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Background: Neuromyelitis optica (NMO) is a severe neurological demyelinating autoimmune disease affecting the optic nerves and spinal cord. The binding of neuromyelitis optica immunoglobulin G (NMO- IgG) and aquaporin-4 (AQP4) on the surface of astrocytes in the serum and cerebrospinal fluid is the main pathogenesis of NMO. Currently, therapeutic strategies for NMO include a reduction of the secondary inflammation response and the number of NMO-IgG, which can only alleviate clinical symptoms rather than fundamentally preventing a series of pathological processes caused by NMO-IgG binding to AQP4. Objective: The purpose of this study was to investigate the blocking effect of melanthioidine on the binding of NMO-IgG to AQP4 and its potential cytotoxicity. Methods: The current study developed a cell-based high-throughput screening approach to identify a molecular blocker of NMO-IgG binding to AQP4 using the Chinese hamster lung fibroblast (V79) cells expressing M23- AQP4. By screening ~400 small molecules, we identified melanthioidine with blocking effects without affecting AQP4 expression or its water permeability. Results: Melanthioidine effectively blocked the binding of NMO-IgG to AQP4 in immunofluorescence assays and reduced complement-dependent cytotoxicity against both NMO-IgG/complement-treated Fischer rat thyroid- AQP4 cells and primary astrocytes. The docking computations identified the putative sites of blocker binding at the extracellular surface of AQP4. Conclusion: This study serves as proof of a potential NMO therapy by using a small-molecule blocker to target NMO pathogenesis.

Supplemental Figures 1-9 with Figure Legends

Myocardial ischemia/reperfusion injury (MIRI), the major pathophysiology of cardiovascular disease, is a crucial therapeutic focus. To date, whether MIRI is centrally mediated and its underlying processing hierarchy remain elusive. We show that the electrical activity of the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) neurons increased after MIRI in a mouse model. We identified a neural circuit involving glutamatergic projections from the paraventricular nucleus (GluPVN) to tyrosine hydroxylase–expressing neurons in the rostral ventrolateral medulla (THRVLM) that contributes to MIRI. Transneuronal tracing with neurotropic viruses indicated that the THRVLM neurons project directly to the spinal preganglionic neurons and then to the stellate ganglion, two critical neural nodes along the brain–heart axis. Chemogenetic inhibition of the GluPVN→THRVLM circuit or cervical sympathetic blockade reduced the level of norepinephrine in the heart and thereby prevented MIRI. Furthermore, pharmacological blockade of myocardium β-receptors also reduced MIRI. This brain–heart circuit that promotes MIRI represents a potential therapeutic target for MIRI treatment.

To clarify the effect of an intraoperative low-dose dexmedetomidine infusion on emergence agitation following general anaesthesia in elderly patients. Eighty elderly patients (> 64-years-old) following elective general anaesthesia for radical cancer surgeries were randomly allocated into two groups (n = 40 each): the dexmedetomidine group (Group D) and the normal saline group (Group C). Anaesthesia was maintained with continuous intravenous infusion of dexmedetomidine at − 0.2 µg kg−1 h−1 in Group D, and an equal volume of normal saline (0.5 ml kg−1 h−1) was given in Group C. All patients were observed for 30 min in the post-anaesthesia care unit (PACU), AFPS and NRS were recorded every 2 min, and the total doses of nalbuphine and fentanyl were calculated in the PACU. MAP and HR were recorded at the time of 10 min (T1), 20 min (T2), 30 min (T3) after dexmedetomidine or saline pumping, and before extubation (T4), immediately after extubation (T5), and 5 min after extubation (T6). We also documented some durations, including anaesthesia duration (D1), surgery duration (D2), duration from the end of surgery to extubation (D3), and emergence agitation duration (D4). The MAP in Group C was significantly higher than that in Group D (P 64-years-old), remain stable in terms of haemodynamics, and not lead to delays in anaesthesia recovery time and extubation time.

