Effect of ginger and P6 acupressure on chemotherapy-induced nausea and vomiting: a randomized controlled study.

OBJECTIVE: To evaluate the effect of ginger with P6 acupressure in preventing and treating chemotherapy-induced nausea and vomiting (CINV) in cancer patients. METHOD: A total of 172 participants were randomly divided into the control, ginger, acupressure, and joint groups, who were hospitalized in the Affiliated Hospital of Xuzhou Medical University from February and September 2022. The baseline characteristics, nausea, vomiting, and retching, benefit finding, functional living index-emesis, treatment satisfaction, and adverse reaction, were used in data collection. RESULTS: No significant difference was found in benefit finding and adverse reactions among the four groups (P > 0.05). Ginger significantly improved delayed CINV and function living index-nausea (P < 0.05) but had no significant effect on acute CINV, retching, and delayed vomiting, functional living index-emesis, and treatment satisfaction (P>0.05). Acute nausea and retching, delayed nausea, vomiting, and retching, functional living index-emesis, and treatment satisfaction were effectively improved in the acupressure and joint groups (P < 0.05). CONCLUSION: Ginger with P6 acupressure may contribute to improving CINV in patients undergoing chemotherapy.

First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

BACKGROUND: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). FINDINGS: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. INTERPRETATION: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. FUNDING: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Association between fresh fruit consumption and the risk of chronic obstructive pulmonary disease-related hospitalization and death in Chinese adults: A prospective cohort study.

BACKGROUND: Existing evidence suggests that fruit consumption is a significant influencing factor for chronic obstructive pulmonary disease (COPD), but this is unclear in the Chinese population. We examined the association of fresh fruit consumption with the risk of COPD-related hospitalization and death in a nationwide, population-based prospective cohort from China. METHODS: Between 2004 and 2008, the China Kadoorie Biobank recruited >0.5 million adults aged 30 to 79 years from ten diverse regions across China. After excluding individuals diagnosed with major chronic diseases and prevalent COPD, the prospective analysis included 421,428 participants. Cox regression was used to calculate the hazard ratios (HRs) for the association between fresh fruit consumption and risk of COPD-related hospitalization and death, with adjustment for established and potential confounders. RESULTS: During a mean follow-up of 10.9 years, 11,292 COPD hospitalization events and deaths were documented, with an overall incidence rate of 2.47/1000 person-years. Participants who consumed fresh fruit daily had a 22% lower risk of COPD-related hospitalization and death compared with non-consumers (HR = 0.78, 95% confidence interval [CI]: 0.71-0.87). The inverse association between fresh fruit consumption and COPD-related hospitalization and death was stronger among non-current smokers and participants with normal body mass index (BMI) (18.5 kg/m 2 ≤ BMI < 24.0 kg/m 2 ); the corresponding HRs for daily fresh fruit consumption were 0.78 (95% CI: 0.68-0.89) and 0.69 (95% CI: 0.59-0.79) compared with their counterparts, respectively. CONCLUSIONS: High-frequency fruit consumption was associated with a lower risk of COPD in Chinese adults. Increasing fruit consumption, together with cigarette cessation and weight control, should be considered in the prevention and management of COPD.

Extracellular Vesicles Derived from Mesenchymal Stem Cells Promote Wound Healing and Skin Regeneration by Modulating Multiple Cellular Changes: A Brief Review.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are biologically active substances secreted by MSCs into the extracellular matrix that play an immunomodulatory role in skin damage repair. To investigate the mechanism of MSC-EVs in reducing inflammation, promoting angiogenesis, promoting the proliferation and migration of epithelial cells and fibroblasts, and extracellular matrix remodeling during wound healing, we focused on the effects of EVs on multiple cell types at various stages of skin injury. A literature review was conducted to explore related research on the influence of MSC-EVs on the types of cells involved in wound healing. MSC-EVs show a strong regulatory ability on immune cells involved in the regulation of inflammation, including macrophages, neutrophils, and T cells, and other cells involved in tissue proliferation and remodeling, such as fibroblasts, keratinocytes, and endothelial cells, during wound healing in in vitro and in vivo experiments, which substantially promoted the understanding of wound healing in the field of trauma medicine. MSC-EVs have potential applications in combating poor skin wound healing. Elucidating the mechanism of action of EVs in the wound-healing process would greatly advance the understanding of therapeutic wound healing.

