The spectrum of phenylalanine hydroxylase variants and genotype-phenotype correlation in phenylketonuria patients in Gansu, China.

BACKGROUND: Phenylketonuria (PKU) is a common, congenital, autosomal recessive, metabolic disorder caused by Phenylalanine hydroxylase (PAH) variants. METHODS: 967 PKU patients from Gansu, China were genotyped by Sanger sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing. We analyzed the variants of PAH exons, their flanking sequences, and introns. RESULTS: The detection of deep intronic variants in PAH gene can significantly improve the genetic diagnostic rate of PKU. The distribution of PAH variants among PKU subtypes may be related to the unique genetic background in Gansu, China. CONCLUSION: The identification of PAH hotspot variants will aid the development of large-scale neonatal genetic screening for PKU. The five new PAH variants found in this study further expand the spectrum of PAH variants. Genotype-phenotype correlation analysis may help predict the prognosis of PKU patients and enable precise treatment regimens to be developed.

[Genetic analysis of eighteen patients from Gansu Province with Tetrahydrobiopterin deficiency].

OBJECTIVE: To explore the genetic basis of eighteen patients with Tetrahydrobiopterin deficiency (BH4D) from Gansu Province. METHODS: Eighteen patients diagnosed with BH4D at Gansu Provincial Maternal and Child Health Care Hospital from January 2018 to December 2021 were selected as the study subjects. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing. RESULTS: All of the thirty-six alleles of the eighteen patients were successfully determined by molecular genetic testing. Sixteen patients were found to harbor variants of the PTS gene, and two had harbored variants of the QDPR gene. Ten variants were detected in the PTS gene, with the most common ones being c.259C>T (34.38%) and c.286G>A (15.63%). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.259C>T was classified as a pathogenic variant, whilst the c.286G>A, c.166G>A, c.200C>T, c.272A>G, c.402A>C, c.421G>T, c.84_291A>G and c.317C>T were classified as likely pathogenic variants. A novel c.289_290insCTT variant was classified as likely pathogenic (PM1+PM2_Supporting+PM3+PP3+PP4). The two variants (c.478C>T and c.665C>T) detected in the QDPR gene were both classified as variants of uncertain significance (PM1+PM2_Supporting+PP3+PP4). CONCLUSION: Genetic testing has clarified the pathogenic variants in these BH4D patients, which has enabled timely and accurate clinical intervention and treatment, and provided a reference for genetic counseling and reproductive guidance for their families.

[Examination of the relationship between tasks in geriatric health service facilities and benefits of working for older assistant care workers].

Objective　In this study, we clarified the characteristics of tasks performed by older assistant care workers at geriatric health services facilities, by individual characteristics and work status. Additionally, we examined the relationship between the tasks and benefits of working for older assistant care workers.Methods　A self-administered questionnaire survey was provided to 2,571 elderly care facilities employing assistant care workers aged ≥60.　A total of 1,606 responses were obtained, and personal characteristics, working conditions, tasks, and benefits of working for older care assistants were surveyed. Thirteen work tasks were established and categorized into four broad categories; user transfer assistance, facility maintenance, meal-related assistance, and managing and talking to users. Seven benefits of working as care assistants were "contribution to society," "social connection," "purpose of life," "income," "learning from caregiving," "health maintenance and promotion," and "time utilization."Results　Most of the respondents were women and relatively young workers. Among tasks, men, younger workers, and those working >5 days weekly represented a high proportion of those performing user transfer assistance tasks. Tasks on managing and talking to users were not correlated with sex, age, and number of days worked, but those with more flexible work patterns were more likely to be engaged in such tasks. Logistic regression analysis showed that user transfer assistance was correlated with benefits of working, such as "contribution to society," "social connection," and "learning from caregiving." Moreover, facility maintenance was associated with "income," "health maintenance and promotion," and "time utilization" and meal-related assistance was associated with "learning from caregiving." Managing and talking to users was associated with "contribution of society," "social connection," "purpose of life," and "learning from caregiving."Conclusion　The tasks of the workers were associated with individual characteristics and work status. The perception of benefits between the working tasks that involved frequent contact with users and those that did not were considerably different.

[Current conditions and challenges of employing older assistant care workers based on geriatric health services facilities' scale].

