Advanced therapy medicinal products in China: Regulation and development.

Advanced therapy medicinal products (ATMPs) have shown dramatic efficacy in addressing serious diseases over the past decade. With the acceleration and deepening of China's drug regulatory reforms, the country sees a continuous introduction of policies that encourage drug innovation. The capacity and efficiency of the Center for Drug Evaluation (CDE), National Medical Products Administration have significantly improved, where substantial resources have been allocated to ATMPs with major innovations and outstanding clinical values that satisfy urgent clinical needs. These changes have greatly stimulated the research and development of biological products in China, ushering in a period of explosive growth in the number of investigational new drug (IND) applications of ATMPs. Here, we described China's ATMP regulatory framework and analyzed data on IND applications for ATMPs submitted to CDE. The data show that China's ATMP industry is expanding dramatically, but lagging behind in terms of the innovative targets and the coverage of indications. However, in recent years, the diversity of product types, targets, and indications is growing. We discussed challenges and opportunities in ATMP regulation. Risk-based regulation and cross-discipline collaborations are encouraged to promote more ATMPs toward market authorization in China.

EPT-Net: Edge Perception Transformer for 3D Medical Image Segmentation.

The convolutional neural network has achieved remarkable results in most medical image seg- mentation applications. However, the intrinsic locality of convolution operation has limitations in modeling the long-range dependency. Although the Transformer designed for sequence-to-sequence global prediction was born to solve this problem, it may lead to limited positioning capability due to insufficient low-level detail features. Moreover, low-level features have rich fine-grained information, which greatly impacts edge segmentation decisions of different organs. However, a simple CNN module is difficult to capture the edge information in fine-grained features, and the computational power and memory consumed in processing high-resolution 3D features are costly. This paper proposes an encoder-decoder network that effectively combines edge perception and Transformer structure to segment medical images accurately, called EPT-Net. Under this framework, this paper proposes a Dual Position Transformer to enhance the 3D spatial positioning ability effectively. In addition, as low-level features contain detailed information, we conduct an Edge Weight Guidance module to extract edge information by minimizing the edge information function without adding network parameters. Furthermore, we verified the effectiveness of the proposed method on three datasets, including SegTHOR 2019, Multi-Atlas Labeling Beyond the Cranial Vault and the re-labeled KiTS19 dataset called KiTS19-M by us. The experimental results show that EPT-Net has significantly improved compared with the state-of-the-art medical image segmentation method.

DHT-Net: Dynamic Hierarchical Transformer Network for Liver and Tumor Segmentation.

Automatic segmentation of liver tumors is crucial to assist radiologists in clinical diagnosis. While various deep learningbased algorithms have been proposed, such as U-Net and its variants, the inability to explicitly model long-range dependencies in CNN limits the extraction of complex tumor features. Some researchers have applied Transformer-based 3D networks to analyze medical images. However, the previous methods focus on modeling the local information (eg. edge) or global information (eg. morphology) with fixed network weights. To learn and extract complex tumor features of varied tumor size, location, and morphology for more accurate segmentation, we propose a Dynamic Hierarchical Transformer Network, named DHT-Net. The DHT-Net mainly contains a Dynamic Hierarchical Transformer (DHTrans) structure and an Edge Aggregation Block (EAB). The DHTrans first automatically senses the tumor location by Dynamic Adaptive Convolution, which employs hierarchical operations with the different receptive field sizes to learn the features of various tumors, thus enhancing the semantic representation ability of tumor features. Then, to adequately capture the irregular morphological features in the tumor region, DHTrans aggregates global and local texture information in a complementary manner. In addition, we introduce the EAB to extract detailed edge features in the shallow fine-grained details of the network, which provides sharp boundaries of liver and tumor regions. We evaluate DHT-Net on two challenging public datasets, LiTS and 3DIRCADb. The proposed method has shown superior liver and tumor segmentation performance compared to several state-of-the-art 2D, 3D, and 2.5D hybrid models.

Plasmonic CuxS Nanocages for Enhanced Solar Photothermal Cell Warming.

