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Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial–mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

To optimize the extraction process of polysaccharide form Solanum lyratum and investigate its in vitro antioxidative activity. In this study, response surface methodology was employed to optimize the ultrasonic-assisted extraction process of polysaccharides from Solanum lyratum. Single-factor experiments were conducted to explore the effects of three factors: Extraction temperature, extraction time, and solid-liquid ratio on the yield. Fourier transform infrared spectroscopy (FTIR) was used to analyze the structure of Solanum lyratum polysaccharide, and in vitro antioxidant activity was investigated. The results showed that the optimal extraction conditions were the material-liquid ratio of 1:57 g/mL, the extraction time of 58 min, and the extraction temperature of 65 ℃. Under these conditions, the yield of polysaccharides was 7.54%±0.12%. Fourier transform infrared spectroscopy of the extracted polysaccharides exhibited a typical polysaccharide absorbance. Moreover, the half-maximal inhibitory concentrations (IC50) of polysaccharides against DPPH and ABTS+ free radicals were 1.104 and 1.408 mg/mL, respectively, indicating significant in vitro antioxidant activity. The results of this study provided a theoretical foundation for the further development and utilization of Solanum lyratum polysaccharides.

This study selected two sweet potato varieties as research subjects and conducted a field experiment using a two-factor design with two potassium (K) levels (K0 and K1) and five nitrogen (N) levels (N0–N4). The physiological changes in sweet potato leaves under different N and K treatments were measured, and nutrients such as the soluble sugar, protein, and starch content of sweet potato roots were analyzed. The results indicate that the activity of glutamine synthetase (GS) and the soluble protein content in sweet potato leaves increase first and then decrease with increasing N application, while K application can significantly increase the activity of GS and the soluble protein content. The N metabolic capacity of leaves is strongest when the fertilizer ratio is K1N2. The SPAD value of sweet potato leaves increases with increasing N application. The net photosynthetic rate, stomatal conductance, and intercellular CO2 concentration first increase and then decrease with increasing N application. K fertilizer has a significant effect on these parameters. As the N application rate increases, the starch and protein content in the tubers increase, while the soluble sugar content decreases. However, the number of tubers per plant, fresh weight of the tubers, and dry weight of the tubers increase initially and then decrease, while the vine length continuously increases. The application of K fertilizer can significantly increase the number of tubers per plant and stem thickness of sweet potato. In conclusion, the appropriate N–K combined application can promote N metabolism, enhance the photosynthetic capacity of sweet potato, increase yield, and improve quality.

Abstract Objective To observe the expression of inflammatory factors and autophagy‐related proteins in granulation tissue of diabetic foot ulcer (DFU) patients and analyze their relationship with infection. Methods This is a retrospective cohort study. One hundred and fifty‐two patients with DFU in our hospital from July 2020 to March 2022 were selected as the DFU group, including 98 cases in infection stage group and 54 cases in infection control group. The patients were further graded as the mild (51 cases), the moderate (65 cases), and the severe infection group (36 cases) according to the Wagner grading criteria. Sixty‐seven patients with foot burns during the same period were selected as the control group. The distribution of pathogenic bacteria on the ulcer surface was examined using fully automated bacterial analyzer. The expression of inflammatory factors (procalcitonin [PCT], tumor necrosis factor‐α [TNF‐α], and interleukin‐6 [IL‐6]) was valued by real‐time fluorescence quantitative PCR (qRT‐PCR). Protein expression was measured by immunohistochemistry (IHC). The correlation was analyzed by Pearson. Results The surface infection of DFU patients was mostly induced by gram‐negative and gram‐positive bacteria, with Pseudomonas aeruginosa predominating among the Gram‐negative bacteria and Staphylococcus aureus among the gram‐positive bacteria. The infection stage group had higher content of PCT, TNF‐α, and IL‐6 and lower content of Beclin‐1 and LC3 than the infection control group (p

Depression is a common disease that affects physical and mental health and imposes a considerable burden on afflicted individuals and their families worldwide. Depression is associated with a high rate of disability and suicide. It causes a severe decline in productivity and quality of life. Unfortunately, the pathophysiological mechanisms underlying depression have not been fully elucidated, and the risk of its treatment is still presented. Studies have shown that the expression of autophagic markers in the brain and peripheral inflammatory mediators are dysregulated in depression. Autophagy-related genes regulate the level of autophagy and change the inflammatory response in depression. Depression is related to several aspects of immunity. The regulation of the immune system and inflammation by autophagy may lead to the development or deterioration of mental disorders. This review highlights the role of autophagy and neuroinflammation in the pathophysiology of depression, sumaries the autophagy-targeting small moleculars, and discusses a novel therapeutic strategy based on anti-inflammatory mechanisms that target autophagy to treat the disease.

