[Analysis of clinical characteristic of children with progressive familial intrahepatic cholestasis type 3].

Objective: To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3). Methods: This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity. Results: Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment. Conclusions: Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.

[17-year study on the curative effect of treatment to prevent the recurrence of hepatitis B in different risk groups after liver transplantation].

Objective: To observe the recurrence condition of hepatitis B in different risk groups after liver transplantation in an attempt to provide useful information on whether to discontinue hepatitis B immunoglobulin (HBIG) in the future at an early stage. Methods: The patient population was divided into high, low-risk, and special groups [especially primary hepatocellular carcinoma (HCC)] according to the guidelines for the prevention and treatment of hepatitis B recurrence after liver transplantation. The recurrence condition and risk factors in this population were observed for hepatitis B. Measurement data were analyzed using a t-test and a rank-sum test. Count data were compared using a χ(2) test between groups. Results: This study finally included 532 hepatitis B-related liver transplant cases. A total of 35 cases had HBV recurrence after liver transplantation, including 34 cases that were HBsAg positive, one case that was HBsAg negative, and 10 cases that were hepatitis B virus (HBV) DNA positive. The overall HBV recurrence rate was 6.6%. The recurrence rate of HBV was 9.2% and 4.8% in the high- and low-risk HBV DNA positive and negative groups before surgery (P = 0.057). Among the 293 cases diagnosed with HCC before liver transplantation, 30 had hepatitis B recurrence after surgery, with a recurrence rate of 10.2%. The independent related factors for the recurrence of hepatitis B in patients with HCC after liver transplantation were HCC recurrence (HR =181.92, 95%CI 15.99~2 069.96, P < 0.001), a high postoperative dose of mycophenolate mofetil dispersible tablets (MMF) ( HR =5.190, 95%CI 1.289~20.889, P = 0.020), and a high dosage of HBIG (HR = 1.012, 95%CI 1.001~1.023, P = 0.035). Among the 239 cases who were non-HCC before liver transplantation, five cases (recurrence rate of 2.1%) arouse postoperative hepatitis B recurrence. Lamivudine was used in all cases, combined with on-demand HBIG prophylaxis after surgery. There was no hepatitis B recurrence in non-HCC patients who treated with entecavir combined with HBIG after surgery. Conclusion: High-barrier-to-resistance nucleotide analogues combined with long-term HBIG have a good effect on preventing the recurrence of hepatitis B after liver transplantation. The discontinuation of HBIG may be considered at an early stage after administration of a high-barrier-to-resistance nucleotide analogue in low-risk patients. Domestically, the HBV infection rate is high, so further research is still required to explore the timing of HBIG discontinuation for high-risk patients, especially those with HCC.

Efficacy and nephrotoxicity of polymyxin B in elderly patients with carbapenem resistant bacterial infection.

BACKGROUND: To study the efficacy and nephrotoxicity of polymyxin B in the treatment of elderly patients with carbapenem-resistant organism (CRO) infection. METHODS: The clinical and microbiological data of patients with CRO-infected sepsis treated with polymyxin B were retrospectively analyzed. The effective rate, bacterial clearance, incidence and recovery rate of acute renal injury (AKI) and prognosis-related indicators in AKI at different stages were compared. RESULTS: The effective rate of 215 elderly patients with CRO infection treated with polymyxin was 50.7%. The total bacterial clearance rate was 44.2%, the total incidence of AKI was 37.2%, the recovery rate of AKI was 35%, and the incidence range of polymyxin B-related AKI was 10.2-37.2%. Logistic multivariate regression analysis showed that the predictors of AKI in elderly patients were high APACHE II score, long duration of polymyxin, chronic renal insufficiency and ineffective outcome; the ROC curve showed that the cutoff value for predicting AKI was a serum creatinine concentration of 73 mmol/L before polymyxin B use, and the AUC was 0.931. CONCLUSIONS: Rational use of polymyxin B is safe and effective in elderly patients with CRO infection, and its effective outcome can improve the recovery rate of AKI.

Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging.

BACKGROUND AND PURPOSE: Routine MR imaging has limited use in evaluating the severity of glutaric aciduria type 1. To better understand the mechanisms of brain injury in glutaric aciduria type 1, we explored the value of diffusional kurtosis imaging in detecting microstructural injury of the gray and white matter. MATERIALS AND METHODS: This study included 17 patients with glutaric aciduria type 1 and 17 healthy controls who underwent conventional MR imaging and diffusional kurtosis imaging. The diffusional kurtosis imaging metrics of the gray and white matter were measured. Then, the MR imaging scores and diffusional kurtosis imaging metrics of all ROIs were further correlated with the morbidity scores and Barry-Albright dystonia scores. RESULTS: The MR imaging scores showed no significant relation to the morbidity and Barry-Albright dystonia scores. Compared with healthy controls, patients with glutaric aciduria type 1 showed higher kurtosis values in the basal ganglia, corona radiata, centrum semiovale, and temporal lobe (P < .05). The DTI metrics of the basal ganglia were higher than those of healthy controls (P < .05). The fractional anisotropy value of the temporal lobe and the mean diffusivity values of basal ganglia in glutaric aciduria type 1 were lower than those in the control group (P < .05). The diffusional kurtosis imaging metrics of the temporal lobe and basal ganglia were significantly correlated with the Barry-Albright dystonia scores. The mean kurtosis values of the anterior and posterior putamen and Barry-Albright dystonia scores were most relevant (r = 0.721, 0.730, respectively). The mean kurtosis values of the basal ganglia had the best diagnostic efficiency with area under the curve values of 0.837 for the temporal lobe, and the mean diffusivity values of the basal ganglia in glutaric aciduria type 1 were lower than those in the control group (P < .05). The diffusional kurtosis imaging metrics of the temporal lobe and basal ganglia were significantly correlated with the Barry-Albright dystonia scores. The mean kurtosis values of the anterior and posterior putamen and Barry-Albright dystonia scores were most relevant (r = 0.721, 0.730, respectively). The mean kurtosis values of the basal ganglia had the best diagnostic efficiency with area under the curve values of 0.837. CONCLUSIONS: Diffusional kurtosis imaging provides more comprehensive quantitative information regarding the gray and white matter micropathologic damage in glutaric aciduria type 1 than routine MR imaging scores.

Preoperative prediction of microvascular invasion and perineural invasion in pancreatic ductal adenocarcinoma with 18F-FDG PET/CT radiomics analysis.

AIM: To develop and validate a predictive model based on 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) radiomics features and clinicopathological parameters to preoperatively identify microvascular invasion (MVI) and perineural invasion (PNI), which are important predictors of poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Preoperative 18F-FDG PET/CT images and clinicopathological parameters of 170 patients in PDAC were collected retrospectively. The whole tumour and its peritumoural variants (tumour dilated with 3, 5, and 10 mm pixels) were applied to add tumour periphery information. A feature-selection algorithm was employed to mine mono-modality and fused feature subsets, then conducted binary classification using gradient boosted decision trees. RESULTS: For MVI prediction, the model performed best on a fused subset of 18F-FDG PET/CT radiomics features and two clinicopathological parameters, with an area under the receiver operating characteristic curve (AUC) of 83.08%, accuracy of 78.82%, recall of 75.08%, precision of 75.5%, and F1-score of 74.59%. For PNI prediction, the model achieved best prediction results only on the subset of PET/CT radiomics features, with AUC of 94%, accuracy of 89.33%, recall of 90%, precision of 87.81%, and F1 score of 88.35%. In both models, 3 mm dilation on the tumour volume produced the best results. CONCLUSIONS: The radiomics predictors from preoperative 18F-FDG PET/CT imaging exhibited instructive predictive efficacy in the identification of MVI and PNI status preoperatively in PDAC. Peritumoural information was shown to assist in MVI and PNI predictions.