Highly efficient plasmonic photothermal nanomaterials are benefitial to the successful resuscitation of cells. Copper sulfide (CuxS) is a type of plasmonic solar photothermal semiconductor material that expands the light collecting range by altering its localized surface plasmonic resonance (LSPR) to the near- to mid-infrared (IR) spectral region. Particularly, nanocages (or nanoshells) have hybridized plasmon resonances as the result of superpositioned nanospheres and nanocavities, which extend their receiving range for the solar spectrum and increase light-to-heat conversion rate. In this work, for the first time, we applied colloidal hollow CuxS nanocages to revive cryopreserved HeLa cells via photothermal warming, which showed improved cell warming rate and cell viability after cell resuscitation. Moreover, we tested the photothermal performance of CuxS nanocages with concentrated light illumination, which exhibited extraordinary photothermal performance due to localized and enhanced illumination. We further quantified each band's contribution during the cell warming process via evaluating the warming rate of cryopreserved cell solution with illumination by monochromatic UV, visible, and NIR lasers. We studied the biosafety and toxicity of CuxS nanocages by analyzing the generated copper ion residue during cell warming and cell incubation, respectively. Our study shows that CuxS nanocages have huge potential for cell warming and are promising for vast range of applications, such as nanomedicine, life science, biology, energy saving, etc.

3D-printed smartphone-based device for fluorimetric diagnosis of ketosis by acetone-responsive dye marker and red emissive carbon dots.

A portable smartphone device is reported that uses 3D printing technology for the primary diagnosis of diseases by detecting acetone. The key part of the device consists of red carbon dots (RCDs), which are used as internal standards, and a sensing reagent (3-N,N-(diacethydrazide)-9-ethylcarbazole (2-HCA)) for acetone. With an excitation wavelength of 360 nm, the emission wavelengths of 2-HCA and RCDs are 443 nm and 619 nm, respectively. 2-HCA effectively captures acetone to form a nonfluorescent acylhydrazone via a condensation reaction occurring in aqueous solution, resulting in obvious color changes from blue-violet to dark red. The detection limit for acetone is 2.62 µM (~ 0.24 ppm). This is far lower than the ketone content in normal human blood (≤ 0.50 mM) and the acetone content in human respiratory gas (≤ 1.80 ppm). The device has good recovery rates for acetone detection in blood and exhaled breath, which are 90.56-109.98% (RSD ≤ 5.48) and 92.80-108.00% (RSD ≤ 5.07), respectively. The method designed here provides a reliable way to provide health warnings by visually detecting markers of ketosis/diabetes in blood or exhaled breath. The portable smart phone device visually detects ketosis/diabetes markers in the blood or exhaled breath through the nucleophilic addition reaction, which effectively captures acetone to form nonfluorescent acyl groups. This will be a reliable tool to warn human health.

Development and evaluation considerations of viral vector production for CAR-T cell products / 中国肿瘤生物治疗杂志

@#Due to the spectacular therapy results in hematologic tumors, chimeric antigen receptor T (CAR-T) cell therapy has been the research hot-spot in the field of cell-immunotherapy. Viral vectors, as the critical raw material in CAR-T cell manufacturing, are closely related to the safety, efficacy and quality control of CAR-T cell products, in the aspects of the structure design of CAR gene, refinement of production process, quality control and setting of characterization and specification etc. Based on the research progress in lentiviral and γ-retroviral vectors development and the evaluation experiences, this paper discusses some common problems that need to be focused on in the preparation of viral vectors, expecting to provide references for the development and the authorization applications of domestic related products in the future.

Rnf138 deficiency promotes apoptosis of spermatogonia in juvenile male mice.

Spermatogenesis, the process by which haploid sperm cells are produced from a diploid precursor cell, is essential for sexual reproduction. Here, we report that RING-finger protein 138 (Rnf138) is highly expressed in testes, especially in spermatogonia and spermatocytes. The role of Rnf138 in spermatogenesis was examined using a Rnf138-knockout mouse model. Rnf138 deficiency resulted in increased apoptosis in spermatogenic cells, loss of proliferative spermatogonia, delayed development of spermatozoa and impaired fertility. The proportion of PLZF+Ki67+ cells within the PLZF+ population decreased in the knockout mice. The phenotype was further assessed by RNA-sequencing (RNA-seq), which determined that the expression levels of many genes involved in spermatogenesis were altered in the testis of Rnf138-knockout mice. Thus, Rnf138 deficiency promotes the apoptosis of spermatogenic cells, which may have been caused by the aberrant proliferation of spermatogonia in mouse testis development.

