Individualized Structural Perturbations on Normative Brain Connectome Restrict Deep Brain Stimulation Outcomes in Parkinson's Disease.

BACKGROUND: Patients with Parkinson's disease (PD) respond to deep brain stimulation (DBS) variably. However, how brain substrates restrict DBS outcomes remains unclear. OBJECTIVE: In this article, we aim to identify prognostic brain signatures for explaining the response variability. METHODS: We retrospectively investigated a cohort of patients with PD (n = 141) between 2017 and 2022, and defined DBS outcomes as the improvement ratio of clinical motor scores. We used a deviation index to quantify individual perturbations on a reference structural covariance network acquired with preoperative T1-weighted magnetic resonance imaging. The neurobiological perturbations of patients were represented as z scored indices based on the chronological perturbations measured on a group of normal aging adults. RESULTS: After applying stringent statistical tests (z > 2.5) and correcting for false discoveries (P < 0.01), we found that accelerated deviations mainly affected the prefrontal cortex, motor strip, limbic system, and cerebellum in PD. Particularly, a negative network within the accelerated deviations, expressed as "more preoperative deviations, less postoperative improvements," could predict DBS outcomes (mean absolute error = 0.09, R2 = 0.15). Moreover, a fusion of personal brain predictors and medical responses significantly improved traditional evaluations of DBS outcomes. Notably, the most important brain predictor, a pathway connecting the cognitive unit (prefrontal cortex) and motor control unit (cerebellum and motor strip), partially mediates DBS outcomes with the age at surgery. CONCLUSIONS: Our findings suggest that individual structural perturbations on the cognitive motor control circuit are critical for modulating DBS outcomes. Interventions toward the circuit have the potential for additional clinical improvements. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Investigation of Efficacy and Safety of Bevacizumab Combined with Chemotherapy in the Treatment of Malignant Pleural Effusion from Lung Cancer.

Objective: To analyze the efficacy and safety of bevacizumab combined with chemotherapy in the treatment of malignant pleural effusion of lung cancer. Methods: Lung cancer patients with malignant pleural effusion (n = 60 cases) treated in our hospital from January 2020 to December 2022 were retrospectively analyzed. They were divided into a control group (patients receiving conventional chemotherapy) and an observation group (patients receiving bevacizumab combined with chemotherapy). The two groups were age and sex-matched. The therapeutic effects, adverse reactions, quality of life (physiological status, social and family status, emotional status, and functional status), levels of serum tumor markers (cytokeratin 19 fragment, tumor-specific growth factor, and carcinoembryonic antigen), pain degree of the two groups before and after treatment, and the psychological states before and after treatment (anxiety and depression scores) of the two groups were compared. Results: The results obtained shows that the observation group has improved treatment outcome than the control group, P < .05. Similarly, the observation group reported higher physiological status, social and family status, emotional status, functional status and other quality of life compared to the control group, P < .05. Interestingly, the observation group showed lower levels of serum tumor markers than the control group, P < .05. Upon comparison of the pain degree of the two groups after treatment, the observation group reported a lesser degree of pain than the control group, P < .05. Although no significant difference was observed in the depression and anxiety scores of the two groups prior to the treatment, the observation group displayed improved psychological state compared to the control group, P < .05. Conclusion: Bevacizumab combined with chemotherapy has outstanding curative effect on malignant pleural effusion of lung cancer.

High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer.

