Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-ß signaling.

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor ß (TGF-ß)-Smad3 signaling with TGF-ß inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-ß inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

Huogu injection protects against SONFH by promoting osteogenic differentiation of BMSCs and preventing osteoblast apoptosis.

To investigate the effect and mechanism of Huogu injection (HG) on steroid-induced osteonecrosis of the femoral head (SONFH), we established a SONFH model in rabbits using horse serum and dexamethasone (DEX) and applied HG locally at the hip joint. We evaluated the therapeutic efficacy at 4 weeks using scanning electron microscopy (SEM), micro-CT, and qualitative histology including H&E, Masson's trichrome, ALP, and TUNEL staining. In vitro, we induced osteogenic differentiation of bone marrow stromal cells (BMSCs) and performed analysis on days 14 and 21 of cell differentiation. The findings, in vivo, including SEM, micro-CT, and H&E staining, showed that HG significantly maintained bone quality and trabecular number. ALP staining indicated that HG promoted the proliferation of bone cells. Moreover, the results of Masson's trichrome staining demonstrated the essential role of HG in collagen synthesis. Additionally, TUNEL staining revealed that HG reduced apoptosis. ALP and ARS staining in vitro confirmed that HG enhanced osteogenic differentiation and mineralization, consistent with the WB and qRT-PCR analysis. Furthermore, Annexin V-FITC/PI staining verified that HG inhibited osteoblast apoptosis, in agreement with the WB and qRT-PCR analyses. Furthermore, combined with the UPLC analysis, we found that naringin enhanced the osteogenic differentiation and accelerated the deposition of calcium phosphate. Salvianolic acid B protected osteoblasts derived from BMSCs against GCs-mediated apoptosis. Thus, this study not only reveals the mechanism of HG in promoting osteogenesis and anti-apoptosis of osteoblasts but also identifies the active-related components in HG, by which we provide the evidence for the application of HG in SONFH.

Analysis of the genomic landscape of primary central nervous system lymphoma using whole-genome sequencing in Chinese patients.

Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin's lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing was performed on 68 newly diagnosed Chinese PCNSL samples, whose genomic characteristics and clinicopathologic features were also analyzed. Structural variations were identified in all patients with a mean of 349, which did not significantly influence prognosis. Copy loss occurred in all samples, while gains were detected in 77.9% of the samples. The high level of copy number variations was significantly associated with poor progression-free survival (PFS) and overall survival (OS). A total of 263 genes mutated in coding regions were identified, including 6 newly discovered genes (ROBO2, KMT2C, CXCR4, MYOM2, BCLAF1, and NRXN3) detected in ⩾ 10% of the cases. CD79B mutation was significantly associated with lower PFS, TMSB4X mutation and high expression of TMSB4X protein was associated with lower OS. A prognostic risk scoring system was also established for PCNSL, which included Karnofsky performance status and six mutated genes (BRD4, EBF1, BTG1, CCND3, STAG2, and TMSB4X). Collectively, this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs, thereby enriching the present understanding of the genetic mechanisms of PCNSL.

The creation of autotetraploid provides insights into critical features of DNA methylome changes after genome doubling in water spinach (Ipomoea aquatica Forsk).

Water spinach (Ipomoea aquatica Forsk) is an essential green leafy vegetable in Asia. In this study, we induced autotetraploid water spinach by colchicine. Furthermore, DNA methylation and transcriptome of tetraploid and diploid were compared using Whole Genome Bisulfite Sequencing (WGBS) and RNA-sequencing techniques. Autotetraploid water spinach was created for the first time. Compared with the diploid parent, autotetraploid water spinach had wider leaves, thicker petioles and stems, thicker and shorter adventitious roots, longer stomas, and larger parenchyma cells. The whole genome methylation level of the autotetraploid was slightly higher than that of the diploid. Compared with the diploid, 12281 Differentially Methylated Regions (DMRs)were found in the autotetraploid, including 2356 hypermethylated and 1310 hypomethylated genes, mainly enriched in 'Arginine and Proline metabolism', 'beta - Alanine metabolism', 'Plant homone signal translation', 'Ribome', and 'Plant - pathgen interaction' pathways. Correlation analysis of transcriptome and DNA methylation data showed that 121 differentially expressed genes undergone differential methylation, related to four pathways 'Other types of O-glycan biosynthesis', 'Terpenoid backbone biosynthesis', 'Biosynthesis of secondary metabolites', and 'Metabolic paths'. This work obtained important autotetraploid resources of water spinach and revealed the genomic DNA methylation changes after genome doubling, being helpful for further studying the molecular mechanism of variations caused by polyploids of the Ipomoea genus.

