Search

Bostrichid beetles are well-known pests of wood and wood products in the world. The Madagascar almond tree, Terminalia neotaliala Capuron (Myrtales: Combretaceae), is uniquely layered and has been introduced and cultivated across several continents, where it is commonly used in urban landscape projects. To assess the damage caused by bostrichid beetles to T. neotaliala, the damage status of T. neotaliala, the classification of bostrichid beetles, and their vertical distribution on host plants were investigated. The primary site of infestation by bostrichid beetles on T. neotaliala living trees was the lateral branches in the fields with the damage symptoms, including unseasonable yellowed leaves, branch breakage, or eventual death of the entire lateral branch. The total percentage of attacked plants was 9.53%. Significant positive correlations existed between the percentage of attacked plants and the diameter at breast height and crown width, but not with the tree height. The percentage of damage by bostrichid beetles to T. neotaliala reached level I and level II over the 2-year observation. A total of nine species from four genera of Bostrichidae infested the T. neotaliala, i.e., Sinoxylon eucerum Lesne, S. flabrarius Lesne, S. japonicum Lesne, S. mangiferae Chûjô, S. pygmaeum Lesne, S. tignarium Lesne, Xylocis tortilicornis Lesne, Xylodectes ornatus (Lesne), and Xylopsocus capucinus (Fabricius). There were no distinct differences in the total number of Bostrichidae species on different crown layers of T. neotaliala, and no significant correlations between the total number of species and individuals, and the number of individuals of each species and the measurements of plants (i.e., diameter at breast height, crown width, and tree height). Our findings provide essential information for the development, implementation and monitoring of effective control strategies against bostrichid beetles on T. neotaliala., Competing Interests: Declarations. Ethical approval: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2025. Sociedade Entomológica do Brasil.)

Selective C-C bond cleavage and transformation of organic small molecules to create products of increased value are one of the central goals in organic chemistry. In this study, we have developed a novel TEMPO-mediated ring-opening α,β-difunctionalization of cyclopropyl alcohols with organic azides to prepare structurally important 4-keto-1,2,3-triazoles under metal- and additive-free conditions. This protocol not only provides a straightforward and efficient method for the synthesis of 4-keto-functionalized 1,2,3-triazoles in one pot but also accomplishes the goal of constructing α,β-double C-N bonds via the ring opening of cyclopropyl alcohols for the first time. Additionally, the application of the skeletons of drugs and natural products and the synthesis of Kv1.5 channel blocker 4u further demonstrate the synthetic potential and practicability of this strategy.

A novel reaction of cyclic and acyclic secondary amines with in situ-generated allene intermediate species from nitro-substituted donor-acceptor cyclopropanes is reported. In the presence of a simple inorganic base, NaOH, tetrasubstituted enamine derivatives can be obtained in moderate to excellent yields. The reaction is operationally easy, features mild reaction conditions and simple inorganic bases, and is free of transition metals.

