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Adoptive cellular therapies are making major strides in the treatment of cancer, both for hematologic and solid tumors. These cellular products include chimeric antigen receptor T cells and T-cell receptor-modified T cells, tumor-infiltrating lymphocytes, marrow-infiltrating T cells, natural killer cells as well as macrophage-based therapeutics. Advancement in genomics, computational biology, immunology, and cell therapy manufacturing has facilitated advancement of adoptive T cell therapies into the clinic, whereas clinical efficacy has driven Food and Drug Administration approvals. The growth of adoptive cellular therapy has, in turn, led to innovation in the preclinical models available, from ex vivo cell-based models to in vivo xenograft models of treatment. This review focuses on the development and application of in vitro models and in vivo models (cell line xenograft, humanized mice, and patient-derived xenograft models) that directly evaluate these human cellular products.

To retrospectively analyze the clinical features and treatment outcomes of patients with diabetic foot ulcers (DFU), and to investigate the effect of controlling nutritional status (CONUT) scores on the amputation risks and hospital length-of-stay of DFU patients.A total of 357 DFU inpatients admitted to the Department of Endocrinology, PLA Strategic Support Force Characteristic Medical Center between January 1, 2016 and December 31, 2018 were enrolled and analyzed retrospectively. Based on their CONUT scores, the patients were divided into 3 groups, a normal nutritional status group consisting of patients with CONUT scores 0-1 (The total amputation rate of DFU patients was 30.6%. Among all amputations, the major amputation (above-the-ankle amputation) rate was 1.8%, and the minor amputation rate was 98.2%. The amputation rate in patients with mild and moderate-to-severe malnutrition were 1.5 and 3.0 times higher than those in the normal nutritional status group, respectively. Logistic regression analysis showed that the moderate-to-severe nutritional status (5-12 scores), white blood cell, Wagner classification and ankle-brachial index were independent risk factors for amputation.CONUT score is closely associated with amputations in DFU patients. Improving the nutritional status of patients in the early stage could reduce the risk of amputation.

To analyze clinical effect of intervention strategies based on Caprini thrombosis risk assessment model for preventing deep vein thrombosis (DVT) after total hip replacement (THR).From January 2018 to December 2021, 197 patients with THR were selected as retrospective cohort study subjects, including 114 males and 83 females, aged from 45 to 80 years with an average of (66.81±10.34) years old. Caprini thrombosis risk assessment model introduced in May 2019 was used as boundary and divided into two groups, 94 patients were performed routine intervention strategies(control group) and 103 patients were received intervention strategies based on Caprini thrombosis risk assessment model (observation group). Incidence of DVT, visual analogue scale (VAS), circumference difference of affected limb, serum D-dimer (D-D) level and Harris score of hip function between two groups were analyzed.One-hundred and ninty-seven patients were followed up from 1 to 3 months with an average of (2.57±0.31) months. Incidence of DVT was 1.94% in observation group and 11.70% in control group, and there was statistical difference between two groups (Intervention strategy based on Caprini thrombosis risk assessment model could reduce incidence of DVT in patients with THR, improve postoperative pain and swelling of the affected limb, and promote recovery of hip joint function.

BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, and its etiology and risk factors remain uncertain. AIM: To investigate the possible influence of Chinese herbal liquid containing geniposide on IMP. METHODS: The detailed formula of herbal liquid prescriptions of all patients was studied, and the herbal ingredients were compared to identify the toxic agent as a possible etiological factor. Abdominal computed tomography (CT) and colonoscopy images were reviewed to determine the extent and severity of mesenteric phlebosclerosis and the presence of findings regarding colitis. The disease CT score was determined by the distribution of mesenteric vein calcification and colon wall thickening on CT images. The drinking index of medicinal liquor was calculated from the daily quantity and drinking years of Chinese medicinal liquor. Subsequently, Spearman's correlation analysis was conducted to evaluate the correlation between the drinking index and the CT disease score. RESULTS: The mean age of the 8 enrolled patients was 75.7 years and male predominance was found (all 8 patients were men). The patients had histories of 5-40 years of oral Chinese herbal liquids containing geniposide and exhibited typical imaging characteristics (e.g., threadlike calcifications along the colonic and mesenteric vessels or associated with a thickened colonic wall in CT images). Calcifications were confined to the right-side mesenteric vein in 6 of the 8 patients (75%) and involved the left-side mesenteric vein of 2 cases (25%) and the calcifications extended to the mesorectum in 1 of them. The thickening of colon wall mainly occurred in the right colon and the transverse colon. The median disease CT score was 4.88 (n = 7) and the median drinking index was 5680 (n = 7). After Spearman's correlation analysis, the median CT score of the disease showed a significant positive correlation with the median drinking index (r = 0.842, P < 0.05). CONCLUSION: Long-term oral intake of Chinese herbal liquid containing geniposide may play a role in the pathogenesis of IMP.

