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The infusion of chimeric antigen receptor (CAR) T cells that target specific tumor-associated antigens is a promising strategy that has exhibited encouraging results in clinical trials. However, few studies have focused on the effectiveness and safety of CD20 CAR T cells in rituximab-refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients, particularly those treated with rituximab for a short time. This prospective study aimed to assess the effectiveness and toxicity of CD20 CAR T cells in R/R B-NHL patients previously treated with rituximab.The authors conducted a prospective, single-center phase I study on the effectiveness and toxicity of CD20 CAR T cells in rituximab-treated R/R B-NHL patients (no. ChiCTR2000036350). A total of 15 patients with R/R B-NHL were enrolled between November 21, 2017, and December 1, 2021.An overall response rate of 100% was shown in enrolled patients, with 12 (80%) achieving complete remission and three (20%) achieving partial remission for the best response. The median follow-up time was 12.4 months. Progression-free survival and overall survival were not yet reached by the data cutoff day. No patient developed grade 4 cytokine release syndrome, and only one patient had immune effector cell-associated neurotoxicity syndrome.All enrolled B-NHL patients who were previously R/R to rituximab achieved different degrees of clinical response with tolerable toxicities. Notably, patients who had received rituximab within 3 months had a poorer prognosis.

Over the last two decades, thousands of genome-scale metabolic network models (GSMMs) have been constructed. These GSMMs have been widely applied in various fields, ranging from network interaction analysis, to cell phenotype prediction. However, due to the lack of constraints, the prediction accuracy of first-generation GSMMs was limited. To overcome these limitations, the next-generation GSMMs were developed by integrating omics data, adding constrain condition, integrating different biological models, and constructing whole-cell models. Here, we review recent advances of GSMMs from the first generation to the next generation. Then, we discuss the major application of GSMMs in industrial biotechnology, such as predicting phenotypes and guiding metabolic engineering. In addition, human health applications, including understanding biological mechanisms, discovering biomarkers and drug targets, are also summarized. Finally, we address the challenges and propose new trend of GSMMs. KEY POINTS: •This mini-review updates the literature on almost all published GSMMs since 1999. •Detailed insights into the development of the first- and next-generation GSMMs. •The application of GSMMs is summarized, and the prospects of integrating machine learning are emphasized.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log

To evaluate the long-term efficacy, prognostic factors, and safety of posteroventral globus pallidus internus deep brain stimulation (DBS) in patients with refractory Tourette syndrome (RTS).This retrospective study recruited 61 patients with RTS who underwent posteroventral globus pallidus internus (GPi) DBS from January 2010 to December 2020 at the Chinese People's Liberation Army General Hospital. The Yale Global Tic Severity Scale (YGTSS), Yale-Brown Obsessive-Compulsive Scale (YBOCS), Beck Depression Inventory (BDI), Gilles de la Tourette Syndrome Quality-of-Life Scale (GTS-QOL) were used to evaluate the preoperative and postoperative clinical condition in all patients. Prognostic factors and adverse events following surgery were analyzed.Patient follow up was conducted for an average of 73.33 ± 28.44 months. The final postoperative YGTSS (32.39 ± 22.34 vs 76.61 ± 17.07), YBOCS (11.26 ± 5.57 vs 18.31 ± 8.55), BDI (14.36 ± 8.16 vs 24.79 ± 11.03) and GTS-QOL (39.69 ± 18.29 vs 78.08 ± 14.52) scores at the end of the follow-up period were significantly lower than those before the surgery (p 0.05). While age and the duration of follow-up were closely related to prognosis, the disease duration and gender were not. No serious adverse events were observed and only one patient exhibited symptomatic deterioration.Posteroventral-GPI DBS provides long-term effectiveness, acceptable safety and can improve the quality of life in RTS patients. Moreover, DBS is more successful among younger patients and with longer treatment duration.

Both environmental factors, such as alcohol consumption and smoking, and genetic factors are strongly associated with the risk of developing chronic pancreatitis (CP). However, comprehensive understanding of their impacts on the progression of CP remains elusive.A prospective cohort study was performed on a large cohort of CP patients with known genetic backgrounds. The cumulative incidence of pancreatic insufficiency after the onset of CP was analyzed using Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression analysis also was performed.A total of 798 patients were enrolled in the study and followed up for 10.5 years. Rare pathogenic genotypes in the SPINK1, PRSS1, CTRC, or CFTR genes were identified in 410 (51.4%) patients. The development of pancreatic insufficiency was significantly earlier in patients with a history of smoking and/or alcohol consumption in both the positive (P.001) and negative (P = .001) gene mutation groups. However, the development of pancreatic insufficiency did not differ significantly between patients with and without gene mutations despite alcohol and/or smoking status, with P values of .064 and .115, respectively. Multivariate Cox regression analysis showed that age at onset of CP (hazard ratio, [HR], 1.02; P.001) and alcohol consumption (HR, 1.86; P.001) were independent risk factors for the development of diabetes, while male sex (HR, 1.84; P = .022) and smoking (HR, 1.56; P = .028) were predictors of steatorrhea.Although rare pathogenic mutations in the 4 major susceptibility genes for CP were not correlated significantly with the development of pancreatic insufficiency, environmental factors (either alcohol consumption or smoking) significantly accelerated disease progression (ClinicalTrials.gov: NCT04574297).

Purpose: Chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical success in treating haematologic malignancies but has not been effective against solid tumours thus far. Trop2 is a tumour-related antigen broadly overexpressed on a variety of tumours and has been reported as a promising target for pancreatic cancers. Our study aimed to determine whether CAR T cells designed with a fully human Trop2-specific single-chain fragment variable (scFv) can be used in the treatment of Trop2-positive pancreatic tumours.Methods: We designed Trop2-targeted chimeric antigen receptor engineered T cells with a novel human anti-Trop2 scFv (2F11) and then investigated the cytotoxicity, degranulation, and cytokine secretion profiles of the anti-Trop2 CAR T cells when they were exposed to Trop2+ cancer cells in vitro. We also studied the antitumour efficacy and toxicity of Trop2-specific CAR T cells in vivo using a BxPC-3 pancreatic xenograft model.Results: Trop2-targeted CAR T cells designed with 2F11 effectively killed Trop2-positive pancreatic cancer cells and produced high levels of cytotoxic cytokines in vitro. In addition, Trop2-targeted CAR T cells, which persistently circulate in vivo and efficiently infiltrate into tumour tissues, significantly blocked and even eliminated BxPC-3 pancreatic xenograft tumour growth without obvious deleterious effects observed after intravenous injection into NSG mice. Moreover, disease-free survival was efficiently prolonged.Conclusion: These results show that Trop2-targeted CAR T cells equipped with a fully human anti-Trop2 scFv could be a potential treatment strategy for pancreatic cancer and could be useful for clinical evaluation.