Objectives　To support care workers, some care facilities employ older individuals as care assistants for peripheral, non-professional tasks. However, the size of the facilities influences their employment needs and support systems for older care workers. Therefore, this study examined the rationale for employing older assistant care workers; the challenges they face; educational systems; and the efforts to facilitate continued employment based on facility size.Methods　Initially, a fax survey was conducted with 3,591 facilities associated with the National Association of Geriatric Health Services Facilities to determine the proportion of older assistant care workers employed. Thereafter, a questionnaire survey was administered to gather more information. Out of 3,591 facilities, 2,170 responded to the survey, and 1,261 responded to the questionnaire. In this study, care assistants aged ≥60 years were classified as older care assistants. The facilities were categorized based on admission capacity into two groups: "small/medium facilities" (≤99 residents) and "large facilities" (≥100 residents). A chi-square test was conducted for data analysis.Results　Of the all geriatric health services facilities, 31.7% employed older assistant care workers. Moreover, the questionnaire survey responses showed they are employed by 687 facilities. Further analysis revealed that larger facilities employed a higher number of older care assistants than small/medium facilities. Small/medium facilities tended to have fewer training systems for older care assistants than larger facilities (30.0% for small/medium facilities vs. 21.6% for large facilities; P=0.014). Furthermore, the work of older care assistants in small/medium facilities was more susceptible to family circumstances than those in larger facilities (15.7% for small/medium facilities vs. 10.2% for large facilities; P=0.033). Compared to small/medium facilities, larger facilities were more likely to state that their employment objective was to reduce the risk of care accidents (19.8% for small/medium facilities vs. 26.3% for large facilities; P=0.046) and provide psychological support, such as periodic interviews, to older care workers to ensure continued employment (24.1% for small/medium facilities vs. for large facilities 37.3%; P<0.001).Conclusion　Larger facilities employeda higher number of older care assistants than small/medium facilities. Furthermore, small/medium facilities were less likely to provide psychological support and had a less structured training system, compared to larger facilities. Additionally, the work of older care assistants in small/medium facilities was more susceptible to family circumstances and other factors, which could affect their work performance. Thus, developing adequate support systems in small/medium facilities is crucial to promoting the employment of older care assistants.

Establishment of a modified Kyoto classification scoring model and its significance in the diagnosis of Helicobacter pylori current infection.

BACKGROUND AND AIMS: We aimed to establish a modified model of the Kyoto classification score and verify its accuracy for predicting Helicobacter pylori (HP) infection during endoscopy. METHODS: Patients who underwent gastroscopy from June 2020 to March 2021 were included in this study. Atrophy, intestinal metaplasia, hypertrophy of the gastric fold, nodularity, diffuse redness, sticky mucus, spotty redness, xanthoma, map-like redness, fundic gland polyp, and regular arrangement of collecting venules (RAC) were recorded according to the Kyoto classification of gastritis. The HP infection status of participants was determined by a 13C breath test, anti-HP antibody, and histopathologic hematoxylin and eosin staining. The modified Kyoto classification scoring model was established based on univariate analysis and logistic regression analysis. The modified scoring model was used to judge the status of HP infection in patients undergoing gastroscopy from July to September 2021 and to evaluate the accuracy of the prediction. RESULTS: Of 667 participants in the derivation dataset, 326 cases had HP infection and 341 cases did not. Atrophy, hypertrophy of the gastric fold, nodularity, diffuse redness, sticky mucus, and spotty redness were associated with HP current infection. Thus, a new scoring model, termed the modified Kyoto classification scoring model, was constructed that included atrophy, hypertrophy of the gastric fold, nodularity, diffuse redness, sticky mucus, spotty redness, fundic gland polyp, and RAC as indicators. To test the model, 808 subjects, including 251 HP-positive patients, comprised the validation dataset. CONCLUSIONS: The modified Kyoto classification scoring model improved the accuracy of endoscopic determination of HP current infection and has clinical application potential in the Chinese population.

Judicial and legislative practice and related suggestions on off-label drug use in China.

