Germline variants of DNA repair and immune genes in lymphoma from lymphoma-cancer families.

The genetic predisposition to lymphoma is not fully understood. We identified 13 lymphoma-cancer families (2011-2021), in which 27 individuals developed lymphomas and 26 individuals had cancers. Notably, male is the predominant gender in lymphoma patients, whereas female is the predominant gender in cancer patients (p = .019; OR = 4.72, 95% CI, 1.30-14.33). We collected samples from 18 lymphoma patients, and detected germline variants through exome sequencing. We found that germline protein truncating variants (PTVs) were enriched in DNA repair and immune genes. Totally, we identified 31 heterozygous germline mutations (including 12 PTVs) of 25 DNA repair genes and 19 heterozygous germline variants (including 7 PTVs) of 14 immune genes. PTVs of ATM and PNKP were found in two families, respectively. We performed whole genome sequencing of diffuse large B cell lymphomas (DLBCLs), translocations at IGH locus and activation of oncogenes (BCL6 and MYC) were verified, and homologous recombination deficiency was detected. In DLBCLs with germline PTVs of ATM, deletion and insertion in CD58 were further revealed. Thus, in lymphoma-cancer families, we identified germline defects of both DNA repair and immune genes in lymphoma patients.

Targeting autophagy to counteract neuroinflammation: A novel antidepressant strategy.

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.

Effects of UV/H2O2 Degradation on the Physicochemical and Antibacterial Properties of Fucoidan.

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.

Novel TCF21high pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix.

OBJECTIVE: Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis. DESIGN: TPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 on TCF21 DNA hypermethylation. Pericyte-conditional Tcf21-knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling. RESULTS: Thirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21high TPCs, termed 'matrix-pericytes', was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM). Tcf21 depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21high TPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impair TCF21 DNA hypermethylation in TCF21high TPCs. CONCLUSION: This study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects.

Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival benefits to many cancer patients, resistance to antiangiogenic drugs frequently occurs during clinical treatment, leading to poor outcomes and treatment failure. Cumulative evidence has demonstrated that the intricate interplay among tumor cells, bone marrow-derived cells, and local stromal cells critically allows for tumor escape from antiangiogenic therapy. Currently, drug resistance has become the main challenge that hinders the therapeutic efficacies of antiangiogenic therapy. In this review, we describe and summarize the cellular and molecular mechanisms conferring tumor drug resistance to antiangiogenic therapy, which was predominantly associated with redundancy in angiogenic signaling molecules (e.g., VEGFs, GM-CSF, G-CSF, and IL17), alterations in biological processes of tumor cells (e.g., tumor invasiveness and metastasis, stemness, autophagy, metabolic reprogramming, vessel co-option, and vasculogenic mimicry), increased recruitment of bone marrow-derived cells (e.g., myeloid-derived suppressive cells, tumor-associated macrophages, and tumor-associated neutrophils), and changes in the biological functions and features of local stromal cells (e.g., pericytes, cancer-associated fibroblasts, and endothelial cells). We also review potential biomarkers to predict the response to antiangiogenic therapy in cancer patients, which mainly consist of imaging biomarkers, cellular and extracellular proteins, a certain type of bone marrow-derived cells, local stromal cell content (e.g., pericyte coverage) as well as serum or plasma biomarkers (e.g., non-coding RNAs). Finally, we highlight the recent advances in combination strategies with the aim of enhancing the response to antiangiogenic therapy in cancer patients and mouse models. This review introduces a comprehensive understanding of the mechanisms and biomarkers associated with the evasion of antiangiogenic therapy in cancer, providing an outlook for developing more effective approaches to promote the therapeutic efficacy of antiangiogenic therapy.

Methyl cinnamate protects against dextran sulfate sodium-induced colitis in mice by inhibiting the MAPK signaling pathway.

