Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies.

Cluster of differentiation 40 (CD40) mediates many immune activities. Preclinical studies have shown that activation of CD40 can evoke massive antineoplastic effects in several tumour models in vivo, providing a rationale for using CD40 agonists in cancer immunotherapy. To date, several potential agonistic antibodies that target CD40 have been investigated in clinical trials. Early clinical trials have shown that the adverse events associated with agonists of CD40 thus far have been largely transient and clinically controllable, including storms of cytokine release, hepatotoxicity and thromboembolic events. An antitumour effect of targeting CD40 for monotherapy or combination therapy has been observed in some tumours. However, these antitumour effects have been moderate. The present review aimed to provide updated details of the clinical results of these agonists, and offer information to further investigate the strategies of combining CD40 activation with chemotherapy, radiotherapy, targeted therapy and immunomodulators. Furthermore, biomarkers should be identified for monitoring and predicting responses and informing resistance mechanisms.

Cognitive characteristics in Chinese non-demented PD patients based on gender difference.

BACKGROUND: Cognitive impairment is one of the non-motor symptoms in Parkinson's disease (PD). In the present study, we aim to examine the cognitive function of non-demented Parkinson's disease patients and compare the results between male and female patients as well as control groups in search of any gender effect. METHODS: Sixty PD Patients (30 males and 30 females) from the Movement Disorders Clinic at Huashan Hospital Affiliated to Fudan University were recruited to participate in the study. One hundred age and gender matched control subjects without neurological or psychiatric disorders were voluntarily recruited. The participants were administered measures of cognition in five domains including memory, language, spatial processing abilities, attention and executive function. RESULTS: PD patients attained significantly lower scores in the visual spatial function, language and attention/executive function compared with the control group. Anti-parkinsonian treated patients performed worse in Rey-copy score, Clock Drawing Test (CDT) and Verbal Fluency-City than untreated ones. In regard to gender differences, though no general cognitive differences were found in Mini-mental State Examination (MMSE), men surpassed women on Boston naming test (BNT) while women were superior on Auditory Verbal Learning Test-long (AVLT) delayed cued recall test. CONCLUSIONS: Cognitive impairments were common in PD patients even in the absence of dementia. PD patients with anti-parkinsonian medication had worse cognitive impairment than untreated patients. Genders may have different manifestations of cognitive impairment in PD patients.

Depressive Symptoms Are Associated With Color Vision but not Olfactory Function in Patients With Parkinson's Disease.

Depressive symptoms and sensory dysfunction, such as reduction in visual and olfactory function, are common in Parkinson's disease (PD). Previous studies have suggested that depressive symptoms are associated with visual impairments and potentially with hyposmia in several types of mood disorders. However, the relationship between depressive symptoms and sensory dysfunction remains unclear in PD. To examine the association of depressive symptoms with color vision and olfactory function in PD, the authors conducted a cross-sectional study in 159 patients with PD. Depressive symptoms were measured with the Beck Depression Inventory-II (BDI-II) and the 30-item Geriatric Depression Scale (GDS-30); color vision was tested with the Farnsworth-Munsell 100 Hue Test (FMT); and olfactory function was tested with the Sniffin' Sticks Screening 12 Test. Results showed that the total error score (TES) for the FMT was significantly and independently correlated with scores on both the BDI-II and GDS-30 in a positive manner, suggesting that more severe depressive symptoms are associated with poorer color vision in PD. In addition, both somatic and effective subscores for the BDI-II were correlated with the TES on the FMT, while no significant correlation was observed between total scores on the Sniffin' Sticks Screening 12 Test and BDI-II or GDS-30. The decrease in color vision but not olfactory function was found to be associated with the severity of depressive symptoms in PD patients, supporting the idea that the occurrence of depressive symptoms in PD is linked with disruption of the visual system.

Autophagic Modulation by Trehalose Reduces Accumulation of TDP-43 in a Cell Model of Amyotrophic Lateral Sclerosis via TFEB Activation.

