[An exploratory clinical study of the efficacy and safety of tumor-infiltrating lymphocytes in the treatment of metastatic osteosarcoma].

Objective: To explore the safety and efficacy of tumor-infiltrating lymphocytes (TILs) extracted from tumor tissue in patients with pulmonary metastasis of osteosarcoma, the TILs were amplified in vitro to reach clinical dosage and reinfused to the patients combined with high-dose interleukin 2 (IL-2). Methods: Twelve subjects with pathologically diagnosed osteosarcoma were enrolled from December 2019 to June 20, 2021 in Shanghai General Hospital. All subjects progressed with metastasis after standard chemotherapy and failed multiple lines of treatments. Fresh tumor tissue was obtained from the metastatic site and extracted and amplified by Good Manufacturing Practice (GMP) workshop to produce TILs to clinical treatment dosage (109-1011). High-dose IL-2 (100 000-200 000 U/kg) was administered immediately after autogenous TILs infusion to promote the activation, proliferation and antitumor cytolytic activity in vivo. Adverse events (AE) were graded according to Common Terminology Criteria for Adverse Events (CTCAE) standard and tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results: One patient did not receive treatment due to failure in isolating TILs, total of 11 patients received a single re-infusion of autologous TILs. There were 10 males and 1 female with a median age of 19.9 years (12-33 years). Six of these patients received higher dose levels of 1.0×1010 TILs. The 11 patients were followed-up for 1 to 13 months and tolerated well. The most common adverse events reported were fever (10/11), constipation (3/11) and elevated gamma-glutamyl transferase (GGT) (3/11). The high incidence of fever was due to the IL-2 infusion. All patients experienced a transient drop in lymphocyte count and leukopenia leading to non-myeloid ablative lymphocyte clearance. The AE included grade 4 hematologic toxicity, including 8 cases of lymphocytopenia, 2 cases of neutropenia and 1 case of thrombocytopenia. No AE of neurotoxicity occurred. Of all the 11 patients, 9 patients got stable disease (SD) and 2 patients had progressive disease (PD). The disease control rate was 9/11. The median duration of SD was more than 4 months, and the maximum tumor volume decreased by close to 20%. Patient number 9 had sustained SD status for more than 6 months. Conclusions: TILs with in vitro expansion ability could be isolated from tumor tissues of advanced osteosarcoma patients. TILs amplified and reinfused in vitro have anti-osteosarcoma activity.

[Analysis on disease burden of stroke in China and the regions with different sociodemographic index from 1990 to 2017].

Objective: To examine the trend of stroke disease burden and its main risk-attributable factors in China and regions with different Socio-Demographic Index (SDI) from 1990 to 2017. Methods: With 2017 Global Burden of Disease (GBD) data, years lived with disability (YLDs), years of life lost (YLLs) and disability-adjusted of life years (DALYs) were applied to describe the disease burden and major risk factors of stroke in China and different SDI regions from 1990 to 2017, and to analyze the changing trend of the disease burden and major risk factors of stroke. Results: From 1990 to 2017, the YLD crude rate, YLL crude rate and DALY crude rate for stroke in China showed an increasing trend and the rate of change was 126.5%, 14.6%, and 24.4%, respectively. In 2017, the YLD crude rate, YLL crude rate and DALY crude rate for stroke in China were 502.6 per 100 000, 2 633.1 per 100 000 and 3 135.7 per 100 000, respectively. Among them, the YLD crude rate, YLL crude rate, and DALY crude rate of stroke were the highest in the ≥70 age group, which were 2 617.2 per 100 000, 16 789.4 per 100 000 and 19 406.6 per 100 000, respectively. The YLD crude rate in male was 475.5 per 100 000, which was slightly lower than that of female (530.9 per 100 000), while the DALY crude rate and YLL crude rate for stroke were 3 657.1 per 100 000 and 3 181.7 per 100 000, respectively, which were significantly higher than that of female (2 591.8 per 100 000 and 2 060.9 per 100 000). Compared with regions with different SDI, the age standardized YLD rate, the age standardized YLL rate, the age standardized DALY rate in China were all at a high level. Among them, the age-standardized YLD rate increased from 286.2 per 100 000 to 374.5 per 100 000, with a rate of change of 30.9%; the age-standardized YLL rate decreased from 3 215.6 per 100 000 to 1 967.8 per 100 000, with a rate of change of -38.8%; the age-standardized DALY rate increased from 3 501.8 per 100 000 to 2 342.3 per 100 000, with a rate of change of -33.1%. The top five risk factors for stroke in China were hypertension, excessive sodium intake, insufficient fruit intake, insufficient cereal intake, and smoking in 1990 and 2017. High Body-Mass Index and Alcohol Use's rankings rose from the 9th and 10th in 1990 to the 6th and 7th in 2017, respectively. Conclusion: The burden of stroke disease in China is at a high level, and hypertension is the primary risk factor.

