-hydroxybutyrate were obtained from genome-wide association studies. The association between Type 1 diabetes and dissection of aorta, the association between Type 2 diabetes and dissection of aorta, and mediation effect of 3-hydroxybutyrate were carried out separately. RESULTS: The IVW method showed that Type 1 diabetes was negatively associated with the risk of aortic dissection (OR 0.912, 95% CI 0.836-0.995), The weighted median, simple mode and weighted mode method showed consistent results. The mediated proportion of 3-hydroxybutyrate on the relationship between Type 1 diabetes and dissection of aorta was 24.80% (95% CI 5.12-44.47%). The IVW method showed that Type 2 diabetes was negatively associated with the risk of aortic dissection (OR 0.763, 95% CI 0.607-0.960), The weighted median, simple mode and weighted mode method showed consistent results. 3-Hydroxybutyrate does not have causal mediation effect on the relationship between Type 2 diabetes and dissection of aorta. CONCLUSION: Mendelian randomization study revealed diabetes as a protective factor for dissection of aorta. The protective effect of type 1 diabetes on aortic dissection was partially mediated by 3-hydroxybutyrate, but type 2 diabetes was not 3-hydroxybutyrate mediated.

Trends in the global, regional, and national burden of testicular cancer from 1990 to 2019: an observational study with 30-year global data.

BACKGROUND: Testicular cancer (TC) is currently the most common malignancy in young and middle-aged men. A comprehensive assessment of TC burden is in lack. METHOD: Global incidence, deaths, and disability-adjusted life-years (DALYs) of TC from 1990 to 2019 were obtained. Estimated annual percentage change (EAPC) was calculated to quantify trends in TC changes during the period. Relationships between disease burden and age, sociodemographic index (SDI) levels, human development index (HDI) were further analyzed. RESULTS: Globally, incident cases of TC more than doubled from 1990 to 2019, together with an increasing of global age-standardized incidence rates (ASIR) of TC from 1.9 to 2.8. The age-standardized deaths rates (ASDR) remained stable from 0.31 to 0.28. The similar results were reflected in the disability-adjusted life-years (DALYs). In 2019, the highest ASIR were found in Southern Latin America, Central Europe and Western Europe. Analogously, the highest ASDR were found in Southern Latin America followed by Central Latin America and Central Europe. The burden of incidence increased with SDI, appropriately reached a peak at about 0.78, and then declined. Similarly, the burden of deaths increased with SDI, met a maximum at about 0.7. CONCLUSIONS: From 1990 to 2019, the ASIR of TC has increased significantly, while the ASDR has been relatively stable and slightly decreased. The disease burden of TC is shifting to regions and countries with moderate to high levels of development. TC remains a rapidly growing global health problem, and new changes in TC burden should be considered when formulating new TC control policies.

Computational Screening of Promising Deep-Ultraviolet Light Emitters.

Deep-ultraviolet (DUV) light sources are technologically highly important, but DUV light-emitting materials are extremely rare; AlN and its alloys are the only materials known so far, significantly limiting the chemical and structural spaces for materials design. Here, we perform a high-throughput computational search for DUV light emitters based on a set of carefully designed screening criteria relating to the sophisticated electronic structure. In this way, we successfully identify 5 promising material candidates that exhibit comparable or higher radiative recombination coefficients than AlN, including BeGeN2, Mg3NF3, KCaBr3, KHS, and RbHS. Further, we unveil the unique features in the atomic and electronic structures of DUV light emitters and elucidate the fundamental genetic reasons why DUV light emitters are extremely rare. Our study not only guides the design and synthesis of efficient DUV light emitters but also establishes the genetic nature of ultrawide-band-gap semiconductors in general.

Development of postoperative bronchopleural fistula after neoadjuvant immunochemotherapy in non-small cell lung cancer: case reports and review of the literature.