Variants of SARS-CoV-2 continue to emerge, posing great challenges in outbreak prevention and control. It is important to understand in advance the impact of possible variants of concern (VOCs) on infectivity and antigenicity. Here, we constructed one or more of the 15 high-frequency naturally occurring amino acid changes in the receptor-binding domain (RBD) of Alpha, Beta, and Gamma variants. A single mutant of A520S, V367F, and S494P in the above three VOCs enhanced infectivity in ACE2-overexpressing 293T cells of different species, LLC-MK2 and Vero cells. Aggregation of multiple RBD mutations significantly reduces the infectivity of the possible three VOCs. Regarding neutralization, it is noteworthy that E484K, N501Y, K417N, and N439K predispose to monoclonal antibodies (mAbs) protection failure in the 15 high-frequency mutations. Most importantly, almost all possible VOCs (single RBD mutation or aggregation of multiple mutations) showed no more than a fourfold decrease in neutralizing activity with convalescent sera, vaccine sera, and immune sera of guinea pigs with different immunogens, and no significant antigenic drift was formed. In conclusion, our pseudovirus results could reduce the concern that the aggregation of multiple high-frequency mutations in the RBD of the spike protein of the three VOCs would lead to severe antigenic drift, and this would provide value for vaccine development strategies.

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively (P = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level (P = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different (P = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs.Trial registration: ClinicalTrials.gov identifier, NCT03919240.

P-TEFb modulates RNA polymerase II elongation through alternative interaction with negative and positive regulation factors. While inactive P-TEFbs are mainly sequestered in the 7SK snRNP complex in a chromatin-free state, most of its active forms are in complex with its recruitment factors, Brd4 and SEC, in a chromatin-associated state. Thus, switching from inactive 7SK snRNP to active P-TEFb (Brd4/P-TEFb or SEC/P-TEFb) is essential for global gene expression. Although it has been shown that cellular signaling stimulates the disruption of 7SK snRNP, releasing dephosphorylated and catalytically inactive P-TEFb, little is known about how the inactive released P-TEFb is reactivated. Here, we show that the Cdk9/CycT1 heterodimer released from 7SK snRNP is completely dissociated into monomers in response to stress. Brd4 or SEC then recruits monomerized Cdk9 and CycT1 to reassemble the core P-TEFb. Meanwhile, the binding of monomeric dephosphorylated Cdk9 to either Brd4 or SEC induces the autophosphorylation of T186 of Cdk9. Finally, the same mechanism is employed during nocodazole released entry into early G1 phase of cell cycle. Therefore, our studies demonstrate a novel mechanism by which Cdk9 and CycT1 monomers are reassembled on chromatin to form active P-TEFb by its interaction with Brd4 or SEC to regulate transcription.

Objectives: The optimal excision margin of primary cutaneous melanoma greater than 2 mm in thickness is still a controversial topic. The aim of the present study was to compare the long-term survival between narrow and wide excision margins in the surgical excision of patients with high-risk primary melanoma. Methods: We chose the patients with primary melanoma of the skin thicker than 2 mm in The Surveillance, Epidemiology, and End Results database. Patients were divided into a narrow margin group (1–2 cm) and a wide margin group (>2 cm) according to the resection margin information. The primary outcome was overall survival and disease-specific survival. Results: From 2004 to 2015, a total of 2,772 patients diagnosed as having melanoma of the skin were recruited into this study and were assigned to the narrow margin group (n = 1996) and the wide margin group (n = 776). A total of 1,098 patients died during the follow-up, and 681 of these were due to melanoma. There were 779 deaths in the narrow margin group and 319 deaths in the wide margin group (HR: 0.96, 95% CI: 0.84–1.10, p = 0.26). A total of 490 melanoma-specific deaths were reported in the narrow margin group and 191 were reported in the wide margin group (HR: 1.01, 95% CI: 0.85–1.19, p = 0.91). Conclusions: Wider excision margin greater than 2 cm did not provide any additional therapeutic benefits compared to narrow excision margin between 1 and 2 cm. A 2-cm margin is adequate and safe for high-risk primary melanoma of the skin thicker than 2 mm.

Over the past two decades, considerable efforts have been made to develop non-invasive methods for determining tumor grade or surrogates for predicting the biological behavior, aiding early treatment decisions, and providing prognostic information. The development of new imaging tools, such as diffusion-weighted imaging, diffusion kurtosis imaging, perfusion imaging, and magnetic resonance spectroscopy have provided leverage in the diagnosis of soft tissue sarcomas. Artificial intelligence is a new technology used to study and simulate human thinking and abilities, which can extract and analyze advanced and quantitative image features from medical images with high throughput for an in-depth characterization of the spatial heterogeneity of tumor tissues. This article reviews the current imaging modalities used to predict the histopathological grade of soft tissue sarcomas and highlights the advantages and limitations of each modality. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

The medial plantar artery (MPA) is often sacrificed as the vascular pedicle of the medial plantar flap (MPF). However, for patients with ankle soft tissue defect caused by traffic accident, the anterior tibial artery (ATA) could be damaged and the blood supply of the distal foot would only come from the MPA and the lateral plantar artery (LPA). In this case, sacrificing the MPA for the MPF means that the LPA will become the mainly source of blood supply of the distal foot. Whether the blood supply of the distal foot is adequately guaranteed remains to be discussed. A total of seven patients with ankle soft tissue defect and ATA injury were enrolled in the study. The digital subtraction angiography (DSA) was performed to observe the hemodynamics of the ipsilateral foot. The MPF was harvested only when the foot arterial network consisting of the MPA, the LPA, the deep plantar arch, and the deep plantar artery of DPA, and the blood redistribution existed. DSA results showed the blood from the posterior tibial artery was redistributed to the ipsilateral foot and the MPA is not the dominant artery in the foot. Seven MPFs were harvested, and all flaps survived completely. No complications, such as pain, ulcer, and necrosis, occurred in the ipsilateral toes. The DSA could accurately and intuitively evaluate the hemodynamics of foot in patients with ATA injury. The DSA data and clinical practice proved that the ATA injury is not the contraindication of the MPF.

Background Antibiotic resistome has been found to strongly interact with the core microbiota in the human gut, yet little is known about how antibiotic resistance genes (ARGs) correlate with certain microbes in large rivers that are regarded as “terrestrial gut.” Results By creating the integral pattern for ARGs and antibiotic-resistant microbes in water and sediment along a 4300-km continuum of the Yangtze River, we found that human pathogen bacteria (HPB) share 13.4% and 5.9% of the ARG hosts in water and sediment but contribute 64% and 46% to the total number of planktonic and sedimentary ARGs, respectively. Moreover, the planktonic HPB harbored 79 ARG combinations that are dominated by “natural” supercarriers (e.g., Rheinheimera texasensis and Noviherbaspirillum sp. Root189) in river basins. Conclusions We confirmed that terrestrial HPB are the major ARG hosts in the river, rather than conventional supercarriers (e.g., Enterococcus spp. and other fecal indicator bacteria) that prevail in the human gut. The discovery of HPB as natural supercarriers in a world’s large river not only interprets the inconsistency between the spatial dissimilarities in ARGs and their hosts, but also highlights the top priority of controlling terrestrial HPB in the future ARG-related risk management of riverine ecosystems globally.

