Chinese medicine as a therapeutic option for pulmonary fibrosis: Clinical efficacies and underlying mechanisms.

ETHNIC PHARMACOLOGICAL RELEVANCE: Pulmonary fibrosis (PF) is a fibrotic interstitial lung disease caused by continuous damage and excessive repair of alveolar epithelial cells, the pathogenesis of which is not fully understood. At present, the incidence of PF has increased significantly around the world. The therapeutic arsenals against PF are relatively limited, with often poor efficacy and many adverse effects. As a conventional and effective therapeutic strategy, traditional Chinese medicine (TCM) has been widely applied in treating lung fibrosis for thousands of years in China. Due to the multi-ingredient, multi-target characteristics, Chinese medicines possess promising clinical benefits for PF treatment. AIM OF THIS REVIEW: This review aims to systematically analyze the clinical efficacy of Chinese medicine on PF, and further summarize the relevant mechanisms of Chinese medicine treating PF in preclinical studies, in order to provide a comprehensive insight into the beneficial effects of Chinese medicines on PF. METHODS: Eight major Chinese and English databases were searched from database inception up to October 2022, and all randomized clinical trials (RCTs) investigating the effects of Chinese medicine intervention on effectiveness and safety in the treatment of PF patients were included. Subsequently, preclinical studies related to the treatment of PF in Chinese medicine, including Chinese medicine compounds, Chinese herbal materials and extracts, and Chinese herbal formulas (CHFs) were searched through PubMed and Web of science to summarize the related mechanisms of Chinese medicine against PF. RESULTS: A total of 56 studies with 4019 patients were included by searching the relevant databases. Total clinical efficacy, pulmonary function, blood gas analysis, lung high resolution CT (HRCT), 6 min walk test (6-MWT), St George's Respiratory Questionnaire (SGRQ) scores, clinical symptom scores, TCM syndrome scores and other outcome indicators related to PF were analyzed. Besides, numerous preclinical studies have shown that many Chinese medicine compounds, Chinese herbal materials and extracts, and CHFs play a preventive and therapeutic role in PF by reducing oxidative stress, ameliorating inflammation, inhibiting epithelial-mesenchymal transition and myofibroblasts activation, and regulating autophagy and apoptosis. CONCLUSION: Chinese medicines show potential as supplements or substitutes for treating PF. And studies on Chinese medicines will provide a new approach to better management of PF.

Cheap and portable paper chip with terrific oxidase-like activity and SERS enhancement performance for SERS-colorimetric bimodal detection of intracellular glutathione.

Glutathione (GSH) acts a crucial role in the normal operation of manifold life activities and is closely bound up with many human diseases. Here, a SERS-colorimetric bimodal paper-based biosensor based on Mn-doped CDs/silver nanoparticles (Mn-CDs/AgNPs) has been fabricated for high-efficiency quantification of intracellular GSH. The Mn-CDs/AgNPs with fine oxidase-like characteristic and SERS enhancement ability has been assembled onto the Whatman filter paper (WFP) to cleverly fabricate paper chip (Mn-CDs/AgNPs@WFP) which can trigger the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue TMBox and simultaneously enhance the SERS signal of TMBox. However, the introduction of GSH inhibits the oxidation of TMB, leading to color fading of paper chip and diminishment of SERS signal. Considering this, the bimodal paper-based sensing platform can be exploited for SERS-colorimetric detection of GSH, manifesting excellent selectivity, reliable stability, and satisfactory precision. The detection limits of SERS and colorimetric detection modes are as low as 0.41 µM and 0.53 µM, respectively. Furthermore, this proposed bimodal biosensor has been successfully utilized for the determination of intracellular GSH and validated by commercial GSH assay kit, which provides a mighty and convenient tool for intracellular GSH detection and can boost future effort about exploitation of other multimode paper-based biosensors as well as promote their appliances in disease diagnosis.

An injectable carboxymethyl chitosan hydrogel scaffold formed via coordination bond for antibacterial and osteogenesis in osteomyelitis.

