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Placenta accreta spectrum disorder (PASD) is a life-threatening obstetric complication. China still lacks high-quality data on the epidemiology of PASD. We intend to examine the major risk factors for PASD, explore the association of PASD with severe adverse perinatal outcomes and describe the geographical variations in China.We used data from the China Labor and Delivery Survey, which included a total of 75,132 births from 96 hospitals in 24 provinces in China in 2015 and 2016. Each participating hospital randomly selected 6-10 weeks within a 12-month period. In the selected weeks, all births with gestational age ≥24 weeks or birth weight ≥500 g were included. We analyzed the demographic characteristics and prevalence of PASD in pregnant women. Multivariable logistic regression was used to examine the association of previous caesarean section (CS) and repeated surgical abortion with PASD. We explored the association of PASD with severe adverse perinatal outcomes, which indicated by Weighted Adverse Outcome Score (WAOS) ≥ 20. Multivariable logistic regression was used to examine the association of PASD with WAOS. We also calculated and compared the prevalence of PASD in different regions of China.The weighted prevalence of PASD was 2.20% (95% CI 0.76 to 4.95) in our population，and there was a substantial difference in the prevalence of PASD by geographic regions in China. Two or more previous CS (adjusted OR 2.34, 95%CI 1.41 to 3.88) and repeated surgical abortion (twice: 2.16, 1.20 to 3.92; 3 times: 4.31, 1.70 to 10.96; ≥4 times: 4.76, 3.12 to 7.26) were significant risk factors for PASD. PASD (adjusted OR 3.77, 95% CI 2.80 to 5.06) was a significant risk factor for severe adverse perinatal outcomes indicated by WAOS score.The prevalence of PASD in China appeared higher than that in other countries, and varied substantially by geographic regions. Two or more previous CS and repeated surgical abortion were major risk factors for PASD. Pregnant women with PASD had more severe adverse pregnancy outcomes. Reducing primary cesarean section and repeated surgical abortion are the key to decreasing PASD.

Expanded clones (>0.1%) percentage in tumor tissue and lymph node.

T lymphocytes infiltrate the microenvironment of breast cancer tumors and play a pivotal role in tumor immune surveillance. Relationships between the T-cell receptors (TCR) borne by T cells within tumors, in the surrounding tissues, and in draining lymph nodes are largely unexplored in human breast cancer. Consequently, information about the relative extent of possible T-cell exchange between these tissues is also lacking. Here, we have analyzed the TCR repertoire of T cells using multiplex PCR and high-throughput sequencing of the TCRβ chain in the tissues of tumor, adjacent nontumor, and axillary lymph nodes of breast cancer patients. T-cell repertoire diversity in tumors was lower than in lymph nodes, but higher than in nontumor tissue, with a preferential use of variable and joining genes. These data are consistent with the hypothesis that most of the T cells in tumors derive from the lymph node, followed by their expansion in tumor tissue. Positive nodes appeared to enhance T-cell infiltration into tumors and T-cell clonal expansion in lymph nodes. Additionally, the similarity in TCR repertoire between tumor and nontumor tissue was significantly higher in luminal-like, rather than basal-like, breast cancer. Our study elucidated the high heterogeneity of the TCR repertoire and provides potential for future improvements in immune-related diagnosis, therapy, and prognosis for breast cancer patients. Cancer Immunol Res; 5(2); 148–56. ©2016 AACR.

Supplementary Figure Legends. Table S1. The reproducibility of IHC scoring of infiltrated T cells. Table S2. The infiltration level of CD4+ and CD8+ T cells in tumors and non-tumors. Table S3. The clinical characteristics of 49 patients.