To compare and analyze the medicinal quality of garlic, a garlic medicinal quality evaluation system was established. Moisture, ash, water-soluble extract, diallyl trisulfide content, alliin content, allicin content and alliinase activity were screened out as indicators to analyze the medicinal quality of garlic from 11 regions, including Minle, Pizhou, Jinxiang, Zhengzhou, Wuxi, Qiemo, Baicheng, Zhongmachang, Hutou, Dayou and Xindi. The correlation analysis, principal component analysis and cluster analysis were performed to determine the quality of garlic in different regions. The results showed that all the above-mentioned indicators of garlic from different regions had significant differences. The correlation analysis showed that alliinase activity had an extremely significant and positive correlation with moisture (P

The applications of fucoidan in the food industry were limited due to its high molecular weight and low solubility. Moderate degradation was required to depolymerize fucoidan. A few studies have reported that fucoidan has potential antibacterial activity, but its antibacterial mechanism needs further investigation. In this study, the degraded fucoidans were obtained after ultraviolet/hydrogen peroxide treatment (UV/H2O2) at different times. Their physicochemical properties and antibacterial activities against Staphylococcus aureus and Escherichia coli were investigated. The results showed that the average molecular weights of degraded fucoidans were significantly decreased (up to 22.04 times). They were mainly composed of fucose, galactose, and some glucuronic acid. Fucoidan degraded for 90 min (DFuc-90) showed the strongest antibacterial activities against Staphylococcus aureus and Escherichia coli, with inhibition zones of 27.70 + 0.84 mm and 9.25 + 0.61 mm, respectively. The minimum inhibitory concentrations (MIC) were 8 mg/mL and 4 mg/mL, respectively. DFuc-90 could inhibit the bacteria by damaging the cell wall, accumulating intracellular reactive oxygen species, reducing adenosine triphosphate synthesis, and inhibiting bacterial metabolic activity. Therefore, UV/H2O2 treatment could effectively degrade fucoidan and enhance its antibacterial activity.

Objective: To compare the intervention effects and pharmacoeconomic advantages of Fufang Huangbai Fluid (FFHB) hydropathic compress versus Antimicrobial Calcium Alginate Wound Dressing (ACAWD) in the treatment of diabetic foot infections (DFI).Methods: Patients with DF who were hospitalized in the peripheral vascular Department of Dongzhimen Hospital of Beijing University of Chinese Medicine from December 2020 to February 2022 and met the inclusion and excluding criteria were allocated into the experimental group and control group through minimization randomization. The experimental group was treated with FFHB hydropathic compress for 2 weeks, while the control group was treated with ACAWD for the same duration. The wound healing of both groups was monitored for 1 month post-discharge. Clinical data from all eligible patients were collected, and differences in various indices between cohorts were analyzed.Results: 22 in the experimental group (including two fell off) and 20 in the control group. After the treatment, the negative rate of wound culture in the experimental group was 30% and that in the control group was 10%, There was no significant difference in the negative rate of wound culture and change trend of minimum inhibitory concentration (MIC) value of drug sensitivity (p > 0.05). The infection control rate of the experimental group was 60%, and that of the control group was 25%. The difference between the two groups was statistically significant (χ2 = 5.013, p = 0.025). The median wound healing rate of the experimental group was 34.4% and that of the control group was 33.3%. There was no significant difference between the two groups (p > 0.05). During the follow-up 1 month later, the wound healing rate in the experimental group was higher, and the difference was statistically significant (p = 0.047). Pharmacoeconomic evaluations indicated that the experimental group had greater cost-effectiveness compared to the control group.Conclusion: In the preliminary study, FFHB demonstrated comparable pathogenic and clinical efficacy to ACAWD in the treatment of mild DF infection, and exhibited superior pharmacoeconomic advantages. With the aid of infection control, the wound healing rate in the FFHB group showed notable improvement. Nevertheless, due to the limited sample size, larger-scale studies are warranted to further validate these findings.Clinical Trial Registration: (https://www.chictr.org.cn/showproj.aspx?proj=66175), identifier (ChiCTR2000041443).

Abstract Background Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC. Methods A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting. Results XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC. Conclusions XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.

Objectives To evaluate the safety and efficacy of high-dose amoxicillin-proton pump inhibitor dual therapy, and to provide a new eradication regimen as a first-line option for patients with H. pylori infection. Methods A total of 971 H. pylori positive patients who received initial treatment were recruited from March to August 2020, and randomly divided into treatment group and control group. The treatment group received of 20 mg esomeprazole four times daily and 750 mg amoxicillin four times daily for 14 days. Control group received of 220 mg bismuth potassium citrate twice daily, 20 mg esomeprazole twice daily, 1000 mg amoxicillin twice daily and 250 mg clarithromycin capsule twice daily for 14 days. Four weeks after the end of treatment, the urea breath test was reviewed to detect whether H. pylori was eradicated. Results There were no statistical differences in age, gender, the total clinical symptom scores before and after initial treatment, the compliance, and the degree of remission of symptoms before and after initial treatment between the two groups. The eradication rates of H. pylori between dual therapy and quadruple therapy were 88.31% and 85.26% (p=.158) by intention-to-treat (ITT) analysis, 88.66% and 85.44% (p=.186) by modified intention-to-treat (mITT) analysis, and 91.63% and 90.60% (p=.116) by PP analysis, respectively. Adverse events in dual therapy group were significantly lower than quadruple therapy group (13.3% vs. 28.2% (p