At diagnosis, more than 70% of bladder cancers (BCs) are at the non-muscle-invasive bladder cancer (NMIBC) stages, which are usually treated with transurethral resection followed by intravesical instillation. For the remaining advanced cancers, systemic therapy is the standard of care, with addition of radical cystectomy in cases of locally advanced cancer. Because of the difference in treatment modalities, different models are needed to advance the care of NMIBC and advanced BC. This article gives a comprehensive review of both in vitro and in vivo BC models and compares the advantages and drawbacks of these preclinical systems in BC research.

Zearalenone (ZEN), a common non-steroidal estrogenic mycotoxin of the Fusarium genus, is one of the most frequent and powerful contaminant of grains and cereal products representing a serious threat for people and livestock health. In fact, ZEN causes cytotoxicity and genotoxicity in a variety of cell types at least in part through binding to estrogen receptors (ERs). The main pathways through which ZEN induces such effects remain, however, elusive. In particular, how the mycotoxin causes DNA damage, dysregulates DNA repair mechanisms, changes epigenome of targeted cells and, not least, affects chromatin conformation and non-coding RNA (ncRNA), is unclear. In the present paper, following extensive review of the literature about such ZEN effects and our own experience in studying the effects of this compound on reproductive processes, we propose that increased production of reactive oxygen species (ROS) and consequently oxidative stress (OS) are central in ZEN genotoxicity. Besides to shed light on the action mechanisms of the mycotoxin, this notion might help to develop effective strategies to counteract its deleterious biological effects.

Background lncRNAs and VEGF have been shown to have close connections with oral squamous cell carcinoma (OSCC). We explored the interaction between lncRNA NEAT1 and VEGF-A in OSCC. Methods RT-qPCR was implemented to measure levels of lncRNA NEAT1 and VEGF-A in OSCC cell lines and normal cell lines. Cell functions then were checked after regulating the expressions of lncRNA NEAT1 and VEGF-A separately. Cell viabilities were examined with CCK-8 and apoptosis rate was checked with flow cytometry. Meanwhile, EMT-related genes E-cadherin, N-cadherin, Vimentin, and Snail and Notch signaling genes Notch1, Notch2, and Jagged were evaluated by RT-qPCR. IMR-1 was applied for impeding Notch signaling pathway. Later, cell viabilities, apoptosis, and EMT were assessed. Results Expressions of lncRNA NEAT1 and VEGF-A were both increased significantly in OSCC cell lines especially in TSCC1 cell line. Suppression of lncNRA NEAT1 was associated with lower cell viabilities and EMT and higher apoptosis rate in the TSCC1 cell line. Meanwhile, knockdown of VEGF-A significantly repressed cell viabilities and EMT in the TSCC1 cell line. Magnifying functions of inhibited lncRNA NEAT1 Notch signaling pathway was obviously activated with overexpressions of lncRNA NEAT1 and VEGF-A. Adding IMR-1 significantly downregulated cell viabilities and EMT and sharply increased apoptosis in the context of lncRNA NEAT1 and VEGF-A overexpression. Conclusion LncRNA NEAT1 may upregulate proliferation and EMT and repress apoptosis through activating VEGF-A and Notch signaling pathway in vitro, suggesting an underlying regulatory factor in OSCC. Nevertheless, further research is necessary to gain a greater understanding of lncRNA NEAT1 and connections with VEGF-A in vivo and in clinical study.

Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, also known as Müllerian agenesis, is characterized by uterovaginal aplasia in an otherwise phenotypically normal female with a normal 46,XX karyotype. Previous studies have associated sequence variants of PAX8, TBX6, GEN1, WNT4, WNT9B, BMP4, BMP7, HOXA10, EMX2, LHX1, GREB1L, LAMC1, and other genes with MRKH syndrome. The purpose of this study was to identify the novel genetic causes of MRKH syndrome. Ten patients with MRKH syndrome were recruited at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Whole-exome sequencing was performed for each patient. Sanger sequencing confirmed the potential causative genetic variants in each patient. In silico analysis and American College of Medical Genetics and Genomics (ACMG) guidelines helped to classify the pathogenicity of each variant. The Robetta online protein structure prediction tool determined whether the variants affected protein structures. Eleven variants were identified in 90% (9/10) of the patients and were considered a molecular genetic diagnosis of MRKH syndrome. These 11 variants were related to nine genes: TBC1D1, KMT2D, HOXD3, DLG5, GLI3, HIRA, GATA3, LIFR, and CLIP1. Sequence variants of TBC1D1 were found in two unrelated patients. All variants were heterozygous. These changes included one frameshift variant, one stop-codon variant, and nine missense variants. All identified variants were absent or rare in gnomAD East Asian populations. Two of the 11 variants (18.2%) were classified as pathogenic according to the ACMG guidelines, and the remaining nine (81.8%) were classified as variants of uncertain significance. Robetta online protein structure prediction analysis suggested that missense variants in TBC1D1 (p.E357Q), HOXD3 (p.P192R), and GLI3 (p.L299V) proteins caused significant structural changes compared to those in wild-type proteins, which in turn may lead to changes in protein function. This study identified many novel genes, especially TBC1D1, related to the pathogenesis of MRKH syndrome. The identification of these variants provides new insights into the etiology of MRKH syndrome and a new molecular genetic reference for the development of the reproductive tract.

Multiple sclerosis disproportionally affects women. The present study was undertaken to determine whether NFAT5 contributed to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, and if it did, whether the impact was sex associated. NFAT5 haplodeficiency reduced the disease severity only in female mice. This effect was associated with significant increases in frequency of T regulatory (Treg) cells in the CNS (from 1.45 ± 0.39% to 3.73 ± 0.94%) and spleen from (0.31 ± 0.06% to 0.94 ± 0.29%) without significantly affecting the CNS CD4

Previous works have shown that zearalenone (ZEA), as an estrogenic pollutant, has adverse effects on mammalian folliculogenesis. In the present study, we found that prolonged exposure of female mice to ZEA around the end of pregnancy caused severe impairment of primordial follicle formation in the ovaries of newborn mice and altered the expression of many genes in oocytes as revealed by single-cell RNA sequencing (scRNA-seq). These changes were associated with morphological and molecular alterations of mitochondria, increased autophagic markers in oocytes, and epigenetic changes in the ovaries of newborn mice from ZEA-exposed mothers. The latter increased expression of HDAC2 deacetylases was leading to decreased levels of H3K9ac and H4K12ac. Most of these modifications were relieved when the expression of Hdac2 in newborn ovaries was reduced by RNA interference during in vitro culture in the presence of ZEA. Such changes were also alleviated in offspring ovaries from mothers treated with both ZEA and the coenzyme Q10 (CoQ10), which is known to be able to restore mitochondrial activities. We concluded that impaired mitochondrial activities in oocytes caused by ZEA are at the origin of metabolic alterations that modify the expression of genes controlling autophagy and primordial follicle assembly through changes in epigenetic histones.

OBJECTIVE To evaluate the ability of macular ganglion cell and inner plexiform layer (mGCIPL) and retinal nerve fiber layer (RNFL) thickness measurements by long-wavelength swept-source optical coherence tomography (SS-OCT) to assess retinal ganglion cell (RGC) damage in nonarteritic anterior ischemic optic neuropathy (NAION). METHODS A retrospective study of 20 patients with unilateral NAION was performed. SS-OCT scanning of the macular and peripapillary areas was performed to measure the total and six-sector thicknesses of macular RNFL (mRNFL) and mGCIPL, as well as peripapillary RNFL (pRNFL) thicknesses in global and 12 clock-hour sectors. Further comparison of these thicknesses between NAION involved eyes and uninvolved counterparts was performed in 12 of the 20 patients at 4 visits. The thickness map and en face images generated by volume data of the posterior pole over a 12 × 9-mm area were used for RNFL analysis. RESULTS Median time intervals between the visual symptom onset and first thinning occurrences of mGCIPL, mRNFL, and pRNFL were 17 days (95% Confidence Interval [CI] 14-18 days), 43 days (95% CI 32-48 days), and 70 days (95% CI 62-80 days), respectively. The thickness map indicated a significantly reduced pRNFL in the superior temporal sectors or temporal sectors after 9 weeks, and retinal damage corresponded to the superior hemisphere's mRNFL and mGCIPL. En face images showed that the RNFL thinning area gradually expanded along the retinal nerve fiber direction and progressed toward the optic nerve head. CONCLUSIONS The patterns of RGC damage in the macular and peripapillary areas of NAION eyes can be revealed by SS-OCT. Objective measurement of SS-OCT is valuable in characterizing NAION.