PURPOSE: The treatment of leptomeningeal metastasis (LM), a serious complication of advanced non-small cell lung cancer (NSCLC), presents challenges, particularly in patients with EGFR exon 20 insertion (ex20ins) mutations. METHODS: This study retrospectively analyzed data from 10 EGFR ex20ins-mutated NSCLC patients with LM admitted at our institution from May 2011 to June 2023. Circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) and matched plasma samples was analyzed using next-generation sequencing. All patients received high-dose furmonertinib combined with intraventricular chemotherapy (IVC) as salvage therapy. Data on patient demographics, treatment efficacy, and safety outcomes were collected. RESULTS: The most common insertion mutation identified in this study was p.A767_V769dup (n = 4, 40%), followed by D770-N771insY (n = 2, 20%). Nine patients had EGFR ex20ins occurring in the EGFR loop region following the C-helix, whereas only one patient had an EGFR ex20ins (A763_Y764insFQEA) occurring in the C-helix of the tyrosine kinase domain. LM response assessment using the RANO-LM criteria revealed that 6 patients (60%, 95% CI 26.2-87.8%) achieved a response, 3 had stable disease, and 1 had progressive disease. The median progression-free survival and overall survival were estimated to be 6.5 months and 8.8 months, respectively. The most commonly reported treatment-related adverse events were rash (n = 7) and diarrhea (n = 7), with no treatment-related deaths occurring. CONCLUSIONS: The current study demonstrated that high-dose furmonertinib plus IVC as salvage treatment for patients with LM harboring EGFR ex20ins mutations had promising clinical benefits and a manageable safety profile.

Neutrophil extracellular traps (NETs) and Th-2 dominant immune responses in chronic granulomatous chromobalstomycosis.

Chromoblastomycosis (CBM), a chronic, granulomatous, suppurative mycosis of the skin and subcutaneous tissue, is caused by several dematiaceous fungi. The formation of granulomas, tissue proliferation, and fibrosis in response to these pathogenic fungi is believed to be intricately linked to host immunity. To understand this complex interaction, we conducted a comprehensive analysis of immune cell infiltrates, neutrophil extracellular traps (NETs) formation, and the fibrosis mechanism in 20 CBM lesion biopsies using immunohistochemical and immunofluorescence staining methods. The results revealed a significant infiltration of mixed inflammatory cells in CBM granulomas, prominently featuring a substantial presence of Th2 cells and M2 macrophages. These cells appeared to contribute to the production of collagen I and III in the late fibrosis mechanism, as well as NETs formation. The abundance of Th2 cytokines may act as a factor promoting the bias of macrophage differentiation toward M2, which hinders efficient fungal clearance while accelerates the proliferation of fibrous tissue. Furthermore, the expression of IL-17 was noted to recruit neutrophils, facilitating subsequent NETs formation within CBM granulomas to impede the spread of sclerotic cells. Understanding of these immune mechanisms holds promise for identifying therapeutic targets for managing chronic granulomatous CBM.

The synergetic effect of alginate-derived hydrogels and metal-phenolic nanospheres for chronic wound therapy.

Management of diabetic wounds presents a global health challenge due to elevated levels of ROS in the wound microenvironment, persistent dysregulation of inflammation modulation, and limitations in commercially available dressings. Addressing this issue, we have developed a pH-responsive and glucose-sensitive multifunctional hydrogel dressing that dynamically responds to the wound microenvironment and enables on-demand drug release. The dressing incorporates a matrix material based on aminophenylboronic acid-functionalized alginate and a polyhydroxy polymer, alongside an enhancer phase consisting of self-assembled metal-phenol coordination nanospheres formed by tannic acid and iron ions. Using the dynamic borate ester bonds and catechol-metal ion coordination bonds, the dressing exhibits remarkable shape adaptability, self-healing capability, tissue adhesiveness, antioxidant activity, and photothermal responsiveness, without additional curatives or crosslinking agents. As a wound dressing, it elicits macrophage polarization towards an anti-inflammatory phenotype while maintaining long-lasting antimicrobial effects. In a diabetic mouse model of full-thickness wound infections, it effectively mitigated inflammation and vascular damage, significantly expediting the wound healing process with a commendable 97.7% wound closure rate. This work provides a new direction for developing multifunctional smart hydrogel dressings that can accelerate diabetic wound healing for human health.

The clinical characteristics of non-cystic fibrosis bronchiectasis patients with positive serum tumor markers: a retrospective study.