BACKGROUND: Off-label drug use exists widely in medical practice and is also an area which easily triggers controversy between patients and medical institutions. Previous studies have identified the reasons why off-label drug use long exists. However, there is no multidimensional analysis on real judicial precedents about off-label drug use. This study aimed to investigate the dispute points on off-label drug use based on real cases in China, and proposed suggestions based on newly-leased Physicians Law. METHODS: Our study is a retrospective study with all the 35 judicial precedents on off-label drug use extracted from China Judgments Online from 2014 to 2019. This study mainly used the methods of statistical analysis, inferential analysis, exemplification, literature summarization and comparative analysis. RESULTS: According to the analysis of the 35 precedents of jurisdictions from 11 different aspects, it can be seen that the second-instance and retrial rates of this kind of cases are high, and the disputes between patients and medical institutions are fierce. In judicial practice of off-label drug use, medical institutions are determined whether to bear civil liability according to the constituent elements of medical tort liability: the rate of medical institutions' bearing liability for off-label drug use is not high, and medical institutions are not directly identified as infringing acts and they don't bear tort liability. The clear provisions about off-label drug use in Law of the People's Republic of China on Physicians which was implemented in March 2022 confirm this at the legislative level. CONCLUSIONS: By analyzing the current judicial practice of China's off-label drug use cases, and summarizing the dispute points between medical institution and patients, the constituent elements of tort liability, and the rules of evidence etc., suggestions are proposed to further regulate off-label drug use and promote safe and rational drug use.

The evolutionary origin and domestication history of goldfish (Carassius auratus).

Goldfish have been subjected to over 1,000 y of intensive domestication and selective breeding. In this report, we describe a high-quality goldfish genome (2n = 100), anchoring 95.75% of contigs into 50 pseudochromosomes. Comparative genomics enabled us to disentangle the two subgenomes that resulted from an ancient hybridization event. Resequencing 185 representative goldfish variants and 16 wild crucian carp revealed the origin of goldfish and identified genomic regions that have been shaped by selective sweeps linked to its domestication. Our comprehensive collection of goldfish varieties enabled us to associate genetic variations with a number of well-known anatomical features, including features that distinguish traditional goldfish clades. Additionally, we identified a tyrosine-protein kinase receptor as a candidate causal gene for the first well-known case of Mendelian inheritance in goldfish-the transparent mutant. The goldfish genome and diversity data offer unique resources to make goldfish a promising model for functional genomics, as well as domestication.

[Prenatal diagnosis for a fetus with Walker-Warburg syndrome].

OBJECTIVE: To explore the genetic etiology for a fetus with Walker-Warburg syndrome(WWS). METHODS: A fetus with WWS diagnosed at Gansu Provincial Maternity and Child Health Care Hospital in June 9, 2021 was selected as the study subject. Genomic DNA was extracted from amniotic fluid sample of the fetus and peripheral blood samples from its parents. Trio-Whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor compound heterozygous variants of the POMT2 gene, namely c.471delC (p.F158Lfs*42) and c.1975C>T (p.R659W), which were respectively inherited from its father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), they were respectively rated as pathogenic (PVS1+PM2_Supporting+PP4) and likely pathogenic (PM2_Supporting+PM3+PP3_Moderate+PP4). CONCLUSION: Trio-WES may be used for the prenatal diagnosis of WWS. The compound heterozygous variants of the POMT2 gene probably underlay the disorder in this fetus. Above finding has expanded the mutational spectrum of the POMT2 gene and enabled definite diagnosis and genetic counseling for the family.

[Relationship between the perceived benefits of working and emotional exhaustion among older assistant care workers: A cross-sectional study].