Melatonin enhanced the heavy metal-stress tolerance of pepper by mitigating the oxidative damage and reducing the heavy metal accumulation.

Heavy metals (HMs), like vanadium (V), chromium (Cr), cadmium (Cd), and nickel (Ni) toxicity due to anthropogenic, impair plant growth and yield, which is a challenging issue for agricultural production. Melatonin (ME) is a stress mitigating molecule, which alleviates HM-induced phytotoxicity, but the possible underlying mechanism of ME functions under HMs' phytotoxicity is still unclear. Current study uncovered key mechanisms for ME-mediated HMs-stress tolerance in pepper. HMs toxicity greatly reduced growth by impeding leaf photosynthesis, root architecture system, and nutrient uptake. Conversely, ME supplementation markedly enhanced growth attributes, mineral nutrient uptake, photosynthetic efficiency, as measured by chlorophyll content, gas exchange elements, chlorophyll photosynthesis genes' upregulation, and reduced HMs accumulation. ME treatment showed a significant decline in the leaf/root V, Cr, Ni, and Cd concentration which was about 38.1/33.2%, 38.5/25.9%, 34.8/24.9%, and 26.6/25.1%, respectively, when compared with respective HM treatment. Furthermore, ME remarkably reduced the ROS (reactive oxygen species) accumulation, and reinstated the integrity of cellular membrane via activating antioxidant enzymes (SOD, superoxide dismutase; CAT, catalase; APX, ascorbate peroxidase; GR, glutathione reductase; POD, peroxidase; GST, glutathione S-transferase; DHAR, dehydroascorbate reductase; MDHAR, monodehydroascorbate reductase) and as well as regulating ascorbate-glutathione (AsA-GSH) cycle. Importantly, oxidative damage showed efficient alleviations through upregulating the genes related to key defense such as SOD, CAT, POD, GR, GST, APX, GPX, DHAR, and MDHAR; along with the genes related to ME biosynthesis. ME supplementation also enhanced the level of proline and secondary metabolites, and their encoding genes expression, which may control excessive H2O2 (hydrogen peroxide) production. Finally, ME supplementation enhanced the HM stress tolerance of pepper seedlings.

Gold nanoparticles enhances radiosensitivity in glioma cells by inhibiting TRAF6/NF-κB induced CCL2 expression.

Gliomas are inherently difficult to treat by radiotherapy because glioma cells become radioresistant over time. However, combining radiotherapy with a radiosensitizer could be an effective strategy to mitigate the radioresistance of glioma cells. Gold nanoparticles (AuNPs) have emerged as a promising nanomaterial for cancer therapy, but little is known about whether AuNPs and X-ray radiation have cytotoxic synergistic effects against tumors. In this study, we found that the combination of AuNPs and X-ray irradiation significantly reduced the viabilities, as well as the migration and invasion, of glioma cells. Mechanistically, we observed that the AuNPs inhibited radiation-induced CCL2 expression by inhibiting the TRAF6/NF-κB pathway, which likely manifested the synergistic therapeutic effect between the AuNPs and X-ray radiation. The AuNPs also re-sensitized radioresistant glioma cells by inhibiting CCL2 expression. These results were also observed in another tumor cell line with a different molecular pattern, indicating that the underlying mechanism may be ubiquitous through cancer cells. Lastly, using the glioma mouse model, we observed that AuNPs significantly reduced tumor growth in the presence of X-ray radiation compared to radiotherapy alone.