The relationship between chronic pancreatitis (CP) and acute pancreatitis (AP) is complex and not well understood. CP could be preceded by antecedent episodes of AP.The aim of this study was to explore both genetic and environmental factors associated with AP episodes before the diagnosis of CP.This was a cross-sectional study including 1022 patients. Detailed demographic, genetic, and clinical data were collected. Based on the presence of AP episode(s) before diagnosis of CP, patients were divided into AP group (further classified into single episode of AP group and recurrent AP group) and non-AP group. Related factors among these groups were assessed using multivariate logistic regression model.Before diagnosis of CP, 737 patients (72.1%) had a history of AP. Smoking(P = 0.005) and heavy alcohol consumption(P = 0.002) were risk factors for AP while age at CP onset(P 0.001), harboring the SPINK1 mutation(P 0.001), diabetes(P 0.001) and steatorrhea(P 0.001) were protective factors. Further, alcoholic CP(P = 0.019) was the only independent risk factor for recurrent AP attacks while age at onset of CP(P 0.001), pancreatic stones(P = 0.024). and pseudocysts(P = 0.018) served as protective factors.SPINK1 mutations served as protective factor for AP episodes, suggesting SPINK1 mutation might play a pathogenic role in CP occurrence with occult clinical manifestations.

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease and needs to be stratified. Both, cancer cells and immune cells participate in tumor initiation, growth and progression and might affect clinical outcomes. TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3), an immune checkpoint molecule, is expressed not only on immune cells but also on leukemic stem cells (LSCs) in AML. This prompted us to investigate the prognostic significance of TIM-3 in t(8;21) AML. A total of 47 t(8;21) AML patients were tested for TIM-3 expression by multi-parameter flow cytometry at diagnosis. 35 of these, who received chemotherapy alone or along with allogeneic hematopoietic stem cell transplantation were followed up. The expression pattern of TIM-3 on T-cells and NK (natural killer) cells as a whole (T + NK) and LSCs were evaluated independently. High percentage of T + NK - TIM-3

Objective The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). Methods This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients’ demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. Results PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. In this cohort, SPINK1 c.194+2T > C was the most common variant with a proportion of 39.1%. And the risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14–1.04), P = 0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04–0.80), P = 0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. Conclusions CP patients harboring SPINK1 mutations do not have an elevated risk of PC development compared to mutation-negative CP patients. On the contrary, SPINK1 mutations may be a protective factor in non-smoking patients with CP.

Parkinson's disease (PD) is a neurodegenerative disorder causing severe social and economic burdens. The origin of PD has been usually attributed to mitochondrial dysfunction. To this end, mitochondrial transcription regulators become attractive subjects for understanding PD pathogenesis. Previously, we found that the expression of mitochondrial transcription termination factor 3 (MTERF3) was reduced in MPP+-induced mice model of PD. In the present study, we probe the function of MTERF3 and its role in MPP+-induced cellular model of PD. Initially, we observe that MTERF3 expression is also reduced in MPP+-induced cellular model of PD, which can be mainly attributed to the increase of MTERF3 degradation. Next, we examine the effect of MTERF3 knockdown and overexpression on the replication, transcription, and translation of mitochondrial DNA (mtDNA). We show that knockdown and overexpression of MTERF3 have opposite effects on mtDNA transcript level but similar effects on mtDNA expression level, in line with MTERF3's dual roles in mtDNA transcription and translation. In addition, we examine the effect of MTERF3 knockdown and overexpression on mitochondrial function with and without MPP+ treatment, and find that MTERF3 seems to play a generally protective role in MPP+-induced mitochondrial dysfunction. Together, this work suggests a regulatory role of MTERF3 in MPP+-induced cellular model of PD and may provide clues in designing novel therapeutics against PD.

To assess the bioequivalence of 2 formulations of aripiprazole orally disintegrating tablets and to monitor their safety and tolerability in Chinese subjects, a single-site, open-label, randomized, 2-preparation, single-dose, 2-period crossover design was conducted. All 60 subjects were randomly divided into the fasting group and the fed group. Blood samples were collected at scheduled times after a single oral dose of orodispersible tablets containing 10 mg of aripiprazole. In the fasting state, the geometric mean ratios (90% confidence intervals [CIs]) of the test/reference formulation were 92.22%-100.20% for the area under the concentration-time curve (AUC) from time zero to the last measured concentration (AUC0-t ), 91.73%-100.14% for the AUC from administration to infinite time (AUC0-∞ ), and 98.52%-112.52% for the maximum plasma concentration (Cmax ). In the fed state, AUC0-t , AUC0-∞ , and Cmax were 92.23%-100.20%, 91.73%-100.14%, and 95.91%-105.13%, respectively. The 90%CIs of the test/reference AUC ratio and Cmax ratio were within the acceptance range of 80.00%-125.00% for bioequivalence. Neither the maximum peak plasma concentration (tmax ) nor the terminal elimination half-life (t1/2 ) showed any significant difference. No serious adverse events) were encountered during the study. The test and reference formulations were bioequivalent under both fasting and fed conditions and were found to be safe and tolerated.

Aim Platinum-based chemotherapy is the standard treatment for ovarian cancer. However, tumor cells' resistance to platinum drugs often occurs. This paper provides a review of Forkhead box O (FOXO) protein's role in platinum resistance of ovarian cancer which hopefully may provide some further guidance for the treatment of platinum-resistant ovarian cancer. Methods We reviewed a 128 published papers from authoritative and professional journals on FOXO and platinum-resistant ovarian cancer, and adopts qualitative analyses and interpretation based on the literature. Results Ovarian cancer often has abnormal activation of cellular pathways, the most important of which is the PI3K/AKT pathway. FOXOs act as crucial downstream factor of the PI3K/Akt pathway and are negatively regulated by it. DNA damage response and apoptosis including the relationship between FOXOs and ATM-Chk2-p53 are essential for platinum resistance of ovarian cancer. Through gene expression analysis in platinum-resistant ovarian cancer cell model, it was found that FoxO-1 is decreased in platinum-resistant ovarian cancer, so studying the role of FOXO in the pathway on platinum-induced apoptosis may further guide the treatment of platinum-resistant ovarian cancer. Conclusions There are many drug resistance mechanisms in ovarian cancer, wherein the decrease in cancer cells apoptosis is one of the important causes. Constituted by a series of transcription factors evolving conservatively and mainly working in inhibiting cancer, FOXO proteins play various roles in cells' antitumor response. More and more evidence suggests that we need to re-understand the role that FOXOs have played in cancer development and treatment.