Transcriptome profiling reveals ethylene formation in rice seeds by trichloroisocyanuric acid.

KEY MESSAGE: Ethylene formation via methionine reacting with trichloroisocyanuric acid under FeSO4 condition in a non-enzymatical manner provides one economically and efficiently novel ethylene-forming approach in planta. Rice seed germination can be stimulated by trichloroisocyanuric acid (TCICA). However, the molecular basis of TCICA in stimulating rice seed germination remains unclear. In this study, the molecular mechanism on how TCICA stimulated rice seed germination was examined via comparative transcriptome. Results showed that clustering of transcripts of TCICA-treated seeds, water-treated seeds, and dry seeds was clearly separated. Twenty-two and three hundred differentially expressed genes were identified as TCICA treatment responsive genes and TCICA treatment potentially responsive genes, respectively. Two and one TCICA treatment responsive genes were involved in ethylene signal transduction and iron homeostasis, respectively. Seventeen of the three hundred TCICA treatment potentially responsive genes were significantly annotated to iron ion binding. Meanwhile, level of methionine (ethylene precursor) showed a 73.9% decrease in response to TCICA treatment. Ethylene was then proved to produce via methionine reacting with TCICA under FeSO4 condition in vitro. Revealing ethylene formation by TCICA not only may bring novel insights into crosstalk between ethylene and other phytohormones during rice seed germination, but also may provide one economically and efficiently novel approach to producing ethylene in planta independently of the ethylene biosynthesis in plants and thereby may broaden its applications in investigational and applied purposes.

Effect of L-cysteine treatment to induce postharvest disease resistance of Monilinia fructicola in plum fruits and the possible mechanisms involved.

Plum is an important stone fruit in China, but the fruit is easily perishable and susceptible to infection by pathogens. Traditionally, synthetic fungicides are used to control diseases. However, the side effects of fungicides should not be ignored. Cysteine, generally recognized as safe (GRAS) amino acid, has been reported to play roles in the plant abiotic stress response, but little is known about the role of cysteine to control postharvest diseases in fruits. Therefore, this study was designed to investigate the effect of L-cysteine treatment on control of postharvest brown rot in artificially inoculated plum fruits and the possible biocontrol mechanisms involved. Postharvest plum fruits were inoculated with 1, 10, 100 and 1000 mg L-1 L-cysteine. 100 mg L-1 L-cysteine treatment effectively controlled brown rot in artificially inoculated plum fruits by inducing resistance. Furthermore, 100 mg L-1 L-cysteine treatment increased the activities of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH), enhanced the content of NADPH of the pentose phosphate pathway, as well as improved the contents of H2O2 and some amino acids in the artificially inoculated plum fruits. 100 mg L-1 L-cysteine treatment also elevated the antioxidant content (AsA, GSH) and the antioxidant enzymes activities (APX, GR, MDAR, DHAR) of the ascorbate-glutathione (AsA-GSH) pathway. The protective effects of L-cysteine treatment on postharvest plum fruits likely be due to activating some defense-related responses of the fruit against infection. L-cysteine treatment is a safe promising method for controlling postharvest brown rot in plum fruits.

Establishing gas transport highways in MOF-based mixed matrix membranes.

Achieving percolation pathways in a metal-organic framework (MOF)-based mixed matrix membrane (MMM) without compromising its mechanical properties is challenging. We developed phase separated (PS)-MMMs with an interconnected MOF domain running across the whole membrane. Through demixing two immiscible polyimides, the MOF particles were selectively partitioned into one of the preferred polymer domains at over 50 volume % local packing density, leading to a percolated network at only 19 weight % MOF loading. The CO2 permeability of this PS-MMM is 6.6 times that of the pure polymer membrane, while the CO2/N2 and CO2/CH4 selectivity remain largely unchanged. Meanwhile, benefiting from its unique co-continuous morphology, the PS-MMM also exhibited markedly improved membrane ductility compared to the conventional MMM at similar MOF loading. PS-MMMs offer a practical solution to simultaneously achieve high membrane permeability and good mechanical properties.

Transcriptomic profiling of programmed cell death 1 (PD-1) expressing T cells in early rheumatoid arthritis identifies a decreased CD4 + PD-1 + signature post-treatment.

