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Abstract Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMBR630H) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMBR630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMBR630H knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.

BackgroundGouty arthritis is a common inflammatory arthritis. The recurrent gout attacks severely damage the joint’s function, lead to bone erosion, and affect bone metabolism. The role of magnesium (Mg) ions in bone homeostasis has been recognized, whereas its specific relationship with gouty bone erosion remains unclear. This study examined the association between serum ionized Mg levels and bone erosion in patients with gout arthritis.MethodsA total of 769 patients with gout arthritis were included in the study. Participants were classified into four groups based on the quartiles of the serum ionized Mg level. Logistic regression analysis assessed the association between serum ionized Mg and bone erosion.ResultsCompared to patients without bone erosion, serum ionized Mg levels were lower in gout patients with bone erosion (p

Abstract This study aimed to evaluate the association between low-density lipoprotein cholesterol (LDL-C) and serum uric acid to serum creatinine (SUA/SCr) ratio in male gout patients at different BMIs. This real-world study included 956 male gout patients aged 18–83 years. We retrospectively analyzed the medical records of Chinese male gout patients from 2017 to 2019. The correlation between LDL-C and SUA/SCr was tested after adjusting for confounding factors. We found a nonlinear relationship between LDL-C and SUA/SCr in the whole study population. Stratification analysis showed that there was actually a nonlinear relationship between LDL-C and SUA/SCr in men with a BMI of 24–28, the inflection point of LDL-C was 1.8 mmol/L, when LDL-C was greater than 1.8 mmol/L, there was a positive correlation between LDL-C levels and SUA/SCr (β = 0.67, 95% CI 0.35–0.98, P

Abstract The structure-activity relationship in catalytic ozonation remains unclear, hindering the understanding of activity origins. Here, we report activity trends in catalytic ozonation using a series of single-atom catalysts with well-defined M1-N3C1 (M: manganese, ferrum, cobalt, and nickel) active sites. The M1-N3C1 units induce locally polarized M − C bonds to capture ozone molecules onto M atoms and serve as electron shuttles for catalytic ozonation, exhibiting excellent catalytic activities (at least 527 times higher than commercial manganese dioxide). The combined in situ characterization and theoretical calculations reveal single metal atom-dependent catalytic activity, with surface atomic oxygen reactivity identified as a descriptor for the structure-activity relationship in catalytic ozonation. Additionally, the dissociation barrier of surface peroxide species is proposed as a descriptor for the structure-activity relationship in ozone decomposition. These findings provide guidelines for designing high-performance catalytic ozonation catalysts and enhance the atomic-level mechanistic understanding of the integral control of ozone and methyl mercaptan.

ABSTRACT Introduction The relationship between progesterone (P) and diabetic nephropathy (DKD) is unclear. Herein, we investigated the relationship between progesterone and DKD in men and postmenopausal women with type 2 diabetes mellitus. Materials and Methods We recruited 3,556 male and postmenopausal female patients and obtained the dominance ratio (OR) and corresponding 95% confidence intervals (CIs) associated with progesterone by logistic regression analysis after adjusting for potentially confounding variants. Results We found that progesterone levels were significantly lower in the massive proteinuria and microproteinuria groups compared with the non‐DKD group for male patients. Also, microproteinuria and massive proteinuria prevalence were higher in the first (lowest) progesterone quartile than in the second to fourth quartiles. After adjusting for confounders, compared with the first (lowest) progesterone quartile group, the OR for the second to fourth quartiles in the male microproteinuria subgroup, were: Q2: 0.846 (95% CI: 0.581–1.233, P = 0.385); Q3: 0.667 (95% CI: 0.45–0988, P = 0.044); Q4: 0.597 (95% CI: 0.393–0.907, P = 0.016). In the male massive proteinuria subgroup, the OR for the third quartile group was 0.418 (95% CI: 0.201–0.867, P = 0.019). In contrast, no significant association was detected between progesterone and DKD prevalence in the female group. Conclusions Progesterone levels were negatively associated with DKD incidence in hospitalized male patients with type 2 diabetes mellitus.

