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Abstract Purpose Cutaneous metastasis (CM) accounts for 5–30% of patients with breast cancer (BC) and presents unfavorable response to treatment and poor prognosis. A better understanding of the molecular alterations involved in metastasis is essential, which would help identify diagnostic and efficacy biomarkers for CM. Materials : We retrospectively reviewed a total of 13 patients with histological or cytological diagnosis of breast cancer and CM. Clinical information was extracted from the medical records. The mutational landscape of matched primary tumors with their lymph nodes or CM tissues were analyzed using next-generation sequencing (NGS) of 425 cancer-relevant genes. All tissues were also analyzed by immunohistochemistry (IHC). The association of prognosis with various clinical and molecular factors was also evaluated. Results More than half of the patients were Ki67 low ( 50%) showed significantly shorter T1 than the Ki67 low group (≤ 50%) (median 12.5 vs. 50.0 months, P = 0.036). TP53, PIK3CA mutations, and TERT amplification group were associated with inferior T2 (median 11 vs. 36 months, P = 0.065; 8 vs. 36 months, P = 0.013, 7 vs. 36 months, P = 0.003, respectively). All p values were not adjusted. Conclusion We compared the genomic features of primary breast cancer tissues with their corresponding CM tissues and discussed potential genes and pathways that may contribute to the skin metastasis of advanced breast cancers patients. TP53, PIK3CA mutant, and TERT amplification may serve as biomarkers for poor prognosis for CM patients.

Abstract Background Peripheral lung lesions can be sampled using various techniques, including computer tomography-guided transthoracic needle aspiration, electromagnetic navigation bronchoscopy, virtual navigation bronchoscopy, and radial probe endobronchial ultrasound transbronchial lung biopsy. Mediastinal lesions can be sampled using techniques like convex probe endobronchial ultrasound-guided transbronchial needle aspiration (CEBUS-TBNA) and endoscopic ultrasound-fine-needle aspiration. However, effective, safe techniques for lesions adjacent to the segmental or subsegmental bronchi are lacking. Herein, we retrospectively evaluated the diagnostic yield and safety of radial probe endobronchial ultrasound-assisted transbronchial needle aspiration (REBUS-TBNA) for lesions adjacent to the segmental bronchi, and explored the factors related to diagnostic yield. Methods We retrospectively analyzed the diagnostic yield and safety of REBUS-TBNA cases performed in our department from January 2019 to December 2022. Observation group patients had undergone REBUS-TBNA for lesions adjacent to the segmental bronchi; control group patients had undergone CEBUS-TBNA for mediastinal or hilar lesions. Patient characteristics and lesion sizes, diagnostic yield, adverse events, and relations between diagnostic yield and clinical characteristics were analyzed. Results There were not statistically significant between-group differences in sex, age, diagnostic yield, or rate of adverse events. The observation group (n = 25; 17 male, 8 female) had a mean age of 64.76 ± 10.75 years. The average lesion size was 4.66 ± 1.07 cm, and lesions were predominantly in the upper lobes (80%). REBUS-TBNA diagnostic yield was 84%, with no adverse events reported. Diagnostic yield was not associated with lesion size or extent of bronchial stenosis; however, it was positively correlated with number of punctures. Patients with > 3 punctures had a significantly higher diagnostic yield than those with ≤ 3 punctures. Conclusions REBUS-TBNA is a safe, effective diagnostic technique, particularly for lesions adjacent to the segmental or subsegmental bronchi of the upper lobe. Performing more than three punctures during the procedure improves the diagnostic yield. Larger-scale studies are warranted to confirm these results, and to further explore the clinical value of REBUS-TBNA.

Abstract Parkinson’s disease (PD) is the second most common neurodegenera­tive disorder after Alzheimer disease accompanied by the death of dopaminergic neurons and brain nigrostriatal mitochondrial damage in the elderly population. The features of the disease include tremor, rigidity, postural instability, and motor retardation. The pathogenesis of Parkinson’s disease is complex, and abnormal lipid metabolism resulting in ferroptosis due to the excessive accumulation of free radicals from oxidative stress in the substantia nigra of the brain was thought to be one of the factors causing the disease. Morroniside has been reported to have significant neuroprotective effects, although it has not been studied in PD. Therefore, this study focused on determining the neuroprotective effects of morroniside (25, 50, and 100 mg/kg) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg)-induced mice models of PD and explored 1-methyl-4-phenylpyridinium MPP+-induced ferroptosis in PC12 cells. Morroniside restored impaired motor function in the PD mice models while reducing neuronal injury. The activation of nuclear factor erythroid 2-related factor 2/antioxidant response elements (Nrf2/ARE) by morroniside promoted antioxidation, the content of reducing agent glutathione (GSH) increased, and the level of the lipid metabolite malondialdehyde (MDA) decreased. Notably, morroniside inhibited ferroptosis in substantia nigra of the brain and PC12 cells, reduced iron levels, and upregulated the expression of the iron-regulated proteins glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH-1), and ferroportin (FPN). More importantly, morroniside repaired the mitochondrial damage, restored the mitochondrial respiratory chain, and inhibited the production of reactive oxygen species (ROS). These data indicated that morroniside could activate the Nrf2/ARE signaling pathway to increase the antioxidant capacity, thereby inhibiting abnormal lipid metabolism and protecting dopaminergic neurons from ferroptosis in PD.