To address the issue of local drug delivery in tumor treatment, a novel nanoparticle-hydrogel superstructure, namely semi-interpenetrating polymer networks (semi-IPNs) hydrogel composed of poly (ethylene glycol) diacrylate (PEGDA) and hyaluronic acid (HA) and incorporated with paclitaxel (PTX) loaded PLGA nanoparticles (PEGDA-HA/PLGA-PTX), was prepared by in situ UV photopolymerization for the use of local drug delivery.Using the gelation time, swelling rate and degradation rate as indicators, the optimal proportion of Irgacure 2959 initiator and the concentration of HA was screened and obtained for preparing hydrogels. Next, paclitaxel (PTX) loaded PLGA nanoparticles (PLGA-PTX NPs) were prepared by the emulsion solvent evaporation method.The mass ratio of the initiator was 1%, and the best concentration of HA was 5 mg/mL in PEGDA-HA hydrogel. In vitro experiments showed that PLGA-PTX NPs had similar cytotoxicity to free PTX, and the cell uptake ratio on NCI-H460 cells was up to 96% by laser confocal microscopy and flow cytometry. The drug release of the PEGDA-HA/PLGA-PTX hydrogel local drug delivery system could last for 13 days. In vivo experiments proved that PEGDAHA/PLGA-PTX hydrogel could effectively inhibit the tumor growth without causing toxic effects in mice.This study demonstrated that the PEGDA-HA/PLGA-PTX hydrogel is a promising local drug delivery system in future clinical applications for tumor therapy. A photopolymerized semi-interpenetrating polymer networks-based hydrogel incorporated with paclitaxel-loaded nanoparticles was fabricated by in situ UV photopolymerization, providing a promised nanoplatform for local chemotherapy of tumors.

The Omicron SARS-CoV-2 variant has spread quickly worldwide due to its effects on virus transmission and vaccine effectiveness. Interferon(IFN) has been shown to have a protective effect against SARS-CoV because of its broad antiviral activity. This study aimed to analyze the treatment effects of IFN α-2b spray in virus clearance of the Omicron SARS-CoV-2 variant.We examined the effectiveness and safety of IFN α-2b spray in Shanghai, China, with participants infected with the Omicron SARS-CoV-2 variant in an open, prospective cohort study from April 16th to May 5th, 2022.A total of 871 confirmed patients were enrolled in this study. Four hundred and thirteen patients were allocated to the IFN α-2b spray group, and 458 patients were allocated to the control group. The viral shedding time was significantly different between experimental group and control group (11.90 vs.12.58,IFN α-2b spray shortened the viral shedding time of the Omicron SARS-CoV-2 variant when administrated within three days since the first positive test for SARS-CoV-2.

Chronic hepatitis E virus (HEV) infection is frequently reported in immunocompromised patients, but has also been increasingly reported in non-immunocompromised individuals. We characterized the course of chronic HEV infection in immunocompetent rabbits. In two independent experiments, 40 specific-pathogen-free rabbits were infected with a rabbit HEV genotype 3 strain in serial diluted titers (108 to 104 copies/mL). Serum and fecal samples were collected weekly and were tested for HEV RNA, antigen, anti-HEV and liver enzymes. Rabbits that spontaneously cleared the infection before 10 weeks post-inoculation (wpi) were kept to the end of the study as recovery control. Liver tissues were collected from HEV-infected rabbits at 5, 10 and 26 wpi for histopathological analysis. Nineteen rabbits (47.5%) developed chronic HEV infection with persistent viraemia and fecal HEV shedding for >6 months. Seroconversion to anti-HEV was observed in 84.2% (16/19) of the chronically infected rabbits. Serum levels of aminotransferase were persistently elevated in most of the rabbits. Characterizations of chronic HEV infection in immunocompetent settings could be recapitulated in rabbits, which can serve as a valuable tool for future studies on pathogenesis.

Recent studies highlighted that CD8+ T cells are necessary for restraining reservoir in HIV-1-infected individuals who undergo antiretroviral therapy (ART), whereas the underlying cellular and molecular mechanisms remain largely unknown. Here, we enrolled 60 virologically suppressed HIV-1-infected individuals, to assess the correlations of the effector molecules and phenotypic subsets of CD8+ T cells with HIV-1 DNA and cell-associated unspliced RNA (CA usRNA). We found that the levels of HIV-1 DNA and usRNA correlated positively with the percentage of CCL4+CCL5- CD8+ central memory cells (TCM) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (TEMRA). Moreover, a virtual memory CD8+ T cell (TVM) subset was enriched in CCL4-CCL5+ TEMRA cells and phenotypically distinctive from CCL4+ TCM subset, supported by single-cell RNA-Seq data. Specifically, TVM cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ TCM subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, TVM cells inhibited HIV-1 reactivation more effectively than non-TVM CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting TVM cells subset as a potential determinant of HIV-1 reservoir size. This might be helpful to design CD8+ T cell-based therapeutic strategies for cure of the disease.

Non-destructive testing of carbon-fiber-reinforced plastic (CFRP) laminates with bidirectional fiber bundles (twill-weave) using a mechanoluminescence (ML) technique was proposed. The dynamic strain distributions and fracture phenomena of the CFRP laminates in the tensile testing were evaluated by the fabricated ML sensor consisting of SrAl

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide. However, the effect of NSAIDS on postoperative renal function is still unclear. Few studies have assessed the effects of parecoxib on renal function. Our aim is to investigate a correlation between parecoxib and the presence or absence of AKI postoperatively after a breast cancer surgery operation. Methods This was a retrospective cohort study that we performed on our hospitalized database. From January 2012 to August 2021, 3542 female patients undergoing radical mastectomy were enrolled, all data including the patients' information and laboratory results were obtained from electronic medical system. The main outcome was the incidence of AKI postoperatively. AKI was defined in accordance with the KDIGO criteria. Study groups were treated with or without parecoxib. Univariable and multivariable logistic regression analyses were performed. Results In our study, about 5.76% experienced AKI. The incidence rate of postoperative AKI (3.49%) within 7 days in the parecoxib group was lower than that in the control group (6.00%, P = 0.05). Compared to the control group, the AKI’s incidence was reduced by 49% (OR = 0.46; 95%CI 0.27–0.97) in parecoxib group in multivariable logistic regression analysis. There was a reduction in the incidence of postoperative AKI in other three subgroups: preoperative eGFR Conclusions Parecoxib was associated with incidence of postoperative acute kidney injury.