Astrocytes play a key role in the response to injury and noxious stimuli, but its role in myocardial ischemia–reperfusion (I/R) injury remains largely unknown. Here we determined whether manipulation of spinal astrocyte activity affected myocardial I/R injury and the underlying mechanisms. By ligating the left coronary artery to establish an in vivo I/R rat model, we observed a 1.7-fold rise in glial fibrillary acidic protein (GFAP) protein level in spinal cord following myocardial I/R injury. Inhibition of spinal astrocytes by intrathecal injection of fluoro-citrate, an astrocyte inhibitor, decreased GFAP immunostaining and reduced infarct size by 29% relative to the I/R group. Using a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) chemogenetic approach, we bi-directionally manipulated astrocyte activity employing GFAP promoter-driven Gq- or Gi-coupled signaling. The Gq-DREADD-mediated activation of spinal astrocytes caused transient receptor potential vanilloid 1 (TRPV1) activation and neuropeptide release leading to a 1.3-fold increase in infarct size, 1.2-fold rise in serum norepinephrine level and higher arrhythmia score relative to I/R group. In contrast, Gi-DREADD-mediated inhibition of spinal astrocytes suppressed TRPV1-mediated nociceptive signaling, resulting in 35% reduction of infarct size and 51% reduction of arrhythmia score from I/R group, as well as lowering serum norepinephrine level from 3158 ± 108 to 2047 ± 95 pg/mL. Further, intrathecal administration of TRPV1 or neuropeptide antagonists reduced infarct size and serum norepinephrine level. These findings demonstrate a functional role of spinal astrocytes in myocardial I/R injury and provide a novel potential therapeutic approach targeting spinal cord astrocytes for the prevention of cardiac injury.

Cancer stem cells (CSCs), also known as tumor-initiating cells, are a sub-population of tumor cells found in many human cancers that are endowed with self-renewal and pluripotency. CSCs may be more resistant to conventional anticancer therapies than average cancer cells, as they can easily escape the cytotoxic effects of standard chemotherapy, thereby resulting in tumor relapse. Despite significant progress in related research, effective elimination of CSCs remains an unmet clinical need. CSCs are localized in a specialized microenvironment termed the niche, which plays a pivotal role in cancer multidrug resistance. The niche components of CSCs, such as the extracellular matrix, also physically shelter CSCs from therapeutic agents. Colorectal cancer is the most common malignancy worldwide and presents a relatively transparent process of cancer initiation and development, making it an ideal model for CSC niche research. Here, we review recent advances in the field of CSCs using colorectal cancer as an example to illustrate the potential therapeutic value of targeting the CSC niche. These findings not only provide a novel theoretical basis for in-depth discussions on tumor occurrence, development, and prognosis evaluation, but also offer new strategies for the targeted treatment of cancer.

Neuromyelitis optica (NMO) is a severe neurological demyelinating autoimmune disease that affects the optic nerves and spinal cord. There is currently no effective cure or therapy. Aquaporin‑4 (AQP4) is a known target of the autoimmune antibody NMO‑IgG. Therefore, binding of NMO‑IgG to AQP4, and subsequent activation of antibody‑mediated and complement‑dependent cytotoxicity (CDC), are thought to underlie the pathogenesis of NMO. In the present study, a cell‑based high‑throughput screening approach was developed to identify molecular inhibitors of NMO‑IgG binding to AQP4. Using this approach, extracts from the herb Petroselinum crispum were shown to have inhibitory effects on NMO‑IgG binding to AQP4, and the natural compound geraldol was purified from the herb extracts. Analytical high performance liquid chromatography, electrospray ionization‑mass spectrometry and nuclear magnetic resonance analyses confirmed the identity of the isolated compound as geraldol, a flavonoid. Geraldol effectively blocked binding of NMO‑IgG to AQP4 in immunofluorescence assays and decreased CDC in NMO‑IgG/complement‑treated FRTL‑AQP4 cells and primary astrocytes. Geraldol exhibited low cytotoxicity, with no effect on proliferation or apoptosis of FRTL‑AQP4 cells and primary astrocytes. Permeability assays indicated that geraldol did not alter the water transport function of AQP4 in either cell system. The present study suggests the potential therapeutic value of geraldol for NMO drug development.