Water contamination poses a significant challenge to environmental and public health, necessitating sustainable wastewater treatment solutions. Adsorption is one of the most widely used techniques for purifying water, as it effectively removes contaminants by transferring them from the liquid phase to a solid surface. Bio-based hydrogel adsorbents are gaining popularity in wastewater treatment due to their versatility in fabrication and modification methods, which include blending, grafting, and crosslinking. Owning to their unique structure and large surface area, modified hydrogels containing reactive groups like amino, hydroxyl, and carboxyl, or functionalized hydrogels with inorganic nanoparticles particularly graphene nanomaterials, have demonstrated promising adsorption capabilities for both inorganic and organic contaminants. Bio-based hydrogels have excellent physicochemical properties and are non-toxic, environmentally friendly, and biodegradable, making them extremely effective at removing contaminants like heavy metal ions, dyes, pharmaceutical pollutants, and organic micropollutants. The versatility of hydrogels allows for various forms to be used, such as films, beads, and nanocomposites, providing flexibility in handling different contaminants like dyes, radionuclides, and heavy metals. Additionally, researchers also have shown the potential for recycling and regenerating post-treatment hydrogels. This approach not only addresses the challenges of wastewater treatment but also offers sustainable and effective solutions for mitigating water pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient's sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1- 13 C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Catalase (CAT), a ubiquitous enzyme in all oxygen-exposed organisms, effectively decomposes hydrogen peroxide (H 2 O 2 ), a harmful by-product, into water and oxygen, mitigating oxidative stress and cellular damage, safeguarding cellular organelles and tissues. Therefore, CAT plays a crucial role in maintaining cellular homeostasis and function. Owing to its pivotal role, CAT has garnered considerable interest. However, many challenges arise when used, especially in multiple practical processes. "Immobilization", a widely-used technique, can help improve enzyme properties. CAT immobilization offers numerous advantages, including enhanced stability, reusability, and facilitated downstream processing. This review presents a comprehensive overview of CAT immobilization. It starts with discussing various immobilization mechanisms, support materials, advantages, drawbacks, and factors influencing the performance of immobilized CAT. Moreover, the review explores the application of the immobilized CAT in various industries and its prospects, highlighting its essential role in diverse fields and stimulating further research and investigation. Furthermore, the review highlights some of the world's leading companies in the field of the CAT industry and their substantial potential for economic contribution. This review aims to serve as a discerning, source of information for researchers seeking a comprehensive cutting-edge overview of this rapidly evolving field and have been overwhelmed by the size of publications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Hemifacial spasm (HFS) is a debilitating disease characterized by involuntary tonic and clonic contractions of muscles innervated by the facial nerve. Botulinum toxin A (BTX-A) is the first-line option and the most effective medical treatment for HFS. The objective of this study was to evaluate the effect of BTX-A therapy on the physical and mental health of HFS patients., Methods: Participants included 65 HFS patients and 65 matched healthy controls in the study. Cornell Medical Index (CMI) self-assessment questionnaire was used to detect the psychological health of all participants. Local injection of BTX-A was applied, and the Cohen hierarchical criteria were employed to stratify the degree of spasticity, further evaluating the efficacy of BTX-A before and two months after treatment in HFS patients. The HFS patients at two months post-treatment were re-evaluated by CMI self-assessment questionnaire, and the evaluated factors of these patients were compared with those of patients before treatment., Results: The scores of somatization, depression, anxiety, inadaptation, sensitivity, anger, tension, M-R, and total scores in the HFS group were significantly higher than those in the control group (all P<0.05). Two months post-treatment, among 65 HFS patients who received with BTX-A treatment, 42 (64.6%) were completely relieved, 16 (24.6%) were significantly relieved, 7 (10.8%) were partially relieved, and 0 (0%) cases were invalid, and the total effective rate was 89.2%. Two months after BTX-A treatment, the scores of somatization, tension, anxiety, depression, sensitivity, M-R and total scores of patients with HFS were lower than those before treatment (all P<0.05)., Conclusions: Patients with HFS are often accompanied by somatization, anger, inadaptation, sensitivity, anxiety, depression, and tension. BTX-A can not only alleviate the symptoms of HFS, but also improve the somatization, tension, anxiety, depression, and sensitivity., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine receptor in rhabdomyosarcoma (RMS), are already in the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy of the co-stimulatory and targeting properties of a FGFR4 CAR. We replace the CD8 hinge and transmembrane domain and the 4-1BB co-stimulatory domain with those of CD28. The resulting CARs display enhanced anti-tumor activity in several RMS xenograft models except for an aggressive tumour cell line, RMS559. By searching for a direct target of the RMS core-regulatory transcription factor MYOD1, we identify another surface protein, CD276, as a potential target. Bicistronic CARs (BiCisCAR) targeting both FGFR4 and CD276, containing two distinct co-stimulatory domains, have superior prolonged persistent and invigorated anti-tumor activities compared to the optimized FGFR4-specific CAR and the other BiCisCAR with the same 4-1BB co-stimulatory domain. Our study thus lays down the proof-of-principle for a CAR T-cell therapy targeting both FGFR4 and CD276 in RMS., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To understand the health status of solar greenhouse workers, to provide scientific basis for the development of occupational high incidence diseases prevention and control strategies. Methods: In July 2019, a random cluster sampling method was used to select 245 workers engaged in solar greenhouse vegetable cultivation in Daba Village, Jingyuan County, Baiyin City, Gansu Province as the solar greenhouse operation group. Matched by gender, age, marital status, body mass index (BMI), 282 people from adjacent Shaliang Village who did not engage in solar greenhouse operation were selected as the control group. Field investigation and health examination were carried out among the study subjects. The general situation, facial features examination results, ophthalmic examination results, bone and joint examination results and skin examination results were compared between the two groups. And the multiple logistic regression analysis was used to analyze the influencing factors of abnormal bone and joint examination (upper limbs, lower limbs, hands and spine bone joints) in study subjects. Results: There were statistically significant differences in smoking age and alcohol consumption between the two groups ( P <0.001). Compared with the control group, the abnormal detection rates of nose examination, throat examination, slit lamp examination, conjunctival examination, lower limb bone joint examination, hand bone joint examination, spine examination, head and neck skin examination, trunk skin examination, upper limb skin examination, and lower limb skin examination in the solar greenhouse operation group were higher, and the differences were statistically significant (χ(2)=11.53, 7.94, 9.92, 27.93, 79.32, 81.42, 9.43, 6.79, 9.76, 4.34, 8.29, P <0.05). Multivariate logistic regression analysis showed that after adjusting for gender, age, marital status, education level, BMI, compared with the control group, solar greenhouse operation was a risk factor for abnormal bone and joint examination ( OR =1.178, 95% CI : 1.151-2.143, P =0.001) . Conclusion: Solar greenhouse operation has a certain harmful effect on health of workers, and solar greenhouse workers have an increased risk of abnormal diseases of upper limbs, lower limbs, hands and spine bone joints.

Background: Nasal trauma presents a risk of foreign body invasion into the nasal cavity. However, in the early treatment stage of nasal trauma, patients and doctors are not always aware of possible foreign body invasion, resulting in delayed detection. We describe the case of an adult patient admitted to the hospital due to left nasal congestion accompanied by yellow, purulent, and bloody discharge., Case Summary: Consultation with the patient revealed a history of nasal trauma 30 years prior that did not receive thorough examinations and imaging during treatment, resulting in a glass fragment retained in the nasal cavity adjacent to the orbit. After admission, computerized tomography (CT) confirmed the presence of the foreign body in the patient's left nasal-maxillary sinus. The nasal foreign body led to symptoms such as chronic sinusitis, nasal polyps, fungal infection, and deviated nasal septum. The foreign body was successfully removed by nasal endoscopy, polypectomy, sinus fungal removal, left middle turbinate conchoplasty, fenestration via the right inferior meatus, nasal endoscopic maxillary sinus cystectomy, and septolplasty. The operation was successful and without any complications., Conclusion: CT scans should be performed in addition to necessary debridement sutures to avoid possible foreign body invasion during nasal trauma. Surgical planning should be tailored to the patient's specific situation. The surgical method should be carefully selected, and sufficient preparation should be undertaken before the surgery to avoid possible displacement of the nasal foreign body., Competing Interests: Conflict-of-interest statement: All authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Neopetrotaurines A-C ( 1 - 3 ), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a Neopetrosia sp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond 1 H- 13 C and 1 H- 15 N heteronuclear correlation data. Thus, the application of LR-HSQMBC and HMBC NMR experiments optimized to detect 4- and 5-bond long-range 1 H- 13 C heteronuclear correlations facilitated the structure elucidation of these unusual taurine-bridged marine metabolites. Neopetrotaurines A-C ( 1 - 3 ) showed significant inhibition of transcription driven by the oncogenic fusion protein PAX3-FOXO1, which is associated with alveolar rhabdomyosarcoma, and cytotoxic activity against PAX3-FOXO1-positive cell lines.