[Survival efficacy of MDS/AML patients with TP53 abnormal received allogeneic hematopoietic stem cell transplantation].

Objective: TP53-abnormal MDS/acute myeloid leukemia (AML) patients' allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment's effectiveness and influencing factors should be studied. Methods: 42 patients with TP53 gene status change MDS/AML who underwent allo-HSCT from 2014.8.1 to 2021.7.31 at the Hematology Hospital of the Chinese Academy of Medical Sciences were the subject of a retrospective analysis. The 42 patients were divided into three groups: the TP53 deletion group (group A) , TP53 mono-alle mutation group (group B) , and TP53 multi-hit group (group C) . The differences in clinical features and prognostic factors after transplantation were analyzed. Results: There were 42 MDS/AML patients, including 21 patients with MDS, and 21 patients with AML. The median follow-up period was 34.0 (7.5-75.0) months and the median patient age at the time of transplantation was 41.5 (18-63) years old. The total OS was 66.3% (95% CI 53.4%-82.4%) in 3 years after transplantation, and EFS was 61.0% (95% CI 47.7%-78.0%) in 3 years. For 3 years after receiving hematopoietic stem cell transplantation, there were no statistically significant differences in 3-year OS and EFS in groups A, B, and C (P≥0.05) . The 3 years OS was 82.5% (95% CI 63.1%-100.0%) in group A, 60.6% (95% CI 43.5%-84.4%) in group B, and 57.1% (95% CI 30.1%-100.0%) in group C. Univariate analysis revealed that the number of co-mutant genes, pre-HSCT treatment, and disease type did not affect prognosis, while age, karyotype, co-mutation, positive blast cell before transplantation, and positive blast cell after transplantation were common prognostic factors for OS and EFS (P<0.1) . MRD levels before transplantation were found to be independent risk factors for OS (P=0.037, HR=33.40, 95% CI 1.24-901.17) in a multivariate analysis. Conclusion: Patients with MDS/AML who have TP53 mutations can benefit from allo-HSCT, but patients with complex karyotypes have a worse prognosis. Meanwhile, the final flow cytometry (FCM) monitoring blast cell test before HSCT has a certain guiding significance for prognostic assessment.

Buntanetap, a Novel Translational Inhibitor of Multiple Neurotoxic Proteins, Proves to Be Safe and Promising in Both Alzheimer's and Parkinson's Patients.

BACKGROUND: Previously we reported the clinical safety and pharmacological activity of buntanetap (known as Posiphen or ANVS401) in healthy volunteers and mild cognitive impaired (MCI) patients (21). The data supported continued clinical evaluation of buntanetap for treating Alzheimer's Disease (AD). Neurodegenerative diseases such as AD and Parkinson's disease (PD) share several pathological manifestations, including increased levels of multiple neurotoxic protein aggregates. Therefore, a treatment strategy that targets toxic species common to both disorders can potentially provide better clinical outcomes than attacking one neurotoxic protein alone. To test this hypothesis, we recently completed a clinical study in early AD and early PD participants and report the data here. OBJECTIVES: We evaluated safety, pharmacokinetics, biomarkers, and efficacy of buntanetap in treating early AD and PD patients. DESIGN: Double-blind, placebo-controlled, multi-center study. SETTING: 13 sites in the US participated in this clinical trial. The registration number is NCT04524351 at ClinicalTrials.gov. PARTICIPANTS: 14 early AD patients and 54 early PD patients. INTERVENTION: AD patients were given either 80mg buntanetap or placebo QD. PD patients were given 5mg, 10mg, 20mg, 40mg, 80mg buntanetap or placebo QD. MEASUREMENTS: Primary endpoint is safety and tolerability; secondary endpoint is pharmacokinetics of buntanetap in plasma; exploratory endpoints are 1) biomarkers in cerebrospinal fluid (CSF) in both AD and PD patients 2) psychometric tests specific for AD (ADAS-Cogs and WAIS coding test) or PD (MDS-UPDRS and WAIS coding test). RESULTS: Buntanetap was safe and well tolerated. Biomarker data indicated a trend in lowering levels of neurotoxic proteins and inflammatory factors and improving axonal integrity and synaptic function in both AD and PD cohorts. Psychometric tests showed statistically significant improvements in ADAS-Cog11 and WAIS coding in AD patients and MDS-UPDRS and WAIS coding in PD patients. CONCLUSIONS: Buntanetap is well tolerated and safe at doses up to 80mg QD in both AD and PD patients. Cmax and AUC increase with dose without evidence for a plateau up to 80mg QD. The drug shows promising evidence in exploratory biomarker and efficacy measures. Further evaluation of buntanetap in larger, longer-term clinical trials for the treatment of AD and PD are warranted.