BACKGROUND: Serum tumor markers (STM), extensively used for the diagnosis, monitoring and prognostic assessment of tumors, can be increased in some non-malignant lung diseases. To date, there is a paucity of studies regarding the clinical characteristics of non-cystic fibrosis bronchiectasis patients with positive STMs. OBJECTIVE: To investigate the clinical characteristics and indicators of bronchiectasis with positive STMs. METHODS: The clinical data of 377 bronchiectasis patients was retrospectively collected from January 2017 to December 2019 from Beijing Chaoyang Hospital. Patients were divided into the STM negative group, the single STM positive group and the ≥2 STMs positive group according to the number of the positive STMs. The clinical characteristics are described and compared separately. The multivariate logistic regression analysis model was used to investigate the indicators regarding positive STMs. RESULTS: Patients in the ≥2 STMs positive group were older (P = 0.015), had higher mMRC scores (P < 0.001) and developed higher fever (P = 0.027). Additionally, these patients also had lower Albumin/Globulin Ratio (A/G), albumin (ALB), prealbumin (PAB) (P < 0.001, P < 0.001, P < 0.001, respectively) and higher CRP, ESR and Fbg (P < 0.001, P < 0.001 and P < 0.001, respectively). Age (OR 1.022, 95%CI 1.003-1.042; P = 0.026) and the number of affected lobes (OR 1.443, 95%CI 1.233-1.690; P < 0.001) were independently associated with one and ≥ 2 positive STMs in bronchiectasis patients. CONCLUSION: The ≥2 positive STMs are associated with a higher inflammation status and severer radiologic manifestations in bronchiectasis patients.

The Lnc-ENST00000602558/IGF1 axis as a predictor of response to treatment with tripterygium glycosides in rheumatoid arthritis patients.

AIMS: Growing clinical evidence suggests that not all patients with rheumatoid arthritis (RA) benefit to the same extent by treatment with tripterygium glycoside (TG), which highlights the need to identify RA-related genes that can be used to predict drug responses. In addition, single genes as markers of RA are not sufficiently accurate for use as predictors. Therefore, there is a need to identify paired expression genes that can serve as biomarkers for predicting the therapeutic effects of TG tablets in RA. METHODS: A total of 17 pairs of co-expressed genes were identified as candidates for predicting an RA patient's response to TG therapy, and genes involved in the Lnc-ENST00000602558/GF1 axis were selected for that purpose. A partial-least-squares (PLS)-based model was constructed based on the expression levels of Lnc-ENST00000602558/IGF1 in peripheral blood. The model showed high efficiency for predicting an RA patient's response to TG tablets. RESULTS: Our data confirmed that genes co-expressed in the Lnc-ENST00000602558/IGF1 axis mediate the efficacy of TG in RA treatment, reduce tumor necrosis factor-α induced IGF1 expression, and decrease the inflammatory response of MH7a cells. CONCLUSION: We found that genes expressed in the Lnc-ENST00000602558/IGF1 axis may be useful for identifying RA patients who will not respond to TG treatment. Our findings provide a rationale for the individualized treatment of RA in clinical settings.

Quercetin ameliorates ferroptosis of rat cardiomyocytes via activation of the SIRT1/p53/SLC7A11 signaling pathway to alleviate sepsis­induced cardiomyopathy.

