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• Graph convolutional network was used to automatically diagnose schizophrenia based on brain region and connectivity features. • A quantification method was used to construct sparse functional brain networks. • Implemented generalizability evaluation based on 200 train/test data splits. • Better performance than the traditional machine learning, MLP and CNN methods. • Functional characteristics (ALFF, ReHo, and DC) performed better than node property characterisitics (NE, BC, and DC). Recent studies in human brain connectomics have widely reported brain connectivity abnormalities associated with schizophrenia. However, most previous discriminative studies of SZ patients using machine learning methods were based on MRI features of brain regions, ignoring brain connectivity and its network topology. We addressed these limitations by applying a graph convolutional network (GCN) to classify schizophrenia patients with brain region and connectivity features derived from a combined functional MRI and connectomics analysis. In this study, 140 schizophrenia patients and 205 normal controls were included, and resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired for each subject. Brain region features, including the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality (DC), were computed by MRI analysis and connectomics analysis, respectively. Moreover, brain connectivity features were explored by connectomics analysis. A GCN method was proposed to learn network representations to discriminate patients with schizophrenia from normal controls. Compared with the traditional machine learning and deep learning methods based on MRI features of brain regions, the proposed method based on a combined functional MRI and connectomics analysis can effectively improve classification performance. Specifically, we obtained an average accuracy of 92.47%, and the area under the curve (AUC), sensitivity, specificity, precision and F1-score reached 95.36%, 88.70%, 95.06%, 92.87%, and 90.45%, respectively. These findings indicated that GCN based on brain connectivity and network topology is a promising method to improve the classification performance of schizophrenia patients. [ABSTRACT FROM AUTHOR]

Bispecific antibodies have been exploited both as cancer immunodiagnostics and as cancer therapeutics, and have shown promise in several clinical trials in cancer imaging and therapy. A number of bispecific antibodies against B-cell markers have been shown to be effective in vitro in mediating tumor cell lysis and in vivo in inhibiting tumor growth in animal models. We have constructed a bispecific diabody from the variable genes encoding two hybridoma-derived monoclonal antibodies directed against human CD20 on B cells and CD3 on T cells. The anti-CD20×anti-CD3 diabody was expressed in a single Escherichia coli host and purified by a one-step affinity chromatography. The bispecific diabody bound as efficiently to both CD20- and CD3-positive cells as the respective parental antibodies, and was capable of cross-linking CD20-positive tumor cells and human T lymphocytes as shown by cellular rosetting. The diabody effectively lysed human B-lymphoma cells in the presence of T-enriched human peripheral blood lymphocytes (PBL). Further, when combined with human PBL and interleukin-2, the diabody significantly prolonged the survival of nude mice inoculated with human B-lymphoma cells. Taken together, our results suggest that an anti-CD20×anti-CD3 diabody may have significant clinical application in the treatment of human CD20-positive B-cell malignancies. [Copyright &y& Elsevier]

Does euploidy status differ among patients of different ages treated with progestin-primed ovarian stimulation (PPOS) or gonadotrophin releasing hormone antagonist (GnRH-a) protocols? Patients undergoing PGT-A (n = 418; 440 cycles) were enrolled and grouped according to female age (<35 years and ≥35 years). Protocols were as follows: PPOS: <35 years (n = 131; 137 cycles); ≥35 years (n = 72; 80 cycles); GnRH-a: <35 years (n = 149; 152 cycles); ≥35 years (n = 66; 71 cycles). For cycles treated with PPOS in the older group, rates of euploid blastocyst per metaphase Ⅱ oocyte (15.48% versus 10.47%) and per biopsied blastocyst (54.94% versus 40.88%) were significantly higher than those treated with GnRH-a (P < 0.05). The mosaic rate per biopsied blastocyst was significantly lower for cycles treated with PPOS than cycles treated with GnRH-a (8.64% versus 23.36%) (P < 0.001). In the younger group, no significant difference was found between treatments (P > 0.05). In older and younger groups, the drug to inhibit LH surge was cheaper for cycles treated with PPOS compared with GnRH-a (P < 0.001). Generalized estimation equations based on binomial distribution female age and euploidy rate was significantly negatively correlated for all participants (β –0.109, 95% CI –0.183 to –0.035, P = 0.004), and between GnRH-a protocol (reference: PPOS) and the euploidy rate in the older group (β –0.126, 95% CI –0.248 to –0.004, P = 0.042). Multiple logistic regression indicated that ovarian stimulation protocol was not associated with ongoing pregnancy rate (OR 0.652, 95% CI 0.358 to 1.177; P = 0.14). PPOS is suitable for patients undergoing PGT-A, particularly older patients for the higher euploid blastocyst rate attained by PPOS protocol. [ABSTRACT FROM AUTHOR]