Dual targets of lethal apoptosis and protective autophagy in liver cancer with periplocymarin elicit a limited therapeutic effect.

Cardiac glycosides (CGs) are candidate anticancer agents that function by increasing [Ca2+]i to induce apoptotic cell death in several types of cancer cells. However, new findings have shown that the anti­cancer effects of CGs involve complex cell­signal transduction mechanisms. Hence, exploring the potential mechanisms of action of CGs may provide insight into their anti­cancer effects and thus aid in the selection of the appropriate CG. Periplocymarin (PPM), which is a cardiac glycoside, is an active ingredient extracted from Cortex periplocae. The role of PPM was evaluated in HepG2 cells and xenografted nude mice. Cell proliferation, real­time ATP rate assays, western blotting, cell apoptosis assays, short interfering RNA transfection, the patch clamp technique, electron microscopy, JC­1 staining, immunofluorescence staining and autophagic flux assays were performed to evaluate the function and regulatory mechanisms of PPM in vitro. The in vivo activity of the PPM was assessed using a mouse xenograft model. The present study demonstrated that PPM synchronously activated lethal apoptosis and protective autophagy in liver cancer, and the initiation of autophagy counteracted the inherent pro­apoptotic capacity and impaired the anti­cancer effects. Specifically, PPM exerted a pro­-apoptotic effect in HepG2 cells and activated macroautophagy by initiation of the AMPK/ULK1 and mTOR signaling pathways. Activation of macroautophagy counteracted the pro­apoptotic effects of PPM, but when it was combined with an autophagy inhibitor, the anti­cancer effects of PPM in mice bearing HepG2 xenografts were observed. Collectively, these results indicated that a self­limiting effect impaired the pro­apoptotic effects of PPM in liver cancer, but when combined with an autophagy inhibitor, it may serve as a novel therapeutic option for the management of liver cancer.

A deleterious Sar1c variant in rice inhibits export of seed storage proteins from the endoplasmic reticulum.

KEY MESSAGE: We identified a dosage-dependent dominant negative form of Sar1c, which confirms the essential role of COPII system in mediating ER export of storage proteins in rice endosperm. Higher plants accumlate large amounts of seed storage proteins (SSPs). However, mechanisms underlying SSP trafficking are largely unknown, especially the ER-Golgi anterograde process. Here, we showed that a rice glutelin precursor accumulation13 (gpa13) mutant exhibited floury endosperm and overaccumulated glutelin precursors, which phenocopied the reported RNAi-Sar1abc line. Molecular cloning revealed that the gpa13 allele encodes a mutated Sar1c (mSar1c) with a deletion of two conserved amino acids Pro134 and Try135. Knockdown or knockout of Sar1c alone caused no obvious phenotype, while overexpression of mSar1c resulted in seedling lethality similar to the gpa13 mutant. Transient expression experiment in tobacco combined with subcellular fractionation experiment in gpa13 demonstrated that the expression of mSar1c affects the subcellular distribution of all Sar1 isoforms and Sec23c. In addition, mSar1c failed to interact with COPII component Sec23. Conversely, mSar1c competed with Sar1a/b/d to interact with guanine nucleotide exchange factor Sec12. Together, we identified a dosage-dependent dominant negative form of Sar1c, which confirms the essential role of COPII system in mediating ER export of storage proteins in rice endosperm.

Genome-wide identification of myeloblastosis gene family and its response to cadmium stress in Ipomoea aquatica.