Worldwide, diabetes and its complications have seriously affected people’s quality of life and become a serious public health problem. C-peptide is not only an indicator of pancreatic β-cell function, but also a biologically active peptide that can bind to cell membrane surface signaling molecules and activate downstream signaling pathways to play antioxidant, anti-apoptotic and inflammatory roles, or regulate cellular transcription through internalization. It is complex how C-peptide is related to diabetic complications. Both deficiencies and overproduction can lead to complications, but their mechanisms of action may be different. C-peptide replacement therapy has shown beneficial effects on diabetic complications in animal models when C-peptide is deficient, but results from clinical trials have been unsatisfactory. The complex pattern of the relationship between C-peptide and diabetic chronic complications has not yet been fully understood. Future basic and clinical studies of C-peptide replacement therapies will need to focus on baseline levels of C-peptide in addition to more attention also needs to be paid to post-treatment C-peptide levels to explore the optimal range of fasting C-peptide and postprandial C-peptide maintenance.

Herein, novel S-scheme heterojunction of Ni doped SnS2 (Ni-SnS2)/BiOBr (NSB) with 2D/2D structures was fabricated by a solvothermal-precipitation route, where 2D BiOBr nanoflakes were intimately deposited on the 2D Ni-SnS2 nanosheets surface. The obtained 2D/2D NSB composite presented largely boosted photocatalytic performances for tetracycline hydrochloride (TC) and dye decomposition compared to single catalyst. The optimized 20% Ni-SnS2/BiOBr (NSB-20) displayed the largest rate constant (0.0488 min−1), which was ca. 2.07 and 44.36 folds those of pure BiOBr and Ni-SnS2, respectively. In addition, it possessed good stability. The improved activity could be ascribed to excellent optical response, high contact areas and 2D/2D S-scheme heterostructures, which expedited efficiently separation and transfer of photocarriers. Furthermore, the effect of some factors on TC degradation was examined and possible degradation routes of TC were proposed. Finally, S-scheme charge transfer mechanism for NSB composite was put forward on the basis of band structure analysis, electron spin resonance (ESR), in situ XPS along with DFT calculations. This investigation contributes to exploit S‐scheme 2D/2D materials for environmental remediation.

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment.

Abstract Background The purpose of this study is to compare serum pancreatic polypeptide (PP), insulin, C‐peptide, and glucagon in different glucose tolerance stages; analyze the influencing factors of PP secretion; and further explore the role of PP in the pathogenesis of diabetes mellitus. Methods Data were collected from 100 subjects from hospital. According to the results of oral glucose tolerance test (OGTT), the subjects were divided into a normal glucose tolerance (NGT) group, an impaired glucose regulation (IGR) group, and a newly diagnosed type 2 diabetes mellitus (T2DM) group. PP and the related parameters were measured, and the area under the curve (AUC) 120 min after OGTT was calculated. AUCpp (AUC of PP) was used as the dependent variable and the potentially influencing factors were used as the independent variable for multiple linear regression analysis. Results Postprandial 60 min PP in the IGR group was higher than those in the NGT group (2973.80 [±547.49] pg·h/mL vs 2663.55 [±594.89] pg·h/mL, p

Abstract Background Diabetic nephropathy (DN) is a critical and the most common microvascular complication and its pathogenesis is still faintly understood. Thus, this study was performed to examine the long non-coding RNA ZNFX1 Antisense Gene Protein 1 (lncRNA ZFAS1) biological function and mechanism of regulation in DN. Method Human glomerular mesangial cells (HGMC) were induced with high glucose (HG, 25 mM) to establish HG-induced cell viability, pro-inflammation observed in DN. After, target miRNA and mRNA were predicted through Lncbase and Targetscan. Subsequently, the expression of ZFAS1, miR-588, and ROCK1 in DN clinical samples and cell-model was examined through qRT-PCR and western blot analysis. We upheld the targeted interaction between miR-588 and ZFAS1 or ROCK1 through a dual-luciferase reporter assay. The proliferation of the cell was also examined through CCK-8 assay, while the level of HG-induced oxidative stress was established by measuring reactive oxygen species (ROS) level, and also the activities of antioxidant enzymes in the cell. Lastly, the level of accumulated extracellular matrix (ECM) protein-fibronectin and collagen type IV, and inflammatory cytokines produced by the cell was analyzed through western blot analysis and ELISA. Results ZFAS1 was significantly upregulated in the DN blood samples and HG-induced HGMC. Prediction result revealed that the ZFAS1 endogenously targets the miR-588 seed sequence while miR-588 plays a role in post-transcriptional regulation of ROCK1 mRNA. Moreover, we found that miR-588 expression was significantly downregulated in DN blood samples and negatively correlates with ZFAS1 expression. Further results show that silencing ZFAS1 had a protective effect on HG-induced proliferation, oxidative stress, fibrosis, and inflammation in HGMC while miR-588 inhibition and ROCK1 overexpression reversed this effect. Conclusions Altogether, our data suggest that ZFAS1 regulates the proliferation, oxidative stress, fibrosis, and inflammation of high glucose-induced diabetic nephropathy through the miR-588/ROCK1 axis.