A novel reporter system, streptavidin (SA)- [sup68/sup Ga]Ga-labeled biotin ([sup68/sup Ga]Ga-DOTA-biotin), was constructed and its ability for PET imaging the behaviors of CAR T cells were also evaluated in this study.In vitro activity and cytotoxicity of the SA transduced anti-CD19-CAR T (denoted as SA-CD19-CAR T) cells were determined. The feasibility of monitoring proliferation profiles of SA-CD19-CAR T cells using [sup68/sup Ga]Ga-DOTA-biotin was firstly investigated in a solid tumor model. Also, the pharmacodynamics and pharmacokinetics of the CAR T cells in whole-body hematologic neoplasms were evaluated by bioluminescence imaging and [sup68/sup Ga]Ga-DOTA-biotin PET imaging simultaneously.After transduction with SA, the activity and cytotoxicity of the modified CAR T cells were not affected. PET images revealed that the uptakes of [sup68/sup Ga]Ga-DOTA-biotin in CD19sup+/supK562 solid tumors were 0.67 ± 0.32 ID%/g and 1.26 ± 0.13 ID%/g at 30 min and 96 h p.i. after administration of SA-CD19-CAR T cells respectively. It confirmed that the SA-CD19-CAR T cells could effectively inhibit the growth of Raji hematologic tumors. However, low radioactivity related to the proliferation of CD19-CAR T cells was detected in the Raji model.SA-CD19-CAR T cells were constructed successfully without disturbing the antitumor functions of the cells. The proliferation of the CAR T cells in solid tumors could be early detected by [sup68/sup Ga]Ga-DOTA-biotin PET imaging.

Wetlands are important ecosystems for biodiversity preservation and environmental regulation. However, the integrity of wetland ecosystems has been seriously compromised and damaged due to the reckless and indiscriminate exploitation of wetland resources during economic development by human society. Hence, wetland restoration has now attracted wide attention. Understanding wetland restoration suitability and its relationship with river grade and river distance is an important step in further implementing wetland restoration and ensuring an orderly wetland development and utilization. In this study, wetland restoration suitability is evaluated combining natural and human factors. Taking its result as an important basis, the spatial distribution characteristics of different levels of wetland restoration suitability are discussed for the studied region; the percentage distribution of different levels of wetland restoration suitability is analyzed for 10 km long buffer zones of rivers of different grades, and the association between the distribution of different levels of wetland restoration suitability and the river distance (2, 4, 6, 8, and 10 km) is also analyzed for different buffer zones of rivers in different grades. Our findings show that the spatial distribution of wetland restoration suitability is closely associated with the grade of rivers and the distance of the wetland patches from the river. The higher the river grade, the higher the percentage of the wetland with high restoration suitability within the same river distance. The percentage of wetlands with high restoration suitability has shown a notably decreasing trend as the river distance increases for the areas beside rivers of all grades, while the percentage of a wetland area with relatively high restoration suitability tends to increase as the river distance increases for the areas beside rivers of grade I and II and does not have a noticeable trend to change as the river distance changes for the area beside rivers of other grades. Results of this can provide technical support for wetland restoration suitability evaluation for plain areas, a spatial reference for wetland restoration prioritizing, and an orderly wetland development and utilization in future studies and planning.

TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines in vitro at subnanomolar concentrations. An in vivo patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 (TNFSFR10A) and/or DR5 (TNFSFR10B) expression levels did not predict the level of response to ABBV-621 activity in vivo, KRAS mutations were associated with elevated TNFSFR10A and TNFSFR10B and were enriched in ABBV-621–responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer. Significance: This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.

The most common malignant tumor of the human endocrine system is thyroid cancer, most used surgical treatment for thyroid cancer is total thyroidectomy with central lymph node dissection. However, surgery and thorough lymph node dissection can easily damage the parathyroid glands and cause corresponding surgery. Symptoms such as permanent hyperparathyroidism, nano-carbon is a common type of new lymphoid tissue tracer, it is mainly used to trace lymphoid tissue in tumor surgery. With the continuous advancement of surgical technology, more and more scholars have used nano-carbon to trace lymphoid tissue during thyroid cancer surgery, and have achieved good results. The results of this study show that thyroid cancer surgery with nano-carbon to negatively develop the parathyroid glands significantly reduces the incidence of serum PTH and blood calcium decline, and largely protects the parathyroid glands. Practice has also shown that the use of nano-carbon tracers is more thorough in lymph node dissection than thyroid cancer surgery without nano-carbon tracers.

Kashin–Beck disease (KBD) is an endemic disease in China with the highest incidence rate in Tibet region. Promoted generation of oxygen free radicals by semiquinone structure of humic substance (HS) in drinking water was considered to be one of its pathogeneses. Therefore, detailed analysis of HS was performed in water and sediment samples collected from three endemic and three disease-free areas in Changdu Region, Tibet, China. After purification of the HS in the samples, the fractions of HS were characterized using electron paramagnetic resonance, 13C nuclear magnetic resonance, fluorescence spectroscopy with parallel factor analysis and Fourier transform infrared spectroscopy (FTIR). The organic carbon content of HS did not show a significant difference between endemic and disease-free areas or correlation with KBD-associated morbidity. Except FTIR, all techniques succeeded in characterization of the quinone redox system, indicating their validity and consistency. The quinone redox system in aquatic HS exhibited significantly higher level of the following indexes in endemic areas than disease-free areas: semiquinone radical content of fulvic acid (FA) (p

Objective To compare the long‐term efficacy of screw fixation and hemiarthroplasty in elderly patients with undisplaced femoral neck fractures. Methods We searched Cochrane Library, EMBASE, and MEDLINE from inception to 10 June 2020 to identify studies about undisplaced femoral neck fracture in elderly patients over 65 years of age. The included studies were assessed by two researchers according to the Cochrane risk‐of‐bias criteria and Newcastle–Ottawa Scale. Meta‐analysis was performed with Revman 5.3 software. The odds ratios (OR) and mean differences (MD) were used to compare dichotomous and continuous variables. Results A total of 750 patients were included in this meta‐analysis. In elderly patients, undisplaced femoral neck fracture treated with hemiarthroplasty had a lower implant‐related complication rate (OR, 4.05 [95% CI, 2.38 to 6.89]; P, In elderly patients with undisplaced femoral neck fractures, hemiarthroplasty provided a lower implant‐related complication rate, lower reoperation rate, superior hip function without increased long‐term mortality. Hemiarthroplasty should be recommended as a better alternative in such patients compared with multiple cannulated screws.

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy., We conducted a pilot study to assess the feasibility of the sequential infusion of CD19 and B‐cell maturation antigen (BCMA)‐specific chimeric antigen receptor T‐cell (CART) for relapsed and/or refractory multiple myeloma treatment with a similar 3 + 3 dose escalation design. Translational Significance: The favorable and persistent responses against RRMM were observed in those patients with a combined infusion of autologous CD19‐CART and BCMA‐CART. The emergence of intolerant adverse event (neurotoxicity and sever CRS) was associated with increased dose level of BCMA‐CARTs infusion.

Polyacetylenes, lobetyol, lobetyolin and lobetyolinin, are responsible for antitumor, antioxidant, anti-inflammatory, immunomodulatory activities of Codonopsis Radix. However, their metabolic pathways are still unknown. The study was purposed to investigate the metabolism of three polyacetylenes in vitro and in vivo by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. Moreover, a rapid, sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantitative and semi-quantitative determination of lobetyol and its 12 metabolites to investigate the metabolic stability and metabolic phenotypes. A total of 47, 30 and 34 metabolites of lobetyol, lobetyolin and lobetyolinin were found in all samples. These metabolites are produced through extensive pathways, mainly involving oxidation, glucuronidation and glutathione conjugation. Lobetyol showed good metabolic stability in liver microsomes. The results of both recombinant human CYP enzymes and chemical inhibition experiments confirmed that CYP2C19, 1A1, 2C9, and 1A2 are the major isozymes mediating lobetyol metabolism.