In this work, we conducted ab initio calculations to evaluate the properties of M-H···π interactions between the metal hydrides MH (M = Li, Na, MgH, CaH, NiH, CuH, ZnH) and inorganic benzenes B3X3H3 (X = O, S, Se). Unlike benzene, inorganic benzene B3X3H3 (X = O, S, Se) supports a large area of positive molecular electrostatic potential above and below the molecule, which acts as a Lewis acid and interacts with the H atom of metal hydride. MP2/6–311++G(d, p) results show that these intermolecular interactions exhibit the characteristics of close shell noncovalent interactions. The electrostatic interaction significantly contributes to stabilizing the complexes. The M-H···π interaction’s strength is associated with the property of group VI atom and metal hydride. X’s atomic number decreasing and the H of MH becoming more negative facilitate stronger interaction. Furthermore, the addition of substituent on the B3O3Y3 (Y = F, Cl, CN, OH, and CH3) significantly impacts the π-hole of inorganic benzene and thus modulates these M-H···π interactions. More elongation and blueshift of the MH bonds upon complexation were found for electron-withdrawing substituents. Analysis of σ and π orbital separation indicates that the π-attractor’s position relative to the B atom in the inorganic benzene changes with different substituents. The M-H···π interaction’s strength is primarily dependent on the π-electron density, not σ-electron density.

Although parental HIV disclosure has benefits for parents and children, the disclosure rate among parents remains low. This study aims to qualitatively examine parental concerns regarding disclosure of their HIV status to their children. Eighty parents were enrolled in a randomized controlled trial of a three-session disclosure-support intervention, with forty receiving the intervention and forty receiving treatment as usual. Intervention sessions were audio recorded, and transcriptions were qualitatively coded for content related to concerns of disclosure. Four themes emerged: Intention to disclose, disclosure approach, indicators for disclosure, and fears about disclosure. These themes reveal struggles that parents experience when considering HIV disclosure suggesting that an effective disclosure intervention must help parents assess pros and cons, discuss the emotions of the children after the disclosure, and monitor the impact on children’s lives after disclosure over time. Future research is needed to implement interventions supporting HIV-positive parents’ disclosure decision-making and actions.

To clarify the effect of an intraoperative low-dose dexmedetomidine infusion on emergence agitation following general anaesthesia in elderly patients.Eighty elderly patients ( 64-years-old) following elective general anaesthesia for radical cancer surgeries were randomly allocated into two groups (n = 40 each): the dexmedetomidine group (Group D) and the normal saline group (Group C). Anaesthesia was maintained with continuous intravenous infusion of dexmedetomidine at - 0.2 µg kgThe MAP in Group C was significantly higher than that in Group D (P 0.05), and there were no significant changes between the two groups in HR and MAP within each time point and D1, D2, D3, and D4. The incidence of agitation, NRS score and total dose of nalbuphine and fentanyl were all lower in Group D than in Group C (P 0.05).An intraoperative low-dose dexmedetomidine continuous infusion can reduce emergence agitation following general anaesthesia in elderly patients ( 64-years-old), remain stable in terms of haemodynamics, and not lead to delays in anaesthesia recovery time and extubation time.