Highlights 1. Up-regulated levels of NNT-AS1 and smad4 in DN samples and HGMCs was manifested. 2. Potential binding sites of NNT-AS1 showed miR-214-5p as its direct target and NNT-AS1 as potential absorber for this microRNA, in turn increasing the expression of transcription factor smad4. 3. The results manifested that knocking-down NNT-AS1 can significantly decrease the inflammation and progression of DN and hence can be used as a potential therapeutic target.

BackgroundBased on the principles of equity and effectiveness, the World Health Organization and COVAX formulate vaccine allocation as a mathematical optimization problem. This study aims to solve the optimization problem using agent-based simulations.MethodsWe built open-sourced agent-based models to simulate virus transition among a demographically representative sample of 198 million people in 148 countries using advanced computational services. All countries continuing their current vaccine progress is defined as the baseline scenario. Comparison scenarios include achieving minimum vaccination rates and allocating vaccines based on pandemic levels.FindingsThe simulations are fitted using the pandemic data from 148 countries from January 2020 to June 2021. Under the baseline scenario, the world will add 24.36 million cases and 468,945 deaths during the projection period of three months. Inoculating at least 10%, 20%, and 26% of populations in all countries requires 1.12, 3.31, and 5.00 million additional vaccine doses every day, respectively. Achieving these benchmarks reduces new cases by 0.56, 2.74, and 3.32 million, respectively. If allocated by the current global distribution, 5.00 million additional vaccine doses will only avert 1.45 million new cases. If those 5.00 million vaccines are allocated based on projected cases in each country, the averted cases will increase more than six-fold to 9.20 million. Similar differences between allocation methods are observed in averted deaths.ConclusionThe global distribution of COVID-19 vaccines can be optimized to achieve better outcomes in terms of both equity and effectiveness. Alternative vaccine allocation methods may avert several times more cases and deaths than the current global distribution. With reasonable requirements on additional vaccines, COVAX could adopt alternative allocation strategies that reduce cross-country inequity and save more lives.

Abstract Aims/Introduction To investigate the associations between parathyroid hormone (PTH) and non‐proliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes mellitus. Materials and Methods Data were collected from 2,322 patients with type 2 diabetes mellitus in hospital between 2017 and 2019. The odds ratio (OR) and the corresponding 95% confidence interval related to the quartiles of PTH were obtained by logistic regression analysis after adjusting the potential confounding variation. Results The patients were stratified into quartiles (Q1–Q4) based on the PTH levels, with the cut‐off limits of ≤23.74, 23.74–29.47, 29.47–37.30 and >37.30 pg/mL in men, and ≤24.47, 24.47–31.22, 31.22–39.49 and >39.49 pg/mL in women. The first quartile (Q1) represents the lowest quartile and the fourth quartile (Q4) is the highest. According to the quartiles (Q1–Q4), the prevalence rate of NPDR in patients showed a significantly decreasing trend (37.9%, 36.3%, 34.0% vs 24.0% in men; 43.2%, 40.5%, 31.1% vs 26.2% in women, both P

Abstract Aims/Introduction The aim of this study was to investigate the relationship between serum progesterone (P) and retinopathy in male patients with type 2 diabetes mellitus, and to investigate whether P is associated with its progression. Materials and methods A total of 1,376 male participants with type 2 diabetes mellitus were recruited from Affiliated Hospital of Medical College Qingdao University (Qingdao, China). Through logistic regression analysis after adjusting the potential confounding variation, the odds ratio (OR) and the corresponding 95% confidence interval related to the quartiles of progesterone were obtained. Results According to the quartiles of P levels, the prevalence rate of diabetic retinopathy (DR) in the last quartile is obviously greater to other quartiles (52.5–34.9%, 31.9%, 37.5%, P