Abstract In chronic infections and cancers, T lymphocytes (T cells) are exposed to persistent antigen or inflammatory signals. The condition is often associated with a decline in T-cell function: a state called “exhaustion”. T cell exhaustion is a state of T cell dysfunction characterized by increased expression of a series of inhibitory receptors (IRs), decreased effector function, and decreased cytokine secretion, accompanied by transcriptional and epigenetic changes and metabolic defects. The rise of immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has dramatically changed the clinical treatment paradigm for patients. However, its low response rate, single target and high immunotoxicity limit its clinical application. The multiple immunomodulatory potential of traditional Chinese medicine (TCM) provides a new direction for improving the treatment of T cell exhaustion. Here, we review recent advances that have provided a clearer molecular understanding of T cell exhaustion, revealing the characteristics and causes of T cell exhaustion in persistent infections and cancers. In addition, this paper summarizes recent advances in improving T cell exhaustion in infectious diseases and cancer with the aim of providing a comprehensive and valuable source of information on TCM as an experimental study and their role in collaboration with ICIs therapy.

Abstract Background The evolutionarily conserved Polycomb Repressive Complex 2 (PRC2) plays a vital role in epigenetic gene repression by depositing tri-methylation on lysine residue K27 of histone H3 (H3K27me3) at the target loci, thus participating in diverse biological processes. However, few reports about PRC2 are available in plant species with large and complicated genomes, like cotton. Results Here, we performed a genome-wide identification and comprehensive analysis of cotton PRC2 core components, especially in upland cotton (Gossypium hirsutum). Firstly, a total of 8 and 16 PRC2 core components were identified in diploid and tetraploid cotton species, respectively. These components were classified into four groups, E(z), Su(z)12, ESC and p55, and the members in the same group displayed good collinearity, similar gene structure and domain organization. Next, we cloned G. hirsutum PRC2 (GhPRC2) core components, and found that most of GhPRC2 proteins were localized in the nucleus, and interacted with each other to form multi-subunit complexes. Moreover, we analyzed the expression profile of GhPRC2 genes. The transcriptome data and quantitative real-time PCR (qRT-PCR) assays indicated that GhPRC2 genes were ubiquitously but differentially expressed in various tissues, with high expression levels in reproductive organs like petals, stamens and pistils. And the expressions of several GhPRC2 genes, especially E(z) group genes, were responsive to various abiotic and biotic stresses, including drought, salinity, extreme temperature, and Verticillium dahliae (Vd) infection. Conclusion We identified PRC2 core components in upland cotton, and systematically investigated their classifications, phylogenetic and synteny relationships, gene structures, domain organizations, subcellular localizations, protein interactions, tissue-specific and stresses-responsive expression patterns. Our results will provide insights into the evolution and composition of cotton PRC2, and lay the foundation for further investigation of their biological functions and regulatory mechanisms.

Abstract Background The Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies. Methods Eighty-six NSCLC patients were categorized into three cohorts based on the time of detecting MET tyrosine kinase domain (TKD) mutations (cohort 1: at baseline; cohort 2: after MET-TKI treatment; cohort 3: after EGFR-TKI treatment). Baseline and paired TKI treatment samples were analyzed by targeted next-generation sequencing. Results MET TKD mutations were highly prevalent in METex14-positive NSCLC patients after MET-TKI treatment, including L1195V, D1228N/H/Y/E, Y1230C/H/N/S, and a double-mutant within codons D1228 and M1229. Missense mutations in MET TKD were also identified at baseline and in post-EGFR-TKI treatment samples, which showed different distribution patterns than those in post-MET-TKI treatment samples. Remarkably, H1094Y and L1195F, absent from MET-TKI-treated patients, were the predominant type of MET TKD mutations in patients after EGFR-TKI treatment. D1228H, which was not found in treatment-naïve patients, also accounted for 14.3% of all MET TKD mutations in EGFR-TKI-treated samples. Two patients with baseline EGFR-sensitizing mutations who acquired MET-V1092I or MET-H1094Y after first-line EGFR-TKI treatment experienced an overall improvement in their clinical symptoms, followed by targeted therapy with MET-TKIs. Conclusions MET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