Strong band renormalization and emergent ferromagnetism induced by electron-antiferromagnetic-magnon coupling.

The interactions between electrons and antiferromagnetic magnons (AFMMs) are important for a large class of correlated materials. For example, they are the most plausible pairing glues in high-temperature superconductors, such as cuprates and iron-based superconductors. However, unlike electron-phonon interactions (EPIs), clear-cut observations regarding how electron-AFMM interactions (EAIs) affect the band structure are still lacking. Consequently, critical information on the EAIs, such as its strength and doping dependence, remains elusive. Here we directly observe that EAIs induce a kink structure in the band dispersion of Ba1-xKxMn2As2, and subsequently unveil several key characteristics of EAIs. We found that the coupling constant of EAIs can be as large as 5.4, and it shows strong doping dependence and temperature dependence, all in stark contrast to the behaviors of EPIs. The colossal renormalization of electron bands by EAIs enhances the density of states at Fermi energy, which is likely driving the emergent ferromagnetic state in Ba1-xKxMn2As2 through a Stoner-like mechanism with mixed itinerant-local character. Our results expand the current knowledge of EAIs, which may facilitate the further understanding of many correlated materials where EAIs play a critical role.

[The impact of diabetic retinopathy on vision-related quality of life].

Objective: To assess the effect of diabetic retinopathy (DR) on vision-related quality of life (VRQoL) in patients with type 2 diabetes. Methods: In this cross-sectional study, patients with type 2 diabetes residing in 15 residency communities in Fushun, Liaoning province were enrolled from July 2012 to May 2013. We measured the VRQoL by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Patients were grouped according to their age, gender, presence of visual impairment, and affected eyes. NEI-VFQ-25 scores were compared between/among groups using the Wilcoxon rank-sum test or Kruskal-Wallis H test. The severity of DR in the eyes was graded into no DR, mild non-proliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR, and proliferative diabetic retinopathy (PDR). Severity scores from both eyes were then summarized to create a single per-person grade ranging from 1 (no DR in either eye) to 7 (bilateral PDR). Generalized linear models were used to assess the linear relationship between NEI-VFQ-25 scores and DR severity. Locally weighted scatterplot smoothing plots were generated to evaluate the possible nonlinear associations between concatenated severity of DR and VRQoL. Results: A total of 1 537 patients were recruited, including 836 (54.4%) with no DR, 479 (31.2%) with mild NPDR, 90 (5.9%) with moderate NPDR, 72 (4.7%) with severe NPDR and 60 (3.9%) with PDR. Compared with patients with unilateral DR, bilaterally involved subjects were statistically significantly compromised in general vision [70.2 (66.5, 72.5) vs. 68.9 (63.9, 71.6), Z=90.222, P=0.038], near activities [90.5 (85.8, 94.0) vs. 88.8 (84.5, 92.5), Z=114.942, P=0.005], dependency [91.1 (85.6, 96.5) vs. 89.3 (83.8, 94.5), Z=91.934, P=0.033], mental health [80.0 (73.4, 84.9) vs. 77.5 (70.8, 82.0), Z=118.388, P=0.003], role difficulties [76.8 (70.1, 82.4) vs. 74.5 (67.6, 80.6), Z =90.791, P=0.036] and NEI-VFQ-25 composite [88.3 (84.2, 91.0) vs. 86.9 (82.8, 90.1), Z=96.207, P=0.024]. Scores on general vision (χ2=85.665), near activities (χ2=78.462), distance activities (χ2=145.489), social function (χ2=53.629), dependency (χ2=86.710), mental health (χ2=68.281), role difficulties (χ2=45.357), color vision (χ2=68.176), peripheral vision (χ2=116.179) and NEI-VFQ-25 composite (χ2=133.291) decreased gradually as DR severity increased (all P<0.001). On role difficulties, locally weighted scatterplot smoothing plots showed significant"turning points"from bilateral mild NPDR to mild NPDR/>mild NPDR (slope m=-4.7) and from moderate NPDR/≥moderate NPDR to severe NPDR/≥severe NPDR (slope m=-12.6). Conclusion: Both greater severity and bilaterality of DR were associated with lower vision-specific VRQoL, particularly role difficulties and mental health.