This paper establishes a shareholder-stock bipartite network based on the data of large shareholders’ shareholding in the Shanghai A-share market of China in 2021. Based on the shareholder-stock bipartite network, the statistically validated network model is applied to establish a shareholder projected network and a stock projected network, whose structural characteristics can intuitively reveal the overlapping portfolios among different shareholders, as well as shareholder allocation structures among different stocks. The degree of nodes in the shareholder projected network obeys the power law distribution, the network aggregation coefficient is large, while the degree of most nodes in the stock projected network is small and the network aggregation coefficient is low. Furthermore, the two projected networks’ community structures are analyzed, respectively. Most of the communities in the shareholder projected network and stock projected network are small-scaled, indicating that the majority of large shareholders hold different shares from each other, and the investment portfolios of large shareholders in different stocks are also significantly different. Finally, by comparing the stock projected sub-network obtained from the shareholder-stock bipartite sub-network in which the degree of shareholder nodes is 2 and the original stock projected network, the effectiveness of the statistically validated network model, and the community division method on the research of the shareholder-stock bipartite network are further verified. These results have important implications for understanding the investment behavior of large shareholders in the stock market and contribute to developing investment strategies and risk management practices.

Abstract Background Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks sensitivity to chemotherapy, endocrine therapy or targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been shown to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Therefore, we investigated whether the CDK4/6 inhibitor palbociclib (PD) could enhance the effects of cisplatin (CDDP) on TNBC. Methods The effects of different drug regimens consisting of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and in vivo. MDA-MB-468 and RB-overexpressing MDA-MB-468 cells were used to assess the effect of the PD-CDDP regimens in vitro. Immunoblotting illustrated the role of the cyclin D1/RB/E2F axis signalling pathway. Results PD induced G1 phase cell cycle arrest in the MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24 h, treatment with PD for 24 h followed by CDDP and treatment with CDDP for 24 h followed by PD had no influence on MDA-MB-231 cell apoptosis. We further investigated the effect of PD or CDDP withdrawal on the effects of sequential treatment and found that PD treatment for 48 h followed by withdrawal for 48 h and subsequent CDDP treatment (PD-CDDP) significantly increased apoptosis and inhibited the cell viability and colony formation of MDA-MB-231 cells, while with other regimens, PD and CDDP had an additive or antagonistic response. The preferential use of PD increased DNA damage induced by CDDP, as measured through γH2AX immunofluorescence. These findings were not observed in sh-MDA-MB-231 cells, and experiments to assess cell function in MDA-MB-468 and RB-overexpressing MDA-MB-468 cells yielded similar results, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in an RB-dependent manner. In vivo, compared with single drug treatment, combination treatment inhibited tumour growth and Ki-67 expression in MDA-MB-231 xenograft models. Western blot analysis revealed that PD enhanced sensitivity to CDDP through the CDK4/6-cyclin D1-RB-E2F pathway. Conclusions Pre-treatment with PD synchronized the tumour cell cycle through the CDK4/6-cyclin D1-RB-E2F pathway, which increased the antitumour effect of CDDP. Thus, PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

Abstract Anthracite sheets were coated by sorbitol fatty acid ester (span80) through ball-milling process. The tribological properties of the span80-coated anthracite sheets as the additive in polyalpha olefin were evaluated through a series of friction tests using a four ball machine. The results revealed that the span80-coated anthracite sheets exhibited excellent dispersion stability in base oil. In addition, compared with base oil, the average coefficient of friction, wear scar diameter, and wear volume of modified oil at a mass fraction of 0.03% span80-coated anthracite sheets decreased by 45.39%, 60.13%, and 95.95%, respectively. The oil containing span80-coated anthracite sheets achieved good friction-reducing and anti-wear effects over a wide range of applied loads, temperatures, or rotating speeds. Control experiments were performed as well. The results obtained using span80-coated anthracite sheets were superior to those obtained using pure anthracite. The lubrication mechanism was attributed to the synergistic action of the crystalline and amorphous carbon in anthracite sheets as they formed a protective film and played a mitigative role on the surface of friction pair, which mitigated the wear extent of the friction pair.