Objective: To investigate the safety and efficacy of the TRIANGLE operation after neoadjuvant chemotherapy in locally advanced pancreatic cancer(LAPC). Methods: This study is a retrospective case series analysis. Between January 2020 and December 2022, a total of 103 patients were diagnosed as LAPC who underwent neoadjuvant chemotherapy at the Pancreas Center, the First Affiliated Hospital of Nanjing Medical University. Among them, 26 patients (25.2%) underwent the TRIANGLE operation. There were 15 males and 11 females,with a age of (59±7) years (range: 49 to 74 years). The pre-treatment serum CA19-9( M (IQR)) was 248.8(391.6)U/ml (range: 0 to 1 428 U/ml),and the serum carcinoembryonic antigen was 4.1(3.8)μg/L(range: 1.4 to 13.4 μg/L). The neoadjuvant chemotherapy regimens included: mFOLFIRINOX regimen in 6 cases(23.1%), GnP regimen in 14 cases(53.8%), and mFOLFIRINOX+GnP regimen in 6 cases(23.1%). The follow-up duration extended until June 2023 or until the occurrence of the patient's death or loss to follow-up. The Kaplan-Meier method was employed to estimate the 1-year and 3-year overall survival rates. Results: After neoadjuvant chemotherapy,CA19-9 levels decreased by 92.3(40.1)%(range:2.1% to 97.7%). Evaluation of the response to treatment revealed 13 cases(50.0%) of stable disease,11 cases(42.3%) of partial response,and 2 cases(7.7%) of complete response. The surgical operation consisted of 12 cases(46.2%) of pancreaticoduodenectomy,12 cases(46.2%) of distal pancreatectomy,and 2 cases(7.7%) of total pancreatectomy. Margin determination was based on the "standardised pathology protocol" and the "1 mm" principle. No R2 and R1(direct) resections were observed,while the R0 resection rate was 61.5%(16/26), and the R1(1 mm) resection rate was 38.5%(10/26).The R1(1 mm) resection rates for the anterior margin,posterior margin,transected margin,portal vein groove margin,and uncinate margin were 23.1%(6/26),19.2%(5/26),12.5%(3/24),2/14, and 1/12, respectively. The overall postoperative complication rate was 57.8%(15/26),with major complications including grade B/C pancreatic fistula 25.0%(6/24,excluding 2 cases of total pancreatectomy),delayed gastric emptying in 23.1%(6/26),wound complications 11.5%(3/26),postoperative hemorrhage 7.7%(2/26), chylous fistula 7.7%(2/26) and bile fistula 3.8%(1/26). No reoperation was performed during the perioperative period(<90 days). One patient died on the 32 nd day postoperatively due to a ruptured pseudoaneurysm. A total of 25 patients were followed up,with a follow-up time of 21(24)months(range: 8 to 42 months). During the follow-up period,8 cases(32.0%) died due to tumor recurrence and metastasis,while 17 patients(68.0%) remained alive,including 11 cases of disease-free survival,5 cases of distant metastasis,and 1 case of local recurrence. The overall survival rates at 1- and 3-year after the initiation of neoadjuvant chemotherapy were 95.8% and 58.9%, respectively. The overall survival rates at 1- and 3-year after surgery were 77.7% and 57.8%, respectively. Conclusion: Performing pancreatoduodenectomy according to the Heidelberg triangle protocol in LAPC patients after neoadjuvant chemotherapy might increase the R0 resection rate without increasing perioperative mortality or the incidence of major postoperative complications.

An one-pot organo- and iodine sequential catalysis strategy for reactions of amides with pyrazole-based primary amines was described to synthesize chiral α-amino amides with a quaternary stereocenter. This methodology exhibited strong asymmetric induction, resulting in a typical enantiomeric excess value exceeding 99% and diastereoselectivity up to >99:1 dr. Moreover, the reaction was conducted without the use of any metals or strong bases.

Background: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear., Methods: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival., Results: We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3)., Conclusions: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive T cell treatment for RMS. The 3A11 CAR T cells induced robust cytokine production and cytotoxicity against RMS cell lines in vitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR T cells, confirming the selectivity of 3A11 CAR T cells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR T cells are persistent in vivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR T cell therapy targeting FGFR4 to treat patients with RMS., Competing Interests: Declaration of interests J. Khan, R.J.O., D.S.D., and A.T.C. are inventors on international patent application no. PCT/US2016/052496. The 3A11 CAR sequence is in this patent application (see https://patents.justia.com/patent/11078286) filed on September 19, 2016, titled “Monoclonal antibodies specific for fibroblast growth factor receptor 4 (FGFR4) and methods of their use.”, (Published by Elsevier Inc.)

The tumor-specific chromosomal translocation product, PAX3::FOXO1, is an aberrant fusion protein that plays a key role for oncogenesis in the alveolar subtype of rhabdomyosarcoma (RMS). PAX3::FOXO1 represents a validated molecular target for alveolar RMS and successful inhibition of its oncogenic activity is likely to have significant clinical applications. Even though several PAX3::FOXO1 function-based screening studies have been successfully completed, a directly binding small-molecule inhibitor of PAX3::FOXO1 has not been reported. Therefore, we screened small-molecule libraries to identify compounds that were capable of directly binding to PAX3::FOXO1 protein using surface plasmon resonance technology. Compounds that directly bound to PAX3::FOXO1 were further evaluated in secondary transcriptional activation assays. We discovered that piperacetazine can directly bind to PAX3::FOXO1 protein and inhibit fusion protein-derived transcription in multiple alveolar RMS cell lines. Piperacetazine inhibited anchorage-independent growth of fusion-positive alveolar RMS cells but not embryonal RMS cells. On the basis of our findings, piperacetazine is a molecular scaffold upon which derivatives could be developed as specific inhibitors of PAX3::FOXO1. These novel inhibitors could potentially be evaluated in future clinical trials for recurrent or metastatic alveolar RMS as novel targeted therapy options., Significance: RMS is a malignant soft-tissue tumor mainly affecting the pediatric population. A subgroup of RMS with worse prognosis harbors a unique chromosomal translocation creating an oncogenic fusion protein, PAX3::FOXO1. We identified piperacetazine as a direct inhibitor of PAX3::FOXO1, which may provide a scaffold for designing RMS-specific targeted therapy., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Single-cell RNA sequencing (scRNA-seq) is an important tool for understanding disease pathophysiology, including airway diseases. Currently, the majority of scRNA-seq studies in airway diseases have used invasive methods (airway biopsy, surgical resection), which carry inherent risks and thus present a major limitation to scRNA-seq investigation of airway pathobiology. Bronchial brushing, where the airway mucosa is sampled using a cytological brush, is a viable, less invasive method of obtaining airway cells for scRNA-seq. Here we describe the development of a rapid and minimal handling protocol for preparing single-cell suspensions from bronchial brush specimens for scRNA-seq. Our optimized protocol maximizes cell recovery and cell quality and facilitates large-scale profiling of the airway transcriptome at single-cell resolution.