A tunable external cavity diode laser (ECDL) system with narrow line-width emission at 410 nm is presented. Based on a commercially available laser diode and a Littrow arranged reflective holographic grating, a maximum output power over 500 mW with line-width of about 50 pm is achieved at the rated current. The power efficiency is over 85% and the threshold decreases over 20% compared to the free-running laser diode. Manual tuning range over 5 nm is achieved around threshold condition and over 2 nm at high injection currents up to 500 mA with side mode suppression ratio larger than 20 dB. [ABSTRACT FROM AUTHOR]

Currently, it is a key challenge to remove the postsurgical residuals and metastasis of hepatocellular carcinoma (HCC). Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer; however, the difficulty remains regarding its intravenous administration. The aim of this study was to develop a targeted therapeutic system which has great potential to overcome the postsurgical residuals and metastasis of HCC. In this system, we developed a conditionally replicative adenovirus (CRAd) loaded on human umbilical cord-derived mesenchymal stem cells (HUMSCs), in which the CRAd contained an adenovirus E1A gene dual regulated by α-fetoprotein promoter and microRNA-122 target sequence. When HUMSCs homed to the tumor sites and differentiated into hepatocyte-like cells within tumor microenvironment, the CRAds were packaged and released strictly to the local tumor. Subsequently, the CRAd lysed tumor cells selectively with the post-infection regulation. The study showed the specific oncolytic effect of the CRAd to HCC cells and the production of the CRAd by differentiated HUMSCs in vitro. Furthermore, we proved the hepatocyte-like transformation of HUMSC in the microenvironment of orthotopic or heterotopic hepatoma. Finally, this therapeutic system exhibited dramatic tumor inhibition on both orthotopic and subcutaneous hepatic xenograft tumor model mice with less toxicity on normal organs. The study results have demonstrated that this targeted therapeutic strategy is a promising method to resolve the problem of postsurgical residuals and metastasis of HCC. [ABSTRACT FROM AUTHOR]

The extremely high mortality of sepsis in intensive care units, caused primarily by sepsis-induced cardiomyopathy, is a pressing issue. Current studies have revealed the importance of the neuregulin-1 (NRG-1)/ErbB signaling axis at the cardiovascular level and the positive effect of NRG-1 on cardiac function in patients with heart failure. To investigate the protective mechanism of NRG-1 against myocardial injury in septic rats, a cecal ligation and puncture (CLP) model was applied. Animals were administered either a vehicle or recombinant human NRG-1 (rhNRG-1, 10 μg/kg). Their survival rates were noted 24 h after CLP. The hemodynamic method was used to evaluate their cardiac function. The myocardial morphology was observed. An enzyme-linked immunosorbent assay was used to detect the level of cardiac troponin-T (cTn-T), cytokines, and angiotensin II (Ang II) in the serum and myocardium. Compared with the vehicle, rhNRG-1 improved survival of rats and prevented hemodynamic derangement, as reflected in the increased mean arterial pressure, left ventricular systolic pressure, ±dp/dt max, and decreased left ventricular end-diastolic pressure (P<0.05). Furthermore, the serum levels of cTn-T and pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6) were significantly increased in vehicle-treated rats but reduced in rhNRG-1-treated rats. The latter also showed decreased concentration of macrophage inhibitory factor and Ang II in the myocardium (P<0.05). These results suggest that NRG-1 improved cardiac function and protected cardiomyocytes of rats from CLP-induced sepsis by suppressing the immune inflammatory response and excessive activation of the renin–angiotensin–aldosterone system. Ultimately, NRG-1 increased the survival rate of rats. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells and is verified to be effective in various cancers. However, a variety of cancer cells are found to be resistant to TRAIL and the mechanisms are largely unknown. Moreover, multidrug resistance to traditional chemotherapeutic agents still remains a tough problem in clinical practice. Fortunately, our previous work proved the ability of PH II-7 in overcoming MDR phenotype through reactive oxygen species production in K562 and its MDR counterpart K562/A02 cells. Additionally, we further explored its potential in augmenting TRAIL induced apoptosis in cancer cells with various tissue origins. Our results showed PH II-7 up-regulated DR4/DR5 expression and augment TRAIL cytotoxicity through reactive oxygen species production, which provide a solid foundation for TRAIL in combination with PH II-7 in future clinical application. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal stem cells (MSCs) are promising vehicles for delivering therapeutic agents in tumor therapy. Human umbilical cord-derived mesenchymal stem cells (HUMSCs) resemble bone marrow-derived MSCs with respect to hepatic differentiation potential in injured livers in animals, while their hepatic differentiation under the hepatocarcinoma microenvironment is unclear. In this study, HUMSCs were isolated and transduced by lentiviral vectors coding the soluble human tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) gene driven by alpha-fetoprotein (AFP) promoter to investigate the therapeutic effects of these HUMSC against orthotopically implanted hepatocarcinoma in mice. We showed that HUMSCs can be transduced by lentivirus efficiently. HUMSCs developed cuboidal morphology, and expressed AFP and albumin in a two-step protocol. HUMSCs were capable of migrating to hepatocarcinoma in vitro as well as in vivo. In the orthotopical hepatocarcinoma microenvironment, the AFP promoter was activated during the early hepatic differentiation of HUMSCs. After intravenous injected, MSC.AFPILZ-sTRAIL expressed sTRAIL exclusively at the tumor site, and exhibited significant antitumor activity. This effect was stronger when in combination with 5-FU. The treatment was tolerated well in mice. Collectively, our results provide a potential strategy for targeted tumor therapy relying on the use of the tumor tropism and specific differentiation of HUMSCs as vehicles. [Copyright &y& Elsevier]