BACKGROUND: The advent of immune checkpoint inhibitors has dramatically changed the treatment paradigm for advanced non-small-cell lung cancer (NSCLC). Due to the complexity and diversity of stage III disease, the inclusion of immune checkpoint inhibitors (ICIs) in neoadjuvant treatment regimens is also required. However, immune-related adverse events (irAEs) limit the application of ICIs to a certain extent. Bronchopleural fistula (BPF) is a serious and fatal complication after pneumonectomy that is rarely reported, especially in patients who accept neoadjuvant immunotherapy or chemoimmunotherapy. CASE PRESENTATION: Herein, we reported four patients with postoperative BPF who received a neoadjuvant regimen of sintilimab plus chemotherapy. Postoperative BPF occurred in the late stage in three patients; one patient underwent bronchoscopic fistula repair, and the fistula was closed well after surgery, and the other two patients gradually recovered within 1-2 months after symptomatic treatment with antibiotics. One patient with BPF after left pneumonectomy died of respiratory failure due to pulmonary infection. We also reviewed the literature on the development of postoperative BPF in patients receiving immuno-neoadjuvant therapy to discuss the clinical process further, postoperative pathological changes, as well as risk factors of BPF patients. CONCLUSIONS: Central type lung cancer with stage III may be the risk factors of BPF in cases of neoadjuvant immunochemotherapy for lung cancers patients.

Association between Body Mass Index and Medication-Overuse Headache among Individuals with Migraine: A Cross-Sectional Study.

INTRODUCTION: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. METHODS: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd Edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. RESULTS: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.11; p = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤23.9 kg/m2), those with Q4 (BMI ≥28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04-3.17; p = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03-1.24), less than high school (OR, 1.08; 95%, 1.01-1.15), without depression (OR, 1.06; 95%, 1.01-1.12), and without anxiety (OR, 1.06; 95%, 1.01-1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. CONCLUSION: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

IL-6/STAT3 axis is hijacked by GCRV to facilitate viral replication via suppressing type â IFN signaling.

Grass carp reovirus (GCRV) infections and hemorrhagic disease (GCHD) outbreaks are typically seasonally periodic and temperature-dependent, yet the molecular mechanism remains unclear. Herein, we depicted that temperature-dependent IL-6/STAT3 axis was exploited by GCRV to facilitate viral replication via suppressing type Ⅰ IFN signaling. Combined multi-omics analysis and qPCR identified IL-6, STAT3, and IRF3 as potential effector molecules mediating GCRV infection. Deploying GCRV challenge at 18 °C and 28 °C as models of resistant and permissive infections and switched to the corresponding temperatures as temperature stress models, we illustrated that IL-6 and STAT3 expression, genome level of GCRV, and phosphorylation of STAT3 were temperature dependent and regulated by temperature stress. Further research revealed that activating IL-6/STAT3 axis enhanced GCRV replication and suppressed the expression of IFNs, whereas blocking the axis impaired viral replication. Mechanistically, grass carp STAT3 inhibited IRF3 nuclear translocation via interacting with it, thus down-regulating IFNs expression, restraining transcriptional activation of the IFN promoter, and facilitating GCRV replication. Overall, our work sheds light on an immune evasion mechanism whereby GCRV facilitates viral replication by hijacking IL-6/STAT3 axis to down-regulate IFNs expression, thus providing a valuable reference for targeted prevention and therapy of GCRV.

Integrated Full-Length Transcriptomics and Metabolomics Reveal Glycosyltransferase Involved in the Biosynthesis of Flavonol Glycosides in Laportea bulbifera.