Objective: To investigate the clinical efficacy of distal pancreatectomy with celiac axis resection(DP-CAR). Methods: A total of 89 consecutive patients (50 males and 39 females) who were diagnosed with pancreatic body cancer and underwent DP-CAR in Pancreas Center,First Affiliated Hospital of Nanjing Medical University between September 2013 and June 2022 were retrospectively reviewed. There were 50 males and 39 females,with age( M (IQR)) of 63(12) years(range:43 to 81 years). Perioperative parameters,pathology results and follow-up data of these patients were analyzed, χ 2 or Fisher's test for categorical data while the Wilcoxon test for quantitative data. Survival results were estimated by the Kaplan-Meier survival method. Results: Among 89 cases,cases combined with portal vein-superior mesenteric vein or organ resection accounted for 22.5% (20/89) and 42.7% (38/89),respectively. The operative time,blood loss and postoperative hospital stay were 270 (110) minutes,300 (300) ml and 13 (10) days,respectively. The overall morbidity rate was 67.4% (60/89) while the major morbidity was 11.2% (10/89). The increase rate in transient liver enzymes was 42.7% (38/89),3.4% (3/89) for liver failure,53.9% (48/89) for clinically relevant postoperative pancreatic fistula,1.1% (1/89) for bile leak,3.4% (3/89) for chylous leak of grade B and C,11.2% (10/89) for abdominal infection,9.0% (8/89) for postoperative hemorrhage of grade B and C,4.5% (4/89) for delayed gastric emptying,6.7% (6/89) for deep vein thrombosis,3.4% (3/89) for reoperation,4.5% (4/89)for hospital mortality,7.9% (7/89) for 90-day mortality. The pathological type was pancreatic cancer for all 89 cases and pancreatic ductal adenocarcinoma made up 92.1% (82/89). The tumor size was 4.8(2.0) cm, ranging from 1.5 to 12.0 cm. The number of lymph nodes harvested was 14 (13)(range:2 to 33),with a positive lymph node rate of 13.0% (24.0%). The resection R0 rate was 30.0% (24/80) and the R1 (<1 mm) rate was 58.8% (47/80). The median overall survival time was 21.3 months (95% CI : 15.6 to 24.3) and the median disease-free survival time was 19.1 months (95% CI : 11.7 to 25.1). The overall survival at 1-year and 2-year were 69.60% and 39.52%. The median survival time of 58 patients with adjuvant chemotherapy was 24.3 months (95% CI : 17.8 to 32.3) while that of 13 patients without any kind of adjuvant therapy was 8.4 months (95% CI : 7.3 to 22.3). Seven patients accepted neoadjuvant chemotherapy and there was no significant morbidity among them,with a resection rate of R0 of 5/7. Conclusion: DP-CAR is safe and feasible for selective cases,which could be more valuable in improving long-term survival when combined with (neo) adjuvant therapy.

Introduction: Postoperative comprehensive treatment has become increasingly important in recent years. This study was to repair tissue defects resulting from the removal of diseased tissue and to eliminate or inhibit the recurrence and metastasis of residual tumors under the condition of reducing the systemic side effects of chemotherapeutic drugs. To address these challenges, multifunctional scaffolds based local drug delivery systems will be a promising solution. Methods: An optimal drug-loaded scaffold material PHBV-mPEG5k (PP5) was prepared, which is biocompatible, hydrophilic and biodegradable. Furthermore, this material showed to promote bone healing, and could be conveniently prepared into porous scaffold by freeze-drying the solution. By means of introducing melatonin (MT) into the porous surfaces, the MT loaded PP5 scaffold with desirable sustained release ability was successfully prepared. The effectiveness of the MT loaded PP5 scaffold in promoting bone repair and anti-tumor properties was evaluated through both in vivo and in vitro experiments. Results and Discussion: The MT loaded PP5 scaffold is able to achieve the desired outcome of bone tissue repair and anti-bone tumor properties. Furthermore, our study demonstrates that the PP5 scaffold was able to enhance the anti-tumor effect of melatonin by improving cellular autophagy, which provided a therapeutic strategy for the comprehensive postoperative treatment of osteosarcoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Dai, Chen, Guo, Wang and Wei.)