Effective and non-toxic therapeutic agents are lacking for the prevention and treatment of colitis. Previous studies found that methyl cinnamate (MC), extracted from galangal ( Alpinia officinarum Hance), has anti-inflammatory properties. However, whether MC is effective as anti-colitis therapy remains unknown. In this study, we investigate the therapeutic effects of MC on dextran sulfate sodium (DSS)-induced colitis in mice and further explore its potential mechanism of action. MC treatment relieves symptoms associated with DSS-induced colitis, including the recovery of DSS-induced weight loss, decreases the disease activity index score, and increases the colon length without toxic side effects. MC treatment protects the integrity of the intestinal barrier in mice with DSS-induced colitis and inhibits the overexpression of pro-inflammatory cytokines in vivo and in vitro. Moreover, the MAPK signaling pathway is found to be closely related to the treatment with MC of colitis. Western blot analysis show that phosphorylation of the p38 protein in colon tissues treated with MC is markedly reduced and phosphorylation levels of the p38, JNK and ERK proteins are significantly decreased in RAW 264.7 cells treated with MC, indicating that the mechanism of MC in treating DSS-induced colitis could be achieved by inhibiting the MAPK signaling pathway. Furthermore, 16S RNA sequencing analysis show that MC can improve intestinal microbial dysbiosis in mice with DSS-induced colitis. Altogether, these findings suggest that MC may be a novel therapeutic candidate with anti-colitis efficacy. Furthermore, MC treatment relieves the symptoms of colitis by inhibiting the MAPK signaling pathway and improving the intestinal microbiota.

m6A modification: recent advances, anticancer targeted drug discovery and beyond.

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.

Screening of Bufadienolides from Toad Venom Identifies Gammabufotalin as a Potential Anti-inflammatory Agent.

Toad venom (Chansu) is used in the treatment of infectious and inflammatory diseases in China and East/Southeast Asian countries. However, the anti-inflammatory components of toad venom have not yet been systematically evaluated and clearly defined. To investigate the anti-inflammatory effects of toad venom and identify new anti-inflammatory ingredients, we used zebrafish, an alternative drug screening model, to evaluate the anti-inflammatory effects of 14 bufadienolides previously isolated from toad venom. Most of the bufadienolides were found to exert significant anti-inflammatory effects on lipopolysaccharide-, CuSO4-, or tail transection-induced zebrafish inflammatory models. Moreover, gammabufotalin ( 6: ) inhibits lipopolysaccharide-induced inflammation by suppressing the myeloid differentiation primary response 88/nuclear factor-kappa B and STAT3 signal pathways. This study confirms the potential of zebrafish in drug screening, clarifies the anti-inflammatory effects of bufadienolides from toad venom, and indicates that gammabufotalin may be developed as a novel therapeutic agent for inflammatory diseases in the future.

Clinical application of transoral and submental thyroidectomy (TOaST): a series of 54 human cases.

OBJECTIVE: A new endoscopic thyroidectomy approach-transoral and submental endoscopic thyroidectomy (TOaST)-was applied in clinical practice and considered an improved approach for endoscopic thyroid surgery via the oral approach. This paper discusses the feasibility and effectiveness of this surgical method. METHODS: A retrospective analysis was performed on the clinical data of 54 patients who had undergone TOaST in the thyroid disease center of the First Affiliated Hospital of Nanchang University between December 2020 and December 2021. The surgical data and techniques, complications, and cosmetic outcomes of these patients were studied. RESULTS: Among the total 54 patients, 23 underwent unilateral subtotal thyroidectomy, 3 patients underwent bilateral subtotal thyroidectomy, 27 with unilateral thyroid cancer underwent affected thyroid + isthmus + central lymph node resection, and only 1 patient underwent total thyroidectomy. The mean operative time was 88.06 ± 12.03 min (range: 65-135 min), the mean intraoperative blood loss was 8.61 ± 4.60 ml (range: 5-20 ml), the mean postoperative drainage volume was 49.96 ± 9.88 ml (range: 30-60 ml), the mean drainage time was 36.61 ± 2.65 h (range: 32-50 h), and the mean length of hospital stay was 46.63 ± 3.28 h (range 45-70 h). One patient experienced transient recurrent laryngeal nerve injury, and another patient experienced transient parathyroid dysfunction; there was no superior laryngeal nerve injury and other complications, such as postoperative subcutaneous hematoma, hypercapnia, mental nerve injury, tracheoesophageal injury, infection, or lymphatic leakage. CONCLUSION: TOaST cannot only achieve a good therapeutic effect but also avoid mental nerve injury, reduce the discomfort of the patient's jaw, obtain a good cosmetic effect, and facilitate the operation of the operator. It is an endoscopic thyroidectomy technique with a certain clinical value.