The myeloblastosis (MYB) proteins perform key functions in mediating cadmium (Cd) tolerance of plants. Ipomoea aquatica has strong adaptability to Cd Stress, while the roles of the I. aquatica MYB gene family with respect to Cd stress are still unclear. Here, we identified a total of 183 MYB genes in the I. aquatica genome (laMYB), which were classified into 66 1R-type IaMYB, 112 2R-type IaMYB, four 3R-type IaMYB, and one 4R-type IaMYB based on the number of the MYB repeat in each gene. The analysis of phylogenetic tree indicated that most of IaMYB genes are associated with the diverse biological processes including defense, development and metabolism. Analysis of sequence features showed that the IaMYB genes within identical subfamily have the similar patterns of the motif distributions and gene structures. Analysis of gene duplication events revealed that the dispersed duplication (DSD) and whole-genome duplication (WGD) modes play vital roles in the expansion of the IaMYB gene family. Expression profiling manifests that approximately 20% of IaMYB genes had significant role in the roots of I. aquatica under Cd stress. Promoter profiling implied that the differentially expressed genes might be induced by environmental factors or inherent hormones and thereby execute their function in Cd response. Remarkably, the 2R-type IaMYB157 with abundant light-responsive element G-box and ABA-responsive element ABRE in its promoter region exhibited very strong response to Cd stress. Taken together, our findings provide an important candidate IaMYB gene for further deciphering the molecular regulatory mechanism in plant with respect to Cd stress.

Portal vein gas combined with pneumatosis intestinalis and emphysematous cystitis: A case report and literature review.

BACKGROUND: Portal venous gas (PVG) is a rare clinical condition usually indicative of severe disorders, including necrotizing enterocolitis, bowel ischemia, or bowel wall rupture/infarction. Pneumatosis intestinalis (PI) is a rare illness characterized by an infiltration of gas into the intestinal wall. Emphysematous cystitis (EC) is relatively rare and characterized by intramural and/or intraluminal bladder gas best depicted by cross-sectional imaging. Our study reports a rare case coexistence of PVG presenting with PI and EC. CASE SUMMARY: An 86-year-old woman was admitted to the emergency room due to the progressive aggravation of pain because of abdominal fullness and distention, complicated with vomiting and stopping defecation for 4 d. The abdominal computed tomography (CT) plain scan indicated intestinal obstruction with ischemia changes, gas in the portal vein, left renal artery, superior mesenteric artery, superior mesenteric vein, some branch vessels, and bladder pneumatosis with air-fluid levels. Emergency surgery was conducted on the patient. Ischemic necrosis was found in the small intestine approximately 110 cm below the Treitz ligament and in the ileocecal junction and ascending colon canals. This included excision of the necrotic small intestine and right colon, fistulation of the proximal small intestine, and distal closure of the transverse colon. Subsequently, the patient displayed postoperative short bowel syndrome but had a good recovery. She received intravenous fluid infusion and enteral nutrition maintenance every other day after discharge from the community hospital. CONCLUSION: Emergency surgery should be performed when CT shows signs of PVG with PI and EC along with a clinical situation strongly suggestive of bowel ischemia.

Chidamide and sintilimab combination in diffuse large B-cell lymphoma progressing after chimeric antigen receptor T therapy.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is curable with first-line chemoimmunotherapy but patients with relapsed/refractory (R/R) DLBCL still face a poor prognosis. For patients with R/R DLBCL, the complete response rate to traditional next-line therapy is only 7% and the median overall survival is 6.3 mo. Recently, CD19-targeting chimeric antigen receptor T cells (CAR-T) have shown promise in clinical trials. However, approximately 50% of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective. CASE SUMMARY: Here, we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion. They received a PD-1 inhibitor (sintilimab) and a histone deacetylase inhibitor (chidamide). Five of the 7 patients tolerated the treatment without any serious adverse events. Two patients discontinued the treatment due to lung infection and rash. At the 20-mo follow-up, the median overall survival of these 7 patients was 6 mo. Of note, there were 2 complete response rates (CRs) and 2 partial response rates (PRs) during this novel therapy, with an overall response rate (ORR) of 57.1%, and one patient had a durable CR that lasted at least 20 mo. CONCLUSION: In conclusion, chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.

Physiological and Biochemical Responses of Pepper (Capsicum annuum L.) Seedlings to Nickel Toxicity.