Many species of the Urticaceae family are important cultivated fiber plants that are known for their economic and industrial values. However, their secondary metabolite profiles and associated biosynthetic mechanisms have not been well-studied. Using Laportea bulbifera as a model, we conducted widely targeted metabolomics, which revealed 523 secondary metabolites, including a unique accumulation of flavonol glycosides in bulblet. Through full-length transcriptomic and RNA-seq analyses, the related genes in the flavonoid biosynthesis pathway were identified. Finally, weighted gene correlation network analysis and functional characterization revealed four LbUGTs, including LbUGT78AE1, LbUGT72CT1, LbUGT71BX1, and LbUGT71BX2, can catalyze the glycosylation of flavonol aglycones (kaempferol, myricetin, gossypetin, and quercetagetin) using UDP-Gal and UDP-Glu as the sugar donors. LbUGT78AE1 and LbUGT72CT1 showed substrate promiscuity, whereas LbUGT71BX1 and LbUGT71BX2 exhibited different substrate and sugar donor selectivity. These results provide a genetic resource for studying Laportea in the Urticaceae family, as well as key enzymes responsible for the metabolism of valuable flavonoid glycosides.

Endoscopic papillectomy for synchronous adenoma of the major and minor duodenal papilla.

OBJECTIVES: Synchronous adenomas of the major and minor duodenal papilla are seldom reported. The aim of this study was to describe the characteristics of synchronous major and minor papilla adenomas and to evaluate the safety and efficacy of endoscopic papillectomy (EP) for the management of the disease. METHODS: Consecutive patients who underwent endoscopy for synchronous major and minor papilla adenomas from January 1, 2013 to August 31, 2023 were analyzed retrospectively. Patients' characteristics, clinical manifestations, laboratory, imaging and endoscopic findings were collected. RESULTS: The nine patients with synchronous major and minor papilla adenomas had an average age of 50.78 ± 10.70 years. The diameter of major and minor papilla adenomas was 12.11 ± 3.41 mm and 6.11 ± 1.05 mm, respectively. Most major papilla adenomas had R0 horizontal margins (n = 8), while R0 vertical margins were achieved in all patients. While minor papilla adenomas were resected with both R0 horizontal and vertical margins in all patients. Post-EP bleeding was observed in one patient, which was classified as mild. Post-EP hyperamylasemia and pancreatitis was observed in two and four patients, respectively; the latter consisted of three with mild pancreatitis and one with severe pancreatitis. No perforation was observed. The mean follow-up duration was 9.22 ± 5.99 months. Histologically confirmed recurrence at the resection site was detected in one patient at 3 months after the procedure. CONCLUSIONS: Synchronous major and minor papilla adenomas may not be as rare as previously speculated. EP may be an effective and safe alternative modality for their management.

MGFmiRNAloc:predicting miRNA Subcellular Localization Using Molecular Graph Feature and Convolutional Block Attention Module.

MiRNA has distinct physiological functions at various cellular locations. However, few effective computational methods for predicting the subcellular location of miRNA exist, thereby leaving considerable room for improvement. Accordingly, our study proposes the MGFmiRNAloc simplified molecular input line entry system (SMILES) format as a new approach for predicting the subcellular localization of miRNA. Additionally, the graphical convolutional network (GCN) technique was employed to extract the atomic nodes and topological structure of a single base, thereby constructing RNA sequence molecular map features. Subsequently, the channel attention and spatial attention mechanisms (CBAM) were designed to mine deeper for more efficient information. Finally, the prediction module was used to detect the subcellular localization of miRNA. The 10-fold cross-validation and independent test set experiments demonstrate that MGFmiRNAloc outperforms the most sophisticated methods. The results indicate that the new atomic level feature representation proposed in this study could overcome the limitations of small samples and short miRNA sequences, accurately predict the subcellular localization of miRNAs, and be extended to the subcellular localization of other sequences.

The implications of single-cell RNA-seq analysis in prostate cancer: unraveling tumor heterogeneity, therapeutic implications and pathways towards personalized therapy.

In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments in the current era, particularly the emerging integration of single-cell and spatiotemporal transcriptomics, have enabled a detailed molecular comprehension of the complex regulation of cell fate. The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine. Currently, single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors. Starting from the perspective of RNA sequencing technology, this review outlined the significance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, encompassing preclinical medicine and clinical applications. We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies, as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis, treatment, and drug resistance characteristics of prostate cancer. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer. Furthermore, we explore the potential clinical applications stemming from other single-cell technologies in this review, paving the way for future research in precision medicine.