Runhui Wu,1 Jing Sun,2 Weiqun Xu,3 Qun Hu,4 Wenqian Li,5 Jianwen Xiao,6 Feng’e Yang,7 Xiaojing Zeng,8 Yun Zeng,9 Jianfeng Zhou,4 Irina Matytsina,10 Sali Zhang,11 Michael Pluta,12 Renchi Yang13 1Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, National Children’s Health Center, Beijing, People’s Republic of China; 2Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Hematology and Oncology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 4Department of Pediatric Hematology, Tongji Hospital, Tongji Medical College of HUST, Wuhan, People’s Republic of China; 5Department of Hematology and Rheumatology, Qinghai Provincial People’s Hospital, Xining, People’s Republic of China; 6Department of Hematology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 7Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 8Department of Blood Transfusion, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 9Department of Hematology, First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 10Biopharm Medical & Science, Novo Nordisk A/S, Søborg, Denmark; 11Biopharm Clinical, Medical and Regulatory Affairs, Novo Nordisk (China) Pharmaceuticals Co., Ltd, Beijing, People’s Republic of China; 12Statistical Consultancy, Quanticate Ltd, Hitchin, UK; 13Thrombosis and Haemostasis Centre, State Key Laboratory of Experimental Hematology, Tianjin Laboratory of Blood Disease Gene Therapy, CAMS Key Laboratory of Gene Therapy for Blood Diseases, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Renchi YangThrombosis and Haemostasis Centre, State Key Laboratory of Experimental Hematology, Tianjin Laboratory of Blood Disease Gene Therapy, CAMS Key Laboratory of Gene Therapy for Blood Diseases, National Clinical Research Center for Hematological Disorders Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaTel +86 13512078851Email rcyang65@163.comPurpose: Hemophilia care in China is characterized by widespread use of on-demand regimens and low-dose prophylaxis. With a limited number of approved recombinant factor VIII (FVIII) products, the incidence of arthropathy and disability in hemophilia patients remains high in China. The purpose of this trial was to evaluate the safety and efficacy of turoctocog alfa for prophylaxis and treatment of bleeding episodes in patients from China with severe hemophilia A across all age groups.Patients and Methods: In this Phase 3, open-label trial, previously treated males of all ages with severe hemophilia A from China received turoctocog alfa for prophylaxis or on-demand treatment of bleeds. The primary endpoint was hemostatic effect for the treatment of bleeds during the main phase of the trial. Secondary endpoints included annualized bleeding rate during prophylaxis and the frequency of FVIII inhibitor development.Results: Overall, 42 pediatric patients (age < 12 years) and 26 adolescent/adult patients (≥ 12 years) were dosed with turoctocog alfa; 51 patients initiated treatment with prophylaxis, while 17 patients initiated on-demand treatment. During the main phase of the trial (6 months), hemostatic success was 95.1%. During the full trial (up to 24 months), hemostatic success was 95.4%; the overall median ABR was 1.18 bleeds/patient/year for prophylaxis patients; and 25 (51.0%) of 49 patients with target joints at baseline had all target joints resolved. No FVIII inhibitors (≥ 0.6 BU) were reported.Conclusion: Turoctocog alfa was safe and effective for prophylaxis and treatment of bleeding episodes and for surgery in patients from China with severe hemophilia A across all ages.Keywords: hemophilia A, prophylaxis, recombinant factor VIII, turoctocog alfa, China

Inflammatory bowel disease (IBD)-related inflammation is closely associated with the initiation and progression of colorectal cancer. IBD is generally treated with 5-aminosalicylic acid and immune-modulating medication, but side effects and limitations of these therapies are emerging. Thus, the development of novel preventative or therapeutic approaches is imperative. Here, we constructed a dextran sodium sulphate (DSS)-induced IBD mouse model that was infected with monosexual Schistosoma japonicum cercariae (mSjci) at day 1 or administered dexamethasone (DXM) from days 3 to 5 as a positive control. The protective effect of mSjci on IBD mice was evaluated through their assessments of their clinical signs, histopathological lesions and intestinal permeability. To uncover the underlying mechanism, the Th1/Th2 balance and Treg cell population were also examined. Additionally, the alterations in the gut microbiota were assessed to investigate the interaction between the mSjci-modulated immune response and pathogenic microbiome. Mice treated with DSS and mSjci showed fewer IBD clinical signs and less impaired intestinal permeability than DSS-treated mice. Mechanistically, mSjci modulated the Th1/Th2 balance by repressing IFN-γ production, promoting IL-10 expression and enhancing the Treg subset population. Moreover, mSjci notably reshaped the structure, diversity and richness of the gut microbiota community and subsequently exerted immune-modulating effects. Our findings provide evidence showing that mSjci might serve as a novel and effective protective strategy and that the gut microbiota might be a new therapeutic target in IBD.

Congenital melanocytic nevus (CMN) represent a benign proliferative skin disease in the epidermis and dermis. CMN are historically known to be associated with activating NRAS or BRAF mutations. Melanoma frequently harbors the BRAF p.Val600Glu mutation, which is also commonly found in benign nevi. A recent study reported mutation of MAP2K1, a downstream effector of the RAS-RAF-MEK pathway, in melanoma with an overall frequency of 8%. Later, in 2019, Jansen P detected one activating MAP2K1 mutation in acral nevi. However, it is unknown whether MAP2K1 mutations are common in CMN, and how MAP2K1 contributes to the pathogenesis of CMN remains to be determined.In this study, we report one patient clinically and histologically diagnosed with CMN, with the MAP2K1 germline mutation and a BRAF p.Val600Glu somatic hit in the lesion. To the best of our knowledge, this is the first report of the coexistence of mutated BRAF and MAP2K1 in CMN, which may suggest that MAP2K1 mutations contribute to the occurrence and development of nevus expanding our knowledge of the genetics of CMN.