Per- and polyfluoroalkyl substances (PFASs) are a large group of chemicals reported in global environment and are responsible for various adverse impacts on humans and environment. We report a comprehensive study on occurrence of PFASs, including legacy, substitute and emerging ones, from Pakistan. Surface water samples were collected from five ecologically important freshwater reservoirs in Pakistan, namely, Head Panjnad (HP), Head Trimmu (HT), Chashma Barrage (CB), Head Blloki (HB), and Head Qadirabad (HQ). The detection frequencies of PFASs ranged between 37 %-100 %. The highest concentration of ∑

Anti-epidermal growth factor receptor (EGFR) therapy–associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.

Ki67 is an important biomarker of pituitary adenoma (PA) aggressiveness. In this study, PA invasion of surrounding structures is investigated and deep learning (DL) models are established for preoperative prediction of Ki67 labeling index (Ki67LI) status using conventional magnetic resonance (MR) images.We reviewed 362 consecutive patients with PAs who underwent endoscopic transsphenoidal surgery, of which 246 patients with primary PA are selected for PA invasion analysis. MRI data from 234 of these PA patients are collected to develop DL models to predict Ki67LI status, and DL models were tested on 27 PA patients in the clinical setting.PA invasion is observed in 46.8% of cases in the Ki67 ≥ 3% group and 33.3% of cases in the Ki67 3% group. Three deep-learning models are developed using contrast-enhanced T1-weighted images (ceT1WI), T2-weighted images (T2WI), and multimodal images (ceT1WI+T2WI), respectively. On the validation dataset, the prediction accuracy of the ceT1WI model, T2WI model, and multimodal model were 87.4%, 89.4%, and 89.2%, respectively. In the clinical test, 27 MR slices with the largest tumors from 27 PA patients were tested using the ceT1WI model, T2WI model, and multimodal model, the average accuracy of Ki67LI status prediction was 63%, 77.8%, and 70.4%, respectively.Preoperative prediction of PA Ki67LI status in a noninvasive way was realized with the DL model by using MRI. T2WI model outperformed the ceT1WI model and multimodal model. This end-to-end model-based approach only requires a single slice of T2WI to predict Ki67LI status and provides a new tool to help clinicians make better PA treatment decisions.

Patients with central nervous system (CNS) lymphomas have a poor prognosis. Chimeric antigen receptor-modified (CAR) T cells have shown remarkable efficacy for B-cell non-Hodgkin's lymphoma. However, few studies have reported the effects of CAR T cells in the treatment of CNS lymphoma, and the duration of remission is short. In this study, seven CNS lymphoma patients (six patients with secondary CNS lymphomas and one patient with primary CNS lymphoma) were treated with CD19 or CD20 CAR T cell therapy, and the clinical efficacy and toxicity profiles were evaluated. All patients responded to CAR T cell therapy. Four patients achieved complete remission (CR), while three demonstrated partial remission. We also found that either CD19 or CD20 CAR T cells could be detected in the cerebrospinal fluid of four patients. The median progression-free survival and median overall survival were not assessed. The median duration of CR was 22.4 months. Five patients (5/7) in this cohort received combination therapy (bridging with autologous hematopoietic stem cell transplantation and programmed death-1 inhibitor for maintenance treatment) and three (3/7) received CAR T cell therapy as soon as possible after the relapse of CNS lymphoma. This could help explain why these patients achieved long-term remission. After a median follow-up of 10.4 months, three patients demonstrated disease progression, and the antigen loss of CD20 was confirmed as the reason for relapse in one patient. The results of this study suggest that CD19 or CD20 CAR T cells are effective against CNS lymphoma. This research was registered at http://www.chictr.org.cn (No. ChiCTR2000036350).

Purpose: To investigate the antiproliferative effect of carboplatin-loaded surface-modified poly(lactide-co-glycolide) on retinoblastoma cells. Methods: Carboplatin-loaded poly(lactide-co-glycolide) with or without sodium alginate surface modification was prepared using sodium alginate-poly(lactide-co-glycolide) and poly(lactide-co-glycolide). The zeta potential and carboplatin release behavior were investigated. The cellular uptake of the released drug was observed in the retinoblastoma cell line Y79. The inhibitory effect of carboplatin-loaded nanoparticles against the Y79 cell line was evaluated using methyl thiazolyl tetrazolium assay and western blot. Native carboplatin and void nanoparticles without carboplatin loading were used as controls. Results: The zeta potential was -(26.1 ± 3.1) mV for carboplatin-loaded poly(lactide-co-glycolide) and-(43.1 ± 8.1) mV for carboplatin-loaded sodium alginate-poly(lactide-co-glycolide). The burst release percentages of carboplatin-loaded poly(lactide-co-glycolide) and sodium alginate-poly(lactide-co-glycolide) were (40.0% ± 8.2%) and (18.9% ± 4.3%) at 24 hours, respectively. A significant difference was identified regarding drug release between carboplatin-loaded sodium alginate-poly(lactide-co-glycolide) and carboplatin-loaded poly(lactide-co-glycolide). Fluorescence detection revealed that intense uptake of carboplatin into the cytoplasm of the Y79 cell line that was exposed to carboplatin-loaded sodium alginate-poly(lactide-co-glycolide). Carboplatin-loaded poly(lactide-co-glycolide) or sodium alginate-poly(lactide-co-glycolide) exposure inhibited proliferating cell nuclear antigen expression in Y79 cells on day 3. Extension of exposure to day 5 revealed that the sodium alginate-poly(lactide-co-glycolide) surface modification was superior to that of poly(lactide-co-glycolide) in terms of proliferating cell nuclear antigen inhibition. The cell viability test using methyl thiazolyl tetrazolium revealed a similar inhibitory effect. Furthermore, the carboplatin-loaded nanoparticles of lower concentration inhibited cell viability more strongly than native carboplatin of higher concentration in methyl thiazolyl tetrazolium assay. Conclusions: Carboplatin-loaded sodium alginate-poly(lactide-co-glycolide) inhibited retinoblastoma cell proliferation with superior effect as compared with poly(lactide-co-glycolide) and native carboplatin. Sodium alginate surface modification offers a potential strategy for the sustained carboplatin release system. RESUMO Objetivo: Investigar o efeito antiproliferativo de poli (lactídeo-coglicolídeo) com superfície modificada carregada com carboplatina contra células de retinoblastoma. Métodos: Preparou-se poli (lactídeo-co-glicolídeo) carregado com carboplatina com ou sem alginato de sódio para modifição da superfície, poli com alginato de sódio (lactídeo-co-glicolídeo) e poli (lactídeo-co-glicolídeo). O potencial zeta e o comportamento de liberação de carboplatina foram investigados. A captação celular do fármaco liberado foi observada na linha celular de retinoblastoma Y79. O efeito inibitório das nanopartículas carregadas com carboplatina contra a linha celular Y79 foi avaliado através do ensaio de metiltiazol tetrazólio e Western-blot. Carboplatina nativa e nanopartículas vazias sem carga de carboplatina serviram como controles. Resultados: O potencial zeta de poli carregado com carboplatina (lactídeo-co-glicolídeo) foi - (26,1 ± 3,1) mV versus - (43,1 ± 8,1) mV em poli com alginato de sódio carregado com carboplatina (lactídeo-co-glicolídeo). A percentagem de libertação de explosão de poli carregado com carboplatina (lactídeo-co-glicolídeo) e poli com alginato de sódio (lactídeo-co-glicolídeo) foram (40,0 ± 8,2)% e (18,9 ± 4,3)% às 24 horas, respectivamente. Uma diferença significativa foi identificada em relação à liberação de fármaco entre poli com alginato de sódio carregado com carboplatina (lactídeo-co-glicolídeo) e poli carregado com carboplatina (lactídeo-co-glicolídeo). A detecção de fluorescência revelou que a carboplatina foi assimilada intensamente no citoplasma da linha celular Y79 que foi exposta ao poli com alginato de sódio carregado com carboplatina (lactídeo-co-glicolídeo). A exposição de poli carregada com carboplatina (lactídeo-co-glicolídeo) ou poli com alginato de sódio (lactídeo-co-glicolídeo) inibiu a expressão de antígeno nuclear de proliferação celular em células Y79 no 3º dia. A extensão da exposição no 5º dia revelou que poli com alginato de sódio (lactídeo-co-glicolídeo) para modificação da superfície foi superior a poli (lactídeo-co-glicolídeo) em termos de inibição do antígeno nuclear de proliferação celular. O teste de viabilidade celular via metiltiazol tetrazólio mostrou um efeito inibitório semelhante. Além disso, as nanopartículas carregadas com carboplatina de concentração mais baixa inibiram a viabilidade celular mais fortemente em comparação com a carboplatina nativa de concentração mais alta no ensaio de metiltiazol tetrazólio. Conclusões: Poli com alginato de sódio carregado com carboplatina (lactídeo-co-glicolídeo) inibiu a proliferação de células de retinoblastoma com efeito superior em contraste com poli (lactídeo-co-glicolídeo) e carboplatina nativa. O alginato de sódio para modificação da superfície oferece uma estratégia potencial para o sistema de liberação de carboplatina sustentada.

