Prevention against diffuse spinal cord astrocytoma: can the Notch pathway be a novel treatment target?

This study was designed to investigate whether the Notch pathway is involved in the develop-ment of diffuse spinal cord astrocytomas. BALB/c nude mice received injections of CD133＋and CD133？ cell suspensions prepared using human recurrent diffuse spinal cord astrocytoma tissue through administration into the right parietal lobe. After 7–11 weeks, magnetic resonance imaging was performed weekly. Xenografts were observed on the surfaces of the brains of mice receiving the CD133＋ cell suspension, and Notch-immunopositive expression was observed in the xenografts. By contrast, no xenografts appeared in the identical position on the surfaces of the brains of mice receiving the CD133？ cell suspension, and Notch-immunopositive expres-sion was hardly detected either. Hematoxylin-eosin staining and immunohistochemical staining revealed xenografts on the convex surfaces of the brains of mice that underwent CD133＋ astro-cytoma transplantation. Some sporadic astroglioma cells showed pseudopodium-like structures, which extended into the cerebral white matter. However,it should be emphasized that the sub-cortex xenograft with Notch-immunopositive expression was found in the fourth mouse received injection of CD133？ astrocytoma cells. However, these ifndings suggest that the Notch pathway plays an important role in the formation of astrocytomas, and can be considered a novel treat-ment target for diffuse spinal cord astrocytoma.

Clinical outcomes of people living with human immunodeficiency virus(HIV)with diffuse large B-cell lymphoma(DLBCL)in Shanghai,China

Background:Numerous studies have focused on lymphoma among patients infected with human immunodeficiency virus(HIV).However,little is known about the treatment options and survival rate of lymphoma in the Chinese people living with HIV(PLHIV).Our study aimed to investigate the prognosis and compare outcome of dose-adjusted etoposide,prednisone,vincristine,cyclophosphamide,doxorubicin,and rituximab(DA-EPOCH-R)with standard cyclophosphamide,doxorubicin,vincristine,prednisone and rituximab(R-CHOP)as front line therapy for PLHIV with diffuse large B-cell lymphoma(DLBCL)receiving modern combined antiretroviral therapy(cART).Methods:A retrospective analysis evaluating PLHIV with DLBCL was performed in Shanghai Public Health Clinical Center from July 2012 to September 2019.The demographic and clinical data were collected,and overall survival(OS)and progression-free survival(PFS)analyses of patients receiving R-CHOP or DA-EPOCH-R therapy were performed by Kaplan-Meier analysis.Additionally,a Cox multiple regression model was constructed to identify related factors for OS.Results:A total of 54 eligible patients were included in the final analysis with a median follow-up of 14 months(interquartile range[IQR]:8-29 months).The proportion of high international prognostic index(IPI)patients was much larger in the DA-EPOCH-R group(n=29)than that in the R-CHOP group(n=25).The CD4 cell counts and HIV RNA levels were not significantly different between the two groups.The 2-year OS for all patients was 73%.However,OS was not significantly different between the two groups,with a 2-year OS rate of 78%for the DA-EPOCH-R group and 66%for the R-CHOP group.Only an IPI greater than 3 was associated with a decrease in OS,with a hazard ratio of 5.0.The occurrence of grade 3 and 4 adverse events of chemotherapy was not significantly different between the two groups.Conclusions:Outcomes of R-CHOP therapy do not differ from those of DA-EPOCH-R therapy.No HIV-related factors were found to be associated with the OS of PLHIV in the modern cART era.

Risk factors affecting the mortality of HIVinfected patients with pulmonary tuberculosis in the cART era:a retrospective cohort study in China