Abstract: Multidrug resistance (MDR) is a major obstacle that hinders the efficacy of chemotherapy in many human malignancies. PHII-7 is a derivative of indirubin, which was designed and synthesized by our laboratory. Our preliminary work indicated its potent antitumor activities in vitro and in vivo. Furthermore, based on the model of MDR cell line, we found its powerful effects in inhibiting the expression of P-glycoprotein (P-gp) and killing multidrug-resistant (MDR) cells with the detailed mechanism remained to be explored. Reactive oxygen species are known for high reactive activity as they possess unmatched electrons. In this study, we showed that PHII-7 generated equal reactive oxygen species in parental K562 and its counterpart MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine(NAC) almost abolished the cytotoxicity of PHII-7. Moreover, NAC abrogated DNA damage, cell cycle arrests and apoptosis induced by PHII-7. Our results collectively indicated that reactive oxygen species production induced by PHII-7 contributed to both apoptosis and cell cycle arrets in MDR K562/A02 cells, thus extending our prior related findings. Notably, JNK phosphorylation was also induced by PHII-7 and pre-incubated of K562/A02 cells with NAC or inhibitor of JNK(SP006125) eliminated P-gp downregulation. Taken together, our results may provide a detailed biochemical basis for further clinical application of PHII-7. [Copyright &y& Elsevier]

Abstract: Microsomal cytochrome P450 (P450) enzymes, which are important in the metabolism of carcinogens, are expressed in both epithelial and stromal cells in the mammary gland. The aim of this study was to investigate the roles of mammary epithelial P450 enzymes in the bioactivation and disposition of 7,12-dimethylbenz(a)anthracene (DMBA), a breast carcinogen, in the mammary gland. A new mouse model (named MEpi-Cpr-null) was produced, wherein P450 activities in the mammary epithelial cells are suppressed through tissue-specific deletion of the gene for P450 reductase (Cpr), an enzyme required for the activities of all microsomal P450 enzymes. Comparisons between wild-type and MEpi-Cpr-null mice showed that the tissue-specific deletion of Cpr in the mammary epithelial cells was accompanied by significant increases in the levels of DMBA and DMBA–DNA adduct in the mammary gland following a single intraperitoneal injection of DMBA at 50mg/kg. Immunohistochemical and immunoblot analysis further revealed greater induction of CYP1B1 expression by the DMBA treatment in the mammary stroma of the MEpi-Cpr-null mice than in that of the WT mice. These findings not only demonstrate that the epithelial P450 enzymes play important roles in the clearance of DMBA, but also suggest that P450 enzymes in both mammary epithelial and stromal cells contribute to carcinogen-mediated DNA damage. [Copyright &y& Elsevier]

Abstract: Multidrug resistance (MDR) is a major impediment to the effective chemotherapy of many human malignancies, and novel MDR reversal agents are desirable for combination therapy to reduce MDR, enhance anti-tumor activity and reduce side effects. Overexpression of P-glycoprotein (P-gp) is the most prevalent cause of MDR in cancer tissues, and resistance to apoptosis is a common characteristic for the multidrug resistant cancer cells. Our group has synthesized a novel potent anti-tumor indirubin derivative, PHII-7. In this study, MCF-7/ADR cells, an adriamycin (ADR)-selected human breast tumor cell line with the MDR phenotype, were used to investigate the anticancer properties of this novel indirubin derivative. Cytotoxicity and apoptosis assays showed that PHII-7 significantly inhibited cell growth, induced apoptosis, potentiated ADR cytotoxicity and restored chemotherapy sensitivity in the MDR cancer cells. Further studies indicated that by down-regulation of P-gp expression, PHII-7 partially inhibited P-gp efflux pump function and increased intracellular accumulation of Rhodamine 123, a P-gp substrate. These results provide a biochemical basis for possible clinical application of PHII-7 alone or in combination with conventional antineoplastic agents in the treatment MDR tumors. [Copyright &y& Elsevier]