BackgroundDiffuse midline glioma with H3K27-altered (DMG-H3K27a) is a novel tumor entity of the pediatric-type diffuse high-grade tumor in the latest WHO CNS 5. It mostly affects children and is only rarely found in adults. The tumor has a high level of aggressiveness, with a rapid progression and bad prognosis. In adults, the spinal cord is the most common site of DMG-H3K27a. Rare adult cases of primary DMG-H3K27a in the spinal cord were reported in this study, together with clinico-histopathologico-radiographic data.MethodsFrom January 2016 to December 2020, we conducted a retrospective study of five adults with primary DMG-H3K27a in the spinal cord, analyzing their clinical, pathohistological, and radiographic datasets from the first diagnosis to follow-up.ResultsAll five patients were diagnosed for the first time and were given full treatment. In three of the five patients, post-operative follow-up revealed tumor recurrence. The longest survival of the five patients was 45 months at the time of report submission, while the longest progression-free survival (PFS) following surgery was 20 months. Immunohistochemical studies showed the tumors featured aggressive behavior (grade 4) and were positive for the H3K27M mutation. The radiographic appearances were varied, but they were all initially mistaken as benign. DMG-H3K27a in the spinal cord was characterized by isointense/hyperintense on T1WI and isointense/hyperintense on T2WI, as well as cystic necrosis and peripheral spinal cord edema, as well as central canal enlargement and other types of enhancement.ConclusionThis is the first case report focusing on adult DMG-H3K27a of the pediatric-type diffuses high-grade gliomas in the spinal cord. In our cases, we discovered the following: 1) adults had a better prognosis with a longer PFS compared with prior pediatric reports; 2) despite aggressive behavior under the microscope, radiographic appearances of the tumors were less aggressive; and 3) adjuvant treatment, including TCM, may have played a role in the prognosis.

The association between hyperuricemia and cardiovascular disease (CVD) has been reported and studied in the past two decades. Xanthine oxidase (XO) induced uric acid (UA) serves as a risk factor and has the independent prognostic and functional impact of heart failure (HF), but whether it plays a positive role in the pathogenesis of HF has remained unclear. Growing evidence suggest the up-regulated XO avtivity and increased production of free oxygen radical (ROS) correspondingly are the core pathogenesis of HF with hyperuricemia, which results in a whole cluster of pathophysiologic cardiovascular effects such as oxidative stress, endothelial dysfunction, vascular inflammation, left ventricular (LV) dysfunction as well as insulin resistance (IR). The use of XO inhibition represents a promising therapeutic choice in patients with HF due to its dual effect of lowering serum UA levels as well as reducing ROS production. This review will discuss the pathophysiologic mechanisms of hyperuricemia with HF, the targeted therapeutic interventions of UA lowering therapies (ULT) with XO inhibition and mechanism underlying beneficial effects of ULT. In addition, the review also summarizes current evidence on the role of ULT in HF and compares CV risk between allopurinol and febuxostat for practical and clinical purposes. Guidelines and implementation of CV risk management in daily practice will be discussed as well.

Objective To investigate the effect of resin infiltrant on resistance of sound permanent enamel surfaces to demineralization. Method Eighty healthy premolars were sectioned to obtain enamel blocks from the buccal surface. Specimens with baseline surface microhardness values of 320–370 were selected. The experimental group were treated with resin infiltrant, while the control group was not. Specimens from each group were artificially demineralized and the surface microhardness values were measured again. Confocal laser scanning microscopy was used to measure the depth of demineralization and detect the penetration ability of the resin infiltrant. The specimens were subjected to a simulated toothbrushing abrasion test. Scanning electron microscopy was used to observe changes in the surface morphology of specimens after each of these procedures. Results No significant differences between the experimental and control groups were observed in the baseline microhardness values or in the experimental group after resin infiltration compared with the baseline conditions. After artificial demineralization, the microhardness value in the control group was significantly lower than that in the experimental group (266.0 (±34.5) compared with 304.0 (±13.0), P = 0.017). Confocal laser scanning microscopy results showed that the demineralization depth in the control group was significantly deeper than that in the experimental group (97.9 (±22.8) µm vs. 50.4 (±14.3) µm, P < 0.001), and that resin infiltrant completely penetrated the acid-etched demineralized area of the tooth enamel with a mean penetration depth of 31.6 (±9.0) µm. Scanning electron microscopy showed that the surface morphology was more uniform and smoother after simulated toothbrushing. The enamel surface structure was more severely destroyed in the control group after artificial demineralization compared with that of the experimental group. Conclusion Resin infiltrant can completely penetrate an acid-etched demineralized enamel area and improve resistance of sound enamel surfaces to demineralization. Our findings provide an experimental basis for preventive application of resin infiltrant to sound enamel surfaces to protect tooth enamel against demineralization.