Preparation and Characterization of Protein Molecularly Imprinted Poly (Ionic Liquid)/Calcium Alginate Composite Cryogel Membrane with High Mechanical Strength for the Separation of Bovine Serum Albumin.

In order to improve the mechanical strength and imprinting efficiency, a novel bovine serum albumin (BSA) molecularly imprinted poly(ionic liquid)/calcium alginate composite cryogel membrane (MICM) was prepared. The results of the tensile test indicated that the MICM had excellent mechanical strength which could reach up to 90.00 KPa, 30.30 times higher than the poly (ionic liquid) membrane without calcium alginate; the elongation of it could reach up to 93.70%, 8.28 times higher than the poly (ionic liquid) membrane without calcium alginate. The MICM had a very high welling ratio of 1026.56% and macropore porosity of 62.29%, which can provide effective mass transport of proteins. More remarkably, it had a very high adsorption capacity of 485.87 mg g-1 at 20 °C and 0.66 mg mL-1 of the initial concentration of BSA. Moreover, MICM also had good selective and competitive recognition toward BSA, exhibiting potential utility in protein separation. This work can provide a potential method to prepare the protein-imprinted cryogel membrane with both high mechanical strength and imprinting efficiency.

A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma.

Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×105/kg, 1×106/kg and 3×106/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen. Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity. Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.

Distribution of chimeric antigen receptor-modified T cells against CD19 in B-cell malignancies.

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 .

Establishing an endoscopic diagnostic process system (M-system) for gastric MALT lymphoma of superficial-spreading type.

OBJECTIVE: Gastric mucosa-associated lymphoid tissue lymphoma is a rare disease, which is associated with a low endoscopic diagnostic accuracy even on tissue biopsy. We aimed to establish a diagnostic process system (M-system) using detailed magnifying endoscopy images to improve the diagnostic efficiency of this disease. METHODS: First, 34 cases from 16 patients with the diagnosis of mucosa-associated lymphoid tissue lymphoma were collected as the study group. The control group included randomly selected patients who were diagnosed with early differentiated carcinoma, undifferentiated carcinoma or inflammation. Then, the endoscopic images of these patients were analyzed by senior physicians. Finally, the M-system was established based on the data extracted from the images reviewed, and its diagnostic efficiency for mucosa-associated lymphoid tissue lymphoma was validated by the junior physicians. RESULTS: A series of elements with high sensitivity and specificity for the diagnosis of mucosa-associated lymphoid tissue lymphoma on endoscopic images were extracted for the establishment of the M-system. Using the M-system, the diagnostic accuracy, sensitivity, specificity and correct indices of mucosa-associated lymphoid tissue lymphoma rose from 65.4 to 79.4%, 41.2 to 76.5%, 73.5 to 80.4% and 0.147 to 0.569%, respectively, all of which were statistically significant. CONCLUSIONS: The M-system can improve the diagnostic accuracy of mucosa-associated lymphoid tissue lymphoma of the superficial-spreading type on detailed magnifying endoscopy. This would help in the early diagnosis of the disease and treatment, which would translate into improved clinical outcomes.