Bending effect on the Majorana bound states in planar Josephson junctions.

We consider the bending effect on the formation of Majorana bound states (MBSs) in planar Josephson junctions where the normal stripe is tilted in a V shape. Our results show that the MBSs remain robust for moderate bending angles. Beyond some critical angles, the degradation of MBSs can be revealed by its eigenspectrum as well as the Majorana polarization (MP). Our results show that the parameter space of bending angle for robust MBSs can be significantly enlarged by tuning the superconducting phase difference across the Josephson junction. These findings suggest that the interplay of the junction geometry and the device parameters provides richer degree of freedom in designing topological superconducting devices for future applications. The MP analysis is an indispensable tool for characterizing the Majorana states.

Theoretical investigation of the scanning tunneling microscopy of Majorana bound states in topological superconductor vortices.

Scanning tunneling microscopy (STM) is an indispensable tool in detecting Majorana bound states (MBSs) in vortices of topological superconductors. By reducing the computational complexity via non-uniform grids, we systematically study the tunnel coupling as well as the temperature dependence of the differential conductance of MBSs in two dimensional devices. Numerical results show that the conductance peak approaches the quantized value 2e 2/h in strong coupling limit at low temperatures which are characteristic features of MBSs. More interestingly, a conductance local minimum in the spatially scanning is observed when the STM tip is placed at the vortex center. The dip structure can be enhanced with increased temperature or enlarged vortex size. We ascribe this observation to the sensitivity of the Andreev reflection processes of carriers at the vortex center where the thermal energy could be comparable to the vanishing pair potential. We also investigate the STM of two-vortex systems where the hybridization of the vortices can lead to oscillatory behavior of the state energy. With small inter-vortex distances, the original MBSs in vortices can merge into topologically trivial states and the conductance peak can be significantly suppressed.

[Trends of burden on ischemic heart disease and epidemiological transition of related risk factors in China, 1990-2017].

Objective: To examine the trend of burden on ischemic heart disease (IHD) and epidemiological transition on related risk factors among the Chinese population from 1990 to 2017. Methods: Based on open access data from the Global Burden of Disease (GBD) 2017 Study, we used years of life lost (YLD), years lived with disability (YLL), and disability-adjusted of life years (DALY) to describe the changes of IHD burden stratified by different sex and age groups from 1990 to 2017. We applied population-attributable faction (PAF) to analyze the burden attributable to risk factors and epidemiological transition. Results: In 2017, rates on YLD, YLL, and DALY for IHD were 74.2/100 000, 2 459.6/100 000, and 2 523.1/100 000, respectively. DALY rate and YLL rate for IHD in males were invariably higher than those in females except for YLD rate in females. 24 modifiable risk factors were causally associated with IHD. The top five risk factors that influencing DALYs, PAF, and DALY rate in 2017 appeared as: high blood pressure (16.429 million person years, 54.6%, 1 163.1/100 000), high LDL cholesterol (13 941 million person years, 46.3%, 987.0/100 000), diet high in sodium (10.900 million person years, 36.2%, 771.1/100 000), smoking (8.647 million person years, 28.7%, 612.2/100 000), and low-nut diet (7.452 million person years, 24.8%, 527.6/100 000). DALY rate for IHD showed an increase of 90.9%, from 1 116.4/100 000 in 1990 to 2 131.0/100 000 in 2017. Compared with 1990, the YLD rate experienced an evident increase in those aged 15-49 and over 70, in 2017. Annual average growth rate of YLD rate was higher in the ≥70 age group, between 2007 and 2017 (0.4%) than that between 1990 and 2007 (0.2%). The annual average increasing rates of both YLL and DALY were much lower from 2007 to 2017 (0.6%, 0.6%) than those from 1990 to 2007 (1.3%, 1.2%). From 1990 to 2017, DALYs attributed to meaty food (929.7%), beverages with high sugar content (822.7%), and high body-mass index (327.3%) experienced the highest increase. The largest increase in PAF occurred for beverages with high sugar content (400.0%). DALY rates increased for the 8 risk factors whereas decreased on the 7 risk factors, in consecutive rankings between 2007 and 2017. Conclusions: Despite the fact that burden on IHD-caused premature death had been reducing, related disabilities remain challenging with IHD the leading cause of burden, particularly in the ≥70 year-olds. Higher IHD burden from premature death was seen in males but disability appeared higher in females. It is significantly important to strengthen programs on prevention and control for hypertension including reducing modifiable risk factors such as smoking, unreasonable diet habits.