Rapid characterization of non-volatile phenolic compounds reveals the reliable chemical markers for authentication of traditional Chinese medicine Xiang-ru among confusing Elsholtzia species.

The aerial parts of Mosla chinensis Maxim. and Mosla chinensis cv. 'Jiangxiangru' (MCJ) are widely utilized in traditional Chinese medicine (TCM), known collectively as Xiang-ru. However, due to clinical effectiveness concerns and frequent misidentification, the original plants have increasingly been substituted by various species within the genera Elsholtzia and Mosla. The challenge in distinguishing between these genera arises from their similar morphological and metabolic profiles. To address this issue, our study introduced a rapid method for metabolic characterization, employing high-resolution mass spectrometry-based metabolomics. Through detailed biosynthetic and chemometric analyses, we pinpointed five phenolic compounds-salviaflaside, cynaroside, scutellarein-7-O-D-glucoside, rutin, and vicenin-2-among 203 identified compounds, as reliable chemical markers for distinguishing Xiang-ru from closely related Elsholtzia species. This methodology holds promise for broad application in the analysis of plant aerial parts, especially in verifying the authenticity of aromatic traditional medicinal plants. Our findings underscore the importance of non-volatile compounds as dependable chemical markers in the authentication process of aromatic traditional medicinal plants.

[Blocking Effects of Foliar Conditioners on Cadmium, Arsenic, and Lead Accumulation in Wheat Grain in Compound-contaminated Farmland].

Heavy metal contamination of soil has become a hot issue of social concern due to its impact on the safety of agricultural products in recent years. Wheat is one of the most dominant staple food crops worldwide and has become a major source of toxic metals in human diets. Foliar application was considered to be a more efficient and economical method of heavy metal remediation. Field experiments were carried out in Cd-, As-, and Pb-contaminated farmland soils. The effects of foliar conditioners on the accumulation of Cd, As, and Pb in wheat grains were investigated after being sprayed with Zn (0.2% ZnSO4), Mg (0.4% MgSO4), and Mn (0.2% MnSO4) separately and in combination. Thus, the effective foliar conditioners were selected to block the accumulation of Cd, As, and Pb in wheat grains grown in combined heavy metal-contaminated farmland in north China. The results showed that, compared with that in the control, the Cd, As, and Pb contents in wheat grains of the Zn+Mg+Mn foliar treatment were significantly decreased by 18.96%, 23.87%, and 51.31%, respectively, and TFgrain/straw decreased by 14.62%, 27.73%, and 47.70%, respectively. Thus, spraying the compound foliar conditioner of Zn+Mg+Mn could effectively reduce heavy metal accumulation in wheat grains through inhibition translocation of those metals from stem leaves to grain. In addition, the results indicated that Cd and As were mainly distributed at the central endosperm (34.08%-37.08%), whereas Pb was primarily distributed at the pericarp and seed coat (27.78%) of the wheat grain. Compared with that in the control, spraying the compound foliar conditioner of Zn+Mg+Mn extremely decreased Cd and As accumulation in the aleurone layer of the wheat grain by 81.10% and 82.24%, respectively. Except for the pericarp, seed coat, and central endosperm layers, the Pb content in each grain layer was dramatically decreased by 42.85% to 91.15%. There was only a significant negative correlation between heavy metal content and Zn content in the aleurone layer (P2) of wheat flour. In summary, the accumulation of Cd, As, and Pb in wheat grains, especially in the aleurone layer, could be effectively reduced by foliar conditioner application at the jointing, booting, and early filling stages of wheat, separately. Furthermore, besides the foliar treatment, removing wheat bran to reduce Cd contamination in wheat grains is highly recommended to ensure the safe production of wheat.

Multi-omics analysis reveals promiscuous O-glycosyltransferases involved in the diversity of flavonoid glycosides in Periploca forrestii (Apocynaceae).