Jie Wang,1 Huaxin Liang,2 Meiyan Sun,3 Lei Zhang,3 Huijing Xu,3 Wei Liu,3 Yan Li,3 Yue Zhou,4 Yingya Li,5 Miao Li2 1Department of Neurology, The China-Japan Union Hospital of Jilin University, Changchun 130033, China; 2Department of Neurosurgery, The China-Japan Union Hospital of Jilin University, Changchun 130033, China; 3College of Laboratory Medicine, Jilin Medical University, Jilin 132013, China; 4Department of Statistics, North Dakota State University, Fargo, ND 58108, USA; 5Department of Cereal Science, North Dakota State University, Fargo, ND 58108, USA Background: It has been reported that cell inflammation pathways contribute to the development of prostaglandin E2 (PGE2)-inhibitor of DNA-binding protein-1 (ID1)-dependent radioresistance in glioblastoma. Here, we proposed that inhibiting delta-6-desaturase (D6D) could block arachidonic acid synthesis and PGE2 production, thereby reversing PGE2-ID1-dependent radioresistance in glioblastoma cells and xenograft tumor models.Materials and methods: Two glioblastoma cell lines, namely, U-87 MG and LN-229, were used for the in vitro study. The combination effects of SC-26196 (a D6D inhibitor) and radiation were assessed by the MTS assay, colony formation assay, and cell apoptosis analysis. HPLC/MS analysis was performed to quantify the production of arachidonic acid and PGE2. For the in vivo study, 6-week-old nude mice, each bearing a U-87 MG xenograft tumor, were subjected to 4-week treatments of vehicle, SC-26196, radiation, or the combination of both. Tumor growth was monitored during the treatment, and the tumor tissues were collected at the end for further analysis.Results: Treatment with SC-26196 significantly improved radiosensitivity in both glioblastoma cell lines in vitro, and radiosensitivity was associated with inhibited synthesis of arachidonic acid and PGE2. The combination of SC-26196 and radiation synergistically inhibited U-87 MG xenograft tumor growth, in association with the induction of tumor apoptosis and suppressed tumor proliferation. SC-26196 also inhibited arachidonic acid and PGE2 production in vivo and limited expression of ID1.Conclusion: These data suggested that the D6D inhibitor could reverse PGE2-ID1-dependent radioresistance in glioblastoma cells and xenograft tumor models by blocking the synthesis of arachidonic acid and PGE2. Although further investigation is required, the outcomes from this study may guide us in developing a potentially novel combination strategy for current glioblastoma therapy. Keywords: delta-6-desaturase, glioblastoma, radiation therapy, inflammation pathway

Background: Non-large artery atherosclerosis (LAA) infarcts are relatively rare compared to LAA type infarcts. Hemorrhagic transformation (HT) is one of the complications of acute ischemic stroke (AIS), and we aim to investigate the risk factors for the development of HT in patients with non-LAA type AIS.Patients and methods：From January 2015 to January 2020, we included a total of 52 patients with non-LAA type AIS who met the criteria for the occurrence of HT, for which 136 patients without HT were matched. Patients were followed up every 3 months by phone or in the clinic, with a minimum of 1 year of follow-up per patient. The risk factors associated with prognosis were derived after univariate analysis and multifactorial logistic regression analysis, and a nomogram model was developed based on these risk factors. The accuracy of the model was evaluated by creating a calibration plot and the receiver operating characteristic curve (ROC).Results: Through univariate analysis and logistics regression analysis, we found that the patient's creatine kinase-MB (CK-MB), ejection fraction (EF) and platelets (PLT) were independently related to the HT in patients with non-LAA type AIS. We accordingly developed smoothing curves to predict the probability of HT and found that the HT rate increased with increasing CK-MB and decreased with increasing EF and PLT. The nomogram based on these three factors had an area under curve (AUC) of 0.875 for the development group and 0.889 for the external validation group. The calibration plot showed a good prediction accuracy.Conclusions: Patients with non-LAA type AIS are relatively uncommon and presenting with HT is even rarer. Our nomogram built on cardiogenic parameters and PLT can accurately predict the occurrence of HT in these non-LAA type AIS patients, which has good clinical significance.