Abstract Hematogenous metastasis is the main approach for colorectal cancer liver metastasis (CRCLM). However, as the gatekeepers in the tumor vessels, the role of TPCs in hematogenous metastasis remains largely unknown, which may be attributed to the lack of specific biomarkers for TPC isolation. Here, microdissection combined with a pericyte medium‐based approach is developed to obtain TPCs from CRC patients. Proteomic analysis reveals that TRP channel‐associated factor 2 (TCAF2), a partner protein of the transient receptor potential cation channel subfamily M member 8 (TRPM8), is overexpressed in TPCs from patients with CRCLM. TCAF2 in TPCs is correlated with liver metastasis, short overall survival, and disease‐free survival in CRC patients. Gain‐ and loss‐of‐function experiments validate that TCAF2 in TPCs promotes tumor cell motility, epithelial‐mesenchymal transition (EMT), and CRCLM, which is attenuated in pericyte‐conditional Tcaf2‐knockout mice. Mechanistically, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion in TPCs, which facilitates EMT via the activation of the STAT3 signaling pathway in tumor cells. Menthol, a TRPM8 agonist, significantly suppresses Wnt5a secretion in TPCs and CRCLM. This study reveals the previously unidentified pro‐metastatic effects of TPCs from the perspective of cold‐sensory receptors, providing a promising diagnostic biomarker and therapeutic target for CRCLM.

Scientific and reasonable application of potassium fertilizer is an important agronomic measure to achieve high yield and high quality of sweetpotato, and it is of great significance to determine the appropriate amount of potassium fertilizer in the field. For this we constructing a model of the critical K dilution curve (CKDC) of sweetpotato under different N levels to determine crop nutritional statuses. In this study, a 3-year field experiment was conducted in Zhejiang Province in China, using two nitrogen levels (N0: 0 kg ha−1 and N1: 120 kg ha−1) and five K fertilization rates (K0: 0, K1: 75, K2: 150, K3: 225, K4: 300 kg ha−1) for two sweetpotato cultivars of ‘Shang 19’ and ‘Yan 25’. Plant dry matter first increased and then decreased and the K concentration increased continuously with an increase in K application rate. The required amount of K fertilizer to achieve maximum sweetpotato yield under high N conditions was greater than that under low nitrogen conditions. A new CKDC based on dry matter and K concentration was created to assess K nutrition in sweetpotato. At two N levels, CKDC was expressed by the negative power function equation, aboveground: Kc(N0)=5.30W-0.463, R2 = 0.79, and Kc(N1)=4.23W-0.298, R2 = 0.78, under-ground: Kc(N0)=1.38W-0.125, R2 = 0.81, and Kc(N1)=1.32W-0.132, R2 = 0.72;whole-plant: Kc(N0)=4.31W-0.421, R2 = 0.80; Kc(N1)=3.89W-0.415, R2 = 0.79. There is no significantly different for CKDC of whole-plant and underground between N0 and N1 levels, while there is significantly different for CKDC of aboveground between N0 and N1 levels. N fertilizer can strengthen the dilution effect of K concentration, and its effect on the aboveground is greater than that on the underground and whole-plant. Then, potassium nutrition indexes were constructed to identify K nutrition status and could be used as a reliable indicator for K nutrition diagnosis of sweetpotato. The results provide a theoretical basis to improve K fertilization management and sustainability of sweetpotato.

Introduction: Compared with the 3 + 7 regimen, the addition of gemtuzumab ozogamicin (GO) has improved survival in patients with acute myeloid leukemia (AML). We conducted a systematic review and meta-analysis to examine the overall efficacy and safety of GO in combination with conventional chemotherapy regimens in patients with AML. Methods: We searched several databases (MEDLINE, Embase, Web of Science and Cochrane Library). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for overall survival (OS) and relapse-free survival (RFS); odds ratios (ORs) with 95% CIs were calculated for the other outcomes. Results: Ten records involving 11 randomized controlled trials (RCTs) met the inclusion criteria. GO plus induction chemotherapy significantly increased RFS (HR: 0.84, 95% CI: 0.73–0.98), decreased the incidence of relapse (OR: 0.78, 95% CI: 0.68–0.91) and resistant disease (OR: 0.72, 95% CI: 0.61–0.84), and had no significant effect on the rate of complete remission (CR) with or without incomplete platelet recovery (OR: 1.21, 95% CI: 0.94–1.55), 30-day mortality (OR: 1.25, 95% CI: 0.99–1.57). Subgroup analysis showed significant OS benefits for patients with favorable cytogenetic (HR: 0.50, 95% CI: 0.28–0.89) or given GO at induction stage (HR: 0.91, 95% CI: 0.84–1.00). Compared with other dosing schedule groups, 3 mg/m2 fractionated schedule had a greater RFS benefit (HR: 0.52, 95% CI: 0.36–0.76) and lower relapse risk (OR: 0.48, 95% CI: 0.28–0.84). Conclusions: Adding low-dose GO to induction or both induction and post-remission chemotherapy has considerable efficacy and unequivocal safety for newly diagnosed adult AML.