Programmed cell death protein 1 (PD-1)-expressing T cells are expanded in individuals with established rheumatoid arthritis (RA). However, little is known about their functional role in the pathogenesis of early RA. To address this, we investigated the transcriptomic profiles of circulating CD4+ and CD8+ PD-1+ lymphocytes from patients with early RA (n = 5) using fluorescence activated cell sorting in conjunction with total RNA sequencing. Additionally, we assessed for alterations in CD4+PD-1+ gene signatures in previously published synovial tissue (ST) biopsy data (n = 19) (GSE89408, GSE97165) before and after six-months of triple disease modifying anti-rheumatic drug (tDMARD) treatment. Comparisons of gene signatures between CD4+PD-1+ vs. PD-1- cells identified significant upregulation of genes including CXCL13 and MAF, and in pathways including Th1 and Th2, cross talk between dendritic cells and NK cells, B cell development and antigen presentation. Gene signatures from early RA ST before and after six-month tDMARD treatment revealed downregulation of the CD4+PD-1+ signatures following treatment, identifying a mechanism through which tDMARDs exert their effect by influencing T cell populations. Furthermore, we identify factors associated with B cell help that are enhanced in the ST compared with PBMCs, highlighting their importance in driving synovial inflammation.

mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity.

Developmental sevoflurane exposure leads to neuronal cell death, and subsequent learning and memory cognitive defects. The underlyi\ng mechanism remains to be elucidated. Gasdermin D (GSDMD)-mediated pyroptosis is a form of inflammatory cell death and participates in a variety of neurodegenerative diseases. Several studies illustrated that dysregulation of mTOR activity is involved in pyroptotic cell death. The current study was designed to interrogate the role of GSDMD-mediated pyroptosis and mTOR activity in developmental sevoflurane exposure. We found that inhibition of GSDMD pore formation with Disulfiram (DSF) or Necrosulfonamide (NSA) significantly attenuated sevoflurane neurotoxicity in vitro. In addition, treatment with DSF or NSA also mitigated damage-associated molecular patterns (DAMPs) release and subsequent plasma membrane rupture (PMR) induced by sevoflurane challenge. Further investigation showed that the overactivation of mTOR signaling is involved in sevoflurane induced pyroptosis both in vivo and in vitro. Intriguingly, we found that the DAMPs release and subsequent PMR triggered by developmental sevoflurane priming were compromised by knocking down the expression of mTORC1 component Raptor, but not mTORC2 component Rictor. Moreover, sevoflurane induced pyroptosis could also be restored by suppressing mTOR activity or knocking down the expressions of Ras-related small GTPases RagA or RagC. Finally, administration of DSF or NSA dramatically improved the spatial and emotional cognitive disorders without alternation of locomotor activity. Taken together, these results indicate that mTORC1-dependent and GSDMD-mediated pyroptosis contributes to the developmental sevoflurane neurotoxicity. Characterizing these processes may provide experimental evidence for the possible prevention of developmental sevoflurane neurotoxicity.

Effect of ginger and P6 acupressure on chemotherapy-induced nausea and vomiting: a randomized controlled study / Efeitos das compressões de acuponto de gengibre e Neiguan sobre náuseas e vômitos induzidos por quimioterapia: um estudo randomizado e controlado / Efecto del jengibre y la acupresión de P6 en las náuseas y vómitos inducidos por la quimioterapia: estudio controlado aleatorizado

ABSTRACT Objective: To evaluate the effect of ginger with P6 acupressure in preventing and treating chemotherapy-induced nausea and vomiting (CINV) in cancer patients. Method: A total of 172 participants were randomly divided into the control, ginger, acupressure, and joint groups, who were hospitalized in the Affiliated Hospital of Xuzhou Medical University from February and September 2022. The baseline characteristics, nausea, vomiting, and retching, benefit finding, functional living index-emesis, treatment satisfaction, and adverse reaction, were used in data collection. Results: No significant difference was found in benefit finding and adverse reactions among the four groups (P > 0.05). Ginger significantly improved delayed CINV and function living index-nausea (P < 0.05) but had no significant effect on acute CINV, retching, and delayed vomiting, functional living index-emesis, and treatment satisfaction (P>0.05). Acute nausea and retching, delayed nausea, vomiting, and retching, functional living index-emesis, and treatment satisfaction were effectively improved in the acupressure and joint groups (P < 0.05). Conclusion: Ginger with P6 acupressure may contribute to improving CINV in patients undergoing chemotherapy.