Aim To understand COVID patients' experiences of and perspectives on disclosure of their illness and to explore and describe the factors affecting disclosure decisions among COVID patients in China. Background Disease disclosure is a critical component of prevention and control of a virus outbreak, and this is especially true during the COVID-19 pandemic. Understanding COVID patients' experiences and perspectives on disclosure could play a vital role in COVID management. Design A qualitative study. Methods A semi-structured interview guide was used to conduct qualitative in-depth interviews from April to June 2020. All the interviews were audio-recorded and transcribed, and then, a thematic analysis was conducted. The Standards for Reporting Qualitative Research (SRQR) were applied to this study. Results A total of 26 COVID-confirmed patients were recruited for the in-depth interviews. Four themes emerged from the thematic analysis on disclosure: persons disclosed to, reasons for disclosure, reasons for nondisclosure and impact of disclosure. The participants disclosed their COVID diagnosis to different groups, including family, close friends, community members and workplace contacts. The main reasons for disclosure included the following: government policy, social responsibility, gaining support and fear of being blamed for nondisclosure. However, some participants decided not to disclose to some groups for fear of facing stigma and discrimination or to protect family members from discrimination. Despite the potential benefits of obtaining support after disclosure, many participants did experience stigma and discrimination, privacy exposure, psychological distress and social isolation. Conclusions An individual's decision as to whether to disclose their COVID-positive status is affected by many factors. To prevent the spread of COVID-19 and reduce the potential risks of disclosure, such as discrimination and privacy exposure, a balanced intervention should be designed to protect COVID patients and to secure any contact tracing. Therefore, the chances of discrimination could be decreased and patients' confidentiality could be protected. Relevance to clinical practice As the number of COVID patients increases, disclosure of an individual's infectious status is encouraged by health departments. Despite the potential benefits of disclosure, discrimination and privacy exposure should not be ignored. A disclosure protocol is necessary to ensure patients' privacy regarding their COVID status.

Background The combination of KIR-HLA affects the prognosis of HIV infection, and polymorphisms of KIR and its ligand HLA differs between regions and races. Few research has focused on the effects of the KIR-HLA combination on the prognosis of HIV-infected individuals in China. Methods Peripheral blood samples were collected from newly diagnosed and treatment naïve HIV-infected patients and processed according to the study design. Their clinical data and other demographic information were recorded. The genomic DNA of the host was extracted from whole blood samples, and KIR genotyping was performed using sequence specific primer amplification (PCR-SSP). The HLA genotyping was performed using sequence analysis (PCR-SBT), and the HLA-KIR genotyping and combination information were obtained. Fisher’s exact test was used for the comparison of categorical variables between groups, and the Mann-Whitney test was used for continuous variables. Results The baseline HIV level in patients with an HLA-C1+/KIR2DL3+ background was significantly higher than that in patients with an HLA-C1+/KIR2DL3- (4.34 log10 copies/ml vs. 3.72 log10 copies/ml, P=0.02). The baseline CD4/CD8 ratio of HLA-C1+/KIR2DL3+ patients was significantly lower than that of HLA-C1+/KIR2DL3- patients (0.33 vs. 0.56, P=0.02). The plasma soluble CD14 level at baseline was significantly lower in HLA-C1+/KIR2DL3- infected persons than HLA-C1+/KIR2DL3+ patients (P=0.03). Conclusions HIV-infected persons with the combination of HLA-C1+/KIR2DL3+ had a much higher HIV set point, higher baseline sCD14 levels and lower baseline CD4/CD8 than patients without this combination. The receptor-ligand combination of HLA-C1+/KIR2DL3+ has a deleterious effect in Chinese HIV patients.

Tremendous progress has been achieved in the field of immune checkpoint inhibitors (ICIs) therapy in lung cancer in recent years. To generate robust, long-lasting anti-tumor immune responses in lung cancer patients, combinational ICI therapies have been explored deeply. Conventionally, chemotherapy was considered as immunosuppressive. It is now recognized that chemotherapy could also reinstate cancer cell immune-surveillance and enable the perception of cancer cells as dangerous. That is to say that chemotherapeutic drugs are not only a source of direct cytotoxic effects but also an adjuvant for anti-tumor immunity. Recently, multiple clinical studies of ICIs combined with chemotherapeutic drugs have been explored and proved effective. However, there are still crucial questions that are not well addressed, such as the optimal dose and schedule for a given combination may differ across disease indications, and the appropriate strategy of selecting patient population that can benefit from ICIs remains unclear. To facilitate more rational lung cancer ICIs therapy development, this review summarizes the immune-regulatory effects and related mechanisms of chemotherapeutic drugs and the clinical progress of ICIs and their combination with chemotherapies in lung cancer treatment.