Abstract Background Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder diagnosed during adolescence and adulthood. Assessment of the long-term risks of the current drugs for ADHD treatment has been insufficient, and little is known concerning the long-term therapeutic effects of psychostimulants. Commercially available traditional Chinese medicine compound oral preparations [e.g., Dimu Ningshen (DMNS)] have been widely used in the clinical treatment of ADHD, but their influence on the interaction between gut microbes and potential metabolomes remains inconclusive. Methods We used a series of behavioral experiments to evaluate the behavioral effects of DMNS on adolescent and adult ADHD rats and used 16S rDNA sequencing of gut microbes and nontarget metabolomics to evaluate the potential pathogenesis of ADHD and explore the biological mechanism of DMNS in ADHD treatment. Results For the first time, DMNS was shown to reduce the excessive activity of adult and adolescent ADHD rats and improve the attention deficit of adult ADHD rats. DMNS improved the structural composition of the ADHD gut microbiota and reduced the abundance of Ruminococcaceae_NK4A214_group, Ruminococcus_2, and Eubacterium_nodatum_group. Simultaneously, DMNS increased the circulating levels of peripheral monoamine neurotransmitter precursors (e.g., phenylalanine) and reduced the circulating levels of peripheral fatty acid amides (e.g., oleamide). Finally, the changes in the ADHD serum metabolites were strongly correlated with the gut microbiota. Conclusion DMNS has a good effect in treating ADHD, and it may exert this effect by regulating the gut microbiota and affecting metabolites in the peripheral circulation.

Abstract Background The unprecedented efficacy of chimeric antigen receptor T (CAR-T) cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumors. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo. Methods NALM-6, a human B-cell acute lymphoblastic leukemia (B-ALL) cell line, was used as target cells. CAR-T cells were injected into a mice model with or without target cells. Then we measured the distribution of CAR-T cells in mice. In addition, an exploratory clinical trial was conducted in 13 r/r B-cell non-Hodgkin lymphoma (B-NHL) patients, who received CAR-T cell infusion. The dynamic changes in patient blood parameters over time after infusion were detected by qPCR and flow cytometry. Results CAR-T cells still proliferated over time after being infused into the mice without target cells within 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at week 6. In the clinical trial, we found that CAR-T cells peaked at 7–21 days after infusion and lasted for 420 days in peripheral blood of patients. Simultaneously, mild side effects were observed, which could be effectively controlled within 2 months in these patients. Conclusions CAR-T cells can expand themselves with or without target cells in mice, and persist for a long time in NHL patients without serious side effects. Trial registration The registration date of the clinical trial is May 17, 2018 and the trial registration numbers is NCT03528421 .

Abstract Background The treatment outcomes and prognosis of lymphoma are affected by various factors such as hospital types. This study was to describe the temporal trend in the survival of lymphoma in an academic center in China. Methods A total of 3840 consecutive patients with lymphoma diagnosed between 1996 and 2015 were reviewed. Eighty patients were excluded, and finally, 3760 patients were analyzed in this study. The cohort was divided into four groups according to calendar periods at diagnosis: 1996‐2000, 2001‐2005, 2006‐2010, and 2010‐2015. The overall survival (OS) rates among the four groups were compared. Results The 5‐ and 10‐year OS for the whole cohort were 62% and 52%, respectively. The 5‐year OS of patient with classic Hodgkin lymphoma (cHL), mature B‐cell lymphoma (BCL), and peripheral T‐cell lymphoma (PTCL) were 79%, 63%, and 50%, respectively. Among mature BCL, the 5‐year OS was highest in follicular lymphoma (77.8%), followed by Burkitt lymphoma (76.5%), marginal zone lymphoma (74.1%), diffuse large B‐cell lymphoma (61.5%), small lymphocytic lymphoma/chronic lymphocytic leukemia (55.1%), and mantle cell lymphoma (44.3%). Among PTCL, the 5‐year OS was highest in ALK+anaplastic large cell lymphoma (79.0%), followed by ALK−anaplastic large cell lymphoma (63.1%), natural killer/T‐cell lymphoma (57.7%), angioimmunoblastic T‐cell lymphoma (34.9%, and peripheral T‐cell lymphoma not otherwise specified (27.6%). Significant improvement in the survival of lymphoma was observed, with the 5‐year OS increasing from 48% in 1996‐2000 to 65% in 2011‐2015 (P