The intricate, hostile, and diverse nature of osteomyelitis (OM) poses a challenge for complete bacterial eradication and osteogenesis promotion via conventional treatment. Recently, functional hydrogels exhibiting antibacterial and osteogenic properties emerge as a promising avenue for OM wound healing in clinical practice. However, the preparation procedures and associated costs on cytokine and cell therapies for certain functional hydrogels can be complex and prohibitively expensive. In our research, a hybrid hydrogel dressing has been formulated utilizing carboxymethyl chitosan (CMCS) as the base material, and designed with inherent antibacterial, adhesion, proliferation, and differentiation characteristics, showing promise as a candidate for eradicating infection and promoting bone regeneration. The hybrid hydrogel is composed of interconnected networks of Fe3+-induced self-assembled CMCS and the antibacterial drug ciprofloxacin (CIP), resulting in excellent injectability and moldability. Notably, the CMCS/Fe3+/CIP hybrid hydrogel is capable of regulating antibacterial responses and stimulating osteogenesis in infected microenvironments without additional additives. This injectable antibacterial and osteogenic-promoting hydrogel establish a high-potential platform for low-cost, safe and effective treatment of OM by expediting the initial stages of infected bone wound repair.

Mn3O4 nanozymes prevent acetaminophen-induced acute liver injury by attenuating oxidative stress and countering inflammation.

Acetaminophen (APAP) overdose is steadily becoming the chief reason for drug-induced acute liver failure, yet limited treatment is currently clinically available. Considering that the mechanism of APAP-induced hepatotoxicity is inseparable from oxidative stress and inflammation, a biocompatible Mn3O4 nanozyme mimicking superoxide dismutase (SOD) and catalase (CAT) activities and possessing reactive oxygen species (ROS)-scavenging capacity and antiapoptotic properties, is reported herein as a promising nanodrug to treat APAP-induced liver injury (AILI). Possessing bioactive enzyme-like functions, Mn3O4 nanoparticles (NPs) can not only reduce the oxidative stress on the liver by decreasing ROS accumulation but also downregulate the infiltration of inflammatory macrophages that secrete proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6). Notably, the bifunctional Mn3O4 NPs mediate nuclear factor-erythroid 2 p45-related factor 2 signaling pathway activation and nuclear factor kappa B signaling pathway inhibition to effectively prevent the already fragile APAP-overdosed murine hepatocytes from being attacked again, thus mitigating hepatocyte apoptosis and alleviating APAP-induced liver damage. Thus, the Mn3O4 nanozyme (Mn3O4 NPs) evaluated in this study has potential preventive and therapeutic effects on AILI.

Co-precipitation of Cd with struvite during phosphorus recovery.

During the struvite recovery process, Cd, a hazardous metal commonly found in waste streams, can be sequestered by struvite. This study investigated the influence of Cd2+ on the precipitation of struvite. Quantitative X-ray diffraction (QXRD) results showed that the purity of struvite decreased from 99.1% to 73.6% as Cd concentration increased from 1 to 500 µM. Scanning electron microscopy (SEM) revealed a roughened surface of struvite, and X-ray photoelectron spectroscopy (XPS) analysis indicated that the peak area ratio of Cd-OH increased from 19.4% to 51.3%, while the area ratio of Cd-PO4 decreased from 86.6% to 48.7% as Cd concentrations increased from 10 to 500 µM. The findings suggested that Cd2+ disrupted the crystal growth of struvite, and mainly combined with -OH and -PO4 to form amorphous Cd-bearing compounds co-precipitated with struvite. Additionally, Mg-containing amorphous phases were formed by incorporating Mg2+ with -OH and -PO4 during struvite formation.

Buyang Huanwu decoction ameliorates bleomycin-induced pulmonary fibrosis in rats by attenuating the apoptosis of alveolar type II epithelial cells mediated by endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine, the pathogenesis of idiopathic pulmonary fibrosis (IPF) can be attributed to qi deficiency and blood stasis. Buyang Huanwu decoction (BHD), a representative Chinese herbal prescription for qi deficiency and blood stasis syndrome, is widely used to treat IPF in clinical practice. However, its potential mechanisms against IPF remain unclear. AIMS OF THE STUDY: This study was carried out to explore the therapeutic effects and underlying mechanisms of BHD on bleomycin (BLM)-induced pulmonary fibrosis in rats. MATERIALS AND METHODS: UPLC-MS/MS method was performed to identify the quality of BHD used in this study. Concurrently, a IPF rat model was established by single intratracheal injection of BLM. Pulmonary function test, H&E staining, Masson staining, hydroxyproline assay were conducted to evaluate the therapeutic effects of BHD on BLM-induced pulmonary fibrosis in rats, and the regulatory effect of BHD on endoplasmic reticulum stress (ERS)-mediated alveolar type II epithelial cells (AEC2s) apoptosis in rats was further investigated by TUNEL staining, Western blot, real-time fluorescence quantitative PCR and immunofluorescence co-staining to reveal the potential mechanisms of BHD against IPF. RESULTS: The UPLC-MS/MS analysis showed that the BHD we used complied with the relevant quality control standards. The data from animal experiments confirmed that BHD administration ameliorated BLM-induced pulmonary function decline, lung fibrotic pathological changes and collagen deposition in rats. Further mechanism study revealed that BHD increased the Bcl-2 protein expression, decreased the Bax protein expression and inhibited the cleavage of CASP3 via suppressing the activation of PERK-ATF4-CHOP pathway under continuous ERS, thereby alleviating BLM-induced AEC2s apoptosis of rats. CONCLUSION: This study demonstrated that BHD ameliorated BLM-induced pulmonary fibrosis in rats by suppressing ERS-mediated AEC2s apoptosis. Our findings can provide some fundamental research basis for the clinical application of BHD in the treatment of IPF.