Ubiquitylation of Rad51d Mediated by E3 Ligase Rnf138 Promotes the Homologous Recombination Repair Pathway.

Ubiquitylation has an important role as a signal transducer that regulates protein function, subcellular localization, or stability during the DNA damage response. In this study, we show that Ring domain E3 ubiquitin ligases RNF138 is recruited to DNA damage site quickly. And the recruitment is mediated through its Zinc finger domains. We further confirm that RNF138 is phosphorylated by ATM at Ser124. However, the phosphorylation was dispensable for recruitment to the DNA damage site. Our findings also indicate that RAD51 assembly at DSB sites following irradiation is dramatically affected in RNF138-deficient cells. Hence, RNF138 is likely involved in regulating homologous recombination repair pathway. Consistently, efficiency of homologous recombination decreased observably in RNF138-depleted cells. In addition, RNF138-deficient cell is hypersensitive to DNA damage insults, such as IR and MMS. And the comet assay confirmed that RNF138 directly participated in DNA damage repair. Moreover, we find that RAD51D directly interacted with RNF138. And the recruitment of RAD51D to DNA damage site is delayed and unstable in RNF138-depleted cells. Taken together, these results suggest that RNF138 promotes the homologous recombination repair pathway.

Effect of improving the knowledge, attitude and practice of reproductive health among female migrant workers: a worksite-based intervention in Guangzhou, China.

UNLABELLED: Background The sexual and reproductive health (SRH) knowledge and attitudes of female migrant workers are far from optimum in China. A worksite-based intervention program on SRH-related knowledge, attitude and practice (SRH KAP) modification may be an effective approach to improve the SRH status among migrant workers. This study aimed to identify better intervention approaches via the implementation and evaluation of two intervention packages. METHODS: A worksite-based cluster-randomised intervention study was conducted from June to December 2008 in eight factories in Guangzhou, China. There were 1346 female migrant workers who participated in this study. Factories were randomly allocated to the standard package of interventions group (SPIG) or the intensive package of interventions group (IPIG). Questionnaires were administered to evaluate the effect of two interventions. RESULTS: SRH knowledge scores were higher at follow up than at baseline for all participants of the SPIG; the knowledge scores increased from 6.50 (standard deviation (s.d.) 3.673) to 8.69 (s.d. 4.085), and from 5.98 (s.d. 3.581) to 11.14 (s.d. 3.855) for IPIG; SRH attitude scores increased among unmarried women: the attitude scores changed from 4.25 (s.d. 1.577) to 4.46 (s.d. 1.455) for SPIG, and from 3.99 (s.d. 1.620) to 4.64 (s.d. 1.690) for IPIG; most SRH-related practice was also modified (P<0.05). In addition, after intervention, the IPIG had a higher knowledge level than the SPIG; the scores were 11.14 (s.d. 3.855) versus 8.69 (s.d. 4.085), and unmarried women in the IPIG had higher condom use rate than the SPIG (86.4% versus 57.1%). CONCLUSIONS: The interventions had positive influences on improvements in SRH knowledge, attitudes and behaviours. Additionally, IPIs were more effective than SPIs, indicating that a comprehensive intervention may achieve better results.

Small kinetochore associated protein (SKAP) promotes UV-induced cell apoptosis through negatively regulating pre-mRNA processing factor 19 (Prp19).

Apoptosis is a regulated cellular suicide program that is critical for the development and maintenance of healthy tissues. Previous studies have shown that small kinetochore associated protein (SKAP) cooperates with kinetochore and mitotic spindle proteins to regulate mitosis. However, the role of SKAP in apoptosis has not been investigated. We have identified a new interaction involving SKAP, and we propose a mechanism through which SKAP regulates cell apoptosis. Our experiments demonstrate that both overexpression and knockdown of SKAP sensitize cells to UV-induced apoptosis. Further study has revealed that SKAP interacts with Pre-mRNA processing Factor 19 (Prp19). We find that UV-induced apoptosis can be inhibited by ectopic expression of Prp19, whereas silencing Prp19 has the opposite effect. Additionally, SKAP negatively regulates the protein levels of Prp19, whereas Prp19 does not alter SKAP expression. Finally, rescue experiments demonstrate that the pro-apoptotic role of SKAP is executed through Prp19. Taken together, these findings suggest that SKAP promotes UV-induced cell apoptosis by negatively regulating the anti-apoptotic protein Prp19.