Chemoresistance frequently occurs in cancer treatment, which results in chemotherapy failure and is one of the most leading causes of cancer-related death worldwide. Understanding the mechanism of chemoresistance and exploring strategies to overcome chemoresistance have become an urgent need. Autophagy is a highly conserved self-degraded process in cells. The dual roles of autophagy (pro-death or pro-survival) have been implicated in cancers and chemotherapy. MicroRNA (miRNA) is a class of small non-coding molecules that regulate autophagy at the post-transcriptional level in cancer cells. The association between miRNAs and autophagy in cancer chemoresistance has been emphasized. In this review, we focus on the dual roles of miRNA-mediated autophagy in facilitating or combating chemoresistance, aiming to shed lights on the potential role of miRNAs as targets to overcome chemoresistance.

Angiogenesis is required for tumor growth and development. Extracellular vesicles (EVs) are important signaling entities that mediate communication between diverse types of cells and regulate various cell biological processes, including angiogenesis. Recently, emerging evidence has suggested that tumor-derived EVs play essential roles in tumor progression by regulating angiogenesis. Thousands of molecules are carried by EVs, and the two major types of biomolecules, noncoding RNAs (ncRNAs) and proteins, are transported between cells and regulate physiological and pathological functions in recipient cells. Understanding the regulation of EVs and their cargoes in tumor angiogenesis has become increasingly important. In this review, we summarize the effects of tumor-derived EVs and their cargoes, especially ncRNAs and proteins, on tumor angiogenesis and their mechanisms, and we highlight the clinical implications of EVs in bodily fluids as biomarkers and as diagnostic, prognostic, and therapeutic targets in cancer patients.

CD19-targeted chimeric antigen receptor-T (CAR-T) cells with CD28 or 4-1BB (28z CAR-T and BBz CAR-T) have shown great promise to treat relapsed or refractory (r/r) B cell non-Hodgkin’s lymphoma (B-NHL). However, comparison of their clinical outcomes has never been reported. This study investigated their efficacy and adverse events in B-NHL therapy. Six patients with r/r B-NHL were initially enrolled and infused with 28z or BBz CAR-T cells at a dose of 0.75–5 × 105/kg. These CAR-T cells showed similar antitumor efficacies, with a complete response (CR) rate of 67% within 3 months. BBz CAR-T was well tolerated. However, severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in the 28z CAR-T cohort, resulting in the termination of further evaluation of 28z CAR-T. Three more patients were enrolled to investigate BBz CAR-T cells in-depth at an escalated dose (1 × 106/kg). All cases achieved CR within 3 months, and only grade 1/2 adverse events occurred. This study suggests that 4-1BB is more beneficial for the clinical performance of CAR-T cells than CD28 in CD19-targeted B-NHL therapy, at least under our manufacturing process. Keywords: CD19-targeted chimeric antigen receptor-T cells, co-stimulatory domain, B cell non-Hodgkin’s lymphoma

The phase transition pressure, electronic structure, optical properties and stability for ZnSe and Cr2+:ZnSe with different doping concentrations were calculated by first-principles calculation based on density-functional theory. The phase transition pressure was calculated by enthalpy-pressure relation. The introduction of dopant (Cr2+) reduces the phase transition pressure, and the phase transition pressure decreases with the increase of doping concentration. The high pressure enhances the degeneracy of Cr-d orbitals. Under the high-pressure conditions, the absorption peak positions of Cr2+:ZnSe have obvious blue-shift. Meanwhile, the stability of structures for ZnSe and Cr2+:ZnSe were further confirmed by defect formation energy and elastic constants. Keywords: Phase transition pressure, Optical properties, Cr2+:ZnSe, First-principles calculation

Abstract Background Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. However, the molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown. Methods Antibodies specific to phosphorylated ZAP70, ITK and PLCγ1 were used to identify the activation status of intracellular proteins involved in TCR signaling in AITL patients. Malignant T cell lymphoma cells were transduced with a lentiviral construct containing ITK shRNA for cellular and functional assays. The antitumor effects of the selective ITK inhibitor BMS-509744 were determined in vitro and in vivo. Results Immunohistochemistry staining showed that more than half of the AITL patients (n = 38) exhibited continuously activated intracellular TCR signaling pathway. Patients positive for phosphorylated ITK showed a lower rate of complete response (20% vs. 75%, P = 0.004) and a shorter progression-free survival (5.17 months vs. 25.1 months, P = 0.022) than patients negative for phosphorylated ITK. Genetic and pharmacological cellular ITK inhibition significantly compromised the proliferation, invasion and migration of malignant T cells. The selective ITK inhibitor BMS-509744 also induced the pro-apoptotic effects and G2/M phase cell cycle arrest in vitro and in vivo. Finally, inhibition of ITK synergistically enhanced the antitumor effect of vincristine and doxorubicin on malignant T cell lymphoma cell lines. Conclusions Our findings suggest that ITK may be a novel candidate therapeutic target for the treatment of patients with ITK-expressing malignant T-cell lymphomas.