Robust synthesis of free-standing films comprising conjugated microporous polymers nanotubes for water disinfection.

Water environmental pollution especially caused by bacteria, viruses and other microorganisms always would accelerate the spread of infectious diseases and has been one of the issues highly concerned by the World Health Organization for a long time. The development of novel antibacterial materials with high activity for water cleanness was of great importance for public health and ecological sustainable development. In this work, we developed two really free-standing conjugated microprous polymers (CMPs) film with large size and processibility by a simple and convenient solid surface-assisted polymerization between bromo- and aryl-acetylene monomers. With the solid interfacial orientation from silica nanofibers, the resulting CMPs film exhibited nanotube-liked morphology with BET surface area of 379.5 m2 g-1 and 480.1 m2 g-1. The introduction of antibacterial isocyanurate and acetanilide group into polymer skeleton brings the resulting CMPs film intrinsically antimicrobial capability and durability. The growth of E. coli can be completely inhibited by the resulting CMPs film even after several cycles. Our work was suggested to provide a new route for rational design of CMPs film or membrane with antibacterial activity for water treatment and sterilization.

Dynamic simulation and analysis of the influence of urethral morphological changes on urodynamics after benign prostatic hyperplasia surgery: A computational fluid dynamics study.

BACKGROUND AND OBJECTIVE: Computational fluid dynamics (CFD) technology has been widely used in medicine to simulate and analyse urine flow characteristics in urology. In previous studies, researchers have modelled the analysis with a simple circular urethra, ignoring the effect of the patient's true urethral morphology on the urinary flow rate. Moreover, the studies tended to be steady-state simulations rather than dynamic simulations. Therefore, this study is established a relatively realistic model of the posterior urethra based on MRI data combined with the urodynamic data of patients and analysed the urodynamic characteristics of the posterior urethra model after benign prostatic hyperplasia (BPH) surgery using a CFD dynamic simulation. METHODS: Based on clinical MRI data, a three-dimensional real urethral model was established for two patients with BPH after surgery. The boundary conditions were set according to the patients' real urodynamic data, and a Reynolds averaged Navier‒Stokes model was used for transient simulations. The dynamic simulation depicted the entire urination process, and the urine flow characteristics were studied under real urethral morphology after surgery. RESULTS: 1. By comparing the three-dimensional trajectory of urine and the vortex identification cloud map based on the Q criterion, we intuitively observed the distribution of the vortex in the model, and a 'gourd-shaped' urethra was more likely to generate a vortex than a 'funnel-shaped' urethra. 2. After surgery for BPH, the changes in the posterior urethral pressure were mainly concentrated in the urethral membrane, and the velocity increased while the pressure decreased. The curve of the posterior urethral pressure changes during urination was simulated and calculated. The posterior urethral pressure gradients of the two patients were 6.6 cmH2O and 5.26 cmH2O. CONCLUSIONS: The complete urinary discharge process can be dynamically simulated using CFD techniques. By comparing the simulation results, the posterior urethral morphology can have an important impact on the urinary flow characteristics. Determining the location of vortex generation can lay a foundation for personalized surgical plans for patients in the future. Furthermore, numerical simulations can provide a new method for the study of non-invasive posterior urethral pressure gradients.

Environmental stress during adolescence promotes depression-like behavior and endocrine abnormalities in rats.