PURPOSE: To build radiomic prediction models using contrast-enhanced computed tomography (CE-CT) to preoperatively predict malignant potential and mitotic count of gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: A total of 333 GISTs patients were retrospectively included in our study. Radiomic features were extracted from the preoperative CE-CT images. According to postoperative pathology, patients were categorized by malignant potential and mitotic count, respectively. The most valuable radiomic features were chosen to build a logistic regression model to predict the malignant potential and a random forest classifier model to predict the mitotic count. The performance of radiomic models was assessed with the receiver operating characteristics curve. Our study further developed a radiomic nomogram to preoperatively predict malignant potential in a personalized way for patients with GISTs. RESULTS: The predictive model was built to discriminate high– from low–malignant potential GISTs with an area under the curve (AUC) of 0.882 (95% CI 0.823-0.942) in the training set and 0.920 (95% CI 0.870-0.971) in the validation set. Moreover, the other radiomic model was built to differentiate high– from low–mitotic count GISTs with an AUC of 0.820 (95% CI 0.753-0.887) in the training set and 0.769 (95% CI 0.654-0.883) in the validation set. CONCLUSION: The radiomic models using CE-CT showed a good predictive performance for preoperative risk stratification of GISTs and hold great potential for personalized clinical decision making.

Autologous CD19-targeted chimeric antigen receptor-modified T cells (CD19-CART) remarkably improved the outcome of patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, the application and outcomes of allogeneic CART cells is still uncertain. Two patients with advanced B-ALL were enrolled to receive a co-infusion of high-dose human leukocyte antigen-haploidentical donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cells (GPBMCs; 21.01–25.34 × 10 8 /kg) and the same donor-derived CD19-targeted CART cells (8.44–22.19 × 10 6 /kg) without additional in vitro gene-editing following a reinduction chemotherapy as precondition. They achieved complete remission and full donor chimerism (FDC) with ongoing 20- and 4-month leukemia-free survival. A significant amplification of donor CART cells was detected in peripheral blood and/or cerebrospinal fluid and was associated with the formation of FDC. The highest amount of copies of the donor CART cells reached 4962 per µg of genomic DNA (gDNA) and 2449 per µg of gDNA, and the longest persistence was 20 months associated with B cell aplasia. Two patients experienced Grade II or III cytokine release syndromes and developed controllable Grade II intestinal acute graft-versus-host disease (GVHD) or limited chronic oral GVHD. High-dose donor GPBMC infusion may enhance amplification and persistence of haploidentical CD19-targeted CART cells, suggesting an alternative therapy for advanced B-ALL patients.

Tumor-induced immunosuppressive microenvironment in which myeloid-derived suppressor cells (MDSCs) plays an important role, remains an obstacle for effective oncotherapy currently. Inducing MDSCs into maturation was confirmed as an effective method to reduce the tumor-bearing host's immunosuppression. Traditional Chinese medicines (TCM) possess characteristics of alleviating immunosuppression of cancer patients and low toxicity. Jianpi Huayu Decoction (JHD) was an experienced formula of TCM for oncotherapy based on TCM theory and clinical practice. We previously observed that JHD attenuated the expression of interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) in tumor. IL-10 and TGF-β were found to be cytokines positively related to immunosuppression induced by MDSCs. Here, our study was designed to further investigate the regulation of JHD on the immune system in the H22 liver-cancer mouse model. Mainly, flow cytometry was used to detect the proportion of immune cells, to analyze the apoptosis, differentiation and reactive oxygen species of MDSCs. We found that JHD significantly reduced the destruction of spleen structure, reduced the proportion of regulatory T cells (Treg) and T helper 17 cells (Th17), and increased the proportion of cytotoxic T lymphotes (CTL), Dendritic cells (DC) and CD11b+Gr-1+cells in spleen, but with no significant change of T helper 1 cells (Th1), T helper 2 cells (Th2) and macrophages. In vitro experiments showed that apoptosis of MDSCs was decreased as the time of JHD stimulation increased, which partly explained the increase of CD11b+Gr-1+cells in the spleen. Meanwhile, JHD could promote the differentiation of MDSCs into macrophages and dendritic cells, attenuate expression of ROS in MDSCs and reduce its inhibition on the proliferation of CD4+ T cells, in vitro. Therefore, that the proportion of CD11b+Gr-1+ cells increased in the spleen of tumor-bearing hosts may not be villainy after treatment, when these drugs suppress the immunosuppressive ability of CD11b+Gr-1+ cells and promote it mature to replenish dendritic cell, at the same time. Generally, JHD may be a complementary and alternative drug for attenuating the immunosuppressive status induced by hepatocellular carcinoma, possibly by promoting differentiation and inhibiting the immunosuppressive activity of MDSCs.