Objectives　This study is intended to clarify the perceived benefits of working among older assistant care workers employed in geriatric health service facilities and examine the relationship between perceived benefits and emotional exhaustion.Methods　We analyzed data from a mail survey of older assistant care workers employed in geriatric health service facilities that the Japan Association of Geriatric Health Services Facilities conducted in 2020. In this survey, those aged ≥60 were defined as older assistant care workers. Responses were obtained from 1,606 older assistant care workers at 599 facilities. The dependent variable was the emotional exhaustion subscale of the Japanese version of the Burnout Questionnaire. The independent variables were the seven benefits of working as an assistant care worker: 1) I can contribute to society; 2) I am connected to society; 3) I have a sense of purpose in life; 4) I am earning the income I expected since I started working as an assistant care worker; 5) I am learning about care; 6) It has maintained and improved my health; and 7) I can use my time effectively. Latent class analysis (LCA) was performed using these seven benefits as independent variables. Multiple regression analysis was performed using emotional exhaustion and the perceived benefits as dependent and independent variables, respectively. The missing values were supplemented by the multiple imputation method.Results　Overall, 1,601 responses were analyzed after excluding 5 respondents who did not answer all the questions. Four patterns were identified from the LCA results: the "benefit-full type," who perceived all benefits; the "benefit-less type," who perceived few benefits; the "benefit-extroverted type," who perceived social contribution and connection as benefits; and the "benefit-introverted type," who perceived health maintenance and improvement and time utilization as benefits. The multiple regression analysis showed that emotional exhaustion scores were higher for the "benefit-extroverted" and "benefit-less" types than for the "benefit-full" type (b=2.465, P<.001 and b=1.931, P<.001, respectively). No difference was found in the case of the "benefit-introverted" type (b=0.050, P=.851).Conclusion　The perceptions of diverse and introverted benefits were associated with lower emotional exhaustion scores among older assistant care workers. Future intervention studies are needed to examine whether obtaining diverse or introverted benefits can decrease the emotional exhaustion score.

Rambutan genome revealed gene networks for spine formation and aril development.

Rambutan is a popular tropical fruit known for its exotic appearance, has long flexible spines on shells, extraordinary aril growth, desirable nutrition, and a favorable taste. The genome of an elite rambutan cultivar Baoyan 7 was assembled into 328 Mb in 16 pseudo-chromosomes. Comparative genomics analysis between rambutan and lychee revealed that rambutan chromosomes 8 and 12 are collinear with lychee chromosome 1, which resulted in a chromosome fission event in rambutan (n = 16) or a fusion event in lychee (n = 15) after their divergence from a common ancestor 15.7 million years ago. Root development genes played a crucial role in spine development, such as endoplasmic reticulum pathway genes, jasmonic acid response genes, vascular bundle development genes, and K+ transport genes. Aril development was regulated by D-class genes (STK and SHP1), plant hormone and phenylpropanoid biosynthesis genes, and sugar metabolism genes. The lower rate of male sterility of hermaphroditic flowers appears to be regulated by MYB24. Population genomic analyses revealed genes in selective sweeps during domestication that are related to fruit morphology and environment stress response. These findings enhance our understanding of spine and aril development and provide genomic resources for rambutan improvement.

Genome-wide analysis of mitogen-activated protein (MAP) kinase gene family expression in response to biotic and abiotic stresses in sugarcane.

To systematically analyze mitogen-activated protein (MAP) kinase gene families and their expression profiles in sugarcane (Saccharum spp. hybrids; Sh) under diverse biotic and abiotic stresses, we identified 15 ShMAPKs, 6 ShMAPKKs and 16 ShMAPKKKs genes in the sugarcane cultivar R570 genome. These were also confirmed in one S. spontaneum genome and two transcriptome datasets of sugarcane trigged by Acidovorax avenae subsp. avenae (Aaa) and Xanthomonas albilineans (Xa) infections. Phylogenetic analysis revealed that four subgroups were present in each ShMAPK and ShMAPKK family and three sub-families (RAF, MEKK and ZIK) presented in the ShMAPKKK family. Conserved protein motif and gene structure analyses supported the evolutionary relationships of the three families inferred from the phylogenetic analysis. All of the ShMAPK, ShMAPKK and ShMAPKKK genes identified in Saccharum spp. R570 were distributed on chromosomes 1-7 and 9-10. RNA-seq and qRT-PCR analyses indicated that ShMAPK07 and ShMAPKKK02 were defense-responsive genes in sugarcane challenged by both Aaa and Xa stimuli, while some genes were upregulated specifically by Aaa and Xa infection. Additionally, ShMAPK05 acted as a negative regulator under drought and salinity stress, but served as a positive regulator under salicylic acid (SA) treatment. ShMAPK07 plays a positive role under drought stress, but a negative role under SA treatment. ShMAPKKK01 was negatively modulated by both salinity stress and SA treatment, whereas ShMAPKKK06 was positively regulated by both of the two stress stimuli. Our results suggest that members of MAPK cascade gene families regulate adverse stress responses through multiple signal transduction pathways in sugarcane.