BACKGROUND: Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer was first analyzed with The Cancer Genome Atlas (TCGA) database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anti-cancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD-1 immunotherapy. RESULTS: Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 days to 32 days compared to vehicle only controls (p=0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI >3) and in vivo, but significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. CONCLUSIONS: The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.

Background Parents play important role in providing information regarding their children’s health status to healthcare providers. However, parents’ ability in reporting signs and symptoms of eye problems among their children required more in-depth investigation. Our study aimed to compare the differences of parental report regarding eye problems among their children using two different question approaches. Methods A total of 416 parents with children aged between two months old and 17 years old were participated in this cross-sectional survey. The responses of parents’ observation on signs and symptoms of eye problems were compared between one open-ended question and ten close-ended questions. We also examined the demographic contributing factors that could influence parental responses. Results The total count of reported signs and symptoms through open-ended and close-ended question was 164 and 529 reports, respectively. Parents reported more diverse (70% higher) categories of signs and symptoms in open-ended compared to close-ended questions. Parent’s ability to report eye problems using open-ended question was associated with their gender (p

Study Objective The purpose of this study was to determine if there are any genetic changes with whole-exome sequencing associated with distal vaginal atresia. Design This was a retrospective genetics study of 5 patients who presented with distal vaginal atresia who were recruited between 2017 and 2018. Whole-exome sequencing was performed in each subject with distal vaginal atresia. Sanger sequencing was used to confirm the potential causative genetic mutation. Setting Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Participants and Main Outcome Measures The main outcome measure was the rare mutations potentially associated with distal vaginal atresia in 5 patients. Results A truncating mutation c.266delC (p.P89Rfs*5) in the T-box transcription factor 6 (TBX6) gene, which is highly expressed in the human vagina, was identified in 1 patient using whole-exome sequencing. The deletion of the 16p11.2 region containing the TBX6 locus has also been reported previously to have the clinical feature of Mullerian agenesis. This mutation was paternally inherited by the patient. This truncating mutation was absent from all of the databases we checked, suggesting that the variant is rare and pathogenic. Conclusion We showed, to our knowledge, for the first time, that the mutation in TBX6 might be associated with human distal vaginal atresia.

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.

Di(2-ethylhexyl)phthalate (DEHP) has proven characteristics of an endocrine-disrupting compound (EDC), which can threaten the reproductive health of humans and other animals. In mammals, a series of chromosomal events occur during the meiotic stage of oocytes. External toxins may enter the body and cause infertility and other related diseases. Therefore, it is crucial to explore the influence of DEHP exposure on the molecular mechanism of germ cell meiosis. We used single-cell RNA sequencing (scRNA-seq) to analyse the ovaries of foetal mice at embryonic day 12.5 (E12.5) and E14.5 after maternal DEHP exposure. DEHP exposure further activated the pathways related to DNA repair in germ cells, increased the expression of genes related to DNA damage and changed the developmental trajectory of germ cells. DEHP exposure may affect the proliferation of pregranulosa (PG) cells. Moreover, DEHP exposure altered the signal transduction between PG cells and germ cells. We showed that DEHP affects meiosis by causing DNA damage in oocytes and disrupting the signal transduction between PG cells and germ cells. These results provide a strong theoretical basis for the prevention and treatment of DEHP-mediated female reproductive health problems.

To summarize professor总结杨骏教授运用不同针刺手法治疗难治性面瘫经验。杨骏教授认为本病病程迁延、气血亏虚、久病入络，指出临床常规针刺方法很难取得明显疗效，针对本病病因病机及疾病特点，运用“长针透经穴刺”“滞针提拉刺法”“健侧平衡对刺”3种针刺手法，有效改善面部后遗症状，达到牵正纠偏之功。.