RESUMEN Objetivo: Evaluar el efecto del jengibre con acupresión P6 en la prevención y tratamiento de las náuseas y vómitos (nviq) inducidos por la quimioterapia en pacientes con cáncer. Método: Se dividió al azar A un total de 172 participantes en los grupos control, jengibre, acupresión y conjunto, que fueron hospitalizados en el Hospital afiliado de la universidad médica Xuzhou entre febrero y septiembre de 2022. En la recolección de datos se utilizaron las características basales: náuseas, vómitos y náuseas, hallazgo de beneficios, índice de vida funcional, satisfacción con el tratamiento y reacciones adversas. Resultados: No se encontró diferencia significativa en el hallazgo del beneficio y las reacciones adversas entre los cuatro grupos (P >0.05). El jengibre mejoró significativamente las nviq diferidas y el índice de vida funcional (nausea) de forma significativa (P < 0.05), pero no tuvo un efecto significativo en las nvi, las náuseas y el vómito diferidos, la emesis del índice de vida funcional y la satisfacción con el tratamiento (P >0.05). Las náuseas agudas y las arcadas, las náuseas, los vómitos y las arcadas tardías, la medida del índice de vida funcional y la satisfacción con el tratamiento mejoraron efectivamente en los grupos de acupresión y articulares (P < 0,05). Conclusión: El jengibre con acupresión P6 puede contribuir a mejorar las nviq en pacientes sometidos a quimioterapia.

RESUMO Objetivo: Avaliar os efeitos da compressão do acuponto gengibre e Neiguan na prevenção e tratamento de náuseas e vômitos induzidos por quimioterapia em pacientes oncológicos. Métodos: Um total de 172 pacientes hospitalizados no Hospital Afiliado da Xuzhou Medical University de fevereiro a setembro de 2022 foram divididos aleatoriamente em grupo controle, grupo gengibre, grupo acuponto e grupo combinado. A recolha de dados incluiu principalmente dados basais, pontuação de náuseas, vómitos e vómitos, sensação de benefício da doença, índice de vida funcional, satisfação com o tratamento e efeitos adversos. Resultados: Não houve diferenças significativas no benefício da doença e efeitos adversos entre os quatro grupos (P >0,05). O gengibre melhorou significativamente o índice de vida funcional tardia e náusea (P < 0,05), mas não melhorou a NVI tardia e vómitos e vómitos retardados, o índice de vida funcional dos vómitos e a satisfação com o tratamento (P >0,05). Ambos os grupos de acuponto e combinação melhoraram náuseas agudas, vómitos, náuseas tardias, vómitos, vómitos, vómitos, índice de vida funcional e satisfação com o tratamento (P < 0,05). Conclusão: A acupuntura de gengibre e neiguan pode ajudar a melhorar a NVIQ em pacientes submetidos a quimioterapia.

High MEIS3 Expression Indicates a Poor Prognosis for Patients with Stage II/III Colorectal Cancer.

BACKGROUND: The Wnt/ß-catenin signaling pathway plays crucial roles in tumor budding and the epithelial-mesenchymal transition (EMT). Myeloid ecotropic viral insertion site 3 (MEIS3)-a direct target of Wnt/ß-catenin-promotes vagal neural crest cell migration into the gut tissue during development; however, its role in cancer progression remains unclear. In this study, the role of MEIS3 in colorectal cancer (CRC) progression was investigated. METHODS: We analyzed the association between MEIS3 protein expression and the clinical stages of CRC patients, and the effect on tumor cell migration and invasion by wound healing and transwell assays. Finally, we analyzed the association between MEIS3 expression and the disease-free survival (DFS) and overall survival of CRC patients through Kaplan-Meier analysis. RESULTS: We found that MEIS3 expression was strongly associated with CRC progression and could be employed to assess DFS in postoperative patients. MEIS3-positive cells were mainly distributed in the growth front and tumor-stroma interface of the CRC tissues, which contain abundant EMT-active and tumor budding cells dominating cancer metastasis. Moreover, MEIS3 promoted CRC cell migration and invasion by regulating effectors including laminin subunit beta 1, matrix metalloprotein 2, and vimentin. MEIS3 protein expression increased with CRC progression according to the clinical stage, which could be used as a biomarker to stratify CRC patients. The 5-year DFS of MEIS3-high patients was poorer than that of MEIS3-low patients (40.6% vs. 61.7%; p < 0.0001). Moreover, the 5-year DFS of stage II patients with MEIS3-high expression (53.4%) was comparable to that of stage III patients with MEIS3-low expression (49.5%), while the 5-year DFS of MEIS3-high patients in stage III (30.9%) was comparable to that of stage IV patients (29.6%). CONCLUSIONS: This study showed that MEIS3 can promote cancer cell metastasis and thus may be a promising biomarker for higher rates of recurrence in postoperative patients with stage II/III CRC.