Globally, heavy metal pollution of soil has remained a problem for food security and human health, having a significant impact on crop productivity. In agricultural environments, nickel (Ni) is becoming a hazardous element. The present study was performed to characterize the toxicity symptoms of Ni in pepper seedlings exposed to different concentrations of Ni. Four-week-old pepper seedlings were grown under hydroponic conditions using seven Ni concentrations (0, 10, 20, 30, 50, 75, and 100 mg L-1 NiCl2. 6H2O). The Ni toxicity showed symptoms, such as chlorosis of young leaves. Excess Ni reduced growth and biomass production, root morphology, gas exchange elements, pigment molecules, and photosystem function. The growth tolerance index (GTI) was reduced by 88-, 75-, 60-, 45-, 30-, and 19% in plants against 10, 20, 30, 50, 75, and 100 mg L-1 Ni, respectively. Higher Ni concentrations enhanced antioxidant enzyme activity, ROS accumulation, membrane integrity [malondialdehyde (MDA) and electrolyte leakage (EL)], and metabolites (proline, soluble sugars, total phenols, and flavonoids) in pepper leaves. Furthermore, increased Ni supply enhanced the Ni content in pepper's leaves and roots, but declined nitrogen (N), potassium (K), and phosphorus (P) levels dramatically. The translocation of Ni from root to shoot increased from 0.339 to 0.715 after being treated with 10-100 mg L-1 Ni. The uptake of Ni in roots was reported to be higher than that in shoots. Generally, all Ni levels had a detrimental impact on enzyme activity and led to cell death in pepper seedlings. However, the present investigation revealed that Ni ≥ 30 mg L-1 lead to a deleterious impact on pepper seedlings. In the future, research is needed to further explore the mechanism and gene expression involved in cell death caused by Ni toxicity in pepper plants.

Case Report: Primary Cardiac T-Cell Lymphoma With Complete Atrio-Ventricular Block Diagnosed by Endomyocardial Biopsy.

Primary cardiac lymphoma (PCL) is a rare disease, the definite diagnosis of which is sometimes difficult and mainly relies on endomyocardial biopsy. Primary cardiac T-cell lymphoma (PCTL) is an extremely rare sub-type of PCL. Here, we report on a 47-year-old female with PCTL who presented with fever, syncope, palpitations, and a third-degree atrioventricular block (AVB) on electrocardiogram. Chemotherapy was administered with two courses of methotrexate, cyclophosphamide, liposomal doxorubicin, vincristine, and dexamethasone (MTX-CHOP). As the tumor vanished, AVB changed from third degree to second degree and finally to sinus rhythm. In conclusion, endomyocardial biopsy is valuable in the diagnosis of primary cardiac lymphoma. It is worth noting that alterations in the electrocardiogram may indicate an attack on the heart by PCTL.

Aberrantly Activated APOBEC3B Is Associated With Mutant p53-Driven Refractory/Relapsed Diffuse Large B-Cell Lymphoma.

Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.

CD19-targeted BiTE expression by an oncolytic vaccinia virus significantly augments therapeutic efficacy against B-cell lymphoma.

Immunotherapy with CD19-targeting bispecific T-cell engagers (CD19BiTEs) has demonstrated highly effective killing of cancer cells in patients with precursor acute lymphoblastic leukemia and non-Hodgkin's lymphomas. However, there are some drawbacks to this therapy, such as toxicity, short half-life in the serum, and immunosuppressive tumor microenvironment that could limit the use of CD19BiTEs in the clinic. Here, we generate an oncolytic vaccinia virus (OVV) encoding a CD19-specific BiTE (OVV-CD19BiTE). We demonstrate that OVV-CD19BiTE's ability to replicate and induce oncolysis was similar to that of its parental counterpart. Supernatants from OVV-CD19BiTE-infected cells could induce activation and proliferation of human T cells, and the bystander effect of the virus was also demonstrated. In vivo study showed that OVV-CD19BiTE selectively replicated within tumor tissue, and contributed to a more significantly increased percentage of CD3, CD8, and naïve CD8 T subpopulations within tumors in contrast to blinatumomab. More importantly, treatment with OVV-CD19BiTE both in vitro and in vivo resulted in potent antitumor activity in comparison with control OVV or blinatumomab, a first-in-class BiTE, thereby resulting in long-term tumor remissions without relapse. The study provides strong evidence for the therapeutic benefits of CD19-targeting BiTE expression by OVV, and suggests the feasibility of testing the approach in clinical trials.