Flavonoid glycosides are widespread in plants, and are of great interest owing to their diverse biological activities and effectiveness in preventing chronic diseases. Periploca forrestii, a renowned medicinal plant of the Apocynaceae family, contains diverse flavonoid glycosides and is clinically used to treat rheumatoid arthritis and traumatic injuries. However, the mechanisms underlying the biosynthesis of these flavonoid glycosides have not yet been elucidated. In this study, we used widely targeted metabolomics and full-length transcriptome sequencing to identify flavonoid diversity and biosynthetic genes in P. forrestii. A total of 120 flavonoid glycosides, including 21 C-, 96 O-, and 3 C/O-glycosides, were identified and annotated. Based on 24,123 full-length coding sequences, 99 uridine diphosphate sugar-utilizing glycosyltransferases (UGTs) were identified and classified into 14 groups. Biochemical assays revealed that four UGTs exhibited O-glycosyltransferase activity toward apigenin and luteolin. Among them, PfUGT74B4 and PfUGT92A8 were highly promiscuous and exhibited multisite O-glycosylation or consecutive glycosylation activities toward various flavonoid aglycones. These four glycosyltransferases may significantly contribute to the diversity of flavonoid glycosides in P. forrestii. Our findings provide a valuable genetic resource for further studies on P. forrestii and insights into the metabolic engineering of bioactive flavonoid glycosides.

Tumor-Intrinsic Galectin-3 Suppresses Melanoma Metastasis.

Melanoma poses a poor prognosis with high mortality rates upon metastasis. Exploring the molecular mechanisms governing melanoma progression paves the way for developing novel approaches to control melanoma metastasis and ultimately enhance patient survival rates. Extracellular galectin-3 (Gal-3) has emerged as a pleiotropic promoter of melanoma metastasis, exerting varying activities depending on its interacting partner. However, whether intracellular Gal-3 promotes melanoma aggressive behavior remains unknown. In this study, we explored Gal-3 expression in human melanoma tissues as well as in murine melanoma models to examine its causal role in metastatic behavior. We found that Gal-3 expression is downregulated in metastatic melanoma tissues compared with its levels in primary melanomas. Enforced silencing of Gal-3 in melanoma cells promoted migration, invasion, colony formation, in vivo xenograft growth, and metastasis and activated canonical oncogenic signaling pathways. Moreover, loss of Gal-3 in melanoma cells resulted in upregulated the expression of the prometastatic transcription factor NFAT1 and its downstream metastasis-associated proteins, matrix metalloproteinase 3, and IL-8. Overall, our findings implicate melanoma intracellular Gal-3 as a major determinant of its metastatic behavior and reveal a negative regulatory role for Gal-3 on the expression of NFAT1 in melanoma cells.

Comparing efficacies of different exercises on androgen deprivation therapy adverse effects in prostate cancer patients: a network meta-analysis.

INTRODUCTION: Previous studies showed exercise have efficacies for androgen deprivation therapy (ADT) adverse effects. To compare the efficacies of different exercises on ADT adverse effects, we conducted the network meta-analysis (NMA). METHODS: Literature retrieval was performed in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL). 19 studies (1184 participants) were included. All analyses were performed in R 4.1.2 or RevMan 5.4.1. RESULTS: NMA results showed that compared with the control group, both aerobic + resistance training (ART) (MD = 5.92, 95% CI [0.38; 11.46]) and resistance exercise (RE) (MD = 5.62, 95% CI [2.70; 8.55]) improved quality of life (QoL). ART (P score: 0.72) may have superiority over RE (P score: 0.7). ART (MD = -10.89, 95% CI [-17.67; -4.11]) significantly improved the performance of 400-m test. RE could significantly improve leg strength (MD = 118, 95% CI [78.75; 157.25]) and chest strength (MD = 13.30 [4.07; 22.53]). RE ranked first for strength improvements of leg and chest. CONCLUSION: ART showed better efficacy for the QoL, and significantly improved the performance of 400-m test. RE might be superior for the strengths of leg and chest. ART may be appropriate for patients with less significant muscle strength decline but also other adverse effects of ADT, such as decreased cardiopulmonary function.