KRAS is one of the most frequently mutated oncogenes in cancers. Currently no direct and effective anti-KRAS therapies are available. Using the powerful CRISPR-Cas9 technology to target the mutant KRAS promoter, we designed an epigenetic repressor to silence KRAS through epigenome editing. Catalytically dead Cas9 (dCas9) functioned as a DNA binding device, which was fused with a transcriptional repressor histone deacetylase 1 (HDAC1). We designed a panel of three CRISPR RNAs (crRNAs) covering 1500-bp range of the KRAS promoter and identified that crRNA1 and crRNA2 efficiently silenced KRAS. The suppression of K-Ras resulted in a significant inhibition of cell growth, suppression of colony formation in soft agar and induction of cell death in cancer cells with KRAS mutations. In addition, the chromatin immunoprecipitation (ChIP) assay demonstrated dCas9-HDAC1 modified histone acetylation on the KRAS promoter. Furthermore, transfection of dCas9-HDAC1 protein and gRNA ribonucleoprotein complex also inhibited K-Ras and suppressed cell proliferation. In summary, we have developed a new strategy that combines CRISPR-Cas9 technology with HDAC1 epigenetic silencing to target cancers driven by KRAS mutations.

Supplemental material, ISSM_COREQ_Checklist_18-10-26_Appendix_1 for Concerns of Parental HIV Disclosure in China by Meiyan Sun, Wei-Ti Chen, Joyce P. Yang, Shuyuan Huang, Lin Zhang, Mingfeng Shi, Wei Li, Ye Li, Meijuan Bao and Hongzhou Lu in Clinical Nursing Research

People living with HIV/AIDS (PLWHA) in China experience significant psychological distress, due to high rates of stigma and low availability of mental health resources. Recently diagnosed Chinese PLWHA who are men who have sex with men (MSM) are particularly vulnerable to distress, facing both HIV and sexual orientation stigma. Reducing distress and enhancing psychological resilience is critical in promoting wellbeing. However, no research to date has examined evidence-based interventions to reduce psychological symptoms and improve resilience in this population. Based on qualitative research on their mental health needs, we developed a culturally tailored, brief 3-session CBT skills-based intervention for integration into primary care [Yang, J. P., Simoni, J., Cheryan, S., Shiu, C., Chen, W., Zhao, H., & Lu, H. (2018). The development of a brief distress reduction intervention for individuals recently diagnosed with HIV in China. Cognitive Behavioral Practice, 25(2), 319-334. doi: 10.1016/j.cbpra.2017.08.002 ]. The intervention includes cognitive restructuring to address depressive thought patterns, behavioral activation to decrease isolation, and paced breathing to reduce anxiety. We conducted a pilot Type 1 hybrid effectiveness-implementation trial assessing pre-post mental health outcomes as well as feasibility, acceptability, and appropriateness information. Ten recently diagnosed MSM completed the research protocol of three individual weekly sessions. Paired-samples t tests demonstrated significant reduction in HIV-related distress, depression, problems with adjustment, as well as improvements in resilience, and perceived social support. Participants and community advisory board members found the intervention highly acceptable, appropriate, and feasible. Preliminary data from the first known study examining a psychological intervention with evidence-based components for recently diagnosed Chinese MSM suggests that this brief intervention may be useful for reducing distress and promoting resilience.