Sepsis­induced cardiomyopathy (SIC) is a manifestation of multiple organ failure as a result of sepsis and is a serious threat to life. Here, the effect and mechanisms of quercetin (QUE) in SIC were assessed. It was found that patients with SIC expressed lower serum levels of glutathione peroxidase 4 (GPX4) and SIRT1 but higher levels of CK­MB, cTnI, TNF­α, and IL­6 compared with healthy individuals. A dose of 80 µM QUE increased the viability and reduced the ferroptosis of H9C2 cells treated with 1.0 µg/ml LPS in vitro. The administration of QUE decreased the levels of MDA, NADPH, lipid peroxidation and cytoplasmic cytochrome C and upregulated the levels of GSH and TOM 20, thus exerting an anti­oxidative effect via mediating SIRT1 expression. It also activated the SIRT1/p53/SLC7A11 signaling pathway to reduce cellular Fe2+ and PTGS2 levels, decreased cell apoptosis rate, and upregulated the levels of GPX4 and ferritin to inhibit ferroptosis of H9C2 cells in vitro. Injection of QUE into rats activated the SIRT1/p53/SLC7A11 signaling pathway, reduced the levels of CK­MB, cTnI, inflammatory cell infiltration, MDA, NADPH, cytoplasmic cytochrome C, cellular Fe2+, and PTGS2 but upregulated the levels of GSH, TOM 20, GPX4, and ferritin to alleviate SIC in a dose­dependent manner in vivo. To conclude, QUE exerted an anti­ferroptotic effect via activation of the SIRT1/p53/SLC7A11 signaling pathway to dampen SIC both in vivo and in vitro. These findings highlighted a potential therapeutic strategy for the management of SIC.

Systematic review and meta-analysis of the efficacy of olprinone and MEFV gene in treating heart failure.

Cardiovascular failure is the main cause of death in industrialized societies. The results of recent studies have shown that some mutations in the MEFV gene are common in heart failure patients. For this reason, the study of mutations and genetic factors has been of great help in the treatment of this disease, but despite this, due to the heterogeneity of clinical symptoms, multiple pathophysiological processes, and environmental genetic factors, the complete understanding of the genetic causes of this disease is very complicated. As the new generation of phosphodiesterase (PDE) III inhibitor, olprinone, the inhibition of human heart PDE III by olprinone is highly selective. It is suitable for the treatment of acute heart failure (HF) and acute cardiac insufficiency after cardiac surgery. In this study Olprinone, milrinone, PDE inhibitors, cardiac failure, and HF were selected as the search terms to retrieve articles published between January 1999 and March 2022. RevMan5.3 and Stata were employed to analyze and evaluate the risk bias of the included articles. Besides, the Q test and heterogeneity were utilized to evaluate the heterogeneity between articles. The results of this research showed No heterogeneity was found between each research group. The sensitivity (Sen) and specificity (Spe) of the two methods were compared. Olprinone showed more significant therapeutic effects than other PDE inhibitors. Besides, the therapeutic effect on the patients with HF in the two groups was obvious. The incidence of postoperative adverse reactions among the patients without relieving HF was low. The influences on urine flow of the two group's demonstrated heterogeneity, and its effect revealed no statistical meaning. The meta-analysis confirmed that the Spe and Sen of olprinone treatment were higher than those of other PDE inhibitors. In terms of hemodynamics, there was little difference between various treatment methods.

Sequential targeting dual-responsive magnetic nanoparticle for improved therapy of lung metastatic breast cancer.

Lung metastatic breast cancer is a leading cause of cancer-related death in women and difficult to treat due to non-specific drug delivery. Herein a sequential targeting dual-responsive magnetic nanoparticle was fabricated, where Fe3O4 nanoparticle was used as magnetic core, then sequentially coated with tetraethyl orthosilicate, bis[3-(triethoxy-silyl)propyl] tetrasulfide, and 3-(trimethoxysilyl) propylmethacrylate to afford -C = C- on the surface for further polymerisation with acrylic acid, acryloyl-6-ethylenediamine-6-deoxy-ß-cyclodextrin using N, N-bisacryloylcy- stamine as cross-linker, obtaining pH/redox dual-responsive magnetic nanoparticle (MNPs-CD) to delivery doxorubicin (DOX) for suppressing lung metastatic breast cancer. Our results suggested DOX-loaded nanoparticle could target the lung metastases site by sequential targeting, in which they first be delivered to the lung and even the metastatic nodules through size-driven, electrical interaction, and magnetic field-guided mechanisms, then be effectively internalised into the cancer cells followed by intelligently triggering DOX release. MTT analysis demonstrated DOX-loaded nanoparticle exhibited high anti-tumour activity against 4T1 and A549 cells. 4T1 tumour-bearing mice were employed to confirm the higher specific accumulation in lung and improved anti-metastatic therapy efficiency of DOX by focussing an extracorporeal magnetic field on the biological target. Our findings suggested the as-proposed dual-responsive magnetic nanoparticle offered a prerequisite to inhibit lung metastasis of breast cancer tumours.