[Clinical phenotype analysis of 6 cases of TTC21B gene related nephronophthisis].

Objective: To analyze the clinical characteristics of 6 children with TTC21B-related nephronophthisis to provide reference for early clinical diagnosis. Methods: The general condition, clinical manifestations, laboratory tests and other clinical data of 6 children from 4 families diagnosed with nephronophthisis by genetic testing in Shanghai Children's Hospital from January 2015 to December 2020 were analyzed retrospectively. Results: A total of 6 children (3 males and 3 females) developed proteinuria and progressive renal dysfunction in early infancy. The onset age of proteinuria was 18 (6, 25) months. The age at the onset of renal impairment was 22 (10, 36) months. All 6 children progressed to end-stage renal disease (ESRD) within 10 (4, 65) months of onset. Five children had hypertension, 3 children with abnormal liver function, 2 children with visceral translocation and 1 child with growth retardation. The genetic results suggested that all children carried variations TTC21B gene p.C518R. Conclusions: Children with TTC21B gene p.C518R nephronophthisis had proteinuria and progressed to ESRD at the early stage of life. These nephronophthisis patients commonly presented with liver and renal dysfunction.

[Analysis on the sequence mutation and evolution of HBV genome in China].

Objective: To understand immune escape mutation, drug resistance mutation, and genome evolution information of HBV genome sequence in China. Methods: The whole genome sequence information of HBV in China submitted in GenBank from 1998 to 2021 was selected as the object for analysis. MAFFT method was used for cluster analysis. Analysis of immune escape and drug-resistant mutations was performed using the online tool Gen2pheno. The BEAST 1.10.4 was used for analysis the time evolution of HBV sequences. Results: A total of 5 426 sequences were included in the dataset and distributed in 19 provinces of China. Type C accounted for the highest proportion (59.1%, 3 211/5 426), followed by type B (33.7%, 1 833/5 426). Immune escape mutations were found in 764 sequences (14.1%, 764/5 426). At least one reverse transcriptase region mutation occurred in 98.1% of the sequences. The evolutionary roots of most HBV sequences in China date from around 1801 AD. Conclusion: HBV-resistant mutation rate is high in China. HBV genomes evolve slowly.

A new species of Rhodambulyx Mell, 1939 (Lepidoptera: Sphingidae) from Southwest Chongqing, China.

A new species of the genus Rhodambulyx Mell, 1939, Rhodambulyx xinyuae sp. nov., is described from Simianshan Nature Reserve in Southwest Chongqing, China. This species is similar to R. davidi Mell, 1939 and R. kitchingi Brechlin, 2015 in habitus, but can be distinguished by a different wing pattern, male genitalia structure and DNA barcode sequence. In addition, Rhodambulyx namvui Eitschberger Nguyen, 2017 is removed from synonymy with R. kitchingi and synonymized instead with R. davidi, although whether it would be better treated as a subspecies of R. davidi requires further investigation.