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the formation of protein inclusion and progressive loss of motor neurons, finally leading to muscle weakness and respiratory failure. So far, the effective drugs for ALS are yet to be developed. Impairment of transcriptional activator transcription factor EB (TFEB) has been demonstrated as a key element in the pathogenesis of ALS. Trehalose is an mechanistic target of rapamycin-independent inducer for autophagy, which showed autophagic activation and neuroprotective effect in a variety of neurodegenerative diseases. The mechanism for trehalose-induced autophagy enhancement is not clear, and its therapeutic effect on TAR DNA-binding protein-43 (TDP-43) proteinopathies has been poorly investigated. Here we examined the effect of trehalose on TDP-43 clearance in a cell culture model and identified that trehalose treatment significantly reduced TDP-43 accumulation in vitro through modulation of the autophagic degradation pathway. Further studies revealed that activation of TFEB induced by trehalose was responsible for the enhancement of autophagy and clearance of TDP-43 level. These results gave us the notion that TFEB is a central regular in trehalose-mediated autophagic clearance of TDP-43 aggregates, representing an important step forward in the treatment of TDP-43 related ALS diseases.

A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.

BACKGROUND: Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically. CASE PRESENTATION: We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation. CONCLUSIONS: Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.

Evaluation of PDQ-8 and its relationship with PDQ-39 in China: a three-year longitudinal study.

BACKGROUND: Parkinson's disease is characterized by motor and non-motor symptoms with wide ranging impacts on the health-related quality of life. The 39-item Parkinson's disease Questionnaire (PDQ-39) is the most widely used PD-specific health-related quality-of-life questionnaire. The short-form 8-item Parkinson's disease Questionnaire (PDQ-8) was found to produce results similar to that of the PDQ-39 cross-culturally. However, there is no evaluation of the PDQ-8 in the mainland of China. METHODS: In this longitudinal study, 283 patients with Parkinson's disease were recruited. The PDQ-39, the PDQ-8 and other scales were administered. Patients attended the clinic once annually for three years to complete the scales. RESULTS: The PDQ-8 was found to have good validity and reliability. There was a strong correlation between the summary indices of the PDQ-8 and the PDQ-39 (r=0.93, P<0.001). Results suggested that the PDQ-8 was also associated with other clinical scales of mobility, depression and cognition. The convergent validity and discriminant validity of the PDQ-8 were demonstrated by item-to-dimension correlations. There was acceptable internal consistency of the PDQ-8 (Cronbach's α: 0.80; Item-scale correlation efficient: 0.56-0.72). The PDQ-8 replicated the results of the PDQ-39 well at all follow-up time points (intraclass correlation coefficient: 0.96-0.98). In addition, there was good test-retest reliability of the PDQ-8. CONCLUSION: The PDQ-8 is a valid and reliable instrument assessing health-related quality of life for PD patients in the mainland of China.

Associations between cognitive impairment and motor dysfunction in Parkinson's disease.

INTRODUCTION: Numerous studies have been carried out to explore the potential association between neurologic deficits and variable clinical manifestations of Parkinson's disease (PD). The aim of our study was to investigate the association between cognitive performance and motor dysfunction in Chinese patients with PD. METHODS: Data from 96 patients with PD were obtained from the Parkinson's disease patient cohort database of Huashan Hospital. All participants underwent a comprehensive neuropsychological evaluation to assess cognitive status, that included scoring on the Mini-mental state examination (MMSE), followed by more detailed cognitive assessment on five main cognitive domains (verbal memory, nonverbal memory, visuospatial function, language and attention/executive function). Correlations between cognitive and motor scores were investigated after controlling for age, disease duration, education, and gender. RESULTS: We report a significant correlation between subdomains of cognitive impairment and motor dysfunction using analyses of the multiple linear regression. Notably, executive function and attention was significantly associated with bradykinesia and rigidity, while visuospatial function was associated with bradykinesia and tremor. CONCLUSIONS: The association between motor dysfunction and cognitive decline in PD might highlight deficits represented by a shared neurochemical pathway.

Olfaction in Parkin carriers in Chinese patients with Parkinson disease.