OBJECTIVE: To assess the ability of environmental stress (ES) during adolescence on depression-like behaviors and endocrinology in rats. METHODS: Male and female Sprague-Dawley rats before or during puberty were divided into three groups: control group (CON), low-frequency ES group (LF), and high-frequency ES group (HF). ES included water/food deprivation and reversal of day and night. After 4 weeks of ES, the behavioral tests were performed. Plasma concentrations of hormones and peptides were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ES induced a significant decrease in sucrose preference value in female adolescent rats but not males. In prepubertal rats, the reductions in sucrose preference upon ES were observed without a sex-specific effect. Compared with the CON group, female adolescent rats showed a significant increase, while male adolescent rats showed a significant decrease in plasma corticosterone (CORT) after ES. Also, ES significantly increased plasma leptin in female and male adolescent rats. Moreover, ES significantly increased plasma cholecystokinin (CCK), neuropeptide Y (NPY), and testosterone (TS) levels in adolescent female rats but not in males. No significant differences were found in plasma progesterone and E2 among adolescent rats. The prepubertal male rats showed significant plasma E2 and TS increase after ES, while there were no significant differences between groups in plasma CORT, leptin, CCK, NPY, and progesterone. CONCLUSIONS: ES may cause depression-like behaviors in adolescent female rats. Our findings supplement the scientific basis for formulating strategies to treat and prevent adolescent depression.

Straw-based compost cultivation disproportionally contributes to the environmental persistence of antibiotic resistance from raw cattle manure to organic vegetables.

Cattle manure, is a reservoir of antimicrobial resistance genes, but the mechanisms by which they migrate from farm to table remain obscure. Here, we chose Agaricus bisporus as a model vegetable to examine such migration and characterized the resistome in 112 metagenomes covering samples from raw manure, composting substrates, rhizosphere, and surfaces of mushrooms. A total of 1864 resistance genes, representing 113 unique mechanisms of resistance, were identified. Monensin treatment on beef specifically enriched fecal resistance genes within Moraxellaceae, but this effect did not persist in downstream mushrooms. Interestingly, we found that resistance genes were significantly more enriched on mushroom surfaces when cultivated with corn-based compost compared to rice and wheat, likely a result of the disproportional propagation of Pseudomonadaceae and varied ability of lateral gene transfer. Importantly, our sequence alignment together with genome-centric analysis observed that 89 resistance genes, mainly conferring resistance to drug and biocide (20.22%) and mercury (19.10%), were shared across all types of samples, indicating an efficient transmission of resistance in food production. Moreover, co-occurrence of genes conferring resistance to different compounds frequently occurred in parallel with microbial migration. Together, we present the influences of antibiotic treatment and straw-based composting on resistome along the mushroom production chain (from manure to straw-based compost, rhizosphere of compost cultivated mushroom and surface of mushroom) and highlighted the risks of resistance genes migration.

A novel surgical strategy of three column osteotomy at non-lesioned area for correcting severe angular kyphosis due to Pott's disease: a retrospectively study.

Severe sharp angular kyphosis resulting from Pott's disease typically necessitates surgical intervention. The deployment of three-column osteotomy within the lesion and apical regions has been validated as an effective modality for the amelioration of angular kyphosis. Nonetheless, a propensity for residual kyphosis persists, accompanied by a significant perioperative risk profile. In pursuit of optimizing correctional outcomes and diminishing complication rates, we proposed an innovative surgical approach, utilizing osteotomy in the non-lesioned zones for the rectification of severe angular kyphosis associated with Pott's disease. This retrospective investigation encompasses 16 subjects who underwent this novel surgical tactic, involving osteotomies in non-lesioned vertebral segments, at our institution from 2016 to 2018. Radiographic measures, encompassing kyphotic angle and sagittal vertical axis (SVA), were documented at baseline and during terminal follow-up. Neurological status was evaluated via the American Spinal Injury Association (ASIA) grading system. Operative duration, volume of hemorrhage, and perioperative complications were systematically recorded. The cohort included 6 males and 10 females with an average age of 30.7 ± 11.41 years. Follow-up intervals spanned 24 to 42 months. Mean operative time and blood loss were 492 ± 127.3 min and 1791 ± 788.8 ml, respectively. The kyphotic angle improved from 97.6 ± 14.6° to 28.8 ± 18.70°. In cases with lumbar afflictions, vertebral restoration was achieved (L1-L5 and L2-S1). Initial mean SVA of 6.7 ± 3.58 cm was reduced to 3.3 ± 1.57 cm at follow-up. Neurological function enhancement was observed in six patients, while ten maintained baseline status. Complication rates, including wound infection and rod fracture at 12 months, were observed in approximately 11.8% of cases. Our findings suggest that the surgical strategy is both effective and safe for addressing severe angular kyphosis due to Pott's disease, contingent upon the expertise of the surgical unit.