Abstract Background Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma. Although durable remissions can be achieved in more than half of these patients, DLBCL remains a significant clinical challenge, with approximately 30% of patients not being cured. BCR-associated kinases (SYK, BTK, and PI3K) inhibitors have exhibited encouraging pre-clinical and clinical effects, as reported by many researchers. Early studies demonstrated that protein kinase C-β (PKCβ) inhibitors alter phosphorylation level the Bruton’s tyrosine kinase (BTK), which leads to enhanced BTK signaling. Here, for the first time, we investigate whether the combination of PKCβ inhibitor enzastaurin and BTK inhibitor ibrutinib has synergistic anti-tumor effects in DLBCL. Methods In vitro cell proliferation was analyzed using Cell Titer-Glo Luminescent Cell Viability Assay. Induction of apoptosis and cell cycle arrest were measured by flow cytometry. Western Blotting analysis was used to detect the essential regulatory enzymes in related signaling pathways. RNA-seq was conducted to evaluate the whole transcriptome changes brought by co-treatment with low doses of enzastaurin and ibrutinib. The synergistic anti-tumor effects of enzastaurin and ibrutinib were also evaluated in vivo. Results Combination of enzastaurin and ibrutinib produced a lasting synergistic effect on the survival and proliferation of DLBCL cells, including reduction of proliferation, promoting apoptosis, inducting G1 phase arrest, preventing cell invasion and migration, and down-regulating activation of downstream signaling. More importantly, whole-transcriptome changes results showed that combination therapy worked synergistically to regulate whole-transcriptome expression compared with enzastaurin and ibrutinib alone. Co-treatment with low doses of enzastaurin and ibrutinib could effectively downregulate BCR, NF-κB, JAK and MAPK related signaling pathway. Furthermore, the mRNA expression analysis further indicated that co-treatment significantly decreased the mRNA levels of NOTCH1. The combination effect in inhibiting proliferation of DLBCL cells probably was realized through suppression of NOTCH1 expression. Finally, the anti-tumor activity of co-treatment also was demonstrated in vivo. Conclusions Combination of enzastaurin and ibrutinib had synergistic anti-tumor effects in DLBCL, independent of molecular subtype. These results provided a sound foundation for an attractive therapeutic treatment, and the simultaneous suppression of BTK and PKCβ might be a new treatment strategy for DLBCL.

As an emerging diabetes diagnostic indicator and a dynamic change index, HbA1c can not only reflect the average blood glucose level over a period of time but can also well predict the incidence of related microvascular complications. It is important to develop a detection method that can dynamically characterize HbA1c. Silicon nanowire (SiNW) devices were mass-produced using top-down sputtering technology, and a microdialyzer was installed in a SiNW field effect tube biosensor detection system. Finally, the detection system was used to detect HbA1c levels quantitatively and dynamically in experimental rabbits. Various measurements showed that mass-produced SiNW devices have ideal dimensions, stable structures, and good performance. A series of microscopy results showed that the SiNW surface can be functionalized for intermolecular interactions. The addition of a dialysis device can effectively overcome Debye shielding, making the blood test similar to the pure standard test. Finally, the dynamic detection of HbA1c within 40 h was realized. SiNW biosensors are capable of the dynamic detection of biomolecules, and dynamic observation of the interaction between blood glucose and HbA1c provides new ideas for the diagnosis and treatment of patients with diabetes. Therefore, the SiNW biosensor can reflect the dynamic changes in HbA1c in a shorter time, which has a certain potential value in the clinical treatment of diabetes.

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1β, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.