BACKGROUND: Olfactory identification was reported to be better among PD (Parkinson disease) patients with Parkin mutations, but previous studies didn't eliminate the interference of other PD related genes on olfaction, and whether olfaction of Parkin mutations patients was better in Chinese population was still unknown. OBJECTIVE: To assess olfaction function among PD patients with Parkin mutations in Chinese population. MATERIALS AND METHODS: A total of 226 PD patients with a positive family history or an early-onset age (<50 years) were enrolled for genetic testing of PD related genes by target sequencing and multiple ligation-dependent probe amplification. The clinical data including olfactory function test were investigated. Linear regression was performed to adjust for the covariates between all groups. RESULTS: There were 68 patients found having a negative result in PD genetic testing and 43 patients carrying homozygous or compound heterozygous Parkin mutations. Among them, 49 PD panel negative patients and 33 PD-Parkin patients had results of olfactory assessment. PD -Parkin patients performed significantly better on the Sniffin' Sticks tests than panel negative patients (8.0 ± 1.7 vs. 5.7 ± 1.9, p < .001), but still worse compared to healthy controls (9.4 ± 1.5, p = .003). These differences persisted after adjusting for confounders. CONCLUSIONS: Among Chinese population, PD -Parkin patients had relatively preserved olfaction compared to PD panel negative patients after eliminating the interference of other PD related genes, but were still worse than healthy controls.

The spatial-temporal interaction in the LTP induction between layer IV to layer II/III and layer II/III to layer II/III connections in rats' visual cortex during the development.

During the early developmental period, long-term potentiation (LTP) can be induced in both vertical and horizontal connections in the rat visual cortex. However, the temporal difference in LTP change between the two pathways during animal development remains unclear. In this study, LTP in vertical (from layer IV to layer II/III) and horizontal (from layer II/III to layer II/III) synaptic connections were recorded in brain slices from the same rats, and the developmental changes of LTP in both directions were compared within the animals' eye-opening period. The results showed that the LTP amplitudes declined to unobservable levels on P16 in the horizontal connections and on P20 in the vertical synaptic connections. Meanwhile, V-LTP (LTP induced in the vertical direction) was always stronger than H-LTP (LTP induced in the horizontal direction) under the same conditions of pairing stimulus (PS). Next, H-LTP and V-LTP were induced from the same neuron in layer II/III to determine the spatiotemporal interactions between layer II/III horizontal inputs and ascending synaptic inputs during the maturation of rat visual cortex. The data show that the weak PS, which failed to induce H-LTP alone, was able to induce H-LTP effectively while V-LTP was performed on P10. Our results suggest that V-LTP can strengthen H-LTP induction in the visual cortex during the early developmental period. In contrast, the regulatory effect of H-LTP on V-LTP was much weaker.

The heterozygous R1441C mutation of leucine-rich repeat kinase 2 gene in a Chinese patient with Parkinson disease: A five-year follow-up and literatures review.

BACKGROUND: Leucine-rich repeat kinase 2 gene (LRRK2) was recognized associated with both familial and sporadic Parkinson Disease (PD). Seven missense mutations (G2019S, R1441C, R1441G, R1441H, Y1699C, I2020T, N1437H) of it have been confirmed disease- causing. They were common among Caucasian PD patients, but rarely reported in Asian, especially in Chinese Han population. OBJECTIVES: We aimed to identify the frequencies of these seven mutations of LRRK2 in Chinese early-onset PD (EOPD) patients and analyze the phenotypes. METHODS: One hundred and thirty seven EOPD patients were enrolled for genetic testing. The seven disease-causing mutations of LRRK2 were carried out by target sequencing using Illumina HiSeq 2000 Sequencer. The identified variants were further confirmed by Sanger sequence. The clinical materials were investigated retrospectively. RESULTS: Only one patient (0.73%) was found carrying pathogenetic LRRK2 mutation of R1441C. The age at onset of the female patient was 44. She manifested typical motor symptoms of PD and responded well to levodopa therapy. Longitudinal evaluation showed progression of motor symptoms and depression but no cognitive impairment. The dopamine transporter (DAT) imaging via [11C]-2ß-carbomethoxy-3ß-(4-fluorophenyl) tropan (CFT) and Positron emission computed tomography (PET) revealed typical dopamine transporter uptake reduction. CONCLUSIONS: The LRRK2 R1441C mutation was found in a Chinese EOPD patient for the first time. The manifestations of LRRK2-R1441C carriers were indistinguishable from sporadic PD patients.