Viral Ejection Proteins: Mosaically Conserved, Conformational Gymnasts.

Bacterial viruses (or bacteriophages) have developed formidable ways to deliver their genetic information inside bacteria, overcoming the complexity of the bacterial-cell envelope. In short-tailed phages of the Podoviridae superfamily, genome ejection is mediated by a set of mysterious internal virion proteins, also called ejection or pilot proteins, which are required for infectivity. The ejection proteins are challenging to study due to their plastic structures and transient assembly and have remained less characterized than classical components such as the phage coat protein or terminase subunit. However, a spate of recent cryo-EM structures has elucidated key features underscoring these proteins' assembly and conformational gymnastics that accompany their expulsion from the virion head through the portal protein channel into the host. In this review, we will use a phage-T7-centric approach to critically review the status of the literature on ejection proteins, decipher the conformational changes of T7 ejection proteins in the pre- and post-ejection conformation, and predict the conservation of these proteins in other Podoviridae. The challenge is to relate the structure of the ejection proteins to the mechanisms of genome ejection, which are exceedingly complex and use the host's machinery.

Veliparib monotherapy following carboplatin/paclitaxel plus veliparib combination therapy in patients with germline BRCA-associated advanced breast cancer: results of exploratory analyses from the phase III BROCADE3 trial.

BACKGROUND: In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P = 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported. PATIENTS AND METHODS: Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days -2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases. RESULTS: A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo). CONCLUSIONS: Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy.

Insight into biosorption of heavy metals by extracellular polymer substances and the improvement of the efficacy: a review.

Heavy metals are continuously released into aquatic environments in which they accumulate. This phenomenon endangers public health because heavy metals accumulate along the food chain. However, conventional remediation methods are inefficient, expensive and yield toxic intermediate products, which adversely affect the environment. The discovery of green bio-adsorbents such as microbial extracellular polymer substance (EPS) has quickly attracted considerable worldwide attention because of their low cost, high removal efficiency of heavy metals and industrial availability. Hence, this review considers the sources, hazards and treatment methods of heavy metals pollution, particularly the biosorption mechanism of EPS to heavy metals and the influencing factors of the bio-adsorption process, which are significant in the efficient removal of heavy metals-containing wastewater treatment. This review also focuses on strengthening the process of EPS adsorption of heavy metals, which can further contribute to heavy metals removal. Finally, it has been proposed that improving the yield, stability, selectivity and recoverability of EPS is the key direction of further research.

[G-protein coupled receptor Smo positively regulates proliferation and migration of adult neural stem cells in vitro].

OBJECTIVE: To investigate the role of G-protein coupled receptor Smoothened (Smo) in regulating proliferation and migration of adult neural stem cells (ANSCs) and explore the underlying mechanism. METHODS: Cultured ANSCs were treated with purmorphamine (PM, an agonist of Smo) or cyclopamine (CPM, an inhibitor of Smo), and the changes in cell proliferation migration abilities were assessed using cell counting kit-8 (CCK8) assay and wound healing assay, respectively. The mRNA expressions of membrane receptor Patched 1 (Ptch1), Smo, glioma-associated oncogene homolog 1 (Gli1), axon guidance cue slit1 (Slit1) and brain-derived neurotrophic factor (BDNF) in the treated cells were detected using real-time quantitative PCR (RT-PCR). RESULTS: PM significantly promoted the proliferation (P < 0.01) and migration of ANSCs (P < 0.01), and up-regulated the mRNA expressions of Ptch1, Smo, Gli1, Slit1 and BDNF. Treatment with CPM significantly inhibited the proliferation and migration of ANSCs. CONCLUSION: Modulating Smo activity can positively regulate the proliferation and migration of ANSCs possibly by regulating the expressions of BDNF and Slit1.

[Preliminary study of the fourth-generation CAR-T cells targeting CS1 in the treatment of refractory and recurrent multiple myeloma].