The prevalence and molecular spectrum of α- and ß-globin gene mutations in 14,332 families of Guangdong Province, China.

OBJECTIVE: To reveal the familial prevalence and molecular variation of α- and ß-globin gene mutations in Guangdong Province. METHODS: A total of 40,808 blood samples from 14,332 families were obtained and analyzed for both hematological and molecular parameters. RESULTS: A high prevalence of α- and ß-globin gene mutations was found. Overall, 17.70% of pregnant women, 15.94% of their husbands, 16.03% of neonates, and 16.83% of couples (pregnant women and their husbands) were heterozygous carriers of α- or ß-thalassemia. The regions with the highest prevalence were the mountainous and western regions, followed by the Pearl River Delta; the region with the lowest prevalence was Chaoshan. The total familial carrier rate (both spouses were α- or ß-thalassemia carriers) was 1.87%, and the individual carrier rates of α- and ß-thalassemia were 1.68% and 0.20%, respectively. The total rate of moderate-to-severe fetal thalassemia was 12.78% among couples in which both parents were carriers. CONCLUSIONS: There was a high prevalence of α- and ß-thalassemia in Guangdong Province. This study will contribute to the development of thalassemia prevention and control strategies in Guangdong Province.

Effectiveness of a prevention of mother-to-child HIV transmission program in Guangdong province from 2007 to 2010.

BACKGROUND: To achieve the goal of United Nations of elimination of new HIV infections, a program of prevention of mother-to-child transmission (PMTCT) was launched in Guangdong province. The objective of this study is to evaluate the effectiveness of the PMTCT program. METHODS: The retrospective cross-section analysis was conducted using the data of case reported cards of HIV positive mothers and their infants from 2007 to 2010 in Guangdong province, and 108 pairs of eligible subjects were obtained. We described the data and compared the rates of MTCT by various PMTCT interventions respectively. RESULTS: The overall rate of HIV MTCT was 13.89% (15) among 108 pairs of HIV positive mothers and their infants; 60.19% (65) of the mothers ever received ARVs, 80.56% (87) of infants born to HIV positive mothers ever received ARVs, but 16.67% (18) of the mothers and infants neither received ARVs. Among all the mothers and infants, who both received ARVs, received triple ARVs, mother received ARVs during pregnancy, and both received ARVs and formula feeding showed the lower rates of HIV MTCT, and the rates were 8.06%, 2.50%, 5.77%, and 6.67% respectively. In infants born to HIV positive mother, who received mixed feeding had a higher HIV MTCT up to 60.00%. Delivery mode might not relative to HIV MTCT. CONCLUSIONS: The interventions of PMTCT program in Guangdong could effectively reduce the rate of HIV MTCT, but the effectiveness of the PMTCT program were heavily cut down by the lower availability of the PMTCT interventions.

Sexual and reproductive health status and related knowledge among female migrant workers in Guangzhou, China: a cross-sectional survey.

OBJECTIVE: The objective of this study was to investigate the current sexual and reproductive health (SRH) status including SRH-related knowledge and associated factors, self-reported symptoms of reproductive tract infection (RTI), medical assistance seeking behavior, sexual experience and contraceptive use, reproductive information approach and reproductive service utilization among female migrant workers in Huangpu district, Guangzhou city, China. STUDY DESIGN: A cross-sectional study was conducted in 2008 in eight factories, which were selected randomly from 32 eligible factories in the Huangpu district in Guangzhou. Descriptive statistics were used to describe the SRH status of migrant workers. Factors associated with the level of SRH knowledge were determined by a logistic regression model. RESULTS: Of 1346 female migrant workers, 831(61.7%) were unmarried and 515 (38.3%) were married. 27.2% of the unmarried respondents and 40.2% of the married respondents had suffered self-reported RTI symptoms. Among unmarried respondents, the median knowledge score was 5 points, compared to 8 points for the married. For unmarried migrant workers, factors associated with the knowledge level were age, education level, access to SRH information and service, sexual experiences and RTI symptoms. For married migrant workers, factors associated with the knowledge level were age, education level, access to SRH services and RTI symptoms. CONCLUSIONS: A high prevalence of self-reported RTI symptoms and a low knowledge level were found among young female migrant workers. Unmarried migrant workers are more vulnerable to SRH problems. Those findings demand more specific interventions targeting female migrants and in particular the unmarried.