Genetic variants at 6p21.1 and 7p15.3 Identified by GWASs of multiple cancers and ovarian cancer risk: a case-control study in Han Chinese women.

A recent study summarized several published genome-wide association studies (GWASs) of cancer and reported two pleiotropic loci at 6p21.1 and 7p15.3 contributing to multiple cancers including lung cancer, noncardia gastric cancer (NCGC), and esophageal squamous-cell carcinoma (ESCC) in Han Chinese. However, it is not known whether such genetic variants have similar effects on the risk of gynecologic cancers, such as ovarian cancer. Hence, we explored associations between genetic variants in 6p21.1 and 7p15.3 and ovarian cancer risk in Han Chinese women. We performed an independent case-control study by genotyping the two loci (rs2494938 A > G at 6p21.1 and rs2285947 A > G at 7p15.3) in a total of 377 ovarian cancer cases and 1,034 cancer-free controls using TaqMan allelic discrimination assay. We found that rs2285947 at 7p15.3 was significantly associated with risk of ovarian cancer with per allele odds ratio (OR) of 1.33 [95% confidence interval (CI): 1.08-1.64, P=0.008]. However, no significant association was observed between rs2494938 and ovarian cancer risk. Our results showed that rs2285947 at 7p15.3 may also contribute to the development of ovarian cancer in Han Chinese women, further suggesting pleiotropy of 7p15.3 in multiple cancers.

[Experimental study on inhibition of cervical carcinoma siha cell proliferation by siRNA expression vector].

OBJECTIVE: To observe the effect of HPV16E7 specific expression vector on cell proliferation in cervical carcinoma SiHa cells. METHODS: The HPV16E7 siRNA expression vector and empty expression vector were transfected into SiHa cells by liposome. The effects on E7 mRNA and E7 protein expression, cell cycle phase and cell growth rate were examined respectively by real-time RT-PCR, FCM and MTT assay. RESULTS: The HPV16E7 siRNA expression vector significantly inhibited the expression levels of E7 mRNA and E7 protein, the inhibition rates being 92.15% and 84.30% respectively. It also inhibited the transition from G, phase to S phase and the growth of SiHa cell line. CONCLUSION: HPV16E7 specific siRNA expression vector could specifically and efficiently inhibit the expression of E7 gene and hence it could regulate cell cycle and inhibit cell proliferation in cervical carcinoma SiHa cells. siRNA expression vector

[Inhibiting E7 oncogene in CaSki cells of cervical cancer by vector-based RNA interference technique].

OBJECTIVE: To test of the effect of vector-based RNA interference (RNAi) technique on inhibiting HPV16E7 gene in CaSki cells of cervical cancer. METHODS: The HPV16E7-specific siRNA expression vectors P1, P2 and P3 were constructed and transfected into CaSki cells by liposome. The expression of HPV16E7 mRNA and protein were detected by real-time RT-PCR and Western blot. RESULTS: The expression of HPV16E7 mRNA and protein decreased with the transfection of P1, P2 and P3. Vector P1 had the strongest inhibition effect, with an inhibition rates of 92.86% and 81.0% for the expression of HPV16E7 mRNA and protein respectively three weeks after transfection. CONCLUSION: The expression of E7 gene in CaSki cells can be inhibited by HPV16E7-specific siRNA expression vector.

[The inhibitory effects of siRNA expression vector on the expression of human papillomavirus E6 gene].

OBJECTIVE: To investigate the inhibitory effects of RNAi(RNA interference)expression vector on the expression of human papilomavirus E6 gene. METHODS: siRNA expression vectors were constructed to be aimed directly at HPV16 E6 gene. The recombinants were transfected into cervical cancer cell line, caski, with liposomes. Expression of E6 was detected with fluorescence quantitative PCR (FQ-PCR) and flow cytometry. RESULTS: Three kinds of expression vectors could reduce the expression of E6 mRNA and protein all in caski-B cell. The expression of E6 mRNA reduced to 21.7% of control group, and the protein inhibition ratio reached 98.1%. CONCLUSION: The RNAi expression vector can effectively inhibit the expression of HPVE6 gene.