Objective: To design the fourth-generation chimeric antigen receptor-T (CAR-T) cells that secrete interleukin-7 (IL7) and chemokine C legend 19 (CCL19) on the basis of the second-generation CAR, and to analyze and compare the differences in proliferation, chemotaxis, tumor cell clearance and persistence in the microenvironment of multiple myeloma (MM) between them. Methods: The fourth-generation CAR vector plasmid was constructed by using 2A self-cleaving peptide technology. The third-generation lentiviral packaging system was used to prepare high-titer lentivirus. Flow cytometry was used to monitor the transduction efficiency of lentivirus and the subtype changes of CAR-T cells. The enzyme-linked immunosorbent assay (ELISA) was used to quantify the IL7 and CCL19 secreted by CAR-T cells.The calculation of absolute number of CAR-T cells during culture was used to analysis cell proliferation activity. Transwell migration assay was used to verify the chemotactic ability of CAR-T cells. The specific killing activity of CAR-T cells was detected by using the luciferase bioluminescence method. The NOD-Prkdcem26Cd52Il2rgem26Cd22/Nju (NOD) mouse xenograft model was used to verify the anti-myeloma activity and safety of CAR-T cells in vivo. Results: Flow cytometry results showed that the stable CAR expression rates of the second-generation anti-CS1 CAR-T and fourth-generation anti-CS1-IL7-CCL19 CAR-T cells were (91.50±0.29)% and (46.7±0.12)%, respectively. CAR-T cells were successfully constructed. Subtype analysis demonstrated that the ratio of stem memory T cell (TSCM) in anti-CS1-IL7-CCL19 CAR-T cells was (67.58±0.59)%, which was significantly higher than (50.74 ± 1.01)% of anti-CS1 CAR-T (P=0.000 1), with more strong immune memory function and better durability. Anti-CS1-IL7-CCL19 CAR-T cells can continuously secrete IL7 and CCL19 compared to MOCK-T and anti-CS1 CAR-T (P<0.000 1). The number of anti-CS1-IL7-CCL19 CAR-T cells reached (22.77±0.79)×10(6) on the 9th day after lentivirus transduction, which was significantly higher than (9.40±0.79)×10(6) of anti-CS1 CAR-T cells (P=0.000 1), with stronger proliferation ability. The number of chemotaxis cells of anti-CS1-IL7-CCL19 CAR-T cells to reactive T cells was (109.0±4.04), which was significantly higher than (9.33±1.20) of MOCK-T (P<0.000 1) and (7.33±0.88) of anti-CS1 CAR-T (P<0.000 1), with stronger chemotactic ability. The specific killing activity showed that both anti-CS1-IL7-CCL19 CAR-T and anti-CS1 CAR-T cells had specific killing efficacies when compared with the MOCK-T cells (P<0.000 1). Animal experiment indicated that anti-CS1-IL7-CCL19 CAR-T cells significantly reduced the tumor burden (P<0.000 1) and extended the overall survival time (P=0.006 1) of tumor-bearing mice. Conclusions: The anti-CS1-IL7-CCL19 CAR-T cells designed in this study show stronger proliferative activity, chemotactic ability, and durability without affecting the anti-myeloma activity in vivo and in vivo, which provides strategies for overcoming the defects of low survival rate, poor durability and inhibition by tumor microenvironment of traditional CAR-T cells, and offers preliminary experimental basis for the clinical application of the fourth-generation CAR-T cells.