Case report of extranodal natural killer/T-cell lymphoma that induced secondary hemophagocytic syndrome-related histiocytic glomerulopathy.

Hemophagocytic syndrome (HPS) is a proliferative disease of the mononuclear macrophage system involving multiple organs and systems. We report a 50-year-old Asian woman who presented with unexplained fever and proteinuria. Laboratory tests showed cytopenia, considerably elevated serum ferritin and IL-2 receptor concentrations, and evidence of hemophagocytosis in the bone marrow. A renal biopsy showed macrophage infiltration into the glomerulus, resulting in podocyte and endothelial cell damage. We finally diagnosed the patient with extranodal natural killer/T-cell lymphoma, nasal type that induced HPS-related histiocytic glomerulopathy. Proteinuria and inflammation responded to treatment with high-dose pulsed methylprednisolone combined with VP-16 and cyclosporine. To the best of our knowledge, this is the first documented case of HPS-related histiocytic glomerulopathy triggered by a malignant tumor.

Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury.

BACKGROUND AND AIMS: Drug-induced liver injury (DILI) remains a critical issue and a hindrance to clinical application of Tripterygium Glycosides Tablet (TGT) despite its favorable therapeutic efficacy in rheumatoid arthritis. Herein, we aimed to elucidate the molecular mechanisms underlying TGT-induced hepatotoxicity. METHODS: Chemical profiling of TGT was identified by UPLC-Q/TOF-MS/MS and its putative targets were predicted based on chemical structure similarity calculation. Following "DILI-related gene-TGT putative target" interaction network construction, a list of key network targets was screened according to nodes' topological importance and functional relevance. Both in vivo and in vitro experiments were performed to determine drug hepatotoxicity and the underlying mechanisms. RESULT: A total of 49 chemical components and 914 putative targets of TGTs were identified. Network calculation and functional modularization screened RAS-ERK and mTOR signalings-associated autophagy to be one of the candidate targets of TGT-induced hepatotoxicity. Experimentally, TGT significantly activated RAS-ERK axis, elevated the number of autophagosomes and the expression of LC3II protein, but reduced the expression of p62 protein and suppressed mTOR phosphorylation in the liver tissues of TGT-induced acute liver injury mice and chronic liver injury mice in vivo and AML12 cells in vitro. Moreover, TGT and mL-098 (an activator of RAS) co-treatment reduced AML12 cell viability via regulating autophagy and TGT-induced liver injury-related indicators more dramatically than TGT treatment alone, whereas Salirasib (an inhibitor of RAS) had an opposite effect. CONCLUSION: RAS-ERK-mTOR cross-talk may play a crucial role in TGT-induced hepatocyte autophagy, offering a promising target for developing novel therapeutics to combat TGT-induced hepatotoxicity.

Combining single-cell transcriptomics and CellTagging to identify differentiation trajectories of human adipose-derived mesenchymal stem cells.