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

CD19 chimeric antigen receptor T-cell therapy (CD19-CAR) has changed the treatment landscape and outcomes for patients with pre-B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, primary nonresponse (PNR), sustained CD19+ disease, and concurrent expansion of CD19-CAR occur in 20% of the patients and is associated with adverse outcomes. Although some failures may be attributable to CD19 loss, mechanisms of CD19-independent, leukemia-intrinsic resistance to CD19-CAR remain poorly understood. We hypothesize that PNR leukemias are distinct compared with primary sensitive (PS) leukemias and that these differences are present before treatment. We used a multiomic approach to investigate this in 14 patients (7 with PNR and 7 with PS) enrolled in the PLAT-02 trial at Seattle Children's Hospital. Long-read PacBio sequencing helped identify 1 PNR in which 47% of CD19 transcripts had exon 2 skipping, but other samples lacked CD19 transcript abnormalities. Epigenetic profiling discovered DNA hypermethylation at genes targeted by polycomb repressive complex 2 (PRC2) in embryonic stem cells. Similarly, assays of transposase-accessible chromatin-sequencing revealed reduced accessibility at these PRC2 target genes, with a gain in accessibility of regions characteristic of hematopoietic stem cells and multilineage progenitors in PNR. Single-cell RNA sequencing and cytometry by time of flight analyses identified leukemic subpopulations expressing multilineage markers and decreased antigen presentation in PNR. We thus describe the association of a stem cell epigenome with primary resistance to CD19-CAR therapy. Future trials incorporating these biomarkers, with the addition of multispecific CAR T cells targeting against leukemic stem cell or myeloid antigens, and/or combined epigenetic therapy to disrupt this distinct stem cell epigenome may improve outcomes of patients with B-ALL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: To evaluate the positive rate of left posterior lymph nodes of the superior mesenteric artery (14cd-LN) in patients undergoing pancreaticoduodenectomy for pancreatic head carcinoma,to analyze the impact of 14cd-LN dissection on lymph node staging and tumor TNM staging. Methods: The clinical and pathological data of 103 consecutive patients with pancreatic cancer who underwent pancreaticoduodenectomy at Pancreatic Center,the First Affiliated Hospital of Nanjing Medical University from January to December 2022 were analyzed,retrospectively. There were 69 males and 34 females,with an age( M (IQR))of 63.0 (14.0) years (range:48.0 to 86.0 years). The χ 2 test and Fisher's exact probability method was used for comparison of the count data between the groups,respectively. The rank sum test was used for comparison of the measurement data between groups. Univariate and multivariate Logistic regression analyzes were used for the analysis of risk factors. Results: All 103 patients underwent pancreaticoduodenectomy successfully using the left-sided uncinate process and the artery first approach. Pathological examination showed pancreatic ductal adenocarcinoma in all cases. The location of the tumors was the pancreatic head in 40 cases,pancreatic head-uncinate in 45 cases,and pancreatic head-neck in 18 cases. Of the 103 patients,38 cases had moderately differentiated tumor and 65 cases had poorly differentiated tumor. The diameter of the lesions was 3.2 (0.8) cm (range:1.7 to 6.5 cm),the number of lymph nodes harvested was 25 (10) (range:11 to 53),and the number of positive lymph nodes was 1 (3) (range:0 to 40). The lymph node stage was stage N0 in 35 cases (34.0%),stage N1 in 43 cases (41.7%),and stage N2 in 25 cases (24.3%). TNM staging was stage ⅠA in 5 cases (4.9%),stage ⅠB in 19 cases (18.4%),stage ⅡA in 2 cases (1.9%),stage ⅡB in 38 cases (36.9%),stage Ⅲ in 38 cases (36.9%),and stage Ⅳ in 1 case (1.0%). In 103 patients with pancreatic head cancer,the overall positivity rate for 14cd-LN was 31.1% (32/103),and the positive rates for 14c-LN and 14d-LN were 21.4% (22/103) and 18.4% (19/103),respectively. 14cd-LN dissection increased the number of lymph nodes ( P <0.01) and positive lymph nodes ( P <0.01). As a result of the 14cd-LN dissection,the lymph node stage was changed in 6 patients,including 5 patients changed from N0 to N1 and 1 patient changed from N1 to N2. Similarly,the TNM stage was changed in 5 patients,including 2 patients changed from stage ⅠB to ⅡB,2 patients changed from stage ⅡA to ⅡB,and 1 patient changed from stage ⅡB to Ⅲ. Tumors located in the pancreatic head-uncinate ( OR =3.43,95% CI :1.08 to 10.93, P =0.037) and the positivity of 7,8,9,12 LN ( OR =5.45,95% CI :1.45 to 20.44, P =0.012) were independent risk factors for 14c-LN metastasis; while tumors with diameter >3 cm ( OR =3.93,95% CI :1.08 to 14.33, P =0.038) and the positivity of 7,8,9,12 LN ( OR =11.09,95% CI :2.69 to 45.80, P =0.001) were independent risk factors for 14d-LN metastasis. Conclusion: Due to its high positive rate in pancreatic head cancer,dissection of 14cd-LN during pancreaticoduodenectomy should be recommended,which can increase the number of lymph nodes harvested,provide a more accurate lymph node staging and TNM staging.

Objective: The hypersensitivity of the kidney makes it susceptible to hypoxia injury. The involvement of neutrophil extracellular traps (NETs) in renal injury resulting from hypobaric hypoxia (HH) has not been reported. In this study, we aimed to investigate the expression of NETs in renal injury induced by HH and the possible underlying mechanism., Methods: A total of 24 SD male rats were divided into three groups (n=8 each): normal control group, hypoxia group and hypoxia+pyrrolidine dithiocarbamate (PDTC) group. Rats in hypoxia group and hypoxia+PDTC group were placed in animal chambers with HH which was caused by simulating the altitude at 7000 meters (oxygen partial pressure about 6.9 kPa) for 7 days. PDTC was administered at a dose of 100 mg/kg intraperitoneally once daily for 7 days. Pathological changes of the rat renal tissues were observed under a light microscope; the levels of serum creatinine (SCr), blood urea nitrogen (BUN), cell-free DNA (cf-DNA) and reactive oxygen species (ROS) were measured; the expression levels of myeloperoxidase (MPO), citrullinated histone H3 (cit-H3), B-cell lymphoma 2 (Bcl-2), Bax, nuclear factor kappa B (NF-κB) p65 and phospho-NF-κB p65 (p-NF-κB p65) in rat renal tissues were detected by qRT-qPCR and Western blotting; the localization of NF-κB p65 expression in rat renal tissues was observed by immunofluorescence staining and the expression changes of NETs in rat renal tissues were detected by multiplex fluorescence immunohistochemical staining., Results: After hypoxia, the expression of NF-κB protein in renal tissues was significantly increased, the levels of SCr, BUN, cf-DNA and ROS in serum were significantly increased, the formation of NETs in renal tissues was significantly increased, and a large number of tubular dilatation and lymphocyte infiltration were observed in renal tissues. When PDTC was used to inhibit NF-κB activation, NETs formation in renal tissue was significantly decreased, the expression level of Bcl-2 in renal tissues was significantly increased, the expression level of Bax was significantly decreased, and renal injury was significantly alleviated., Conclusion: HH induces the formation of NETs through the NF-κB signaling pathway, and it promotes apoptosis and aggravates renal injury by decreasing Bcl-2 and increasing Bax expression., (© 2023. Huazhong University of Science and Technology.)