The therapeutic effect of CAR-T is often accompanied by sCRS, which is the main obstacle to the promotion of CAR-T therapy. The JAK1/2 inhibitor ruxolitinib has recently been confirmed as clinically effective in maintaining control over sCRS, however, its mechanism remains unclear. In this study, we firstly revealed that ruxolitinib significantly inhibited the proliferation of CAR-T cells without damaging viability, and induced an efficacy-favored differentiation phenotype. Second, ruxolitinib reduced the level of cytokine release not only from CAR-T cells, but also from other cells in the immune system. Third, the cytolytic activity of CAR-T cells was restored once the ruxolitinib was removed; however, the cytokines released from the CAR-T cells maintained an inhibited state to some degree. Finally, ruxolitinib significantly reduced the proliferation rate of CAR-T cells in vivo without affecting the therapeutic efficacy after withdrawal at the appropriate dose. We demonstrated pre-clinically that ruxolitinib interferes with both CAR-T cells and the other immune cells that play an important role in triggering sCRS reactions. This work provides useful and important scientific data for clinicians on the question of whether ruxolitinib has an effect on CAR-T cell function loss causing CAR-T treatment failure when applied in the treatment of sCRS, the answer to which is of great clinical significance.

Adult acute myeloid leukaemia (AML) patients with complex karyotype (CK) generally have unfavourable outcomes. CK commonly co-exists with characteristic chromosomal and genetic abnormalities such as monosomal karyotype (MK), -17 or 17p- [abn(17p)] and TP53 mutations. Their individual prognostic significance needs to be clarified.Seventy-three adult CK-AML patients and eleven adult non-CK-AML patients with TP53 mutations (non-CK/TP53Among CK-AML patients, those with TP53 mutations (CK/TP53Adult CK-AML patients have varied risks and TP53 mutations seem to be an independent adverse prognostic factor.

BackgroundPopulations of natural killer cells lacking CD56 expression [CD56neg natural killer (NK) cells] have been demonstrated to expand during human immunodeficiency virus (HIV)-1 infection. However, their phenotypic and functional characteristics have not been systematically analyzed, and their roles during disease progression remain poorly understood.MethodsIn this study, 84 donors, namely 34 treatment-naïve HIV-1-infected patients (TNs), 29 HIV-1-infected patients with successful antiretroviral therapy (ARTs), and 21 healthy controls (HCs), were enrolled. The phenotypic and functional characteristics of CD56neg NK cells were analyzed using single-cell RNA-sequencing (scRNA-seq) and flow cytometry. A potential link between the characteristics of CD56neg NK cells and the clinical parameters associated with HIV-1 disease progression was examined.ResultsThe frequency of the CD56neg NK cell population was significantly increased in TNs, which could be partially rescued by ART. Flow cytometry analyses revealed that CD56neg NK cells were characterized by high expression of CD39, TIGIT, CD95, and Ki67 compared to CD56dim NK cells. In vitro assays revealed reduced IFN-γ and TNF-α secretion, as well as decreased expression of granzyme B and perforin in CD56neg NK cells. In line with the data obtained by flow cytometry, scRNA-seq analysis further demonstrated impaired cytotoxic activities of CD56neg NK cells. Notably, a negative correlation was observed between CD39, CD95, and Ki67 expression levels in CD56neg NK cells and CD4+ T cell counts.ConclusionsThe results presented in this study indicate that the CD56neg NK cell population expanded in HIV-1-infected individuals is dysfunctional and closely correlates with HIV-1 disease progression.

Cryptococcal meningitis (CM) is the leading fungal infection of the central nervous system. Globally, most CM cases have been reported from patients with compromised immunities, especially those infected with HIV. However, reports from China have shown that most CM infections were from HIV-negative, immunocompetent hosts. Here, we reviewed the published reports and found those studies were almost exclusively based on patients from hospitals associated with Chinese universities but not from specialized infectious diseases hospitals where most Chinese HIV-infected patients have been treated. Thus, we believe CM cases among China’s HIV-infected population may have been severely under-reported. Analyses of CM cases in specialized infectious diseases hospitals are needed to identify the true epidemiological pattern of CM in China.