[Cohort studies on the association between maternal smoking during pregnancy and autism spectrum disorders of children: a Meta-analysis].

Objective: To examine the association between maternal smoking during pregnancy and autism spectrum disorders (ASD) of children through Meta-analysis. Methods: We searched data on relative risk (RR) and 95% confidence interval (CI) on cohort studies published between January 2000 and July 2019 from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang database. We used Stata software 15.1 to perform the Meta analysis with random effect model applied to pool RRs according to the results of heterogeneity test through subgroup analysis and Meta regression analysis to explore the potential heterogeneity, publication bias and sensitivity. Results: A total of eleven cohort studies involving 1 631 618 samples and 9 276 ASD cases were included in this Meta-analysis. Results showed that maternal smoking was associated with the increased risk of autism spectrum disorder (RR=1.16, 95%CI: 1.02-1.32). For subgroup analysis, the pooled RR for prospective studies (RR=1.16, 95%CI: 1.10-1.23) appeared higher than that in the retrospective studies (RR=0.92, 95%CI: 0.83-1.06). The pooled RR for studies with adjusted confounding factors (RR=1.13, 95%CI: 1.04-1.23) was higher than that without (RR=1.12, 95%CI: 1.04-1.20). In studies that exposure to smoking assessed before delivery, inter-study heterogeneity appeared higher than those after delivery. Sample size and time of assessment on smoking seemed the sources of heterogeneity. No significant publication bias was observed in this study, and the results were quite stable. Conclusions: Maternal smoking was associated with the increased risk of autism spectrum disorder. However, value of the combined effect seemed low. High-quality, large-sample, and prospective cohort studies should be conducted to further verify the causal relationship, based on the correction of potential confounding factors.

Characterization of the complete mitochondrial genome sequence of Tracheophilus cymbius (Digenea), the first representative from the family Cyclocoelidae.

Tracheophilus cymbius (Trematoda: Cyclocoelidae) is a common tracheal fluke of waterfowl, causing serious loss in the poultry industry. However, taxonomic identification of T. cymbius remains controversial and confused. Mitochondrial (mt) genomes can provide genetic markers for the identification of closely related species. We determined the mt genome of T. cymbius and reconstructed phylogenies with other trematodes. The T. cymbius mt genome is 13,760 bp in size, and contains 12 protein-coding genes (cox 1-3, nad 1-6, nad 4L, cyt b and atp 6), 22 transfer RNA (tRNA) genes, two ribosomal RNA genes and one non-coding region. All are transcribed in the same direction. The A + T content is 62.82%. ATG and TAG are the most common initiation and termination codons, respectively. Phylogenetic analyses of concatenated nucleotide sequences show T. cymbius grouping in suborder Echinostomata, and clustering together, with high statistical support, as a sister taxon with Echinochasmus japonicus (Echinochasmidae), the two forming a distinct branch rooted to the ancestor of all Echinostomatidae and Fasciolidae species. This is the first report of the T. cymbius mt genome, and the first reported mt genome within the family Cyclocoelidae. These data will provide a significant resource of molecular markers for studying the taxonomy, population genetics and systematics of trematodes.

Quantum interference of Josephson current in topological Anderson insulator junctions.