Capillary malformation-arteriovenous malformation syndrome (CM-AVM), a rare vascular malformation, is autosomal dominant and characterized by hereditary capillary malformations (CMs) and potential fast-flow vascular malformation underlying CMs in around one-third of patients, affecting approximately 0.3-0.5% of newborns. CM-AVM was first discovered in association with germline RASA-1 mutation and termed CM-AVM type 1 in 2003. Later, germline EPHB4 mutations were detected in RASA-1-negative CM-AVMs, also known as CM-AVM type 2. Although there have been recent genetic studies confirming the molecular basis of CM-AVM, few have focused on Asian populations, leading to the lack of comprehensive molecular profiling. In this study, we report a female patient diagnosed as CM-AVM2 with a novel stop-gain mutation causing loss of function of the EPHB4 gene. As far as we know, this is the first genetic report of germline EPHB4 loss-of-functional mutation related CM-AVM 2 in Asians, extending our understanding of CM-AVM.

As antimicrobial resistance continues to threaten the efficacy of conventional antibiotic therapy, it is paramount that we investigate innovative approaches to treat infectious diseases. In this study, we investigated the antimicrobial capabilities of the innovative combination of antimicrobial blue light (aBL; 405 nm wavelength) with the Pseudomonas aeruginosa pigment pyocyanin against methicillin resistant Staphylococcus aureus (MSRA. We explored the effects of different radiant exposures of aBL and increasing concentrations of pyocyanin against planktonic cells and those within biofilms. In addition, we investigated the effect of the aBL/pyocyanin on the endogenous staphyloxanthin pigment, as well as the role of hydrogen peroxide and singlet oxygen scavenging in the efficacy of this combination. Lastly, we investigated the potential for the aBL/pyocyanin to reduce the MRSA burden within a proof-of-principle mouse abrasion infection model. We found pyocyanin to be a powerful potentiator of aBL activity under all in vitro conditions tested. In addition, we serendipitously discovered the capability of the aBL/pyocyanin combination to bleach staphyloxanthin within colonies of MRSA. Furthermore, we established that singlet oxygen is an important mediator during combined aBL/pyocyanin exposure. Moreover, we found that the combination of aBL and pyocyanin could significantly reduce the viability of MRSA within a proof-of-principle early onset MRSA skin abrasion infection. Exposure to the treatment did not have deleterious effects on skin tissue. In conclusion, the combination of aBL and pyocyanin represents a potentially powerful therapeutic modality for the treatment of infections caused by MRSA.

Capillary malformation-arteriovenous malformations (CM-AVMs) caused by a RASA-1 or EPHB4 mutation are characterized as hereditary sporadic or multifocal capillary malformations (CMs), associated with potential fast-flow vascular anomalies underlying erythema lesions. Because of the similar phenotype, CM-AVMs should be considered in the differential diagnosis of isolated CMs as well as other disorders with an erythema phenotype, such as hereditary hemorrhagic telangiectasia (HHT).Herein, we report a male patient with facial erythema. Red lesions were located in the V1 region of his left face, the V2 and V3 regions on his right side, and the nasal back. The patient was initially thought to have PWSs because of the unilateral and segmental distribution of his red facial lesions. In contrast to a previous diagnosis, we diagnosed the child with capillary malformation-arteriovenous malformation type 2 (CM-AVM2) based on a family history of erythema, the results of physical examination and ultrasound raising potential fast-flow lesions, and a genetic study revealing a germline EPHB4 mutation. This study emphasizes the importance of differential diagnosis for PWS and CM-AVM. A single clinical diagnosis can be limited, and molecular diagnosis is recommended to provide more information for the evaluation of the potential risk of fast-flow lesions underlying erythema lesions if necessary.