Differential expansion of T peripheral helper cells in early rheumatoid arthritis and osteoarthritis synovium.

OBJECTIVES: Programmed cell death protein 1 (PD-1)-expressing T cells are implicated in the pathogenesis of autoimmune inflammatory diseases such as rheumatoid arthritis. A subset of CXCR5- T cells, termed T peripheral helper (Tph) cells, which drive B cell differentiation, have been identified in ectopic lymphoid structures in established rheumatoid arthritis synovial tissue. Here, we aimed to characterise these in treatment-naïve, early rheumatoid arthritis to determine whether these cells accumulate prior to fully established disease. METHODS: Fresh dissociated tissue and peripheral blood mononuclear cell (PBMC) suspensions were stained with Zombie UV, followed by anti-CD45RO, PD-1, CD3, ICOS, CD8, CD4, CD20, CXCR5, TIGIT and CD38 antibodies prior to analysis. For histology, rheumatoid arthritis synovial sections were prepared for Opal multispectral immunofluorescence with anti-CD45RO, CD20, PD-1 and CXCR5 antibodies. Images were acquired on the Perkin Elmer Vectra V.3.0 imaging system and analysed using InForm Advanced Image Analysis software. RESULTS: Flow cytometry revealed T cell infiltration in the rheumatoid arthritis synovium with differential expression of PD-1, CD45RO, ICOS, TIGIT and CD38. We observed a higher frequency of PD1hiCXCR5- Tph in rheumatoid arthritis synovial tissue and PBMCs versus controls, and no significant difference in T follicular helper cell frequency. Microscopy identified a 10-fold increase of Tph cells in early rheumatoid arthritis synovial follicular and diffuse regions, and identified Tph adjacent to germinal centre B cells. CONCLUSIONS: These data demonstrate that PD-1hi Tph cells are present in early rheumatoid arthritis, but not osteoarthritis synovium, and therefore may provide a target for treatment of patients with early rheumatoid arthritis.

Application of mammography-based radiomics signature for preoperative prediction of triple-negative breast cancer.

OBJECTIVE: This study is aimed to explore the value of mammography-based radiomics signature for preoperative prediction of triple-negative breast cancer (TNBC). MATERIALS AND METHODS: Initially, the clinical and X-ray data of patients (n = 319, age of 54 ± 14) with breast cancer (triple-negative-65, non-triple-negative-254) from the First Affiliated Hospital of Soochow University (n = 211, as a training set) and Suzhou Municipal Hospital (n = 108, as a verification set) from January 2018 to February 2021 are retrospectively analyzed. Comparing the mediolateral oblique (MLO) and cranial cauda (CC) mammography images, the mammography images with larger lesion areas are selected, and the image segmentation and radiomics feature extraction are then performed by the MaZda software. Further, the Fisher coefficients (Fisher), classification error probability combined average correlation coefficients (POE + ACC), and mutual information (MI) are used to select three sets of feature subsets. Moreover, the score of each patient's radiomics signature (Radscore) is calculated. Finally, the receiver operating characteristic curve (ROC) is analyzed to calculate the AUC, accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of TNBC. RESULTS: A significant difference in the mammography manifestation between the triple-negative and the non-triple-negative groups (P < 0.001) is observed. The (POE + ACC)-NDA method showed the highest accuracy of 88.39%. The Radscore of triple-negative and non-triple-negative groups in the training set includes - 0.678 (- 1.292, 0.088) and - 2.536 (- 3.496, - 1.324), respectively, with a statistically significant difference (Z = - 6.314, P < 0.001). In contrast, the Radscore in the validation set includes - 0.750 (- 1.332, - 0.054) and - 2.223 (- 2.963, - 1.256), with a statistically significant difference (Z = - 4.669, P < 0.001). In the training set, the AUC, accuracy, sensitivity, specificity, positive predictive value and negative predictive value of TNBC include 0.821 (95% confidence interval 0.752-0.890), 74.4%, 82.5%, 72.5%, 41.2%, and 94.6%, respectively. In the validation set, the AUC, accuracy, sensitivity, specificity, positive predictive value and negative predictive value of TNBC are of 0.809 (95% confidence interval 0.711-0.907), 80.6%, 72.0%, 80.7%, 55.5%, and 93.1%, respectively. CONCLUSION: In summary, we firmly believe that this mammography-based radiomics signature could be useful in the preoperative prediction of TNBC due to its high value.