Mutation analysis of TCOF1 gene in Chinese Treacher Collins syndrome patients.

BACKGROUND: Treacher Collins syndrome (TCS) is a rare autosomal dominant or recessive disorder, that involves unique bilateral craniofacial malformations. The phenotypes of TCS are extremely diverse. Interventional surgery can improve hearing loss and facial deformity in TCS patients. METHOD: We recruited seven TCS families. Variant screening in probands was performed by targeted next-generation sequencing (NGS). The variants identified were confirmed by Sanger sequencing. The pathogenicity of all the mutations was evaluated using the guidelines of the American College of Medical Genetics and Genomics (ACMG) and InterVar software. RESULTS: Three frameshift variants, two nonsense variants, one missense variant, and one splicing variant of TCOF1 were identified in the seven TCS probands. Five variants including c.1393C > T, c.4111 + 5G>C, c.1142delC, c.2285_2286delCT, and c.1719delG had not been previously reported. Furthermore, we report the c.149A > G variant for the first time in a Chinese TCS patient. We provided prenatal diagnosis for family 4. Proband 7 chose interventional surgery. CONCLUSION: We identified five novel variants in TCOF1 in Chinese patients with TCS, which expands the mutation spectrum of TCOF1 in TCS. Bone conduction hearing rehabilitation can improve hearing for TCS patients and prenatal diagnosis can provide fertility guidance for TCS families.

Comparative analysis of sucrose phosphate synthase (SPS) gene family between Saccharum officinarum and Saccharum spontaneum.

BACKGROUND: Sucrose phosphate synthase (SPS) genes play vital roles in sucrose production across various plant species. Modern sugarcane cultivar is derived from the hybridization between the high sugar content species Saccharum officinarum and the high stress tolerance species Saccharum spontaneum, generating one of the most complex genomes among all crops. The genomics of sugarcane SPS remains under-studied despite its profound impact on sugar yield. RESULTS: In the present study, 8 and 6 gene sequences for SPS were identified from the BAC libraries of S. officinarum and S. spontaneum, respectively. Phylogenetic analysis showed that SPSD was newly evolved in the lineage of Poaceae species with recently duplicated genes emerging from the SPSA clade. Molecular evolution analysis based on Ka/Ks ratios suggested that polyploidy reduced the selection pressure of SPS genes in Saccharum species. To explore the potential gene functions, the SPS expression patterns were analyzed based on RNA-seq and proteome dataset, and the sugar content was detected using metabolomics analysis. All the SPS members presented the trend of increasing expression in the sink-source transition along the developmental gradient of leaves, suggesting that the SPSs are involved in the photosynthesis in both Saccharum species as their function in dicots. Moreover, SPSs showed the higher expression in S. spontaneum and presented expressional preference between stem (SPSA) and leaf (SPSB) tissue, speculating they might be involved in the differentia of carbohydrate metabolism in these two Saccharum species, which required further verification from experiments. CONCLUSIONS: SPSA and SPSB genes presented relatively high expression and differential expression patterns between the two Saccharum species, indicating these two SPSs are important in the formation of regulatory networks and sucrose traits in the two Saccharum species. SPSB was suggested to be a major contributor to the sugar accumulation because it presented the highest expressional level and its expression positively correlated with sugar content. The recently duplicated SPSD2 presented divergent expression levels between the two Saccharum species and the relative protein content levels were highest in stem, supporting the neofunctionalization of the SPSD subfamily in Saccharum.

Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and most patients die within one year after diagnosis. This cancer is resistant to almost all current therapies, so there is an urgent need to identify novel druggable targets. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that functions in carcinogenesis, but its role in PDAC is unknown. Our experiments indicated that several subtypes of PDAC cells are sensitive to USP7 inhibition. In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell death in vitro and in vivo. Pharmaceutical inhibition of USP7 in P22077-resistant PDAC cells allowed them to overcome chemoresistance. Genetic silencing experiments supported the importance of USP7 in the pathogenesis of PDAC. In particular, genetic disruption of USP7 greatly reduced cell proliferation and chemoresistance in vitro and prevented PDAC growth in vivo. Protein profiling by mass spectrometry (MS) indicated USP7 was associated 4 ontology terms: translation, localization and protein transporting, nucleotide or ribonucleotide binding, and ubiquitin-dependent catabolic processes. Puromycin labeling indicated that P22077 greatly reduced protein synthesis, and transcriptional analysis indicated that P22077 significantly altered the extracellular space matrix. In summary, we provided multiple lines of evidence which indicate that USP7 plays a critical role in PDAC, and may therefore be a suitable target for treatment of this cancer.