Bladder cancer (BlCa) exhibits a gender disparity where men are three times more likely to develop the malignancy than women suggesting a role for the androgen receptor (AR). Here we report that BlCa cells express low molecular weight (LMW) AR isoforms that are missing the ligand binding domain (LBD). Isoform expression was detected in most BlCa cells, while a few express the full-length AR. Immunofluorescence studies detect AR in the nucleus and cytoplasm, and localization is cell dependent. Cells with nuclear AR expression exhibit reduced viability and increased apoptosis on total AR depletion. A novel AR-LMW variant, AR-v19, that is missing the LBD and contains 15 additional amino acids encoded by intron 3 sequences was detected in most BlCa malignancies. AR-v19 localizes to the nucleus and can transactivate AR-dependent transcription in a dose dependent manner. AR-v19 depletion impairs cell viability and promotes apoptosis in cells that express this variant. Thus, AR splice variant expression is common in BlCa and instrumental in ensuring cell survival. This suggests that targeting AR or AR downstream effectors may be a therapeutic strategy for the treatment of this malignancy.

Near work, accommodative inaccuracy and ambient lighting conditions have all been implicated in the development of myopia. However, differences in accommodative responses with age and refractive error under different visual conditions remain unclear. This study explores differences in accommodative ability and refractive error with exposure to differing ambient illumination and visual demands in Malay schoolchildren and adults.Sixty young adults (21-25 years) and 60 schoolchildren (8-12 years) were recruited. Accommodative lag and accommodative fluctuations at far (6 m) and near (25 cm) were measured using the Grand Seiko WAM-5500 open-field autorefractor. The effects of mesopic room illumination on accommodation were also investigated.Repeated-measures ANOVA indicated that accommodative lag at far and near differed significantly between schoolchildren and young adults [F(1.219, 35.354) = 11.857, p 0.05]. Post hoc tests using the Bonferroni correction showed that at near, there was a greater lag in schoolchildren (0.486 ± 0.181 D) than young adults (0.259 ± 0.209 D, p 0.05). Repeated-measures ANOVA also revealed that accommodative lag at near demands differed statistically between the non-myopic and myopic groups in young adults and schoolchildren [F(3.107, 31.431) = 12.187, p 0.05]. Post hoc tests with Bonferroni correction showed that accommodative lag at near was significantly greater in myopic schoolchildren (0.655 ± 0.198 D) than in non-myopic schoolchildren (0.202 ± 0.141 D, p 0.05) and myopic young adults (0.316 ± 0.172 D, p 0.05), but no significant difference was found between myopic young adults (0.316 ± 0.172 D) and non-myopic young adults (0.242 ± 0.126 D, p 0.05). Accommodative lag and fluctuations were greater under mesopic room conditions for all ages [all p 0.05].Greater accommodative lag was found in myopes than in emmetropes, in schoolchildren than in adults, and under mesopic conditions than under photopic conditions. Accommodative fluctuations were greatest in myopes and in mesopic conditions. These results suggest that differences exist in the amount of blur experienced by myopes and non-myopes at different ages and under different lighting conditions.

Two new p-terphenyls, strepantibins A and B (1 and 2), along with the first representative of a naturally occurring bisphenyltropone, strepantibin C (3), were characterized from a Streptomyces sp. associated with the larvae of the mud dauber wasp Sceliphron madraspatanum. Their structures were determined by high-resolution electrospray ionization mass spectrometry, NMR, and X-ray crystallography data interpretation. Strepantibins A-C inhibited hexokinase II (HK2) activity and displayed antiproliferative activity against hepatoma carcinoma cells HepG-2, SMMC-7721 and plc-prf-5. In SMMC-7721 cells treated with strepantibin A, the morphological characteristics of apoptosis were observed.

Purpose A meta-analysis on sleep duration and patterns in patients with diabetes in China. Design and methods Two investigators independently carried out a systematic literature search in both international and Chinese databases. Findings A total of 47 studies with 98 911 patients were included. The pooled mean sleep duration was 7.15 hours/day in patients with diabetes and 7.49 hours/day in healthy controls. The estimated percentage of short sleep duration of less than 6 hours/day was 23.0% in patients with diabetes and 12.3% in healthy controls, while the proportion of short sleep duration of less than 7 hours/day was 38.0% in patients with diabetes and 14.1% in healthy controls. Practice implications Short sleep duration was common in Chinese patients with diabetes.