BACKGROUND: Mesenchymal stromal cells (MSCs) have attracted great attention in the application of cell-based therapy because of their pluripotent differentiation and immunomodulatory ability. Due to the limited number of MSCs isolated from donor tissues, a large number of MSCs need to be expanded in a traditional two-dimensional cell culture device to obtain a sufficient therapeutic amount. However, long-term cultivation of MSCs in vitro has been proven to reduce their differentiation potential and change their immunomodulatory characteristics. We aimed to explore the cellular heterogeneity and differentiation potential of different MSCs expanded in vitro and reconstruct the complex cloning track of cells in the process of differentiation. METHODS: Single cell transcriptome sequencing was combined with 'CellTagging', which is a composite barcode indexing method that can capture the cloning history and cell identity in parallel to track the differentiation process of the same cell over time. RESULTS: Through the single-cell transcriptome and CellTagging, we found that the heterogeneity of human adipose tissue derived stem cells (hADSCs) in the early stage of culture was very limited. With the passage, the cells spontaneously differentiated during the process of division and proliferation, and the heterogeneity of the cells increased. By tracing the differentiation track of cells, we found most cells have the potential for multidirectional differentiation, while a few cells have the potential for unidirectional differentiation. One subpopulation of hADSCs with the specific osteoblast differentiation potential was traced from the early stage to the late stage, which indicates that the differentiation trajectories of the cells are determined in the early stages of lineage transformation. Further, considering that all genes related to osteogenic differentiation have not yet been determined, we identified that there are some genes that are highly expressed specifically in the hADSC subsets that can successfully differentiate into osteoblasts, such as Serpin Family E Member 2 (SERPINE2), Secreted Frizzled Related Protein 1 (SFRP1), Keratin 7 (KRT7), Peptidase Inhibitor 16 (PI16), and Carboxypeptidase E (CPE), which may be key regulatory genes for osteogenic induction, and finally proved that the SERPINE2 gene can promote the osteogenic process. CONCLUSION: The results of this study contribute toward the exploration of the heterogeneity of hADSCs and improving our understanding of the influence of heterogeneity on the differentiation potential of cells. Through this study, we found that the SERPINE2 gene plays a decisive role in the osteogenic differentiation of hADSCs, which lays a foundation for establishing a more novel and complete induction system.

Gender differences in clinical characteristics of patients with non-cystic fibrosis bronchiectasis in different age groups in northern China.

INTRODUCTION: Patient gender has clinical and prognostic implications in non-cystic fibrosis bronchiectasis, yet the potential effect of gender on clinical characteristics of patients with non-cystic fibrosis bronchiectasis is still unclear. OBJECTIVES: This study aimed to investigate the gender differences in clinical characteristics of patients with bronchiectasis in different age groups in northern China. METHODS: A total of 777 patients diagnosed with bronchiectasis were retrospectively included in Beijing Chaoyang Hospital and divided into two groups by gender: the male group and the female group. Each group was then subdivided into two according to their age (≤65 and >65 years). Gender differences in clinical characteristics were compared in all patients with bronchiectasis in the two age groups, respectively. RESULTS: A total of 777 bronchiectasis patients were included. Of these patients, the prevalence of female non-smokers was substantially higher than that of male non-smokers (94.0% vs. 36.8%). There were gender differences in etiology of bronchiectasis, with more post-measles and connective tissue disease in females (p = 0.006 and 0.002 separately) and more chronic obstructive pulmonary disease (COPD) in males (p < 0.001). The male group had a significantly higher C-reactive protein (CRP) on admission (p = 0.03). Female patients showed a higher forced expiratory volume in 1 s as percentage of predicted volume (FEV1%pred) and forced vital capacity rate of 1 s (FEV1/FVC) (p < 0.001), lower partial pressure of carbon dioxide (PaCO2 ) (p = 0.04) and hospital costs (p = 0.02) than males, and a higher prevalence of infection with Pseudomonas aeruginosa in >65-year-old group (p = 0.019). CONCLUSIONS: There were many differences between male and female patients in smoking status, etiology, lung function, blood gas analysis, and hospital costs in all patients or different age groups.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Alleviate Peritoneal Dialysis-Associated Peritoneal Injury.