Abstract: Aims: The aim was to determine whether increased CK8 and BCRP expression cooperatively contribute to multidrug resistance (MDR) in MCF-7/MX cells. Accumulating evidence suggests that the development and maintenance of cancer MDR involves complex multimodal mechanisms that interact concomitantly and complementarily. In this report, we observed elevated expression of cytokeratin 8 (CK8) in MCF-7/MX, a mitoxantrone (MX)-selected human breast tumor cell line with the MDR phenotype known as overexpression of breast cancer resistant protein (BCRP). Main methods: Gene transfection methods were used to express CK8 and BCRP in NIH3T3 fibroblasts, individually or in combination. Key findings: Taken together, our present study suggests that CK8 together with BCRP may play significant roles in conferring the multifactorial MDR phenotype of MCF-7/MX cells, but may act independently via potentially different mechanisms. Although expressing either CK8 or BCRP alone was able to confer resistance to mitoxantrone, cells co-expressing both proteins demonstrated significantly increased drug resistance. Furthermore, RNAi knockdown of CK8 and BCRP, alone and in combination, in MCF-7/MX cells significantly attenuated their resistance to chemotherapeutic agents. Interestingly, in contrast to inhibition of BCRP expression via anti-BCRP shRNA vector transfection, reversal of mitoxantrone resistance by transfection with anti-CK8 shRNA was not accompanied by an increase in intracellular drug accumulation. Significance: Combinational approaches that target multiple drug-resistance-related molecules/pathways in cancer cells may represent more efficacious strategies to overcome MDR. [Copyright &y& Elsevier]

Abstract: Sorcin, or soluble resistance-related calcium-binding protein, is a 22kD calcium-binding protein initially identified in many mutlidrug resistant (MDR) cell lines. We previously observed by gene profiling that sorcin is significantly up-regulated in a doxorubicin-induced MDR leukemia cell line, K562/A02, over its parent cells. We have also demonstrated that the level of sorcin expression in leukemia patients correlates not only directly with that of the mdr1 gene, but also inversely with patients’ response to chemotherapies and overall prognosis. In this report, we have carried out experiments to dissect out the contribution of sorcin by itself to drug resistant phenotype in K562 cells. Overexpression of sorcin protein by gene transfection in K562 cells resulted in increased drug resistance, from 4.1- to 22.5-fold, to a variety of chemotherapeutic agents, including doxorubicin, etoposide, homoharringtonine and vincristine. On the other hand, inhibition of sorcin expression in both MDR K562/A02 and the sorcin-transfected K562 cells with sorcin-targeting small interfering RNA led to varying extent of reversal of drug resistance. These results confirm that sorcin is an important gene associated with the development of MDR in leukemia cells. [Copyright &y& Elsevier]

Monoclonal antibodies (mAb) directed against CD20, either unmodified or in radiolabeled forms, have been successfully used in clinic as effective therapeutic agents in the management of non-Hodgkin''s B-cell lymphoma. Despite all clinical success the exact mechanisms of action of various anti-CD20 antibodies remains mostly unclear. Several mechanisms have been proposed to be responsible for the therapeutic activity of anti-CD20 antibodies, including antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity, and direct inhibition of tumor growth via induction of apoptosis. We previously produced an anti-CD20 mAb, HI47, and showed that the antibody effectively blocked human B-cell proliferation in vitro and inhibited xenografted B-cell lymphoma in nude mice. In this study, we engineered the chimeric versions of both the Fab and F(ab)′2 fragments of HI47 and produced the fragments in E. coli. Both fragments competed efficiently with HI47 for binding to CD20+ B cells, and inhibited proliferation of B-lymphoma cells in a dose-dependent manner. Mechanistic studies revealed that both antibody fragments induced significant degree of B-cell apoptosis that is independent of any cross-linking agents. Further, both the F(ab)′2 and Fab fragments when administered in vivo significantly inhibited the growth of human B-cell lymphoma xenografts in nude mice. The bivalent F(ab)′2 fragment showed consistently better efficacy compared to its monovalent Fab counterpart in inducing apoptosis and inhibiting B-cell lymphoma growth both in vitro and in vivo. Taken together, these observations suggest that HI47 and its fragments most likely exert their antitumor activity through induction of cell apoptosis, and cross-linking/dimerization of CD20 molecules on B- cell surface is an important, but not essential, process for therapeutic efficacy of HI47 and its fragments. [Copyright &y& Elsevier]