Primary central nervous system T-cell lymphoma (PCNSTCL) is a rare neoplasm with few data regarding its common features and survival characteristics.To explore the Surveillance, Epidemiology, and End Results 18 (SEER 18) database to determine the epidemiology of PCNSTCL.The SEER 18 registry database was queried to identify patients diagnosed with PCNSTCL from 1973 to 2014 and extract their information. Age-specific rates and Kaplan-Meier overall survival (OS) were calculated. A Cox proportional hazards model was applied to investigate relationships between various demographic/treatment variables and OS.The age-specific incidence rates were higher in the older population (≥60 years). Among 59 PCNSTCL cases from the SEER 18, the mean age at presentation was 55.8 years (SD, ±17.95), with a male predominance (1.36:1.00). The median follow-up was 8 months, and the median OS was 8 months (SE, ±4.162). The 1-, 3-, and 5-year OS was 46.3% [95% CI, 33.4%-59.2%], 32.8% [20.3%-45.3%], and 32.8% [20.3%-45.3%], respectively. Seventeen of the 59 patients survived at last follow-up. Patients 60 years had a greater 3-year OS compared with patients ≥ 60 years (52.6% [33.6%-71.6%] vs 13.9% [1.4%-26.4%]. Multivariate analysis has demonstrated that only age at diagnosis (≥60/60 years) exhibited a significant relationship with OS (HR, 3.495 [1.688-7.235];p = 0.001). Sex (female/male) was observed to have a doubted trend towards significance (HR, 0.487 [0.231-1.030]; p = 0.060).PCNSTCL is generally of poor prognosis but younger age at diagnosis (60 years) predicts a better prognosis.

The reverse medial plantar flap (RMPF) raised from the nonweight-bearing region of the plantar foot represents a viable option for the soft tissue defect in planter forefoot. The anatomical basis of RMPF is the complex anastomotic branches between medial plantar artery (MPA) and deep plantar arch. Those anastomotic branches have high variation rate and may be damaged by trauma such as electric injury. Therefore, it is very important to know whether those anastomotic branches are present and intact before harvesting RMPF. Five patients with soft tissue defect in planter forefoot were enrolled into the study. The digital subtraction angiography (DSA) was performed to evaluate the plantar hemodynamics in the ipsilateral foot. The RMPF was harvested only after the anastomotic connections between MPA and deep plantar arch was confirmed. Anastomosis between superficial branch of MPA and deep plantar arch was observed in all DSA examinations. All 5 patients received the repair of soft tissue defect in plantar forefoot with RMPF. All flaps survived completely. The DSA can effectively evaluate the blood supply basis of RMPF and provide imaging evidence for the design and harvest of the flap. The main anatomical basis of RMPF is the anastomotic connections between superficial branch of MPA and deep plantar arch.

Although previous research has indicated that five-year-olds can use acoustic cues to disambiguate compounds (N1 + N2) from lists (N1, N2) (e.g., ‘ice-cream’ vs. ‘ice, cream’) (Yoshida & Katz, 2004, 2006), their productions are not yet fully adult-like (Wells, Peppé & Goulandris, 2004). The goal of this study was to examine this issue in Australian English-speaking children, with a focus on their use of F0, word duration, and pauses. Twenty-four five-year-olds and 20 adults participated in an elicited production experiment. Like adults, children produced distinct F0 patterns for the two structures. They also used longer word durations and more pauses in lists compared to compounds, indicating the presence of a boundary in lists. However, unlike adults, they also inappropriately inserted more pauses within the compound, suggesting the presence of a boundary in compounds as well. The implications for understanding children's developing knowledge of how to map acoustic cues to prosodic structures are discussed.

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is continuously and rapidly circulating at present. Asymptomatic patients have been proven to be contagious and thus pose a significant infection control challenge. Here we describe the characteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, Shandong province, China. A total of 47 patients with confirmed COVID-19 were recruited. Among them, 11 patients were categorized as asymptomatic cases. We found that the asymptomatic patients in Jinan were relatively young and were mainly clustered cases. The laboratory indicators and lung lesion on chest CT were mild. No special factors were found accounting for the presence or absence of symptoms. The presence of asymptomatic patients increased the difficulty of screening. It is necessary to strengthen the identification of such patients in the future.

Background. To evaluate the feasibility of using a single device to close multiple atrial septal defects (ASDs) under the guidance of transthoracic echocardiography (TTE) and with the aid of three-dimensional (3D) printing models. Methods. Sixty-two patients with multiple ASDs were retrospectively analyzed. Thirty of these patients underwent TTE-guided closure (3D printing and TTE group) after a simulation of occlusion in 3D printing models. The remaining 32 patients underwent ASD closure under fluoroscopic guidance (conventional group). Closure status was assessed immediately and at 6 months after device closure. Results. Successful transcatheter closure with a single device was achieved in 26 patients in the 3D printing and TTE group and 27 patients in the conventional group. Gender, age [18.8 ± 15.9 (3–51) years in the 3D printing and TTE group; 14.0 ± 11.6 (3–50) years in the conventional group], mean maximum distance between defects, prevalence of 3 atrial defects and large defect distance (defined as distance ≥7 mm), and occluder size used were similarly distributed between groups. However, the 3D printing and TTE group had lower frequency of occluder replacement (3.8% vs 59.3%, p<0.0001), prevalence of mild residual shunts (defined as p<0.05) and at 6 months (7.7% vs 29.6%, p<0.05) after the procedure, and cost (32960.8 ± 2018.7 CNY vs 41019.9 ± 13758.2 CNY, p<0.01). Conclusion. The combination of the 3D printing technology and ultrasound-guided interventional procedure provides a reliable new therapeutic approach for multiple ASDs, especially for challenging cases with large defect distance.

Significance Barrier-to-autointegration factor (BAF), a highly conserved small protein in metazoans, plays multiple functions during the cell cycle; however, the regulation of BAF function is largely unclear. Here we find that the SUMOylation and de-SUMOylation cycle of BAF regulates these functions. We reveal that BAF is SUMOylated at K6, and that de-SUMOylation at this site is catalyzed by SENP1 and SENP2. SUMOylation of BAF regulates binding to lamin A/C, which is essential for nuclear retention of BAF. SUMOylation of BAF also regulates the interaction of BAF with nuclear DNA. De-SUMOylation facilitates cytoplasmic retention of BAF and loss of nuclear function. Non-SUMOylatable BAF is not efficiently retained in the nucleus, leading to structurally abnormal nuclear formation and DNA replication failure., Barrier-to-autointegration factor (BAF) is a highly conserved protein in metazoans that has multiple functions during the cell cycle. We found that BAF is SUMOylated at K6, and that this modification is essential for its nuclear localization and function, including nuclear integrity maintenance and DNA replication. K6-linked SUMOylation of BAF promotes binding and interaction with lamin A/C to regulate nuclear integrity. K6-linked SUMOylation of BAF also supports BAF binding to DNA and proliferating cell nuclear antigen and regulates DNA replication. SENP1 and SENP2 catalyze the de-SUMOylation of BAF at K6. Disrupting the SUMOylation and de-SUMOylation cycle of BAF at K6 not only disturbs nuclear integrity, but also induces DNA replication failure. Taken together, our findings demonstrate that SUMOylation at K6 is an important regulatory mechanism that governs the nuclear functions of BAF in mammalian cells.