This study aimed at investigating the gastroprotective effect of Evodiae fructus polysaccharide (EFP) against ethanol-induced gastric ulcer in mice. Biochemical indexes along with untargeted serum and liver metabolomics were determined. Results showed that pre-treatment of EFP alleviated ethanol-induced gastric ulcer in mice. EFP lessened oxidative stress and inflammation levels of stomachs, showing as increments of SOD and GSH-Px activities, GSH content and IL-10 level, and reductions of MDA and IL-6 levels. Meanwhile, EFP activated the Keap1/Nrf2/HO-1 signaling pathway through increasing Nrf2 and HO-1 protein expressions, and decreasing Keap1 protein expression. Serum and liver metabolomics analyses indicated that 10 metabolic potential biomarkers were identified among normal control, ulcer control and 200 mg/kg·bw of EFP groups, which were related to 5 enriched metabolic pathways including vitamin B6 metabolism, nicotinate and nicotinamide metabolism, pentose phosphate pathway, bile secretion and ascorbate and aldarate metabolism. Further pearson's correlation analysis indicated that there were some positive and negative correlations between the biomarkers and the biochemical indexes. It could be concluded that the gastroprotection of EFP might be related to anti-oxidative stress, anti-inflammation, activation of Keap1/Nrf2/HO-1 signaling pathway and alteration of metabolic pathways. This study supports the potential application of EFP in preventing ethanol-induced gastric ulcer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Malignant mesothelioma is an aggressive cancer with limited treatment options and poor prognosis. A better understanding of mesothelioma genomics and transcriptomics could advance therapies. Here, we present a mesothelioma cohort of 122 patients along with their germline and tumor whole-exome and tumor RNA sequencing data as well as phenotypic and drug response information. We identify a 48-gene prognostic signature that is highly predictive of mesothelioma patient survival, including CCNB1, the expression of which is highly predictive of patient survival on its own. In addition, we analyze the transcriptomics data to study the tumor immune microenvironment and identify synthetic-lethality-based signatures predictive of response to therapy. This germline and somatic whole-exome sequencing as well as transcriptomics data from the same patient are a valuable resource to address important biological questions, including prognostic biomarkers and determinants of treatment response in mesothelioma., Competing Interests: Declaration of interests E.R. is a co-founder of Medaware, Metabomed, and Pangea Biomed (divested from the latter). He serves as a non-paid scientific consultant to Pangea Biomed under a collaboration agreement between Pangea Biomed and the NCI. R.H. has received funding for conduct of clinical trials via a cooperative research and development agreement between NCI and Bayer AG and TCR2 Therapeutics. J.S.L. is a scientific consultant of Pangea Therapeutics., (Published by Elsevier Inc.)

Background: Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown., Results: We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1 W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated K v 1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring K v 1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice., Conclusions: These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy., (© 2023. The Author(s).)

Purpose: To investigate the regulation of long non-coding RNA (LncRNA) RUNX1-IT1 on microrna (mir-195)/CyclinD1 (CyclinD1) in malignant pleomorphic adenoma (MPA)., Methods: The MPA tissues and para-carcinoma tissues were collected and the expression levels of LncRNA RUNX1-IT1, miR-195 and CyclinD1 mRNA were detected, the correlation and clinical pathology of MPA was analyzed and compared. MPA cell line SM-AP1 was cultured and transfected with negative control(NC) siRNA, LncRNA RUNX1-IT1siRNA, miR-NC and miR-195 inhibitor. Cell proliferation level A490 and expression levels of miR-195 and CyclinD1 were detected. LncRNA RUNX1-IT1 targeting miR-195 and miR-195 targeting CyclinD1 were analyzed by dual luciferase reporter gene assay. SPSS 21.0 software package was used for data analysis., Results: The expression level of LncRNA RUNX1-IT1 and CyclinD1 in MPA were higher than those in para tumor tissues, and the expression level of miR-195 was lower than that in para tumor tissues(P＜0.05). LncRNA RUNX1-IT1was negatively correlated with miR-195, positively correlated with CyclinD1, and miR-195 was negatively correlated with CyclinD1. The expression of LncRNA RUNX1-IT1 and CyclinD1 in MPA tissue with tumor diameter≥3 cm, recurrence and distant metastasis increased(P＜0.05), while the expression of miR-195 decreased(P＜0.05). After knockdown of LncRNA RUNX1-IT1, A490 level and CyclinD1 expression level decreased, while miR-195 expression level increased(P＜0.05). miR-195 decreased the fluorescence activity of LncRNA RUNX1-IT1 and CyclinD1 reporter genes(P＜0.05). After miR-195 was inhibited, the effect of LncRNA RUNX1-IT1 knockdown on decreasing A490 level and CyclinD1 expression level weakened(P＜0.05)., Conclusions: LncRNA RUNx1-IT1 may participate in the development of MPA by regulating the expression of miR-195/CyclinD1.

Importance: Neuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear., Objective: To define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients., Design Setting and Participants: Germline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival., Main Outcomes and Measures: Rare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival., Results: We observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10 -5 , Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10 -7 ; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10 -3 ; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10 -3 ), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01)., Conclusions and Relevance: Neuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.

Purpose: Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in RMS, which strongly correlated with survival; however, predicting these mutations or high-risk disease at diagnosis remains a significant challenge. In this study, we utilized convolutional neural networks (CNN) to learn histologic features associated with driver mutations and outcome using hematoxylin and eosin (H&E) images of RMS., Experimental Design: Digital whole slide H&E images were collected from clinically annotated diagnostic tumor samples from 321 patients with RMS enrolled in Children's Oncology Group (COG) trials (1998-2017). Patches were extracted and fed into deep learning CNNs to learn features associated with mutations and relative event-free survival risk. The performance of the trained models was evaluated against independent test sample data (n = 136) or holdout test data., Results: The trained CNN could accurately classify alveolar RMS, a high-risk subtype associated with PAX3/7-FOXO1 fusion genes, with an ROC of 0.85 on an independent test dataset. CNN models trained on mutationally-annotated samples identified tumors with RAS pathway with a ROC of 0.67, and high-risk mutations in MYOD1 or TP53 with a ROC of 0.97 and 0.63, respectively. Remarkably, CNN models were superior in predicting event-free and overall survival compared with current molecular-clinical risk stratification., Conclusions: This study demonstrates that high-risk features, including those associated with certain mutations, can be readily identified at diagnosis using deep learning. CNNs are a powerful tool for diagnostic and prognostic prediction of rhabdomyosarcoma, which will be tested in prospective COG clinical trials., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: In recent years, peroxisome proliferator-activated receptor γ (PPARγ) has been found to be closely associated with hypoxia renal disease. The aim of this study was to investigate the relationship between rosiglitazone and mitochondrial apoptosis in renal tissue and its associated mechanisms., Methods: Twenty-four male Sprague-Dawley rats were randomly divided into three groups ( n  = 8 in each): normal control group, hypoxia injury group (equal volume of 0.9% saline), and PPARγ agonist group (Rosiglitazone, 10 mg/kg · d, intraperitoneally). The hypoxia injury group and PPARγ agonist group were placed in a hypoxia chamber and the simulated altitude was set at 7,000 m for 7 days. Blood and kidney samples were collected after 7 days. The quantitative real-time polymerase chain reaction and Western blot methods were used to determine the expression of PPARγ, nuclear factor kappa-B (NF-κB), B-cell lymphoma-2 (Bcl-2), and Bax., Results: The results showed that compared with the normal control group, the renal tissue of rats after hypoxia was severely damaged, as shown by massive renal tubular epithelial cell degeneration and detachment, and renal tubular dilation. The NF-κB protein expression significantly increased, the Bcl-2 protein and mRNA expression significantly decreased, and Bax protein and mRNA expression significantly increased ( p  < .05 for all). Renal injury was much less severe in the PPARγ agonist group compared to the hypoxia injury group., Conclusions: Rosiglitazone can alleviate hypoxia renal injury, with the possible mechanism involving attenuation of apoptosis by inhibiting the activation of the NF-κB signaling pathway in a PPARγ-dependent manner and increasing Bcl-2 and decreasing Bax expression.