Diosbulbin C, a novel active ingredient in Dioscorea bulbifera L. extract, inhibits lung cancer cell proliferation by inducing G0/G1 phase cell cycle arrest.

BACKGROUND: Despite the critical progress of non-small cell lung cancer (NSCLC) therapeutic approaches, the clinical outcomes remain considerably poor. The requirement of developing novel therapeutic interventions is still urgent. In this study, we showed for the first time that diosbulbin C, a natural diterpene lactone component extracted from traditional Chinese medicine Dioscorea bulbifera L., possesses high anticancer activity in NSCLC. METHODS: A549 and NCI-H1299 cells were used. The inhibitory effects of the diosbulbin C on NSCLC cell proliferation were evaluated using cytotoxicity, clone formation, EdU assay, and flow cytometry. Network pharmacology methods were used to explore the targets through which the diosbulbin C inhibited NSCLC cell proliferation. Molecular docking, qRT-PCR, and western blotting were used to validate the molecular targets and regulated molecules of diosbulbin C in NSCLC. RESULTS: Diosbulbin C treatment in NSCLC cells results in a remarkable reduction in cell proliferation and induces significant G0/G1 phase cell cycle arrest. AKT1, DHFR, and TYMS were identified as the potential targets of diosbulbin C. Diosbulbin C may inhibit NSCLC cell proliferation by downregulating the expression/activation of AKT, DHFR, and TYMS. In addition, diosbulbin C was predicted to exhibit high drug-likeness properties with good water solubility and intestinal absorption, highlighting its potential value in the discovery and development of anti-lung cancer drugs. CONCLUSIONS: Diosbulbin C induces cell cycle arrest and inhibits the proliferation of NSCLC cells, possibly by downregulating the expression/activation of AKT, DHFR, and TYMS.

The larger patellar tilt angle and lower intercondylar notch angle might increase posterior cruciate ligament injury risk: a retrospective comparative study.

BACKGROUND: Posterior cruciate ligament (PCL) injuries are common ligament injuries of the knee, and previous studies often focused on the associations between the morphology of the knee and PCL injuries. Studies on the correlation between PCL injuries and patellofemoral alignment are limited. METHODS: This retrospective study included 92 patients with PCL injured and 92 patients with PCL intact. Measurement parameters were compared between the two groups, including patellar tilt angle, congruence angle, patellar height, hip-knee-ankle angle, lateral trochlear inclination, femoral condyle ratio, bicondylar width, intercondylar notch width and index, notch angle, trochlear facet asymmetry, and trochlear sulcus depth and angle. Independent risk factors associated with PCL injuries were identified by logistic regression analyses. RESULTS: In the PCL injured group, the patellar tilt angle was significantly larger (13.19 ± 5.90° vs. 10.02 ± 4.95°, P = 0.04); the intercondylar notch angle was significantly lower (60.97 ± 7.83° vs. 67.01 ± 6.00°, P = 0.004); the medial and lateral femoral condyle ratio were significantly larger (0.63 ± 0.64 vs. 0.60 ± 0.56, P = 0.031; 0.65 ± 0.60 vs. 0.58 ± 0.53, P = 0.005) than in the PCL intact group. There were 11 patients with patellar dislocation in the PCL injured group, accounting for 12%. In these patients, the patellar height was higher (1.39 ± 0.17 vs. 1.09 ± 0.25, P = 0.009); the trochlear sulcus angle was larger (157.70 ± 8.7° vs. 141.80 ± 8.78°, P < 0.001); and the trochlear sulcus depth was shallower (3.10 ± 1.20mm vs. 5.11 ± 1.48mm, P = 0.003) than those in the patients without patellar dislocation. Multivariate analyses showed that patellar tilt angle (each increase 1 degree, OR = 1.14) and intercondylar notch angle (each increase 1 degree, OR = 0.90) were independent risk factors for PCL injuries. CONCLUSION: The patients with PCL injuries had larger patellar tilt angles, lower intercondylar notch angles, and longer posterior femoral condyles than patients with PCL intact. The larger patellar tilt angle and lower intercondylar notch angle might be risk factors for PCL injuries.

An updated meta-analysis of Chinese herbal medicine for the prevention of COVID-19 based on Western-Eastern medicine.