Sample size determination for interval estimation of the prevalence of a sensitive attribute under non-randomized response models.

A sufficient number of participants should be included to adequately address the research interest in the surveys with sensitive questions. In this paper, sample size formulas/iterative algorithms are developed from the perspective of controlling the confidence interval width of the prevalence of a sensitive attribute under four non-randomized response models: the crosswise model, parallel model, Poisson item count technique model and negative binomial item count technique model. In contrast to the conventional approach for sample size determination, our sample size formulas/algorithms explicitly incorporate an assurance probability of controlling the width of a confidence interval within the pre-specified range. The performance of the proposed methods is evaluated with respect to the empirical coverage probability, empirical assurance probability and confidence width. Simulation results show that all formulas/algorithms are effective and hence are recommended for practical applications. A real example is used to illustrate the proposed methods.

Small cell lung cancer with dermatomyositis: a case report.

Dermatomyositis represents an autoimmune disorder characterized by notable skin and muscular manifestations. The annual incidence of dermatomyositis stands at approximately (5~10)/1 million individuals. Notably, patients with malignant tumors exhibit an elevated risk of developing dermatomyositis compared to the general population. However, in cases where dermatomyositis co-occurs with malignancy, the efficacy of hormone therapy alone tends to be suboptimal. Moreover, reports addressing the correlation between tumor treatment and the management of dermatomyositis are scarce. A 60-year-old male patient presented with dermatomyositis, initially manifesting through symptoms such as rash, muscle weakness, and dysphagia. Despite undergoing standard hormone therapy, there was no discernible improvement in the dermatomyositis symptoms. Considering the patient's concomitant troublesome cough, further investigations were conducted, including CT, PET-CT, and pathological biopsy. These assessments confirmed the diagnosis of limited-stage small cell lung cancer (T1cN3M0 IIIB). Notably, in this patient, dermatomyositis was suspected to be a paraneoplastic syndrome associated with small cell lung cancer. Standard chemotherapy and radiotherapy were employed to treat the small cell lung cancer, resulting in partial remission after two treatment cycles. As the malignancy regressed, a notable improvement in dermatomyositis symptoms was observed, subsequently leading to a gradual reduction in the prescribed hormone dosage. In conclusion, we present a comprehensive case study of dermatomyositis as a paraneoplastic syndrome throughout the treatment process. The response to tumor therapy coincided with the amelioration of dermatomyositis symptoms. Therefore, diligent malignancy screening is imperative for patients diagnosed with dermatomyositis.

Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage IIIA/IIIB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial.

Background: Some locally advanced (IIIA/IIIB) non-small cell lung cancers (NSCLCs) might have surgical options available. However, information regarding the effectiveness of neoadjuvant immunotherapy for potentially resectable IIIA/IIIB NSCLC is limited. The intent of this investigation was to offer a more favourable alternative to the standard approach of chemoradiotherapy (concurrent or sequential chemoradiotherapy) followed by immunotherapy for potentially resectable stage III NSCLC. Methods: This prospective, single-arm, phase 2 clinical trial (NCT04326153) enrolled treatment-naïve patients with 'potentially resectable' IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection upon initial diagnosis. The study period was between March 20, 2020, and August 20, 2021. Patients underwent neoadjuvant chemoimmunotherapy (sintilimab combined with nab-paclitaxel and carboplatin) for two to three cycles prior to surgical resection of the lung carcinoma and systematic nodal dissection within 30-45 days. The primary endpoint was the 2-year disease-free survival (DFS) rate, with secondary endpoints encompassing major pathological response (MPR) rate, pathological complete response (pCR) rate, overall survival, objective response rate (ORR), downstaging rate, and adverse events (AEs). Tumour immune cell infiltrates, identified via immunohistochemistry, were assessed as biomarkers at baseline and after surgery. Findings: Among 30 patients who received neoadjuvant chemoimmunotherapy, 20 underwent complete resection. The disease control rate was 96.7% (95% CI: 90.3%-99.99%), with an ORR of 55% (95% CI: 37.2%-72.8%) and a downstaging rate of 80% (95% CI: 65.7%-94.3%). In the subgroup of 20 patients who underwent surgery, the MPR rate was 65% (95% CI: 43.3%-82.9%), and the pCR rate was 40% (95% CI: 21.2%-46.3%). The 2-year DFS rate in the surgical group was 75% (95% CI 56%-94%). Notably, the MPR group demonstrated significantly prolonged DFS compared with the non-MPR group (p = 0.00024). A significant increase in pretreatment CD8 expression correlated with improved DFS (p = 0.00019). Three patients (10%) experienced grade 3 or higher immune-related AEs-one case of grade 3 elevated myocardial enzymes, one case of grade 3 interstitial pneumonia, and one case of grade 5 bronchopleural fistula. Interpretation: Neoadjuvant immunotherapy markedly enhanced the rate of pathological response and 2-year DFS in patients with potentially resectable IIIA/IIIB NSCLC. Overexpression of CD8 before treatment (H score≥3) may serve as a potential predictive biomarker for DFS. Consequently, the treatment landscape for potentially resectable IIIA/IIIB NSCLC could undergo changes. Funding: This study did not receive any financial support.