Background:Tuberculosis infection still places a great burden on HIV-infected individuals in China and other developing countries.Knowledge of the survival of HIV-infected patients with pulmonary tuberculosis(PTB)would provide important insights for the clinical management of this population,which remains to be well described in current China.Methods:HIV-infected patients with PTB admitted to Shanghai Public Health Clinical Center from January 2011 to December 2015 were retrospectively enrolled.In this cohort,the survival prognosis was estimated by the Kaplan-Meier method,while univariate and multivariate Cox proportional hazards models were used to determine the risk factors affecting mortality.Results:After reviewing 4914 admitted patients with HIV infection,359 PTB cases were identified.At the time of PTB diagnosis,the patients’median CD4+T cell count was 51/mm3(IQR:23-116),and 27.30%of patients(98/359)were on combination antiretroviral therapy(cART).For the 333 cases included in the survival analysis,the overall mortality was 15.92%(53/333)during a median 27-month follow-up.The risk factors,including age older than 60 years(HR:3.18;95%CI:1.66-6.10),complication with bacterial pneumonia(HR:2.64;95%CI:1.30-5.35),diagnosis delay(HR:2.60;95%CI:1.42-4.78),CD4+T cell count less than 50/mm3(HR:2.38;95%CI:1.27-4.43)and pulmonary atelectasis(HR:2.20;95%CI:1.05-4.60),might independently contribute to poor survival.Among patients without cART before anti-TB treatment,the later initiation of cART(more than 8 weeks after starting anti-TB treatment)was found to increase the mortality rate(OR:4.33;95%CI:1.22-15.36),while the initiation of cART within 4-8 weeks after starting anti-TB treatment was associated with the fewest deaths(0/14).Conclusions:The subjects in this study conducted in the cART era were still characterized by depressed immunological competence and low rates of cART administration,revealing possible intervention targets for preventing TB reactivation in HIV-infected individuals under current circumstances.Furthermore,our study indicated that the timely diagnosis of PTB,prevention of secondary bacterial pneumonia by prophylactic management and optimization of the timing of cART initiation could have significant impacts on decreasing mortality among HIV/PTB co-infected populations.These findings deserve further prospective investigations to optimize the management of HIV/PTB-co-infected patients.Trial registration:NCT01344148,Registered September 14,2010.

Epithelial defect repair in the auricle and auditory meatus by grafting with cultured adipose-derived mesenchymal stem cell aggregate-extracellular matrix

Background: Several patients experience persistent otorrhea after a flawless surgical procedure because of insufficient epithelial healing. Several efforts, such as autologous tissue allograft and xenograft, have been made to halt otorrhea. However, a stable technology to induce temporal epithelial repair is yet to be established. Therefore, this study aims to investigate whether implantation of seeding adipose-derived mesenchymal stem cell (ADMSC) aggregates on extracellular matrix (ECM;herein, ADMSC aggregate-ECM) into damaged skin wound promotes skin regeneration. Methods: ADMSC aggregate-ECM was prepared using a previously described procedure that isolated ADMSCs from rabbits and applied to the auricle and auditory meatus wound beds of New Zealand white rabbits. Wound healing was assessed by general observation and hematoxylin and eosin (H&E) staining. Secretion of growth factor of the tissue was evaluated by western blotting. Two other groups, namely, ECM and control, were used. Comparisons of three groups were conducted by one-way analysis of variance analysis. Results: ADMSCs adhered tightly to the ECM and quickly formed cell sheets. At 2 weeks, general observation and H&E staining indicated that the wound healing rates in the ADMSC aggregate-ECM (69.02±6.36%) and ECM (59.32 + 4.10%) groups were higher than that in the control group (43.74± 12.15%;P=0.005, P<0.001, respectively) in ear auricle excisional wounds. At 7 weeks, The scar elevation index was evidently reduced in the ADMSC aggregate-ECM (2.08±0.87) and ECM (2.31 ±0.33) groups compared with the control group (4.06 ±0.45;P < 0.001, P < 0.001, respectively). In addition, the scar elevation index of the ADMSC aggregate-ECM group reached the lowest rate 4 weeks in advance. In auditory meatus excisional wounds, the ADMSC aggregate-ECM group had the largest range of normal skin-like structure at 4 weeks. The ADMSC aggregate-ECM and ECM groups secreted increased amounts of growth factors that contributed to skin regeneration at weeks 1 and 2, respectively. Conclusions: ADMSC aggregate-ECM and ECM are effective repair materials for wound healing, especially ADMSC aggregate- ECM. This approach will provide a meaningful experimental basis for mastoid epithelium repair in subsequent clinical trials.

Solid Lipid Nanoparticles Loaded with Edaravone for Inner Ear Protection After Noise Exposure

Background：Antioxidants and the duration of treatment after noise exposure on hearing recovery are important.We investigated the protective effects of an antioxidant substance,edaravone,and its slow-release dosage form,edaravone solid lipid nanoparticles （SLNs）,in steady noise-exposed guinea pigs.Methods：SLNs loaded with edaravone were produced by an ultrasound technique.Edaravone solution or edaravone SLNs were administered by intratympanic or intravenous injection after the 1st day of noise exposure.Guinea pigs were exposed to 110 dB sound pressure level （SPL） noise,centered at 0.25-4.0 kHz,for 4 days at 2 h/d.After noise exposure,the guinea pigs underwent auditory brainstem response （ABR） threshold measurements,reactive oxygen species （ROS） were detected in their cochleas with electron spin resonance （ESR）,and outer hair cells （OHCs） were counted with silvernitrate （AgNO3） staining at 1,4,and 6 days.Results：The ultrasound technique was able to prepare adequate edaravone SLNs with a mean particle size of 93.6 nm and entrapment efficiency of 76.7%.Acoustic stress-induced ROS formation and edaravone exerted a protective effect on the cochlea.Comparisons of hearing thresholds and ROS changes in different animal groups showed that the threshold shift and ROS generation were significantly lower in treated animals than in those without treatment,especially in the edaravone SLN intratympanic injection group.Conclusions：Edaravone SLNs show noticeable slow-release effects and have certain protective effects against noise-induced hearing loss （NIHL）.