Abstract Background Leaf senescence, the final stage of leaf growth and development, is regulated by numerous internal factors and environmental cues. Ethylene is one of the key senescence related hormones, but the underlying molecular mechanism of ethylene-induced leaf senescence remains poorly understood. Results In this study, we identified one AT-hook like (AHL) protein, AHL9, as a positive regulator of leaf senescence in Arabidopsis thaliana. Overexpression of AHL9 significantly accelerates age-related leaf senescence and promotes dark-induced leaf chlorosis. The early senescence phenotype observed in AHL9 overexpressing lines is inhibited by the ethylene biosynthesis inhibitor aminooxyacetic acid suggesting the involvement of ethylene in the AHL9-associated senescence. RNA-seq and quantitative reverse transcription PCR (qRT-PCR) data identified numerous senescence-associated genes differentially expressed in leaves of AHL9 overexpressing transgenic plants. Conclusions Our investigation demonstrates that AHL9 functions in accelerating the leaf senescence process via ethylene synthesis or signalling.

Abstract Background Idiopathic CD4 + T lymphocytopenia (ICL) is a rare immunodeficiency syndrome, unaccompanied by various opportunistic infections. Cryptococcus and varicella-zoster viruse are the most common opportunistic infections. Method We described a case of disseminated cryptococcosis with varicella-zoster virus coinfection in a patient with ICL and reviewed all published reports. A total of 26 cases with cryptococcal meningitis in ICL were enrolled. Discussion ICL remains poorly understood to clinicians. Patients with cryptococcal meningitis in ICL mostly suffered with headache and fever in a subacute or chronic period, while some patients might have atypical manifestations which makes a difficulty for early diagnosis. Some characteristics of cerebrospinal fluid can help to predict the prognosis of the disease. Cryptococcosis with varicella-zoster virus coinfection is rare but serious. Conclusion We recommed CD4 + T cells should be assessed in patients with unusual or recurrent infections. As the underlying pathophysiology is poorly understood, there is no standard therapy for ICL. Increased awareness of the disease and early prevention for CD4 reduction are needed.

Abstract Purpose This study aimed to explore the feasibility and safety of the tunnel approach in laparoscopic radical right hemicolectomy for colon cancer. Methods From July 2016 to October 2018, a total of 106 consecutive patients with colon cancer who underwent laparoscopic radical right hemicolectomy at the Affiliated Cancer Hospital of Zhengzhou University were enrolled. The patients were stratified into either a tunnel approach (TA) (n = 56) group or traditional medial approach (MA) (n = 50) group according to the surgical technique performed. The baseline demographics, perioperative outcomes and oncologic outcomes were compared between the two groups. Results The baseline characteristics did not differ between groups. The TA group had significantly less blood loss [20.0 (10.0–40.0) vs. 100 (100.0–150.0) ml, p

Abstract Background Monomorphic epitheliotropic T-cell lymphoma (MEITL) is an aggressive non-Hodgkin lymphoma with a high fatality rate. This study was aimed to explore the clinicopathological and molecular genetic features of MEITL in the Chinese population. Methods A retrospective analysis was performed based on the clinical manifestations and pathological features of 20 Chinese MEITL. 9 cases with paired diseased-normal tissues were also analyzed for molecular information by whole-exome sequencing. Results There were 14 men and 6 women with a median age of 58.5 (28-81) years. 17(17/20) lesions were located in the jejunum or ileum; 13(13/20) cases had ulcers or perforations. Microscopically, except for 1(1/20) case of pleomorphic cells, the monomorphic, middle-sized tumor cells infiltrating into the intestinal epithelial and peripheral intestinal mucosa recess could be seen in the other 19 cases. Immunohistochemistry showed that most of the tumor cells in MEITL were positive for CD3(20/20), CD8(17/20), CD43(19/20), and CD56(15/20), but negative for CD5(20/20). The most frequently mutated genes of these Chinese cases were STAT5B (4/9) and TP53 (4/9), not SETD2(2/9). JAK3 mutations (3/9) were also detected with a high mutated frequency. We demonstrated that mutations of JAK-STAT pathway-related genes and the amplification of Chromosome 9q appeared at the same time in most cases(5/9). Conclusions The clinicopathological features were consistent with that in previous western studies, but a special case with pleomorphic cells was found in this study. The co-occurrence of JAK-STAT pathway-related gene mutations and the amplification of Chr9q is a molecular feature of MEITL.