Background and aims: Chinese herbal medicine (CHM) was used to prevent and treat coronavirus disease 2019 (COVID-19) in clinical practices. Many studies have demonstrated that the combination of CHM and Western medicine can be more effective in treating COVID-19 compared to Western medicine alone. However, evidence-based studies on the prevention in undiagnosed or suspected cases remain scarce. This systematic review and meta-analysis aimed to investigate the effectiveness of CHM in preventing recurrent, new, or suspected COVID-19 diseases. Methods: We conducted a comprehensive search using ten databases including articles published between December 2019 and September 2023. This search aimed to identify studies investigating the use of CHM to prevent COVID-19. Heterogeneity was assessed by a random-effects model. The relative risk (RR) and mean differences were calculated using 95% confidence intervals (CI). The modified Jadad Scale and the Newcastle-Ottawa Scale (NOS) were employed to evaluate the quality of randomized controlled trials and cohort studies, respectively. Results: Seventeen studies with a total of 47,351 patients were included. Results revealed that CHM significantly reduced the incidence of COVID-19 (RR = 0.24, 95% CI = 0.11-0.53, p = 0.0004), influenza (RR = 0.37, 95% CI = 0.18-0.76, p = 0.007), and severe pneumonia exacerbation rate (RR = 0.17, 95% CI = 0.05-0.64, p = 0.009) compared to non-treatment or conventional control group. Evidence evaluation indicated moderate quality evidence for COVID-19 incidence and serum complement components C3 and C4 in randomized controlled trials. For the incidence of influenza and severe pneumonia in RCTs as well as the ratio of CD4+/CD8+ lymphocytes, the evidence quality was low. The remaining outcomes including the disappearance rate of symptoms and adverse reactions were deemed to be of very low quality. Conclusion: CHM presents a promising therapeutic option for the prevention of COVID-19. However, additional high-quality clinical trials are needed to further strengthen evidential integrity.

Recombinant Human Adenovirus Type 5 (H101) Intra-Tumor Therapy in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer: Genomic Profiling Relating to Clinical Efficacy.

Objective: Genomic profiles relating to H101 treatment-induced alterations are yet to be achieved. Here, we evaluated the impact of H101 via exome-sequencing approaches aiming to probe for potential biomarkers that are actionable in the treatment of persistent/recurrent/metastatic (P/R/M) cervical cancer. Methods: Whole exome sequencing (WES) was performd on paired pre- and post-H101 samples from 17 P/R/M cervical cancer patients who received serial intra-tumor injections of H101. Somatic mutations, including high-frequency mutations, microsatellite instability (MSI) status, tumor mutation burden (TMB), clonal evolution, and mutational signature were analyzed. Results: The median follow-up time after the H101 treatment was 14 months. Complete response was achieved in 9 patients, 3 patients achieved partial response, and 2 patients had stable disease, resulting in an objective response rate (ORR) of 70.6% (95% CI: 46.4%-96.7%). WES analysis showed no difference in treatment-related mutation characteristics, including non-synonymous-SNVs and TMB status. Patients with lower TMB were correlated with improved H101 response rates (P=0.044), whereas the same was not evident in high MSI (MSI-H) versus non-MSI-H patients (P=0.528). We observed a few high-frequency mutation genes (TTN, KMT2D, ALDOA, DNAH7, ADAP1, PTPN23, and THEMIS2) that probably carry functional importance in response to H101 treatment, among which KMT2D and ADAP1 mutations were associated with inferior progression-free survival (PFS) and/or overall survival (OS) (P<0.05). Notably, H101 treatment-induced accumulating subclones or clusters in primary tumors and some (Signature 2) were associated with shorter PFS. Conclusion: We conducted an unprecedented work via a WES-based approach and provided preliminary insights into H101 treatment-induced genetic aberrations in which some genes (TTN, KMT2D, ALDOA, DNAH7, ADAP1, PTPN23, and THEMIS2) could be considered potential therapeutic targets of H101-containing treatment in cervical carcinoma. Moreover, the therapy-associated characteristics such as clonal evolution and a mutational signature may warrant further evaluation of H101 in clinical settings for treating cervical carcinoma.

Deep Learning-Enabled MS/MS Spectrum Prediction Facilitates Automated Identification Of Novel Psychoactive Substances.