Peritoneal fibrosis is a critical sequela that limits the application of peritoneal dialysis (PD). This study explored the role and mechanism of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in preventing PD-associated peritoneal injury. C57BL/6 mice were randomized into three groups: a control (saline), peritoneal injury [2.5% glucose peritoneal dialysate + lipopolysaccharide (LPS)], and peritoneal injury + exosome group. After 6 weeks, mice were dissected, and the parietal peritoneum was collected. The level of peritoneal structural and functional damage was assessed. Additionally, transcriptome analysis of the peritoneum and miRNA sequencing on BMSC-Exos were performed. The parietal peritoneum had significantly thickened, and peritoneal function was impaired in the peritoneal injury group. Peritoneal structural and functional damage was significantly reduced after exosome treatment, while peritoneal inflammation, fibrosis, angiogenesis, and mesothelial damage significantly increased. Transcriptomic analysis showed that the BMSC-Exos affected the cell cycle process, cell differentiation, and inflammatory response regulation. Significant pathways in the exosome group were enriched by inflammation, immune response, and cell differentiation, which constitute a molecular network that regulates the peritoneal protective mechanism. Additionally, inflammatory factors (TNF-α, IL-1ß), fibrosis markers (α-SMA, collagen-III, fibronectin), profibrotic cytokines (TGF-ß1), and angiogenesis-related factor (VEGF) were downregulated at the mRNA and protein levels through BMSC-Exos treatment. BMSC-Exos treatment can prevent peritoneal injury by inhibiting peritoneal fibrosis, inflammation, and angiogenesis, showing a multitarget regulatory effect. Therefore, BMSC-Exos therapy might be a new therapeutic strategy for treating peritoneal injury.

Exosomes in malignant pleural effusion from lung cancer patients impaired the cytotoxicity of double-negative T cells.

CD3+CD4-CD8- double-negative T (DNT) cells are new weapons in cancer immunotherapy. Here, we explored DNT cells in malignant pleural effusions (MPEs) from lung cancer patients. DNT cells, especially TCRαß+CD56- DNT cells, were increased in MPE from lung cancer patients. DNT cells highly expressed PD-1, TRAIL, NKG2D and DNAM-1. In contrast, FasL was barely detected in DNT cells. Compared with non-MPE cells, MPE-derived DNT cells expressed much higher levels of PD-1 and TRAIL. DNT cells from healthy peripheral blood donors potentially killed lung cancers, which was decreased by MPE supernatant. Exosomes from MPE supernatant expressed PD-1 and CEACAM1 and impaired the cytotoxicity of DNT cells. Blocking PD-1 and TIM3 rescued the cytotoxicity of DNT cells treated with MPE-derived exosomes. Overall, we demonstrated that the frequency of DNT cells in MPE from lung cancer patients was increased and that MPE-derived exosomes impaired the cytotoxicity of DNT cells via the PD-1/PD-L1 and CEACAM1/TIM3 pathways.

Phototheranostics for NIR fluorescence image guided PDT/PTT with extended conjugation and enhanced TICT.

Introducing donor and acceptor into conjugated system can facilitate the intersystem crossing (ISC) rate to increase the generation of ROS. Twisted intramolecular charge transfer (TICT) state could favor enhance the nonradiative transition and photothermal conversion efficiency (PCE). Herein, diketopyrrolopyrrole (DPP) core functionalized benzene (PDDP), thiophene (TDPP), triphenylamine-conjugated benzene (TPA-PDDP) and thiophene (TPA-TDPP) derivatives were designed and synthesized. Electrochemistry experiments revealed the heavy atom effect and the introduction of triphenylamine reduced the energy level of TPA-TDPP and improved the ability to generate 1O2 (1O2 QY = 50%). In addition, in the aggregated state, introduction of thiophene, triphenylamine, and long alkyl chains promoted the twisting effect, preventing the intermolecular π-π interaction and enhancing the PCE of TPA-TDPP (38.7%). In vivo fluorescence imaging showed that TPA-TDPP NPs can target the tumor site with the enhanced permeability and retention (EPR) effect and presented excellent synergistic photodynamic/photothermal therapy.

Integrated multi-omics profiling yields a clinically relevant molecular classification for esophageal squamous cell carcinoma.