The traditional Chinese medicine formula Jianpi-Huayu (JPHY) has been reported to be effective in the treatment of hepatocellular carcinoma (HCC). However, its underlying mechanism remains unclear. In this article, we employed an orthotopic transplantation model in nude mice to explore whether JPHY could inhibit the development of HCC by regulating miR-602, which targets the Ras association domain-containing protein 1A (RASSF1A) pathway. HCC SMMC-7721 cells were treated with JPHY to test whether the RASSF1A gene as mediated by miR-602 affected the proliferation and apoptosis of tumor cells. We subsequently detected miR-602, RASSF1A, and tumor cell apoptosis–related markers in cells and liver tumor tissues. We observed that mice treated with JPHY had smaller tumors and higher survival rates than untreated ones. Similarly, JPHY-treated SMMC-7721 cells exhibited alterations in morphology and higher cytotoxicity compared with the control group. Furthermore, we found that JPHY decreased overexpression of miR-602 and increased protein expression levels of the RASS1A gene, which in turn altered protein expression levels of tumor cell apoptosis–related genes in the cells and liver tumor tissues of drug-treated mice. These results indicated that JPHY could potentially be used to treat HCC by targeting miR-602, which targets the RASSF1A gene, which in turn plays a major role in HCC pathogenesis.

Diabetic kidney disease (DKD) is a common cause of end-stage renal disease, and diagnosis and treatment in time can help delay its progress. At present, there are more and more studies on the pathogenesis of DKD; mitochondrial dysfunction plays an important role in DKD. The occurrence and development of DKD is closely related to epigenetic changes and the interaction between mtDNA, ROS, inflammatory factors, and endothelial damage, which continuously aggravates kidney. The change of mtDNA is both the cause of DKD and the result of DKD. It is of great significance to incorporate the change of mtDNA into the monitoring of patients with diabetes. Existing evidence indicates that changes in mtDNA copy number in blood and urine reflect mitochondrial dysfunction and the severity of DKD. However, large-scale, long-term follow-up clinical trials are still needed to determine the threshold range. By the time, mitochondrial-targeted antioxidants will become a new method for the treatment of DKD and other diabetic complications; mtDNA also can be a therapeutic target for them.

This paper studies the community structure of the bank correlation network in the financial system and analyzes the systemic risk of the community sub-networks. Based on the balance sheet data of U.S. commercial banks from 2008, we establish a bank correlation network for each state according to the banks’ investment portfolio ratio. First, we analyze the community structure of each bank’s correlation network and verify the effectiveness of the community division from the point of view of the importance of nodes. Then, combining the data of failed banks after the 2008 financial crisis, we find that for small communities, the financial systemic risk will appear to have obvious volatility, and it is quite likely to reach an extremely high level. With the increase in the number of nodes in the community, systemic risk will tend towards a stable and low level. Furthermore, if only communities with failed banks are considered, the regression analysis shows that systemic risk and the size of the community almost follow a power law distribution trend. These results reveal the importance of supervising the banking system at the level of community sub-networks, which has certain guiding significance for the stability of the financial system.

Abstract Background Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined. Case presentation We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy. Conclusions Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned. Trial registration Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550

Trophoblast cell dysfunction is involved in many disorders during pregnancy such as preeclampsia and intrauterine growth restriction. Few treatments exist, however, that target improving trophoblast cell function. Human umbilical cord mesenchymal stem cells (hUCMSCs) are capable of self-renewing, can undergo multilineage differentiation, and have homing abilities; in addition, they have immunomodulatory effects and paracrine properties and thus are a prospective source for cell therapy. To identify whether hUCMSCs can regulate trophoblast cell functions, we treated trophoblast cells with hUCMSC supernatant or cocultured them with hUCMSCs. Both treatments remarkably enhanced the migration and invasion abilities of trophoblast cells and upregulated their proliferation ability. At a certain concentration, hUCMSCs also modulated hCG, PIGF, and sEndoglin levels in the trophoblast culture medium. Thus, hUCMSCs have a positive effect on trophoblast cellular functions, which may provide a new avenue for treatment of placenta-related diseases during pregnancy.