Human oral squamous cell carcinoma (OSCC) has been one of the most common oral cancers owing to high percentage of betel nuts chewers, smokers, and alcohol consumption. With current treatment strategies in OSCC, more than half patients relapse and develop distant metastases with poor prognosis. To overcome the incident, OSCC poses a challenge in current therapies and treatments. Naringenin, a natural flavonoid, has been noted for antitumor effects on various types of cancers; however, the effects of naringenin on OSCC remain bias. In this study, naringenin demonstrated the potential multifunction in human OSCC cells not only leading to cell apoptosis, but also alternating the general function of autophagy, serving as pro-survival mechanism by inducing the endoplasmic reticulum (ER) stress signaling through intracellular reactive oxygen species (ROS) production. In the process of programmed cell death, naringenin induced apoptotic signaling through caspase-cascade, mitochondrial dysfunction, and ER stress by aberrance of Ca 2+ release. In contrast, under the presence of naringenin, the pro-survival has been altered into pro-death to activate the caspases-mediated apoptosis achieving cell death. The cross-function of apoptosis and autophagy has demonstrated the effect of naringenin-induced intracellular ROS activity in OSCC cells. Therefore, this study found that the effect of naringenin induces intracellular ROS to trigger programmed cell death and ER stress through the mechanisms of apoptosis and autophagy in human oral squamous carcinoma. PRACTICAL APPLICATIONS: This study revealed that naringenin debilitated the OSCC cell viability via the intracellular ROS production, ER stress, and autophagy, leading to cell apoptosis. Based on these studies and findings, naringenin provided an antitumor effect as a novel natural compound to improve the current therapies in OSCC., (© 2022 Wiley Periodicals LLC.)

Objective: To investigate the effects of cigarette smoke extract (CSE) on the mitochondrial function of macrophages. Methods: RAW264.7 macrophages were used for the experiment in this study. When the cell density was about 70%, the old culture medium was abandoned, and the 100% CSE stock solution was diluted with serum-free DMEM and FBS into 1%, 5%, 15%, 25% and 90% CSE and added to the well plate. The cell activity of RAW264.7 cells treated with CSE at different concentrations for 24 h was detected by CCK-8 method. Then the optimal CSE concentration was selected to treat cells for 0 h, 24 h, 48 h or 72 h respectively, and CCK-8 assay was used to detect the cell activity of CSE treated cells at different time groups. After the cells were treated with 0%, 5% and 25% CSE for 24 hours, cell necrosis and apoptosis was detected by Annexin V-FITC /PI staining; Mitochondrial membrane damage of RAW 264.7 was detected by mitochondrial membrane potential assay kit with JC-1; Macrophages were stained with ROS-specific dye DCFH-DA, and then Flow cytometer was used to determine the fluorescence and the proportion of ROS-positive macrophages; the enhanced ATP assay kit was used to detect the intracellular ATP concentration. Results: ①Compared with 0% CSE, cell viability was increased significantly in 1% CSE group ( P ＜0.01), cell viability was decreased significantly when CSE concentration was above 5% ( P ＜0.05); Macrophages were treated with 5% CSE, and cell viability was decreased significantly with the increase of treatment time ( P ＜0.01). ②Compared with 0% CSE, 5% CSE and 25% CSE mainly caused macrophage necrosis, decreased mitochondrial membrane potential, increased ROS production and decreased ATP significantly ( P ＜0.05 or P ＜0.01), and the changes were more significant in 25% CSE treatment group( P ＜0.05 or P ＜0.01). Conclusion: CSE may affect mitochondrial function of macrophages, leading to decreased cell viability and necrosis.

Wurfbainia villosa is a well-known medicinal and edible plant that is widely cultivated in the Lingnan region of China. Its dried fruits (called Fructus Amomi) are broadly used in traditional Chinese medicine for curing gastrointestinal diseases and are rich in volatile terpenoids. Here, we report a high-quality chromosome-level genome assembly of W. villosa with a total size of approximately 2.80 Gb, 42 588 protein-coding genes, and a very high percentage of repetitive sequences (87.23%). Genome analysis showed that W. villosa likely experienced a recent whole-genome duplication event prior to the W. villosa-Zingiber officinale divergence (approximately 11 million years ago), and a recent burst of long terminal repeat insertions afterward. The W. villosa genome enabled the identification of 17 genes involved in the terpenoid skeleton biosynthesis pathway and 66 terpene synthase (TPS) genes. We found that tandem duplication events have an important contribution to the expansion of WvTPSs, which likely drove the production of volatile terpenoids. In addition, functional characterization of 18 WvTPSs, focusing on the TPS-a and TPS-b subfamilies, showed that most of these WvTPSs are multi-product TPS and are predominantly expressed in seeds. The present study provides insights into the genome evolution and the molecular basis of the volatile terpenoids diversity in W. villosa. The genome sequence also represents valuable resources for the functional gene research and molecular breeding of W. villosa., (© 2022 Society for Experimental Biology and John Wiley & Sons Ltd.)