Iridium-Catalyzed C-H Amination of Weinreb Amides: A Facile Pathway toward Anilines and Quinazolin-2,4-diones.

C-H amination of arenes directed by weakly coordinating Weinreb amides has been achieved with an iridium catalyst and 2,2,2-trichloroethoxycarbonyl (Troc) azide as an aminating agent, providing a robust method of producing synthetic useful ortho-TrocNH aryl Weinreb amides. Taking advantage of the reactivity of Weinreb amide and Troc groups in the amination products, selective hydrolysis was achieved as an attractive process for the synthesis of ortho-NH2 aryl Weinreb amides, which are the building blocks useful in the synthesis of bioactive compounds, and cascade aminocyclization with primary amines was successful and provided an efficient pathway for the construction of quinazolin-2,4-diones, which are present in various alkaloids and natural products.

Improving NK1R-targeted gene delivery of stearyl-antimicrobial peptide CAMEL by conjugating it with substance P.

Specificity is a crucial condition that hampers the application of non-viral vectors for cancer gene therapy. In a previous study, we developed an efficient gene vector, stearyl-CAMEL, using N-terminal stearylation of the antimicrobial peptide CAMEL. Substance P (SP), an 11-residue neuropeptide, rapidly enters cells after binding to the neurokinin-1 receptor (NK1R), which is expressed in many cancer cell lines. In this study, the NK1R-targeted gene vector stearyl-CMSP was constructed by conjugating SP to the C-terminus of stearyl-CAMEL. Our results indicated that stearyl-CMSP displayed significant transfection specificity for NK1R-expressing cells compared with that shown by stearyl-CAMEL. Accordingly, the stearyl-CMSP/p53 plasmid complexes had significantly higher antiproliferative activity against HEK293-NK1R cells than they did against HEK293 cells, while the stearyl-CAMEL/p53 plasmid complexes did not show this specificity in antiproliferative activity. Consequently, conjugation of the NK1R-targeted ligand SP is a simple and successful strategy to construct efficient cancer-targeted non-viral gene vectors.

Prognostic Implications of Novel Gene Signatures in Gastric Cancer Microenvironment.

BACKGROUND Increasing studies have shown the important clinical role of immune and stromal cells in gastric cancer microenvironment. Based on information of immune and stromal cells in The Cancer Genome Atlas, this study aimed to construct a prognostic risk assessment model for gastric cancer. MATERIAL AND METHODS Based on the immune/structural scores, differentially expressed genes (DEGs) were filtered and analyzed. Afterwards, DEGs associated with prognosis were screened and the risk assessment model was constructed in the training set. Moreover, the validity of the model was verified both in the testing set and the overall sample. RESULTS In this study, patients were divided into high-score and low-score groups based on immune/stromal score, and 919 DEGs were identified. By applying least absolute shrinkage and selection operator (LASSO) and Cox analysis, 10 mRNAs were selected to form a prognostic risk assessment model, risk score=(0.294*SLC17A9) + (-0.477*FERMT3) + (0.866*NRP1) + (0.350*MMRN1) + (0.381*RNASE1) + (0.189*TRIB3) + (0.230*PGAP3) + (0.087*MAGEA3) + (0.182*TACR2) + (0.368*CYP51A1). In the training set, the low-risk group divided by the model was found to have better overall survival, and the prediction efficiency of the model was demonstrated to be good. Multivariate Cox analysis indicated that the model could work as a prognostic factor independently. Similar results were shown in the testing group and overall patients cohort group. Finally, the risk assessment model and other clinical variables were integrated to construct a nomogram. CONCLUSIONS In general, this study constructs a prognostic risk assessment model for gastric cancer, which could improve the prognosis stratification of patients combined with other clinical indicators.