The market for illicit drugs has been reshaped by the emergence of more than 1100 new psychoactive substances (NPS) over the past decade, posing a major challenge to the forensic and toxicological laboratories tasked with detecting and identifying them. Tandem mass spectrometry (MS/MS) is the primary method used to screen for NPS within seized materials or biological samples. The most contemporary workflows necessitate labor-intensive and expensive MS/MS reference standards, which may not be available for recently emerged NPS on the illicit market. Here, we present NPS-MS, a deep learning method capable of accurately predicting the MS/MS spectra of known and hypothesized NPS from their chemical structures alone. NPS-MS is trained by transfer learning from a generic MS/MS prediction model on a large data set of MS/MS spectra. We show that this approach enables a more accurate identification of NPS from experimentally acquired MS/MS spectra than any existing method. We demonstrate the application of NPS-MS to identify a novel derivative of phencyclidine (PCP) within an unknown powder seized in Denmark without the use of any reference standards. We anticipate that NPS-MS will allow forensic laboratories to identify more rapidly both known and newly emerging NPS. NPS-MS is available as a web server at https://nps-ms.ca/, which provides MS/MS spectra prediction capabilities for given NPS compounds. Additionally, it offers MS/MS spectra identification against a vast database comprising approximately 8.7 million predicted NPS compounds from DarkNPS and 24.5 million predicted ESI-QToF-MS/MS spectra for these compounds.

Immunophilin FKB20-2 participates in oligomerization of Photosystem I in Chlamydomonas.

Photosystem I (PSI) is a sophisticated photosynthesis protein complex that fuels the light reaction of photosynthesis in algae and vascular plants. While the structure and function of PSI have been studied extensively, the dynamic regulation on PSI oligomerization and high light response is less understood. In this work, we characterized a high light responsive immunophilin gene FKB20-2 (FK506-binding protein 20-2) required for PSI oligomerization and high light tolerance in Chlamydomonas (Chlamydomonas reinhardtii). Biochemical assays and 77K fluorescence measurement showed that loss of FKB20-2 led to the reduced accumulation of PSI core subunits and abnormal oligomerization of PSI complexes and, particularly, reduced PSI intermediate complexes in fkb20-2. It is noteworthy that the abnormal PSI oligomerization was observed in fkb20-2 even under dark and dim light growth conditions. Co-immunoprecipitation, mass spectrometry, and yeast two-hybrid assay revealed that FKB20-2 directly interacted with the low molecular weight (LMW) PSI subunit PsaG, which might be involved in the dynamic regulation of PSI-LHCI supercomplexes. Moreover, abnormal PSI oligomerization caused accelerated photodamage to PSII in fkb20-2 under high light stress. Together, we demonstrated that immunophilin FKB20-2 affects PSI oligomerization probably by interacting with PsaG and plays pivotal roles during Chlamydomonas tolerance to high light.

The Role of Thoracic Vertebral Body Dosimetry in Minimizing Acute Hematologic Toxicities of Non-Small Cell Lung Cancer Patients Receiving Lung Radiotherapy and Immunotherapy.

INTRODUCTION: Hematologic toxicities (HTs) are among the most common toxicities of combined immunotherapy and radiotherapy (RT). It remains essential to prevent RT-induced HTs because they can cause treatment discontinuation (influencing antitumoral effects), and because lymphopenia might dampen the effects of immunotherapy. To date, there are no studies examining the impact of thoracic vertebral body (TVB) RT dose on HTs in non-small cell lung cancer (NSCLC) patients receiving combined lung RT and PD(L)-1 immunotherapy. METHODS: For standardization, all doses were reported as 2-Gy equivalents (EQD2). Mirroring publications prior to the immunotherapy era, TVB volumes referred to T1-T10 and specific dosimetric parameters (DmeanEQD2, V5EQD2‒V60EQD2) were analyzed. Logistic regression estimated associations between grade ≥3 HTs (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability (NTCP) models were constructed by logistic regression analysis modeling for HT3+. Receiver operating characteristic (ROC) analysis delineated TVB dosimetric thresholds, stratification of which was able to evaluate post-RT absolute lymphocyte count (ALC) and immunotherapy responses. Areas under the curve (AUCs) for NTCP models were corroborated by bootstrapping (optimism-corrected) methodology. RESULTS: In 132 patients, there were 26 (19.7%) instances of HT3+. On multivariate analysis, DmeanEQD2 and V5EQD2‒V20EQD2 associated with HT3+ (P<0.05 for all). The NTCP models illustrated a 50% probability of HT3+ at a DmeanEQD2=39.8 Gy, V5EQD2=87.4%, V10EQD2=77.0%, and V20EQD2=68.4%. ROC analysis delineated optimal thresholds of HT3+ with DmeanEQD2 ±30.2 Gy, V5EQD2 ±69.1%, V10EQD2 ±64.6%, and V20EQD2 ±53.5%. Patients treated with values above those cutoffs had over double the risk of HT3+, with significant differences in post-RT ALC and immunotherapy responses (P<0.05 for all). AUCs for each individual parameter ranged from 0.743 to 0.798, and combining all four aforementioned cutoffs into a ROC curve resulted in a qualitatively higher AUC (0.836). CONCLUSIONS: This hypothesis-generating work suggests that TVB dosimetry may equate with HT3+ in NSCLC patients undergoing combined lung RT/immunotherapy. Applying TVB dose constraints in this population could reduce HT3+ and avoid dampening of immunotherapy responses, but prospective validation is required.