Objective: Preliminary assessment of rabies virus neutralizing activity, safety and immunogenicity of a recombinant human rabies antibody (NM57) compared with human rabies immunoglobulin (HRIG) in Chinese healthy adults., Methods: Subjects were randomly (1:1:1) allocated to Groups A (20 IU/kg NM57), B (40 IU/kg NM57), or C (20 IU/kg HRIG). One injection was given on the day of enrollment. Blood samples were collected on days -7 to 0 (pre-injection), 3, 7, 14, 28, and 42. Adverse events (AEs) and serious AEs (SAEs) were recorded over a period of 42 days after injection., Results: All 60 subjects developed detectable rabies virus neutralizing antibodies (RVNAs) (> 0.05 IU/mL) on days 3, 7, 14, 28, and 42. The RVNA levels peaked on day 3 in all three groups, with a geometric mean concentration (GMC) of 0.2139 IU/mL in Group A, 0.3660 IU/mL in Group B, and 0.1994 IU/mL in Group C. At each follow-up point, the GMC in Group B was significantly higher than that in Groups A and C. The areas under the antibody concentration curve over 0-14 days and 0-42 days in Group B were significantly larger than those in Groups A and C. Fifteen AEs were reported. Except for one grade 2 myalgia in Group C, the other 14 were all grade 1. No SAEs were observed., Conclusion: The rabies virus neutralizing activity of 40 IU/kg NM57 was superior to that of 20 IU/kg NM57 and 20 IU/kg HRIG, and the rabies virus neutralizing activity of 20 IU/kg NM57 and 20 IU/kg HRIG were similar. Safety was comparable between NM57 and HRIG., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Carbon dioxide as a classic C1 source has long been investigated in organic synthetic chemistry. Diverse catalytic methods for CO 2 activation have been reported over the past several decades. In this minireview, we mainly focus on detailing recent advances (since 2020) in utilizing carbon dioxide to attain the carboxylation of organic motifs via photoredox and metallaphotoredox catalysis.

Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR. Next, using pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), termed P-COCC, we simultaneously analyzed protein and transcriptome expression of CAR T cells to identify high-activity CARs. Finally, we performed cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic "OR" CAR (BiCisCAR). BiCisCAR T cells effectively eliminated tumor cells expressing GPC2 or CD276. Furthermore, the BiCisCAR T cells demonstrated prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study illustrated that targeting multiple TAAs with BiCisCAR may overcome heterogenous expression of target antigens in solid tumors and identified a potent, clinically relevant CAR against NB. Moreover, our multimodal approach integrating competitive expansion, P-COCC, and cytotoxicity assays is an effective strategy to identify potent CARs among a pool of candidates.

Chemical investigation of the marine hydroid Dentitheca habereri led to the identification of eight new diacylated zoanthoxanthin alkaloids, named dentithecamides A-H ( 1 - 8 ), along with three previously reported analogues, zoamides B-D ( 9 - 11 ). The structures of compounds 1 - 11 were elucidated by spectroscopic and spectrometric analyses, including IR, HRESIMS, and NMR experiments, and by comparison with literature data. Compounds 1 - 11 are the first zoanthoxanthin alkaloids to be reported from a hydroid. Dentithecamides A ( 1 ) and B ( 2 ) along with zoamides B-D ( 9 - 11 ), which all share a conformationally mobile cycloheptadiene core, inhibited PAX3-FOXO1 regulated transcriptional activity and thus provided a structural framework for the potential development of more potent PAX3-FOXO1 inhibitors.

Mn 3 O 4 is a promising cathode material for aqueous zinc ion batteries (ZIBs) which is a new type of low cost, eco-friendly, high security energy storage system, while those previously reported electrochemical capacities of Mn 3 O 4 are far from its theoretical value. In this work, Mn 3 O 4 nanoparticles and nitrogen-doped carbon dots (NCDs) are synthesized together through an in-situ hydrothermal route, and then calcined to be a nanocomposite in which Mn 3 O 4 nanoparticles are anchored on a nitrogen-doped carbon skeleton (designated as Mn 3 O 4 /NCDs). Although the carbon content is only 3.9 wt.% in the Mn 3 O 4 /NCDs, the NCDs-derived carbon skeleton provides an electrically conductive network and a stable structure. Such a special nanocomposite has a large specific surface area, plenty of active sites, excellent hydrophilicity and good electronic conductivity. Owing to these structural merits, the Mn 3 O 4 /NCDs electrode exhibits a preeminent specific capacity of 443.6 mAh g -1 and 123.3 mAh g -1 at current densities of 0.1 and 1.5 A g -1 in ZIBs, respectively, which are far beyond the bare Mn 3 O 4 nanoparticles synthesized under the similar condition. The electrochemical measurement results prove that carbon dots, as a new type of carbon nanomaterials, have strong ability to modify and improve the performance of existing electrode materials, which may push these electrode materials forward to practical applications., (© 2022 Wiley-VCH GmbH.)

Human rabies is a serious public health problem that can't be ignored. Rabies immune globulin (RIG) is an indispensable component of rabies post-exposure prophylaxis (PEP). However, current PEP relies on RIG purified from pooled human or equine plasma, which are either in chronic shortage or associated with safety concerns. Monoclonal antibodies have become widely accepted as safer and more cost-effective alternatives to RIG products in recent years. Here, we assessed the neutralization breadth of human monoclonal antibody ormutivimab and its protective efficacy in PEP models. Ormutivimab was able to neutralize a broad panel of Chinese prevalent street RABVs with neutralizing potency form 198-1487.6 IU/mL. Furthermore, ormutivimab offered comparable protection to that with HRIG both at standard doses (20 IU/kg) and higher doses (100 IU/kg and 200 IU/kg). The interference of ormutivimab on vaccine potency was also analyzed and found slightly reduced neutralizing antibody titers similar to HRIG. The broad-spectrum neutralization activities, highly protective potency, and rapid onset of action make ormutivimab an effective candidate for human rabies PEP., (Copyright © 2022 Elsevier Ltd. All rights reserved.)