Abstract Background Increasing attention has been paid to the effect of Epimedium on the nervous system, particularly anti-depression function. In the present study, we applied network pharmacology to introduce a testable hypothesis on the multi-target mechanisms of Epicedium against depression. Methods By reconstructing the network of protein–protein interaction and drug–component–target, we predicted the key protein targets of Epicedium for the treatment of depression. Then, through molecular docking, the interaction of the main active components of Epicedium and predicted candidate targets were verified. Results Nineteen active compounds were selected from Epicedium. There were 200 targets associated with Epicedium and 537 targets related to depression. The key targets of Epicedium for treating depression were IL6, VEGFA, AKT1, and EGF. According to gene ontology functional enrichment analysis, 22 items of biological process (BP), 13 items of cell composition (CC) and 9 items of molecular function (MF) were obtained. A total of 56 signaling pathways (P < 0.05) were identified by Kyoto Encyclopedia of Genes and Genomes analysis, mainly involving depression-related pathways such as dopaminergic synapse, TNF signaling pathway, and prolactin signaling pathway. The results of molecular docking showed that the most important activity components, including luteoklin, quercetin and kaempferol, were well combined with the key targets. Conclusions Luteoklin, quercetin, kaempferol and other active compounds in Epicedium can regulate multiple signaling pathways and targets such as IL6, AKT1, and EGF, therefore playing therapeutic roles in depression.

Abstract Background This study aimed to investigate the clinical and pathological characteristics, and the recurrence and prognostic factors of borderline ovarian tumors (BOTs). Methods The data of 286 patients admitted to hospital and followed up for more than ten months were analyzed retrospectively to study the clinicopathological characteristics and related factors of recurrence. Results The median age of the patients was 42.06 ± 14.97 years, and the duration of the follow-up ranged from 10–109 months. During the follow-up period, 40 patients had a recurrence. Of these patients, 36 were ≤ 40 years, and patients with premenopausal recurrence accounted for 20.5% (36/176). In patients undergoing conservative treatment or radical operations, the recurrence rates were 21.3% and 1.8%, respectively, and they were 13.4% (36/268) in patients at Federation International of Gynecology and Obstetrics (FIGO) stage I, and 22.2% (4/18) in patients at an advanced stage. Postoperative pathology revealed that 40 patients had micropapillary tumors, among whom ten patients (25%) had a recurrence, and 19 patients had complications with interstitial infiltration. Of these 19 patients, six had a recurrence (31.5%). Another 22 patients had complications with calcified sand bodies; among these, eight patients (36.4%) had a recurrence. All the differences were statistically significant (P

Abstract Background Laurel wilt caused by Raffaelea lauricola is a lethal vascular disease of North American members of the Lauraceae plant family. This fungus and its primary ambrosia beetle vector Xyleborus glabratus originated from Asia; however, there is no report of laurel wilt causing widespread mortality on native Lauraceae trees in Asia. To gain insight into why R. lauricola is a tree-killing plant pathogen in North America, we generated and compared high quality draft genome assemblies of R. lauricola and its closely related non-pathogenic species R. aguacate. Results Relative to R. aguacate, the R. lauricola genome uniquely encodes several small-secreted proteins that are associated with virulence in other pathogens and is enriched in secondary metabolite biosynthetic clusters, particularly polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS) and PKS-NRPS anchored gene clusters. The two species also exhibit significant differences in secreted proteins including CAZymes that are associated with polysaccharide binding including the chitin binding CBM50 (LysM) domain. Transcriptomic comparisons of inoculated redbay trees and in vitro-grown fungal cultures further revealed a number of secreted protein genes, secondary metabolite clusters and alternative sulfur uptake and assimilation pathways that are coordinately up-regulated during infection. Conclusions Through these comparative analyses we have identified potential adaptations of R. lauricola that may enable it to colonize and cause disease on susceptible hosts. How these adaptations have interacted with co-evolved hosts in Asia, where little to no disease occurs, and non-co-evolved hosts in North America, where lethal wilt occurs, requires additional functional analysis of genes and pathways.

Abstract Background Reactive airway dysfunction syndrome (RADS), also called irritant-induced asthma, is a type of occupational asthma that can occur within a very short period of latency. The study sought to investigate the influence of sulfur dioxide (SO2) exposure on CD19+ cells and nasal epithelial injury. Methods We investigated the effects of SO2 on CD19 expression and morphological changes of nasal epithelia in rats. In the study, 20 rats were randomly divided into the SO2 exposure group that were exposed to 600 ppm SO2, 2 h/day for consecutive 7 days, and the control group that were exposed to filtered air). Results Inhalation of high concentration of SO2significantly reduced CD19 expression at both the mRNA transcript and protein levels, and reduced the percentages of CD19+ cells and CD19+/CD23+ cells in the nasal septum. However, inhalation of high concentration of SO2 did not affect immunoglobulin (Ig) G, IgA and IgE levels in the serum and nasal septum. More importantly, SO2 exposure also caused mild structural changes of the nasal septum. Conclusion Our results reveal that inhalation of a high concentration of SO2 reduces CD19 expression and causes structural change of the nasal septum in rats.