Background Neonatal alloimmune thrombocytopenia (NAIT), caused by maternal antibodies raised against alloantigens carried on foetal platelets, is a very common haematological abnormality in newborns worldwide. However, baseline data on NAIT in China are lacking. Therefore, this study seeks to explore the incidence of alloantibody against the human platelet antigen (HPA) in pregnant women and its associations with NAIT in China. Methods A multicentre, prospective cohort study design will be used, and 55,497 pregnant women will be recruited for the first screening of the anti-HPA antibody at 12 to 28 weeks of gestational age. Subjects who are positive in the first screening for the anti-HPA antibody will be included in the exposure group. Re-tests of the antibody titre, antigen-specificity and genotyping of HPA and HLA will be conducted during admission. A ratio of 1:1 paired individuals with the same ethnicity and parity but testing negative for the anti-HPA antibody will be randomly selected to be included in the non-exposure group. NAIT will be diagnosed in the newborns on day one of the birth. The HPA of the neonates in the exposure group will also be genotyped by sequencing. Associations of maternal HLA with the occurrence of the anti-HPA antibody and correlation of the severity of NAIT with the titre of the anti-HPA antibody will be further analysed. Discussion The study is expected to provide baseline data on NAIT in China. Besides, we hope to find out a population who expresses particular HLA molecules has significant higher risk of HPA alloimmunization in Chinese individuals. We also hope to find a Chinese-specific cut-off antibody titre for the prediction of the severity of NAIT and to provide a means to evaluate the necessity of antenatal treatment. Trial registration ClinicalTrials.gov: NCT02934906 (date registered: 13.10.2016).

Objective: Progestin was recently used as an alternative of gonadotropin-releasing hormone (GnRH) analog for preventing premature luteinizing hormone (LH) surge with the aid of vitrification techniques, however, limited data were available about the potential of progestin in poor responders undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. We performed a randomized parallel controlled trial to investigate the difference of progestin and GnRH antagonist in poor responders.Methods: A total of 340 poor responders who met with Bologna criteria were randomly allocated into the progestin-primed ovarian stimulation (PPOS) group and GnRH antagonist group. Fresh embryo transfer was preferred in the GnRH antagonist group and freeze-all was performed in the PPOS group. The primary outcome was the incidence of premature LH surge, secondary outcomes were the number of retrieved oocytes, the number of viable embryos and the pregnancy outcomes.Results: The results showed that the incidence of premature LH surge in PPOS group was lower than that in antagonist group (0 vs. 5.88%, P < 0.05). In PPOS group, the average numbers of oocytes and viable embryos were comparable to those in GnRH antagonist group (3.7 ± 2.6 vs. 3.4 ± 2.4; 1.6 ± 1.7 vs. 1.4 ± 1.3, P > 0.05), the live birth rate was similar between the two groups (21.8 vs. 18.2%, RR 1.25 (95% confidence interval 0.73, 2.13), P > 0.05).Conclusions: The study demonstrated that PPOS had a more robust control for preventing premature LH rise than GnRH antagonist in poor responders, but PPOS in combination with freeze-all did not significantly increase the probability of pregnancy than GnRH antagonist protocol for poor responders.

Multifunctionalization of porous organic polymers (POPs) for working in concert on a substrate is now a research topic in CO2 catalysis, yet it remains challenging. This work describes a pre- and post-synthetic strategy to design metalloporphyrin-based azo-hierarchical porous ionic polymers (ZnTPP/QA-azo-PiPs), which were synthesized based on diazo-coupling reaction of tetra(4-aminophenyl) porphyrin zinc with tri/diphenols in aqueous solution under mild conditions, followed by etherification with quaternary ammonium bromide. This synthetic approach endows ZnTPP/QA-azo-PiP1 with features of an improved surface area (181 m2/g), hierarchical porosity, and high-density active sites. ZnTPP/QA-azo-PiP1 presented a noteworthy CO2 uptake of 1.77 mmol/g at 273 K and 1.0 bar and good CO2/N2 selectivity of 44.8. As expected, ZnTPP/QA-azo-PiP1 showed quantitative conversion and selectivity for a range of epoxides under mild conditions (1.0 MPa, 80 °C, 12 h) in the CO2 cycloaddition reaction. ZnTPP/QA-azo-PiP1 could been recycled easily and retained complete retention of activity and selectivity for over 7 cycles. Moreover, with efficacious activity in conversion of diluted CO2 (15% CO2 in 85% N2, v/v), ZnTPP/QA-azo-PiP1 could smoothly catalyze CO2-involved reaction to produce oxazolidinones and N-formylated amines under mild conditions. This work promotes sustainable synthesis of advanced multifunctional POPs and gives great promise for their application in synthetic transformations of CO2.

The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor-infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC.