Improving the sustainability of the wheat supply chain through multi-stakeholder engagement.

Feeding the world's growing population, while producing economic benefits with limited environmental effects, is a major challenge faced by global food supply chains. This is especially apparent when the production stage is predominated by smallholders as they each face varying economic and environmental demands, making it difficult to mobilize them on the ground. This study investigated how the environmental and economic sustainability of wheat supply chains could be improved by analyzing the performance of all stakeholders, especially the smallholders. Results showed that 77% of GHG emissions came from wheat cultivation, and less than 8% of the total economic benefits were recouped during this stage. In contrast, smallholders in the Science and Technology Backyards, reduced their GHG emissions by 16.4% and improved their economic benefits by 1.3- fold. Furthermore, a 2.6-fold increase in profit (1808 USD) with GHG emission reduction was achieved simultaneously by integrating all individual stages as a whole. This study found that the sustainability of the wheat supply chain was mainly affected by wheat cultivation. It also demonstrated the potential efficacy of empowering smallholders and integration of all individual stages as a whole to improve the sustainability of food supply chains.

No evidence of SARS-CoV-2 RNA among blood donors: A multicenter study in Hubei, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA could be detected in the blood of infected cases. From February 9, all blood establishments in Hubei province, China, implemented nucleic acid testing (NAT) for SARS-CoV-2 RNA among blood donors to ensure blood safety. STUDY DESIGN AND METHODS: Nucleic acid test screening individually (ID) or by minipool (MP) testing was performed according to the manufacturer's instructions. Inactivated culture supernatant of SARS-CoV-2-infected Vero cells was quantified by droplet digital polymerase chain reaction (ddPCR) and series diluted with negative plasma to evaluate the assay's performance. RESULTS: The limit of detection of the kit for MP testing was 62.94 and 33.14 copies/mL for N and ORF1ab region, respectively. ID testing could achieve 3.87 and 4.85 copies/mL for two regions using 1600 µL of plasma. Coefficients of variations of two different concentrations of reference samples were all less than 5% in MP testing. As of April 30, 2020, a total of 98,342 blood donations including 87,095 whole blood donations and 11,247 platelet donations were tested by ID or MP testing, and no RNAemia was found. In addition, Hubei province suffered precipitously decreased blood supply, especially in February: 86% reduction compared with the same period of 2019. CONCLUSION: Nucleic acid test screening of SARS-CoV-2 on blood donations is suitable in blood establishments using the commercial real-time PCR detection kit based on available instruments. The negative result indicated that SARS-CoV-2 appears to be no direct threat to blood safety but raises some serious issues for general blood supply.

High-dose chemotherapy followed by autologous stem cell transplantation for patients with refractory/relapsed classical Hodgkin lymphoma: a single center experience from China.

To evaluate the outcomes of refractory/relapsed cHL patients after high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) in Beijing Cancer hospital and to identify the prognostic risk factors. We retrospectively analyzed 115 relapsed/refractory cHL patients who accepted HDCT and ASCT in our cancer center and had complete follow-up data from April 2000 to May 2017. Ages of these 115 patients at ASCT ranged from 14 to 63 (median age 28). Forty-four (38.3%) patients achieved CR and 50 (43.5%) patients achieved PR before ASCT. Thirty-seven (48.7%) patients of those 76 patients who did PET-CT before ASCT had negative PET-CT scans. The median follow-up time was 72 months. A total of 23 patients died in our study. The 5-year OS and PFS rates of all patients after ASCT were 78.7% and 53%, respectively. The 5-year OS rates after ASCT of patients who were in CR or PR or less than PR status before ASCT were 92.8%, 68.2%, and 76.2%, respectively (log-rank = 2.913, p = 0.233). And their 5-year PFS rates after ASCT were 69.2%, 54.2%, and 18.5%, respectively (log-rank = 13.615, p = 0.001). Univariate analysis revealed that ECOG (p = 0.010; hazard ratio = 1.578), disease status before ASCT (CR: p = 0.001; hazard ratio = 0.227) and after ASCT (CR: p < 0.001; hazard ratio = 0.154), and PET-CT results after ASCT (p = 0.023; hazard ratio = 0.438) significantly impact patients' PFS while number of pretransplant salvage chemotherapy (p = 0.037; hazard ratio = 2.521), radiotherapy (p = 0.046; hazard ratio = 0.423), and disease status after ASCT (CR: p = 0.010; hazard ratio = 0.197) significantly affected patients' OS. Multivariate analysis shown only disease status before ASCT (p = 0.002) had significant impact on PFS and disease status after ASCT (p = 0.021) had significant impact on OS. R/R HL patients can still obtain long-term PFS after HDCT and ASCT and disease status before ASCT was the most significant prognostic factor for PFS.