Bridging nanoplatform and vaccine delivery, a landscape of strategy to enhance nasal immunity.

Vaccination is an urgently needed and effective option to address epidemic, cancers, allergies, and other diseases. Nasal administration of vaccines offers many benefits over needle-based injection including high compliance and less risk of infection. Inactivated or attenuated vaccines as convention vaccine present potential risks of pathogenic virulence reversal, the focus of nasal vaccine development has shifted to the use of next-generation (subunit and nucleic acid) vaccines. However, subunit and nucleic acid vaccine intranasally have numerous challenges in development and utilization due to mucociliary clearance, mucosal epithelial tight junction, and enzyme/pH degradation. Nanoplatforms as ideal delivery systems, with the ability to enhance the retention, penetration, and uptake of nasal mucosa, shows great potential in improving immunogenic efficacy of nasal vaccine. This review provides an overview of delivery strategies for overcoming nasal barrier, including mucosal adhesion, mucus penetration, targeting of antigen presenting cells (APCs), enhancement of paracellular transportation. We discuss methods of enhancing antigen immunogenicity by nanoplatforms as immune-modulators or multi-antigen co-delivery. Meanwhile, we describe the application status and development prospect of nanoplatforms for nasal vaccine administration. Development of nanoplatforms for vaccine delivery via nasal route will facilitate large-scale and faster global vaccination, helping to address the threat of epidemics.

Reshaping hypoxia and silencing CD73 via biomimetic gelatin nanotherapeutics to boost immunotherapy.

The ubiquitous hypoxic microenvironment at the tumor site helps to regulate hypoxic inducible factor (HIF-1α), up-regulate downstream CD73-adenosine (CD73-ADO) pathways, and further result in effector T cell function exhaustion, which is regarded as a crucial adverse factor in the poor clinical efficacy of immune checkpoint blockade therapy (ICB). How to reshape hypoxic microenvironment and silence CD73 remains a huge challenge to improve ICB therapeutic outcomes. In this study, cancer cell membrane-camouflaged gelatin nanoparticles (CSG@B16F10) were designed to co-deliver oxygen-generating agent catalase (CAT) and CD73siRNA, thus enhancing tumor oxygenation and alleviating CD73-ADO pathway-mediated T cell immunosuppression. The fabricated biomimetic nanoparticles could efficiently achieve immune evading and homologous targeting by virtue of the retention of cancer cell membrane protein. Matrix metalloproteinases (MMP)-responsive gelatin nanoparticles were gradually disintegrated to accelerate the release of payloads. Rapidly released CAT was found to relieve tumor hypoxia by generating endogenous oxygen, while CD73siRNA effectively silenced target gene, synergically inhibiting CD73 protein expression and facilitating T-cell-specific immunity. Upon introduction of CSG@B16F10 in melanoma-bearing mice, PD-L1 checkpoint blockade achieved optimal tumor suppression (∼83%). The enhanced immune efficacy was mainly manifested by enhanced cytotoxic T cell (CTL), reduced regulatory T cells (Tregs), and increased anti-tumor cytokine secretion. This work presents a new paradigm for the ideal design of biomimetic nanoplatforms and the synergistic treatment of hypoxia alleviation and CD73 silence, greatly promising for enhancing clinical immune potency of PD-1/PD-L1 immune checkpoint blockade.

Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2.