Distinct Kondo Screening Behaviors in Heavy Fermion Filled Skutterudites with 4f

CeOs_{4}Sb_{12} (COS) and PrOs_{4}Sb_{12} (POS) are two representative compounds that provide the ideal vantage point to systematically study the physics of multi-f-electron systems. COS with Ce 4f^{1}, and POS with Pr 4f^{2} configurations show distinct properties of Kondo insulating and heavy fermion superconductivity, respectively. We unveiled the underlying microscopic origin by angle-resolved photoemission spectroscopy studies. Their eV-scale band structure matches well, representing the common characters of conduction electrons in ROs_{4}Sb_{12} systems (R=rare earth). However, f electrons interact differently with conduction electrons in COS and POS. Strong hybridization between conduction electrons and f electrons is observed in COS with band dependent hybridization gaps, and the development of a Kondo insulating state is directly revealed. Although the ground state of POS is a singlet, finite but incoherent hybridization exists, which can be explained by the Kondo scattering with the thermally excited triplet crystalline electric field state. Our results help us to understand the intriguing properties in COS and POS, and provide a clean demonstration of the microscopic differences in heavy fermion systems with 4f^{1} and 4f^{2} configurations.

[Impact of middle- and long-distance running on mental health in college students in Guangzhou during COVID-19 outbreak].

OBJECTIVE: To investigate the impact of middle- and long-distance running on mental health of students in a college in Guangzhou during the COVID-19 outbreak. METHODS: We collected data using online questionnaires from the college students selected via snowball sampling. After exclusion of invalid questionnaires and matching the data of running exercise with physical test scores of the participants, 1022 questionnaires were deemed valid for analysis. Of the 1022 students, 869 completed at least a 60-km running distance each semester as required and 153 students did not complete the task. The mental health status of the students was evaluated using PTSD Checklist-Civilian Version (PCL-C), Zung Self-rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). The scale scores were compared between the students who completed the running task and those who did not, and the factors affecting anxiety and depression were analyzed using univariate analysis and binary logistic regression. RESULTS: The students who completed the running task had significantly higher physical test scores than those who did not complete the task (P < 0.05). The PCL-C, SDS, SAS scale scores or the conditions of PTSD, anxiety, and depression did not differ significantly between two groups (P>0.05). Binary logistic regression analysis indicated that completing the running task or not did not affect the condition of PTSD, anxiety, or depression of the students; a higher physical test score was associated with a decreased risk of PTSD (OR=0.98, 95%CI: 0.97-0.99) and depression (OR=0.99, 95%CI: 0.97-1.00) but an increased risk of anxiety (OR=1.02, 95%CI: 1.01-1.04) during COVID-19 outbreak. CONCLUSION: Regular middleand long-distance running exercise may enhance the physical health to indirectly promote the mental health of the college students during COVID-19 outbreak.

The role of liver metabolism in compensatory-growth piglets induced by protein restriction and subsequent protein realimentation.

The aim of this work was to study the role of hepatic metabolism of compensatory growth in piglets induced by protein restriction and subsequent protein realimentation. Thirty-six weaned piglets were randomly distributed in a control group and a treatment group. The control group piglets were fed with a normal protein level diet (18.83% CP) for the entire experimental period (day 1-28). The treatment group piglets were fed with a protein-restriction diet (13.05% CP) for day 1 to day 14, and the diet was restored to normal protein level diet for day 15 to day 28. RNA-seq is used to analyze samples of liver metabolism on day 14 and day 28, respectively. Hepatic RNA-sequencing analysis revealed that some KEGG signaling pathways involved in glycolipid metabolism (eg, "AMPK signaling pathway," "insulin signaling pathway," and "glycolysis or gluconeogenesis") were significantly enriched on day 14 and day 28. On day 14, protein restriction promoted hepatic lipogenesis by increasing the genes expression level of ACACA, FASN, GAPM, and SREBP1C, decreasing protein phosphorylation levels of AMPKɑ and ACC in AMPK signaling pathway. In contrast, on day 28, protein realimentation promoted hepatic gluconeogenesis by increasing the concentration of G6Pase and PEPCK, decreasing protein phosphorylation levels of IRS1, Akt, and FoXO1 in insulin signaling pathway. In addition, protein realimentation activated the GH-IGF1 axis between the liver and skeletal muscle. Overall, these findings revealed the importance of liver metabolism in achieving compensatory growth.