We investigate the critical supercurrent in Josephson junctions consisting of topological Anderson insulators (TAIs) via the Matsubara Green's function formalism. Our numerical results show that the disorder-induced edge states display distinct differences in dominating normal and supercurrent transport in the TAI phase. Unlike the hallmark of the TAI phase which exhibits a quantized conductance plateau, the critical supercurrent over the disorder strength exhibits a peak structure where the maximum value is reached at the weak-disorder boundary of the TAI phase. Although the magnitude of the averaged critical supercurrent is suppressed with increasing disorder strength, periodic oscillations of the supercurrent on an external magnetic flux survive in the TAI phase. These findings indicate that the supercurrent quantum interference effect can be an effective probe in detecting the emergence of disorder-induced edge state in TAIs.

According to mitochondrial DNA evidence, Parascaris equorum and Parascaris univalens may represent the same species.

Parascarosis is caused mainly by parasitic infections with Parascaris equorum and Parascaris univalens, the most common ascarid nematodes, in the small intestine of equines. Parascarosis often causes severe illness and even death in foals and yearlings. In this study, we obtained the complete sequence of the P. equorum mitochondrial (mt) genome and compared its organization and structure with that of P. equorum Japan isolate (nearly complete), and the complete mtDNA sequences of P. univalens Switzerland and USA isolates. The complete mtDNA genome of P. equorum China isolate is 13,899 base pairs (bp), making it the smallest of the four genomes. All four Parascaris mt genomes are circular, and all genes are transcribed in the same direction. The P. equorum mtDNA genome consists of 12 protein-coding genes, two ribosomal RNA genes, 22 transfer (t) RNA genes and one non-coding region, which is consistent with P. equorum Japan isolate and P. univalens Switzerland isolate but distinct from P. univalens USA isolate, which has 20 tRNA genes. Differences in nucleotide sequences of the four entire mt genomes range from 0.1-0.9%, and differences in total amino acid sequences of protein-coding genes are 0.2-2.1%. Phylogenetic analyses showed that the four Parascaris species clustered in a clade, indicating that P. equorum and P. univalens are very closely related. These mt genome datasets provide genetic evidence that P. equorum and P. univalens may represent the same species, which will be of use in further studies of the taxonomy, systematics and population genetics of ascarids and other nematodes.

Comparative analyses of the complete mitochondrial genomes of Cyathostomum pateratum and Cyathostomum catinatum provide new molecular data for the evolution of Cyathostominae nematodes.

The parasite Cyathostomum pateratum, which occurs in the large intestine of equines, is a common species of the subfamily Cyathostominae. Cyathostominae nematodes are a complex nematode group for which only limited genetic information has been reported. To re-examine the phylogenetic relationships among Cyathostominae nematodes, we sequenced the complete mitochondrial (mt) genome of Cy. pateratum and compared it with the mt genome of the congeneric species Cyathostomum catinatum. The complete mtDNA sequence of Cy. pateratum was 13,822 bp in length, 16 bp shorter than that of Cy. catinatum. The mtDNA sequences of both species contained 12 protein-coding genes, two rRNA genes and 22 tRNA genes, and all 36 genes were transcribed in the same direction and in the same strand. Pairwise comparisons of the 12 predicted amino acid sequences between Cy. catinatum and Cy. pateratum revealed differences of 0.4-3.1%; the least conserved sequence was that of cytochrome c oxidase subunit 3 (cox3). Phylogenetic analysis of the concatenated amino acid sequences using Bayesian inference and maximum likelihood methods showed that Cy. catinatum and Cy. pateratum clustered together with very high nodal support, and Cylicostephanus goldi was closer to the Cyathostomum nematodes than to other Cyathostominae nematodes. The mtDNA sequence of Cy. pateratum is reported here for the first time. The study will shed some light on the genetic evolution among parasitic nematodes in Cyathostomum.

Macrophage activation syndrome with lung involvement complicating adult-onset Still's disease.

Adult-onset Still's disease (AOSD) can progress into macrophage activation syndrome (MAS), which may be fatal. We report on a 19-year-old Han Chinese female, who presented with MAS-related pulmonary parenchymal involvement complicating AOSD, and further associated with disseminated intravascular coagulation and generalized tonic-clonic seizure. She was managed by high-dose corticosteroids and pulse cyclophosphamide therapy with a complete recovery of disease activity.

Systemic lupus erythematosus-associated diffuse alveolar haemorrhage: a single-centre experience in Han Chinese patients.