Bayesian generative adversarial network emulator based end-to-end learning strategy of the probabilistic shaping for OAM mode division multiplexing IM/DD transmission.

Orbital angular momentum (OAM) mode division multiplexing (MDM) has emerged as a new multiplexing technology that can significantly increase transmission capacity. In addition, probabilistic shaping (PS) is a well-established technique that can increase the transmission capacity of an optical fiber to close to the Shannon limit. However, both the mode coupling and the nonlinear impairment lead to a considerable gap between the OAM-MDM channel and the conventional additive white Gaussian noise (AWGN) channel, meaning that existing PS technology is not suitable for an OAM-MDM intensity-modulation direct-detection (IM-DD) system. In this paper, we propose a Bayesian generative adversarial network (BGAN) emulator based on an end-to-end (E2E) learning strategy with probabilistic shaping (PS) for an OAM-MDM IM/DD transmission with two modes. The weights and biases of the BGAN emulator are treated as a probability distribution, which can be accurately matched to the stochastic nonlinear model of OAM-MDM. Furthermore, a BGAN emulator based on an E2E learning strategy is proposed to find the optimal probability distribution of PS for an OAM-MDM IM/DD system. An experiment was conducted on a 200 Gbit/s two OAM modes carrierless amplitude phase-32(CAP-32) signal over a 5 km ring-core fiber transmission, and the results showed that the proposed BGAN emulator outperformed a conventional CGAN emulator, with improvements in modelling accuracy of 29.3% and 26.3% for the two OAM modes, respectively. Moreover, the generalized mutual information (GMI) of the proposed E2E learning strategy outperformed the conventional MB distribution and the CGAN emulator by 0.31 and 0.33 bits/symbol and 0.16 and 0.2 bits/symbol for the two OAM modes, respectively. Our experimental results demonstrate that the proposed E2E learning strategy with the BGAN emulator is a promising candidate for OAM-MDM IM/DD optic fiber communication.

DCLRE1B promotes tumor progression and predicts immunotherapy response through METTL3-mediated m6A modification in pancreatic cancer.

BACKGROUND: DCLRE1B is a 5'-to-3' exonuclease, which is involved in repairing ICL-related DNA damage. DCLRE1B has been reported to cause poor prognosis in a variety of cancers. Nonetheless, there is no research on DCLRE1B's biological role in pan-cancer datasets. Thus, ascertaining the processes via which DCLRE1B modulates tumorigenesis was the goal of the extensive bioinformatics investigation of pan-cancer datasets in the present research. METHODS: In our research, employing internet websites and databases including TIMER, GEPIA, TISIDB, Kaplan-Meier Plotter, SangerBox, cBioPortal, and LinkedOmics, DCLRE1B-related data in numerous tumors were extracted. To ascertain the association among DCLRE1B expression, prognosis, genetic changes, and tumor immunity, the pan-cancer datasets were examined. The DCLRE1B's biological roles in pancreatic cancer cells were ascertained by employing wound healing, in vitro CCK-8, and MeRIP-qPCR assays. RESULT: According to the pan-cancer analysis, in numerous solid tumors, DCLRE1B upregulation was observed. Expression of DCLRE1B was found to be substantially related to the cancer patients' prognoses. Similarly, expression of DCLRE1B exhibited substantial association with immune cells in several cancer types. DCLRE1B expression correlated with immune checkpoint (ICP) gene expression and impacted immunotherapy sensitivity. According to in vitro trials, DCLRE1B promoted PC cells' proliferation and migration capacities. Also, according to GSEA enrichment analysis, DCLRE1B might participate in the JAK-STAT signaling pathway, which was confirmed by western blotting. In addition, we also found that the downregulation of DCLRE1B may be regulated by METTL3-mediated m6A modification. CONCLUSIONS: In human cancer, the overexpression of DCLRE1B was generally observed, which aided cancer onset and advancement via a variety of processes comprising control of the immune cells' tumor infiltration. According to this study's findings, in a few malignant tumors, DCLRE1B is a candidate immunotherapeutic and prognostic biomarker.