Abstract Background The combination of chemotherapy and L-asparaginase (L-ASP) treatment significantly increased survival rate in an adult patient with extranodal natural killer (NK)/T-cell lymphoma (NKTCL). However, hypersensitivity reactions of L-ASP in some patients limited its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and longer circulating half-life than unconjugated L-ASP, and has been reported to be effective and well-tolerated in children with acute lymphoblastic leukemia. Cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisolone (CHOP) is the most common chemotherapy for non-Hodgkin lymphoma. In this report, we sought to study the efficacy and safety of PEG-L- CHOP in NKTCL in adult Chinese patients. Methods Our study is a prospective, multi-center, open-label clinical trial. Patients with newly diagnosed adult NKTCL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included six cycles of PEG-L-CHOP regimen. Radiotherapy was scheduled after 2–4 cycles of PEG-L-CHOP regimen, depending on the stage and primary anatomic site. Results We enrolled a total of 33 eligible patients. All 33 patients completed 170 cycles of chemotherapy combined with radical radiotherapy. The overall response rate was 96.9% (32/33) with 75.8% (25/33) achieving complete responses and 21.2% (7/33) achieving partial responses. The overall survival (OS) at 1, 2, 3-year were 100, 90.61 and 80.54%, respectively. The major adverse effects were bone marrow suppression, reduction of fibrinogen level, liver dysfunction, and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. Conclusions PEG-L-CHOP chemotherapy in combination radiotherapy is safe and durably effective treatment for adult extranodal NK/T-cell lymphoma with fewer allergic reactions. This study was approved by the Peking University Beijing Cancer Hospital Ethics Review Committee (reference number: 2011101104). The clinical trial registration number ChiCTR1800016940 was registered on July 07, 2018 at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx). The clinical trial was registered retrospectively.

Abstract Background To investigate the association between the ratio of apolipoprotein B (apo B) / apolipoprotein A1 (apo A1) with all-cause mortality and cardiovascular events in peritoneal dialysis (PD) patients. Methods Eight hundred and sixty incident PD patients were enrolled from November 1, 2005, to February 28, 2017, and followed until May 31, 2017. Outcomes were all-cause mortality and cardiovascular events. Associations between the apo B/apo A1 ratio with all-cause mortality and cardiovascular events were evaluated using multivariable-adjusted Cox models. Results Of the 860 patients, the mean age was 49.9 ± 14.5 years, 57.6% were men, and 19.3% were diabetic patients. The median apo B/apo A1 ratio was 0.65 (range: 0.22–2.24). During a median follow-up period of 27 months (interquartile range, 13 – 41 months), 202 deaths, and 145 cardiovascular events were recorded. After adjustment for age, sex, body mass index, diabetes, cardiovascular disease, systolic blood pressure, total Kt/V, estimated glomerular filtration rate, hemoglobin level, neutrophil to lymphocyte ratio and albumin, triglyceride, and cholesterol, as well as the use of lipid-lowering agents, the highest apo B/apo A1 ratio tertile was significantly associated with a hazard ratio for all-cause mortality of 1.60 (95% CI: 1.02 to 2.49, P = 0.040) and for cardiovascular events of 2.04 (95% CI: 1.21 to 3.44, P = 0.008). Conclusion An increased apo B/apo A1 ratio was independently associated with all-cause mortality and cardiovascular events in PD patients.

The structural, electrical and mid-infrared optical properties of wurtzite structured ZnSe nanowires with different Chromium impurity distribution are investigated using first-principles calculation based on density-functional theory (DFT). The formation energies have been calculated to study the relative stabilities of different Cr doping positions. It is shown that when the Cr doping position shifted from the center to the edge, the splitting energy between 5T2 and 5E levels of Cr d-orbitals is decreased and a redshift is observed in the calculated infrared absorption spectra. A probable reason for these effects of the impurity distribution is discussed. Keywords: First-principles, Nanowires, Impurity distribution, Cr-doped ZnSe

In this paper, the Doppler frequency shift-based localization problem in the presence of sensor location errors is addressed. Based on the measurement model, we present two methods, an explicit solution and a semidefinite relaxation (SDR) technique, to estimate the position of the stationary source. In the two proposed algorithms, the non-accurate information on sensor position and velocity is considered. In the former algorithm, based on two best linear unbiased estimator, an explicit solution of the source position can be obtained, whereas in the latter one, the SDR technique is applied to relax the original maximum likelihood estimation into a convex semidefinite programming problem, which provides accurate estimate without postprocessing. Compared with the methods where the sensor location errors are not taken into consideration, the proposed algorithms are able to achieve a more accurate localization result. Simulations verify a better performance of these two proposed algorithms.

Abstract Background TP53 Arg72Pro (SNP rs1042522) is associated with risk of non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL. However, the relationship between this SNP and prognosis of DLBCL in Asians is unknown. Methods Genotyping of TP53 Arg72Pro was done in 425 Chinese DLBCL patients. Two hundred and eighty-nine patients were treated with R-CHOP, and 136 patients received CHOP or CHOP-like as frontline regimen. Three hundred and ninety-six patients were assessable for the efficacy. Results Patients with Arg/Arg and Arg/Pro at codon 72 of TP53 had a higher complete response rate (61% vs. 44%, P = 0.007) than those with Pro/Pro. In the subgroup treated with CHOP or CHOP-like therapy, patients with Arg/Arg and Arg/Pro showed a higher 5-year overall survival (OS) rate than those with Pro/Pro (68.8% vs. 23.2%, P = 0.001). Multivariate Cox regression analysis revealed TP53 Arg72 as a favorable prognostic factor in this group. However, the combination of rituximab with CHOP significantly increased the 5-year OS rate of patients with Pro/Pro to 63%. Conclusion This study revealed TP53 Arg72 as a favorable prognostic factor for Chinese DLBCL patients treated with CHOP or CHOP-like as frontline therapy.