Performance of mediator-less double chamber microbial fuel cell-based biosensor for measuring biological chemical oxygen.

Recently, the microbial fuel cell-based biosensor has been considered as an attractive technology for measuring wastewater quality such as biochemical oxygen demand (BOD). In this study, a mediator-less double compartment MFC based biosensor utilizing carbon felt as an anode electrode and inoculated with mixed culture was developed to improve the real application of a rapid BOD detection. This study aims to: (i) establish the effect of the operating conditions (i.e., pH, external resistance, fuel feeding rate) on MFC performance; (ii) investigate the correlation between biochemical oxygen demand (BOD) and signal output, and (iii) evaluate the operational stability of the biosensor. The presented result reveals that the maximum current and power production was obtained while 100 mM NaCl and 50 mM Phosphate buffer saline was used as a catholyte solution, neutral pH condition of media and fuel feeding rate at 0.3 mL min-1. Notably, a wider range of BOD concentration up to 300 mg L -1 can be obtained with the voltage output (R2 > 0.9901). Stable and steady power was produced by running MFC in 30 days when cells operated at 1000 Ω external resistance. Our research has some competition with the previous double chamber MFC in the upper limit of BOD detection. This results might help to increase the real application of MFC based BOD biosensor in real-time measurement.

ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma.

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.

Ginsenoside F1 promotes angiogenesis by activating the IGF-1/IGF1R pathway.

Ischemic stroke is one of the most lethal and highly disabling diseases that seriously affects the human health and quality of life. A therapeutic angiogenic strategy has been proposed to alleviate ischemia-induced injury by promoting angiogenesis and improving cerebrovascular function in the ischemic regions. The insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF1R) axis is crucial for cerebral angiogenesis and neurogenesis. However, effective drugs that prevent cerebral ischemic injury by inducing cerebral angiogenesis via activation of the IGF1R pathway are lacking. Here, we screened a pro-angiogenic agent ginsenoside F1 (GF1), a ginseng saponin isolated from a traditional Chinese medicine that was widely used in ischemic stroke treatment. It promoted the proliferation, mobility and tube formation of human umbilical vein endothelial cells and human brain microvascular endothelial cells, as well as pericytes recruitment to the endothelial tubes. GF1 stimulated vessel sprouting in the rat arterial ring and facilitated neovascularization in chicken embryo chorioallantoic membrane (CAM). In the in vivo experiments, GF1 rescued the axitinib-induced vascular defect in zebrafish. It also increased the microvessel density (MVD) and improved focal cerebral blood perfusion in the rat middle cerebral artery occlusion (MCAO) model. Mechanism studies revealed that GF1-induced angiogenesis depended on IGF1R activation mediated by the autocrine IGF-1 loop in endothelial cells. Based on our findings, GF1-induced activation of the IGF-1/IGF1R pathway to promote angiogenesis is an effective approach to alleviate cerebral ischemia, and GF1 is a potential agent that improves cerebrovascular function and promotes recovery from ischemic stroke.