Nanotechnology offers many benefits, and here we report an advantage of applying RNA nanotechnology for directional control. The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA). Placing membrane-anchoring cholesterol at the tail of the arrow results in display of RNA aptamer or folate on the outer surface of the extracellular vesicle. In contrast, placing the cholesterol at the arrowhead results in partial loading of RNA nanoparticles into the extracellular vesicles. Taking advantage of the RNA ligand for specific targeting and extracellular vesicles for efficient membrane fusion, the resulting ligand-displaying extracellular vesicles were capable of specific delivery of siRNA to cells, and efficiently blocked tumour growth in three cancer models. Extracellular vesicles displaying an aptamer that binds to prostate-specific membrane antigen, and loaded with survivin siRNA, inhibited prostate cancer xenograft. The same extracellular vesicle instead displaying epidermal growth-factor receptor aptamer inhibited orthotopic breast cancer models. Likewise, survivin siRNA-loaded and folate-displaying extracellular vesicles inhibited patient-derived colorectal cancer xenograft.

Anoctamin 7 (ANO7) is a member of the transmembrane protein TMEM16 family. It has a conservative topology similar to other members in this family, such as the typical eight-transmembrane domain, but it also has unique features. Although the ion channel role of ANO7 has been well accepted, evolutionary analyses and relevant studies suggest that ANO7 may be a multi-facet protein in function. Studies have shown that ANO7 may also function as a scramblase. ANO7 is highly expressed in prostate cancer as well as normal prostate tissues. A considerable amount of evidence has confirmed that ANO7 is associated with human physiology and pathology, particularly with the development of prostate cancer, which makes ANO7 a good candidate as a diagnostic and prognostic biomarker. In addition, ANO7 may be a potential target for prostate cancer immunotherapy. Antibody-based or T cell-mediated immunotherapies against prostate cancer by targeting ANO7 have been highly anticipated. ANO7 may also correlate with several other types of cancers or diseases, where further studies are warranted.

Vitamin D is an important hormone that regulates many physiological processes related to human health. Through its nuclear receptor, VDR, vitamin D controls gene expression through genetic and epigenetic mechanisms. Increasing data have demonstrated the anti-cancer activities of vitamin D in various cancers, including colon cancer. This review summarizes the recent progresses in our understanding of the molecular mechanisms of vitamin D and its interaction with the epigenetic machinery in colon cancer. Vitamin D changes the status of DNA methylation and histone modifications, resulting in the activation of tumor suppressors and inhibition of oncogenes. In addition, vitamin D activates the expression of tumor suppressing miRNAs, which contribute to the tumor suppressive activity. Further understanding of the epigenetic action of vitamin D will help the development of therapeutic strategies targeting the vitamin D signaling pathway without inducing the hypercalcemic side effects.

Aiming at the problem of closed-loop performance degradation caused by actuator saturation of airborne photoelectric stabilized aiming platform actuator in the application of traditional sliding mode variable structure control, radial basis function (RBF) neural network (NN) was used as compensator to improve the sliding mode variable structure control law, and a neural network sliding mode control (SMC) method considering the input limitation of actuator was proposed. Simulation results show that the application of the controller can compensate for the limited control input and improve the visual axis stability of airborne photoelectric stabilized sighting platform.

Both siRNA and miRNA can serve as powerful gene-silencing reagents but their specific delivery to cancer cells in vivo without collateral damage to healthy cells remains challenging. We report here the application of RNA nanotechnology for specific and efficient delivery of anti-miRNA seed-targeting sequence to block the growth of prostate cancer in mouse models. Utilizing the thermodynamically ultra-stable three-way junction of the pRNA of phi29 DNA packaging motor, RNA nanoparticles were constructed by bottom-up self-assembly containing the anti-prostate-specific membrane antigen (PSMA) RNA aptamer as a targeting ligand and anti-miR17 or anti-miR21 as therapeutic modules. The 16 nm RNase-resistant and thermodynamically stable RNA nanoparticles remained intact after systemic injection in mice and strongly bound to tumors with little or no accumulation in healthy organs 8 hours postinjection, and subsequently repressed tumor growth at low doses with high efficiency.