Jinlida granules ameliorate the high-fat-diet induced liver injury in mice by antagonising hepatocytes pyroptosis.

CONTEXT: Jinlida (JLD) as a traditional Chinese medicine formula has been used to treat type 2 diabetes mellitus (T2DM) and studies have shown its anti-obesity effect. OBJECTIVE: To investigate the therapeutic effects of JLD in a mouse model of non-alcoholic fatty liver (NAFL). MATERIALS AND METHODS: C57BL/6J mice were divided into three groups and fed a low-diet diet (LFD), high-fat diet (HFD), or HFD + JLD (3.8 g/kg) for 16 weeks, respectively. The free fatty acids-induced lipotoxicity in HepG2 cells were used to evaluate the anti-pyroptotic effects of JLD. The pharmacological effects of JLD on NAFL were investigated by pathological examination, intraperitoneal glucose and insulin tolerance tests, western blotting, and quantitative real-time PCR. RESULTS: In vivo studies showed that JLD ameliorated HFD-induced liver injury, significantly decreased body weight and enhanced insulin sensitivity and improved glucose tolerance. Furthermore, JLD suppressed both the mRNA expression of caspase-1 (1.58 vs. 2.90), IL-1ß (0.93 vs. 3.44) and IL-18 (1.34 vs. 1.60) and protein expression of NLRP3 (2.04 vs. 5.71), pro-caspase-1 (2.68 vs. 4.92) and IL-1ß (1.61 vs. 2.60). In vitro, JLD inhibited the formation of lipid droplets induced by 2 mM FFA (IC50 = 2.727 mM), reduced the protein expression of NLRP3 (0.74 vs. 2.27), caspase-1 (0.57 vs. 2.68), p20 (1.67 vs. 3.33), and IL-1ß (1.44 vs. 2.41), and lowered the ratio of p-IKB-α/IKB-α (0.47 vs. 2.19). CONCLUSION: JLD has a protective effect against NAFLD, which may be related to its anti-pyroptosis, suggesting that JLD has the potential as a novel agent in the treatment of NAFLD.

Associations among resilience, hope, social support, stress, and anxiety severity in Chinese women with abnormal cervical cancer screening results.

This study was to explore the resilience level and its potential correlates and further to evaluate the influence of these resilience-centred variables on anxiety severity among Chinese women with abnormal cervical cancer screening results. One hundred and seventy-five subjects completed self-administered questionnaires to collect relevant variables. The level of resilience of our sample is moderate (70.57 ± 12.14). The data identified hope (ß = 0.218), social support (ß = 0.247) and perceived stress (ß = -0.320) as independent associates for resilience. Finally, among variables, only perceived stress is found to have a direct and positive influence on anxiety severity. Interventions on these variables can be effective for resilience promotion in this population. In addition, anxiety should be preferentially intervened in through the alleviation of perceived stress.

Photoactivated Osmium Arene Anticancer Complexes.