Integrated Observer-based Fixed-time Control with Backstepping Method for Exoskeleton Robot

To achieve the fast convergence and tracking precision of a robotic upper-limb exoskeleton,this paper proposes an observer-based integrated fixed-time control scheme with a backstepping method.Firstly,a typical 5 DoF(degrees of freedom)dynamics is constructed by Lagrange equations and processed for control purposes.Secondly,second-order sliding mode controllers(SOSMC)are developed and novel sliding mode surfaces are introduced to ensure the fixed-time convergence of the human-robot system.Both the reaching time and settling time are proved to be bounded with certain values independent of initial system conditions.For the purpose of rejecting the matched and unmatched disturbances,nonlinear fixed-time observers are employed to estimate the exact value of disturbances and compensate the controllers online.Ultimately,the synthesis of controllers and disturbance observers is adopted to achieve the excellent tracking performance and simulations are given to verify the effectiveness of the proposed control strategy.

Clinical features and treatment outcomes of human immunodeficiency virus-associated cryptococcal meningitis:a 2-year retrospective analysis

Background:Cryptococcal meningitis(CM)is one of the most common opportunistic infections caused by Cryptococcus neoformans in human immunodeficiency virus(HIV)-infected patients,and is complicated with significant morbidity and mortality.This study retrospectively analyzed the clinical features,characteristics,treatment,and outcomes of first-diagnosed HIV-associated CM after 2-years of follow-up.Methods:Data from all patients(n=101)of HIV-associated CM hospitalized in Shanghai Public Health Clinical Center from September 2013 to December 2016 were collected and analyzed using logistic regression to identify clinical and microbiological factors associated with mortality.Results:Of the 101 patients,86/99(86.9%)of patients had CD4 count<50 cells/mm^3,57/101(56.4%)were diagnosed at≥14 days from the onset to diagnosis,42/99(42.4%)had normal cerebrospinal fluid(CSF)cell counts and biochemical examination,30/101(29.7%)had concomitant Pneumocystis(carinii)jiroveci pneumonia(PCP)on admission and 37/92(40.2%)were complicated with cryptococcal pneumonia,50/74(67.6%)had abnormalities shown on intracranial imaging,amongst whom 24/50(48.0%)had more than one lesion.The median time to negative CSF Indian ink staining was 8.50 months(interquartile range,3.25-12.00 months).Patients who initiated antiretroviral therapy(ART)before admission had a shorter time to negative CSF Indian ink compared with ART-naïve patients(7 vs.12 months,χ^2=15.53,P<0.001).All-cause mortality at 2 weeks,8 weeks,and 2 years was 10.1%(10/99),18.9%(18/95),and 20.7%(19/92),respectively.Coinfection with PCP on admission(adjusted odds ratio[AOR],3.933;95%confidence interval[CI],1.166-13.269,P=0.027)and altered mental status(AOR,9.574;95%CI,2.548-35.974,P=0.001)were associated with higher mortality at 8 weeks.Conclusion:This study described the clinical features and outcomes of first diagnosed HIV-associated CM with 2-year follow-up data.Altered mental status and coinfection with PCP predicted mortality in HIV-associated CM.

Spectroscopic and electrochemical properties of Cu-dicyandiamide complex

Dicyandiamide(DICY) is a common ligand that exhibits low toxicity but can irritate the skin and eyes and cause methemoglobinemia on long-term exposure. Crystalline Cu-dicyandiamide(Cu-DICY) was obtained via facile synthesis and its molecular structure and theoretical Raman spectra were simulated by using density functional theory(DFT). The results suggested that the Cu^(2+) coordinates with two H_2 O molecules and two different DICY molecules(an imino DICY and an amino DICY). The stability constants of Cu-DICY were calculated, and the electrochemical properties were studied. Two electrochemical redox processes occur in Cu-DICY in an aqueous solution: a reversible reaction with a formal potential of 0.2 V vs.MSE and an irreversible reaction between –0.4 and –1.2 V vs. MSE. The standard rate constant k0 for the reversible reaction was estimated to be 7.6×10^(-3) cm/s. In addition, based on the reversible reaction of Cu-DICY, square wave voltammetry was used to rapidly determine the concentration of Cu(II) and the detection limit was 66.7 μg/L, which satisfies the detection limit requirements for copper in tap water(2 mg/L) as provided by the World Health Organization.