OBJECTIVE: Despite aggressive therapeutic regimens, diffuse alveolar haemorrhage (DAH) is still associated with a high mortality rate in systemic lupus erythematosus (SLE). This study was carried out in patients with SLE-associated DAH with a focus on their therapeutic modality. METHOD: A retrospective review was performed in 839 Han Chinese lupus patients hospitalized for their DAH manifestation from May 2006 to December 2016. RESULTS: There were 24 episodes in 17 cases (2.0% incidence), 15 females and two males aged 19-67 years (mean ± sd 38.2 ± 15.1 years). High disease activity [Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) 12-31, 19.8 ± 5.6] was found at the onset of DAH. All patients were treated with high-dose corticosteroid, followed by pulse methylprednisolone (70.6%), plasmapheresis (41.2%), pulse cyclophosphamide (35.3%), and rituximab (23.5%). Six patients (35.3%), including three with extracorporeal membrane oxygenation, died owing to acute respiratory failure. All patients receiving rituximab treatment survived with a follow-up period of 12-58 months (40.8 ± 21.1 months), and no further relapse was noted in three cases with a history of recurrent DAH episodes. In addition, there was a significant decrease in their lupus activity (SLEDAI-2K 21.5 ± 6.0 to 6.3 ± 1.7, p = 0.0286). CONCLUSION: In this single-centre series with SLE-associated DAH in Han Chinese patients, a beneficial effect of rituximab therapy was observed.

MicroRNA-222 contributed to cell proliferation, invasion and migration via regulating YWHAG in osteosarcoma.

OBJECTIVE: The aim of this study was to investigate the role of microRNA-222 (miR-222) in osteosarcoma (OS), and to further explore the potential molecular mechanism. PATIENTS AND METHODS: We measured the level of miR-222 in OS tissues and cell lines using quantitative Real-time polymerase chain reaction. Synthesized miR-222 mimics or inhibitors were obtained to up-regulate or down-regulate the expression of miR-222 in U2OS or Saos2 cells. Cell counting kit-8 (CCK8) and colony formation assay were employed to detect the ability of cell proliferation, and transwell assay was used to confirm the ability of cell invasion. Furthermore, luciferase assay and Western blot were applied to verify the target of miR-222 in OS. RESULTS: The level of miR-222 in OS tumor tissue samples was significantly lower than that in normal group. Over-expression of miR-222 decreased cell proliferation and invasion in U2OS cells while knockdown of miR-222 promoted cell growth and metastasis in Saos2 cells. Furthermore, YWHAG was found to be a candidate target of miR-222 using several databases. Elevated level of miR-222 inhibited YWHAG expression while reduced miR-222 promoted YWHAG expression. Also, up-regulation of YWHAG restored the inhibiting effect of miR-222 mimics. CONCLUSIONS: We identified for the first time that the expression level of miR-222 was reduced in OS tissues as well as in OS cell lines. miR-222 could inhibit cell proliferation and invasion via down-regulating YWHAG. These data could provide a potential target for the biological treatment of OS.

Characterization of the complete nuclear ribosomal DNA sequences of Eurytrema pancreaticum.

Eurytrema pancreaticum is one of the most common trematodes of cattle and sheep, and also infects humans occasionally, causing great economic losses and medical costs. In this study, the sequences of the complete nuclear ribosomal DNA (rDNA) repeat units of five E. pancreaticum individuals were determined for the first time. They were 8306-8310 bp in length, including the small subunit (18S) rDNA, internal transcribed spacer 1 (ITS1), 5.8S rDNA, internal transcribed spacer 2 (ITS2), large subunit (28S) rDNA and intergenic spacer (IGS). There were no length variations in any of the investigated 18S (1996 bp), ITS1 (1103 bp), 5.8S (160 bp), ITS2 (231 bp) or 28S (3669 bp) rDNA sequences, whereas the IGS rDNA sequences of E. pancreaticum had a 4-bp length variation, ranging from 1147 to 1151 bp. The intraspecific variations within E. pancreaticum were 0-0.2% for 18S rDNA, 0-0.5% for ITS1, 0% for 5.8S rDNA and ITS2, 0-0.2% for 28S rDNA and 2.9-20.2% for IGS. There were nine types of repeat sequences in ITS1, two types in 28S rDNA, but none in IGS. A phylogenetic analysis based on the 18S rDNA sequences classified E. pancreaticum in the family Dicrocoeliidae of Plagiorchiata, closely related to the suborder Opisthorchiata. These results provide useful information for the further study of Dicrocoeliidae trematodes.