Half-sandwich Os-arene complexes exhibit promising anticancer activity, but their photochemistry has hardly been explored. To exploit the photocytotoxicity and photochemistry of Os-arenes, O,O-chelated complexes [Os(η6-p-cymene)(Curc)Cl] (OsCUR-1, Curc = curcumin) and [Os(η6-biphenyl)(Curc)Cl] (OsCUR-2), and N,N-chelated complexes [Os(η6-biphenyl)(dpq)I]PF6 (OsDPQ-2, dpq = pyrazino[2,3-f][1,10]phenanthroline) and [Os(η6-biphenyl)(bpy)I]PF6 (OsBPY-2, bpy = 2,2'-bipyridine), have been investigated. The Os-arene curcumin complexes showed remarkable photocytotoxicity toward a range of cancer cell lines (blue light IC50: 2.6-5.8 µM, photocytotoxicity index PI = 23-34), especially toward cisplatin-resistant cancer cells, but were nontoxic to normal cells. They localized mainly in mitochondria in the dark but translocated to the nucleus upon photoirradiation, generating DNA and mitochondrial damage, which might contribute toward overcoming cisplatin resistance. Mitochondrial damage, apoptosis, ROS generation, DNA damage, angiogenesis inhibition, and colony formation were observed when A549 lung cancer cells were treated with OsCUR-2. The photochemistry of these Os-arene complexes was investigated by a combination of NMR, HPLC-MS, high energy resolution fluorescence detected (HERFD), X-ray adsorption near edge structure (XANES) spectroscopy, total fluorescence yield (TFY) XANES spectra, and theoretical computation. Selective photodissociation of the arene ligand and oxidation of Os(II) to Os(III) occurred under blue light or UVA excitation. This new approach to the design of novel Os-arene complexes as phototherapeutic agents suggests that the novel curcumin complex OsCUR-2, in particular, is a potential candidate for further development as a photosensitizer for anticancer photoactivated chemotherapy (PACT).

Application of Multiparametric Intraoperative Ultrasound in Glioma Surgery.

Gliomas are the most invasive and fatal primary malignancy of the central nervous system that have poor prognosis, with maximal safe resection representing the gold standard for surgical treatment. To achieve gross total resection (GTR), neurosurgery relies heavily on generating continuous, real-time, intraoperative glioma descriptions based on image guidance. Given the limitations of currently available equipment, developing a real-time image-guided resection technique that provides reliable functional and anatomical information during intraoperative settings is imperative. Nowadays, the application of intraoperative ultrasound (IOUS) has been shown to improve resection rates and maximize brain function preservation. IOUS, which presents an attractive option due to its low cost, minimal operational flow interruptions, and lack of radiation exposure, is able to provide real-time localization and accurate tumor size and shape descriptions while helping distinguish residual tumors and addressing brain shift. Moreover, the application of new advancements in ultrasound technology, such as contrast-enhanced ultrasound, three-dimensional ultrasound, navigable ultrasound, ultrasound elastography, and functional ultrasound, could help to achieve GTR during glioma surgery. The current review describes current advancements in ultrasound technology and evaluates the role and limitation of IOUS in glioma surgery.

Natural killer cells associated with SARS-CoV-2 viral RNA shedding, antibody response and mortality in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is a novel infectious viral disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two consecutively negative SARS-CoV-2 viral RNA test ( interval ≥ 24 hours), improved respiratory symptoms and obvious absorption of inflammation in pulmonary imaging are the discharge criteria for COVID-19 patients. The clearance profile of viral RNA in the upper respiratory tract specimens, including nasopharyngeal swab and/or oropharyngeal swabs, is related to innate immune cells such as Natural Killer cells. A total of 168 patients were included for the study. In this cohort, non-severe and severe groups showed significant differences in white blood cells, neutrophils, lymphocytes, basophils and platelets counts, as well as in infection related parameters such as CRP and serum cytokine IL-6. For lymphocyte subsets tests at admission, the severe group displayed significantly lower cell counts than the non-severe group. Higher counts of total T cells, CD4 + T cells, CD8 + T cells, and NK cells in peripheral blood showed a significant correlation with the shorter time taken to obtain the first negative viral RNA test and first positive IgM/ IgG antibody test. The number of B cells was only correlated with time to achieve the first positive IgM/IgG test. The count of NK cells was also correlated with a higher level of IgG antibody (p = 0.025). The lymphocytopenia group had a significantly worse survival rate (p = 0.022) and a longer duration (p = 0.023) of viral shedding than the normal lymphocyte count group. A lower NK cell count correlates the most with the worse survival rate (p<0.001) and a longer duration (p<0.001) of viral shedding. This study suggests the potential value of allo-Natural Killer cell therapy as an universal COVID-19 treatment strategy.