A mid-infrared (mid-IR) semiconductor saturable absorber mirror (SESAM) based on Fe2+:ZnSe for passively Q-switched Er3+-doped ZBLAN fiber laser has been demonstrated. Fe2+:ZnSe SESAM was fabricated by electron beam evaporation method. Fe2+ was innovatively doped into the reflective Bragg stack, in which ZnSe layer served as both doped matrix and high refractive layer during the fabricating process. By using the Fe2+:ZnSe SESAM, stable passively Q-switched pulses with the minimum pulse width of 0.43 μs under a repetition rate of 160.82 kHz were obtained. The recorded maximum average output power of 873 mW with a peak power of 12.59 W and pulse energy of 5.43 μJ were achieved. The results demonstrated a new method for fabricating Fe2+:ZnSe SESAM, which can be used in compact mid-IR Q-switched fiber laser.

Andrographis paniculata (AP) has been widely used in China for centuries to treat various diseases, and especially to treat inflammation. Diterpenoid lactones are the main anti-inflammatory components of AP. However, systematic chemical composition and biological activities, as well as key pharmacophores, of these diterpenoid lactones from AP have not yet been clearly understood. In this study, 17 diterpenoid lactones, including 2 new compounds, were identified by spectroscopic methods, and most of them attenuated the generation of TNF-α and IL-6 in LPS-induced RAW 274.7 cells examined by ELISA. Pharmacophores of diterpenoid lactones responsible for the anti-inflammatory activities were revealed based on the quantitative structure-activity relationship (QSAR) models. Moreover, new compounds (AP-1 and AP-4) exerted anti-inflammatory activity in LPS microinjection-induced zebrafish, which might be correlated with the inhibition of the translocation of NF-κB p65 from cytoplasm to nucleus. Our study provides guidelines for future structure modification and rational drug design of diterpenoid lactones with anti-inflammatory properties in medical chemistry.

BACKGROUND: A large number of human tumor-associated antigens that are recognized by CD8(+) T cells in a human leukocyte antigen class I (HLA-I)-restricted fashion have been identified. Special AT-rich sequence binding protein 1 (SATB1) is highly expressed in many types of human cancers as part of their neoplastic phenotype, and up-regulation of SATB1 expression is essential for tumor survival and metastasis, thus this protein may serve as a rational target for cancer vaccines. METHODOLOGY/PRINCIPAL FINDINGS: Twelve SATB1-derived peptides were predicted by an immuno-informatics approach based on the HLA-A*02 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from HLA-A*02(+) healthy donors and/or HLA-A*02(+) cancer patients. The recognition of HLA-A*02(+) SATB1-expressing cancer cells was also tested. Among the twelve SATB1-derived peptides, SATB1(565-574) frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and cancer patients. Importantly, SATB1(565-574)-specific T cells recognized and killed HLA-A*02(+) SATB1(+) cancer cells in an HLA-I-restricted manner. CONCLUSIONS/SIGNIFICANCE: We have identified a novel HLA-A*02-restricted SATB1-derived peptide epitope recognized by CD8(+) T cells, which, in turn, recognizes and kills HLA-A*02(+) SATB1(+) tumor cells. The SATB1-derived epitope identified may be used as a diagnostic marker as well as an immune target for development of cancer vaccines.

BACKGROUND: Kin17 is ubiquitously expressed at low levels in human tissue and participates in DNA replication, DNA repair and cell cycle control. Breast cancer cells are characterized by enabling replicative immortality and accumulated DNA damage. However, whether kin17 contributes to breast carcinogenesis remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show for the first time that kin17 is an important molecule related to breast cancer. Our results show that kin17 expression was markedly increased in clinical breast tumors and was associated with tumor grade, Ki-67 expression, p53 mutation status and progesterone receptor expression, which were assessed in a clinicopathologic characteristics review. Knockdown of kin17 inhibited DNA replication and repair, blocked cell cycle progression and inhibited anchorage-independent growth, while increasing sensitivity to chemotherapy in breast cancer cells. Moreover, kin17 silencing decreased EGF-stimulated cell growth. Furthermore, overexpression of kin17 promoted DNA replication and cell proliferation in MCF-10A. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that up-regulation of kin17 is strongly associated with cellular proliferation, DNA replication, DNA damage response and breast cancer development. The increased level of kin17 was not only a consequence of immortalization but also associated with tumorigenesis. Therefore, kin17 could be a novel therapeutic target for inhibiting cell growth in breast cancer.