Acute B lymphoblastic leukemia (B-ALL) is one of the most common types of childhood cancer worldwide and chemotherapy is the main treatment approach. Despite good response rates to chemotherapy regiments, many patients eventually relapse and minimal residual disease (MRD) is the leading risk factor for relapse. The evolution of leukemic clones during disease development and treatment may have clinical significance. In this study, we performed immunoglobulin heavy chain (IGH) repertoire high throughput sequencing (HTS) on the diagnostic and post-treatment samples of 51 pediatric B-ALL patients. We identified leukemic IGH clones in 92.2% of the diagnostic samples and nearly half of the patients were polyclonal. About one-third of the leukemic clones have correct open reading frame in the complementarity determining region 3 (CDR3) of IGH, which demonstrates that the leukemic B cells were in the early developmental stage. We also demonstrated the higher sensitivity of HTS in MRD detection and investigated the clinical value of using peripheral blood in MRD detection and monitoring the clonal IGH evolution. In addition, we found leukemic clones were extensively undergoing continuous clonal IGH evolution by variable gene replacement. Dynamic frequency change and newly emerged evolved IGH clones were identified upon the pressure of chemotherapy. In summary, we confirmed the high sensitivity and universal applicability of HTS in MRD detection. We also reported the ubiquitous evolved IGH clones in B-ALL samples and their response to chemotherapy during treatment.

T lymphocytes infiltrate the microenvironment of breast cancer tumors and play a pivotal role in tumor immune surveillance. Relationships between the T-cell receptors (TCR) borne by T cells within tumors, in the surrounding tissues, and in draining lymph nodes are largely unexplored in human breast cancer. Consequently, information about the relative extent of possible T-cell exchange between these tissues is also lacking. Here, we have analyzed the TCR repertoire of T cells using multiplex PCR and high-throughput sequencing of the TCRβ chain in the tissues of tumor, adjacent nontumor, and axillary lymph nodes of breast cancer patients. T-cell repertoire diversity in tumors was lower than in lymph nodes, but higher than in nontumor tissue, with a preferential use of variable and joining genes. These data are consistent with the hypothesis that most of the T cells in tumors derive from the lymph node, followed by their expansion in tumor tissue. Positive nodes appeared to enhance T-cell infiltration into tumors and T-cell clonal expansion in lymph nodes. Additionally, the similarity in TCR repertoire between tumor and nontumor tissue was significantly higher in luminal-like, rather than basal-like, breast cancer. Our study elucidated the high heterogeneity of the TCR repertoire and provides potential for future improvements in immune-related diagnosis, therapy, and prognosis for breast cancer patients. Cancer Immunol Res; 5(2); 148–56. ©2016 AACR.

Y-chromosomal microdeletion (YCM) serves as an important genetic factor in non-obstructive azoospermia (NOA). Multiplex polymerase chain reaction (PCR) is routinely used to detect YCMs by tracing sequence-tagged sites (STSs) in the Y chromosome. Here we introduce a novel methodology in which we sequence 1,787 (post-filtering) STSs distributed across the entire male-specific Y chromosome (MSY) in parallel to uncover known and novel YCMs. We validated this approach with 766 Chinese men with NOA and 683 ethnically matched healthy individuals and detected 481 and 98 STSs that were deleted in the NOA and control group, representing a substantial portion of novel YCMs which significantly influenced the functions of spermatogenic genes. The NOA patients tended to carry more and rarer deletions that were enriched in nearby intragenic regions. Haplogroup O2* was revealed to be a protective lineage for NOA, in which the enrichment of b1/b3 deletion in haplogroup C was also observed. In summary, our work provides a new high-resolution portrait of deletions in the Y chromosome.

High-throughput sequencing has recently been applied to profile the high diversity of antibodyome/B cell receptors (BCRs) and T cell receptors (TCRs) among immune cells. To date, Multiplex PCR (MPCR) and 5′RACE are predominately used to enrich rearranged BCRs and TCRs. Both approaches have advantages and disadvantages; however, a systematic evaluation and direct comparison of them would benefit researchers in the selection of the most suitable method. In this study, we used both pooled control plasmids and spiked-in cells to benchmark the MPCR bias. RNA from three healthy donors was subsequently processed with the two methods to perform a comparative evaluation of the TCR β chain sequences. Both approaches demonstrated high reproducibility (R2 = 0.9958 and 0.9878, respectively). No differences in gene usage were identified for most V/J genes (>60%), and an average of 52.03% of the CDR3 amino acid sequences overlapped. MPCR exhibited a certain degree of bias, in which the usage of several genes deviated from 5′RACE, and some V-J pairings were lost. In contrast, there was a smaller rate of effective data from 5′RACE (11.25% less compared with MPCR). Nevertheless, the methodological variability was smaller compared with the biological variability. Through direct comparison, these findings provide novel insights into the two experimental methods, which will prove to be valuable in immune repertoire research and its interpretation.