The Dirac equation across the horizons of the 5D Myers-Perry geometry: separation of variables, radial asymptotic behaviour and Hamiltonian formalism.

We analytically extend the 5D Myers-Perry metric through the event and Cauchy horizons by defining Eddington-Finkelstein-type coordinates. Then, we use the orthonormal frame formalism to formulate and perform separation of variables on the massive Dirac equation, and analyse the asymptotic behaviour at the horizons and at infinity of the solutions to the radial ordinary differential equation (ODE) thus obtained. Using the essential self-adjointness result of Finster-Röken and Stone's formula, we obtain an integral spectral representation of the Dirac propagator for spinors with low masses and suitably bounded frequency spectra in terms of resolvents of the Dirac Hamiltonian, which can in turn be expressed in terms of Green's functions of the radial ODE.

Versatile CYP98A enzymes catalyse meta-hydroxylation reveals diversity of salvianolic acids biosynthesis.

Salvianolic acids (SA), such as rosmarinic acid (RA), danshensu (DSS), and their derivative salvianolic acid B (SAB), etc. widely existed in Lamiaceae and Boraginaceae families, are of interest due to medicinal properties in the pharmaceutical industries. Hundreds of studies in past decades described that 4-coumaroyl-CoA and 4-hydroxyphenyllactic acid (4-HPL) are common substrates to biosynthesize SA with participation of rosmarinic acid synthase (RAS) and cytochrome P450 98A (CYP98A) subfamily enzymes in different plants. However, in our recent study, several acyl donors and acceptors included DSS as well as their ester-forming products all were determined in SA-rich plants, which indicated that previous recognition to SA biosynthesis is insufficient. Here, we used Salvia miltiorrhiza, a representative important medicinal plant rich in SA, to elucidate the diversity of SA biosynthesis. Various acyl donors as well as acceptors are catalysed by SmRAS to form precursors of RA and two SmCYP98A family members, SmCYP98A14 and SmCYP98A75, are responsible for different positions' meta-hydroxylation of these precursors. SmCYP98A75 preferentially catalyses C-3' hydroxylation, and SmCYP98A14 preferentially catalyses C-3 hydroxylation in RA generation. In addition, relative to C-3' hydroxylation of the acyl acceptor moiety in RA biosynthesis, SmCYP98A75 has been verified as the first enzyme that participates in DSS formation. Furthermore, SmCYP98A enzymes knockout resulted in the decrease and overexpression leaded to dramatic increase of SA accumlation. Our study provides new insights into SA biosynthesis diversity in SA-abundant species and versatility of CYP98A enzymes catalytic preference in meta-hydroxylation reactions. Moreover, CYP98A enzymes are ideal metabolic engineering targets to elevate SA content.