Epidemiological and clinical characteristics of patients with COVID-19 have been reported in the last two years. A few studies reported clinical course of illness of median 22 days, including viral shedding of median 20 days, but there are several cases with a longer time of viral shedding. In this study, we included four cases with a longer illness course of more than 40 days who had been discharged or still in hospital by March 15, 2020. Demographic, clinical treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records. We described the epidemiological and clinical characteristics and the course of viral shedding. Two patients had comorbidity, one with hypertension and the other with diabetes. We found smoking was not an independent risk factor. D-dimer maybe related to the severity of illness but not to the course of the illness. Nucleic acid detection suggested that maybe more sampling sites represented more virus replication sites and longer course of illness. In this study we found some non-critical severe relatively young patients whose character was different from former studies described to provide a basis for reference to assess the risk of transmission and the isolation duration of patients.

Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis.

OBJECTIVES: Immune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation. METHODS: Single cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters. RESULTS: Global transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor-ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-ß and macrophage interleukin (IL)-1ß synergy in driving the transcriptional profile of FAPα+THY1+ invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-ß and IL-1ß treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.

Blocking the A2B adenosine receptor alleviates myocardial damage by inhibiting spleen-derived MDSC mobilisation after acute myocardial infarction.

BACKGROUND: Myeloid-derived suppressor cell (MDSC) mobilisation is an important immune event in acute myocardial infarction (AMI). The A2B adenosine receptor (A2BAR) plays key role in regulating MDSC function, but its specific involvement in MDSC mobilisation in AMI remains unclear. METHODS: In AMI patients, the circulating MDSC ratio and A2BAR mRNA expression were measured. A mouse AMI model was established by left anterior descending coronary artery (LADCA) ligation. MDSCs were analysed by FACS and immunofluorescence staining (of heart tissue). A2BAR mRNA expression was assessed by qRT-PCR. Myocardial injury was detected by HE staining. Myocardial cell apoptosis was analysed by immunohistochemistry. Cardiac systolic function was evaluated by transthoracic echocardiography. RESULTS: In AMI patients, the circulating MDSC ratio was increased and positively correlated with A2BAR mRNA expression (r = 0.86, p < 0.01). In AMI model mice, the percentage of MDSCs was increased in the circulation and infarcted heart and decreased in the spleen. MRS-1754-mediated A2BAR inhibition decreased the MDSC ratio in the circulation and infarcted heart and prevented the decrease in MDSC number in the spleens of mice with AMI. A2BAR blockade inhibited myocardial cell apoptosis, alleviated myocardial inflammatory injury, and improved myocardial systolic function in the AMI mouse model. Similar results were found in mice after splenectomy. Additionally, spleen-derived MDSC injection increased the MDSC ratio in the infarcted heart, increased myocardial cell apoptosis, aggravated myocardial injury, and decreased cardiac systolic function in mice with AMI. CONCLUSION: Blocking A2BAR alleviates myocardial damage and improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation after AMI. Key MessagesSpleen-derived MDSC mobilisation aggravates myocardial inflammatory injury within 24 h of AMI.A2BAR promotes spleen-derived MDSC mobilisation within 24 h of AMI.Blocking A2BAR improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation.

Ticagrelor Protects against Sepsis-Induced Acute Kidney Injury through an Adenosine Receptor-Dependent Pathway.

OBJECTIVE: Ticagrelor is a widely used anti-platelet drug. However, the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury (AKI) have not been clearly demonstrated. We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms. METHODS: C57BL6J mice received oral ticagrelor (20 mg/kg and 50 mg/kg) for 7 days, and then caecal ligation and puncture (CLP) were performed. An adenosine receptor antagonist, CGS15943, was administered (10 mg/kg, intraperitoneal injection) to block the adenosine pathway 2 h before CLP. After 24 h, serum creatinine levels were measured. Periodic acid-Schiff (PAS) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were employed to analyze pathological changes and cell apoptosis. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and mRNA expression of tissue TNF-α and IL-1ß were detected. Western blotting analysis was used to determine AKT and mammalian target of rapamycin (mTOR) protein expression in the kidney. RESULTS: PAS staining showed less swelling of renal tubules, and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group. Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group. Moreover, significantly lower serum and kidney levels of TNF-α and IL-1ß were observed in the ticagrelor group. CGS15943 blocked the effects of ticagrelor. Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group. The adenosine receptor antagonist inhibited the activation of AKT and mTOR. CONCLUSION: This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.