Integrated molecular analysis of human cancer has yielded molecular classification for precise management of cancer patients. Here, we analyzed the whole genomic, epigenomic, transcriptomic, and proteomic data of 155 esophageal squamous cell carcinomas (ESCCs). Multi-omics analysis led to the classification of ESCCs into four subtypes: cell cycle pathway activation, NRF2 oncogenic activation, immune suppression (IS), and immune modulation (IM). IS and IM cases were highly immune infiltrated but differed in the type and distribution of immune cells. IM cases showed better response to immune checkpoint blockade therapy than other subtypes in a clinical trial. We further developed a classifier with 28 features to identify the IM subtype, which predicted anti-PD-1 therapy response with 85.7% sensitivity and 90% specificity. These results emphasize the clinical value of unbiased molecular classification based on multi-omics data and have the potential to further improve the understanding and treatment of ESCC.

Pan-cancer surveys indicate cell cycle-related roles of primate-specific genes in tumors and embryonic cerebrum.

BACKGROUND: Despite having been extensively studied, it remains largely unclear why humans bear a particularly high risk of cancer. The antagonistic pleiotropy hypothesis predicts that primate-specific genes (PSGs) tend to promote tumorigenesis, while the molecular atavism hypothesis predicts that PSGs involved in tumors may represent recently derived duplicates of unicellular genes. However, these predictions have not been tested. RESULTS: By taking advantage of pan-cancer genomic data, we find the upregulation of PSGs across 13 cancer types, which is facilitated by copy-number gain and promoter hypomethylation. Meta-analyses indicate that upregulated PSGs (uPSGs) tend to promote tumorigenesis and to play cell cycle-related roles. The cell cycle-related uPSGs predominantly represent derived duplicates of unicellular genes. We prioritize 15 uPSGs and perform an in-depth analysis of one unicellular gene-derived duplicate involved in the cell cycle, DDX11. Genome-wide screening data and knockdown experiments demonstrate that DDX11 is broadly essential across cancer cell lines. Importantly, non-neutral amino acid substitution patterns and increased expression indicate that DDX11 has been under positive selection. Finally, we find that cell cycle-related uPSGs are also preferentially upregulated in the highly proliferative embryonic cerebrum. CONCLUSIONS: Consistent with the predictions of the atavism and antagonistic pleiotropy hypotheses, primate-specific genes, especially those PSGs derived from cell cycle-related genes that emerged in unicellular ancestors, contribute to the early proliferation of the human cerebrum at the cost of hitchhiking by similarly highly proliferative cancer cells.

Ixazomib Combined With Autologous Stem Cell Transplantation for POEMS Syndrome: A Case Report and Meta-Analysis.

Objective: Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a rare monoclonal plasma cell proliferation disorder. At present, there is no unified treatment for POEMS syndrome. Here, we describe one case with POEMS syndrome with obvious neurological symptoms diagnosed in September 2020. We made a meta--analysis to assess the efficacy of treatment strategies in recent years. Methods: We retrospectively analyzed the diagnosis and treatment of this patient, and searched relevant articles in PubMed, Embase, and MEDLINE databases using MedicalSubject Headings (MeSH) (eg, POEMS, Therapy, Drug Therapy, Biological Therapy, Combined Modality Therapy, Hematopoietic Stem Cell Transplantation, Immunotherapy, Molecular Targeted Therapy, Chemoradiotherapy, and Salvage Therapy) and free words, and performed the statistical analysis. Results: The patient's efficacy evaluation was complete response (CR) after treatment with ixazomib combined with autologous stem cell transplantation (ASCT). Overall, 20 articles consist of 6 clinical trials, 14 retrospective studies, and 936 patients were included in this meta-analysis. There was no significant difference in complete hematologic response (CRH) rate between people who underwent ASCT and those who did not. However, ASCT might have a better survival rate. Conclusions: Ixazomib combined with ASCT therapy may be a safe and effective method for patients with POEMS syndrome.