Maternal UPD of chromosome 7 in a patient with Silver-Russell syndrome and Pendred syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is a heterogeneous imprinting disorder featuring severe intrauterine and postnatal growth retardation and dysmorphic features. Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the SLC26A4 gene characterized by sensorineural hearing loss. METHODS: Karyotyping analysis was performed to investigate any chromosomal abnormalities. Whole-genome copy number variation and loss of heterozygosity were analyzed using an Affymetrix CytoScan 750 K Microarray. Variant screening was performed by targeted next-generation sequencing on all known deafness-causing genes. RESULTS: The proband was a patient with SRS caused by maternal uniparental disomy 7. The PDS of the proband was caused by homozygous variant c.919-2A > G of SLC26A4; both mutated alleles were inherited from his mother. CONCLUSION: This is the first report of uniparental disomy 7 leading to SRS and Pendred syndrome. Patients with intrauterine growth retardation or those born small for gestational age and exhibiting postnatal growth failure should undergo molecular testing to reach a clinical diagnosis.

Facile Fabrication of Oxidation-Responsive Polymeric Nanoparticles for Effective Anticancer Drug Delivery.

Reactive oxygen species (ROS) are highly overproduced in cancerous tissues, and thus oxidation-responsive nanoparticles (NPs) have emerged as a promising drug carrier for cancer-targeted drug delivery. In this study, we successfully synthesized poly(vanillyl alcohol- co-oxalate) (PVAX) polymer with an excellent ROS-responsive capacity. A well-established emulsion-solvent evaporation method was used to fabricate PVAX-based curcumin (CUR)-loaded NPs (PVAX-NPs) and their counterparts (poly(lactic- co-glycolic acid)-based CUR-loaded NPs, PLGA-NPs). It was found that these NPs had a hydrodynamic particle size of approximately 245 nm, narrow size distribution (polydispersity index less than 0.1), negative zeta potential (around -18 mV), smooth surface appearance, and high drug encapsulation efficiency. Moreover, we found that the CUR release rate of PVAX-NPs was greatly increased in the presence of a hydrogen peroxide-rich environment due to the cleavage of polyoxalate ester bonds in PVAX polymer, resulting in the evenly distribution of CUR within the whole cancer cells. More importantly, PVAX-NPs exhibited much stronger anticancer activities and pro-apoptotic capacities than PLGA-NPs both in vitro and in vivo. These results clearly demonstrate that these ROS-responsive PVAX-NPs can be exploited as a robust anticancer drug delivery platform in chemotherapy.

[Application of probe-based confocal laser endomicroscopy in diagnosis of gastric carcinoma and precancerous lesions].

OBJECTIVE: To assess the application of probe-based confocal laser endomicroscopy (pCLE) in diagnosis of gastric carcinoma and precancerous lesions. METHODS: Patients underwent pCLE in the First Affiliated Hospital of Zhejiang University School of Medicine during December 2013 and November 2014 and in the First Affiliated Hospital of Zhejiang Chinese Medical University during January 2014 and December 2017 were enrolled. The consistency between pCLE diagnosis and pathological diagnosis of gastric lesions, including atrophic gastritis, gastric intestinal metaplasia, low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia (including gastric carcinoma) was analyzed. RESULTS: Totally 154 gastric lesions from 119 patients were detected by pCLE. Using pathological diagnosis as gold standard, the sensitivity, specificity, coincidence rate and κ value of pCLE diagnosis for atrophic gastritis were 94.34%, 91.09%, 92.21%and 0.83; those indicators for gastric intestinal metaplasia were 84.47%, 92.16%, 87.01% and 0.72. The coincidence rate and κ value of pCLE diagnosis of complete gastric intestinal metaplasia were 0.75 and 0.49; for incomplete gastric intestinal metaplasia were 0.79 and 0.48, respectively. The sensitivity, specificity, coincidence rate and κ value of pCLE diagnosis for low-grade intraepithelial neoplasia were 85.29%, 87.50%, 87.01%and 0.66; those for high-grade intraepithelial neoplasia (including gastric carcinoma) were 95.83%, 97.17%, 96.75%and 0.92. CONCLUSIONS: pCLE can be used for diagnosis of gastric carcinoma and pericancerous lesions and also for typing of gastric intestinal metaplasia.