The purpose of this study was to identify fecal bacterial microbiome changes in patients with chronic human immunodeficiency virus (HIV) infection in China. Bacterial 16S rRNA genes were amplified, sequenced (454 pyrosequencing), and clustered into operational taxonomic units using the QIIME software. Relative abundance at the phylum and genus levels were calculated. Alpha diversity was determined by Chao 1 and observed-species indices, and beta diversity was determined by double principal component analysis using the estimated phylogeny-based unweighted Unifrac distance matrices. Fecal samples of the patients with chronic HIV-infection tended to be enriched with bacteria of the phyla Firmicutes (47.20% ± 0.43 relative abundance) and Proteobacteria (37.21% ± 0.36) compared with those of the non-HIV infected controls (17.95% ± 0.06 and 3.81% ± 0.02, respectively). Members of the genus Bilophila were exclusively detected in samples of the non-HIV infected controls. Bacteroides and arabacteroides were more abundant in the chronic HIV-infected patients. Our study indicated that chronic HIV-infected patients in China have a fecal bacterial microbiome composition that is largely different from that found in non-HIV infected controls, and further study is needed to evaluate whether microbiome changes play a role in disease complications in the distal gut, including opportunistic infections.

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)—a free-radical gas—plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future.

Background Mesenchymal stem cells (MSCs) are multipotent, genomic stable, self-renewable, and culturally expandable adult stem cells. MSCs facilitate tissue development, maintenance and repair, and produce secretory factors that support engraftment and trophic functions, marking them an attractive option in cell therapy, regenerative medicine and tissue engineering. Method In this review, we summarize the recent researches regarding the isolation and characterization of MSCs, therapeutic applications and advanced engineering techniques. We also discuss the advantages and limitations that remain to be overcome for MSCs based therapy. Results It has been demonstrated that MSCs are able to modulate endogenous tissue and immune cells. Preclinical studies and early phase clinical trials have shown their great potential for tissue engineering of bone, cartilage, marrow stroma, muscle, fat, and other connective tissues. Conclusions MSC-based therapy show considerable promise to rebuild damaged or diseased tissues, which could be a promising therapeutic method for regeneration medicine.

The dietary effect on gut health has long been recognized through the empirical practice of soothing gastric discomfort with certain types of food, and recently the correlation between specific diets with lower incidences of several gastrointestinal diseases has been revealed. Ingredients from those considered beneficial foods have been isolated and studied, and some of them have already been put into the supplement market. In this review, we focus on latest studies of these food-derived ingredients for their proposed preventive and therapeutic roles in gastrointestinal disorders, with the attempt of drawing evidence-based suggestions on consuming these products.

Although the initiation of antiretroviral therapy (ART) has promoted the reconstitution of CD4+ T-cell count in the HIV infected population, not all patients can achieve the normalization of their immunologic functions. We analysed the variables associated with immunologic recovery, which is commonly regarded as the increase of CD4 to 350 cell/μL after a year of ART. We collected data from 3,485 patients attending a university-based HIV clinic from June 2005 to July 2014 in Shanghai, China. Logistic regression test was performed to analyse the risk factors for suboptimal CD4+ recovery following yearlong ART. The CD4+ T-cell of 723 participants (41.5% of the 1744 subjects) showed more than 350 cell/μL after one year of ART. Compared with baseline CD4 > 350 cell/μL, patients with baseline CD4 ≤ 200 cell/μL or 200 < CD4 ≤ 350 cell/μL were 42.6, 4.5 times more likely to be incomplete CD4 recovery, respectively. The risk of suboptimal immunologic recovery among patients with regimen including AZT or d4T were 2.1, 2.4 times higher compared with TDF, respectively. In our study, between optimal CD4 recovery group and suboptimal recovery group, there were no significant differences in age, gender, marital status, transmission routes, WHO stage, and CD4 recovery rates. As for the dynamic CD4 change, we found the CD4 recovery rates were 49.9% and 61.8% in the second and third year of ART, respectively. Patients who had a low level of CD4+ T-cell count (< 200 cell/μL) during the initiation of ART exhibited more difficulties recovering to a normal level. Furthermore, the regimen, including AZT or d4T, was not beneficial to CD4 recovery. So, more efforts should be made to guarantee the early diagnosis and timely treatment for HIV/AIDS patients, and simultaneously optimize antiretroviral therapy.