Endothelial damage and blood brain barrier disruption contribute to ischemic stroke and brain injury. Gliptins are a novel class of treatment agents for diabetes, and recent studies have linked the use of gliptins to neuroprotection. Alogliptin is a type of orally available gliptin that was approved for clinical use by the FDA in 2013. In this study, we investigated the neurovascular protective effects of alogliptin both in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) stroke model, administration of alogliptin ameliorated cerebral infarction and disruption of brain vascular permeability, and restored expression of the endothelial tight junction proteins occludin and zona occludens 1 (ZO-1). In brain vascular endothelial cells exposed to oxygen and glucose deprivation/reperfusion (OGD/R), alogliptin prevented OGD/R-induced high permeability of the endothelial monolayer. Alogliptin treatment recovered the reduction in occludin and ZO-1 induced by OGD/R. Moreover, alogliptin treatment prevented OGD/R-induced induction of metalloproteinase (MMP)-2 and MMP-9, and restored expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Collectively, our data indicate that alogliptin can improve neurovascular integrity and exerts neuroprotective effects.

Increasing studies revealed that aberrant expression of long non-coding RNAs (lncRNAs) play critical roles in ovarian cancer (OC) progression. However, the roles and underlying mechanisms of ADAMTS9-AS2 in OC remain unclear. In the present study, we showed that ADAMTS9-AS2 expression was significantly decreased in OC tissues and cell lines. Low ADAMTS9-AS2 expression was correlated with advanced FIGO stage, lymph-node metastasis, and poor overall survival of OC patients. Function assays showed that ADAMTS9-AS2 reduced OC cells proliferation, invasion, and epithelial-mesenchymal transition (EMT) processes in vitro and restrained tumor growth in vivo. The underlying mechanism studies indicated that ADAMTS9-AS2 functioned as a competing endogenous RNA (ceRNA) for miR-182-5p to promote cell proliferation and invasion. In addition, we revealed that FOXF2 acted as a direct target of miR-182-5p and mediated the effects of ADAMTS9-AS2 on OC cells progression. Taken together, our data suggested that lncRNA ADAMTS9-AS2 decreased OC progression by regulating miR-182-5p/FOXF2 axis, indicating ADAMTS9-AS2 could serve as a potential therapeutic target for OC treatment.

Objective To explore the genetic causes of Herlyn-Werner-Wunderlich syndrome (HWWS) using whole-exome sequencing. Design Retrospective genetic study. Setting Academic medical center. Patient(s) Twelve patients with HWWS. Intervention(s) Whole-exome sequencing was performed for each patient. Sanger sequencing was used to confirm the potential causative genetic variants. In silico analysis and American College of Medical Genetics and Genomics guidelines were used to classify the pathogenicity of each variant. Main Outcome Measure(s) Rare sequence variants associated with mullerian duct development and renal agenesis were identified and included in subsequent analyses. Result(s) A total of 11 variants were identified in 10 of 12 patients (83.3%) and were considered to constitute a molecular genetic diagnosis of HWWS. These 11 variants were related to 9 genes: CHD1L, TRIM32, TGFBR3, WNT4, RET, FRAS1, FAT1, FOXF1, and PCSK5. All variants were heterozygous and confirmed by Sanger sequencing. The changes included one frameshift variant, one splice-site variant, and eight missense variants. All of the identified variants were absent or rare in Genome Aggregation Database East Asian populations. One of the 11 variants (9.1%) was classified as a pathogenic variant according to the American College of Medical Genetics and Genomics guidelines, and 8 of the 11 variants (72.7%) were classified as variants of uncertain significance. Conclusion(s) To our knowledge, this is the first report of the genetic causes of HWWS. Renal agenesis-related genes, such as CHD1L, TRIM32, RET, and WNT4, may be associated with HWWS. Identification of these variants can not only help us understand the etiology of HWWS and the relationship between reproductive tract development and urinary system development, but additionally improve the level of genetic counseling for HWWS.

Zearalenone (ZEN) is a secondary metabolite, which is mainly produced by Fusarium fungi and exists in various feeds and agricultural products. Recently, an increasing amount of data has shown that ZEN, as an estrogen-like hormone, can have harmful effects on the female reproductive system, especially on oogenesis and folliculogenesis. Breast milk is considered to be the ideal form of nutrition for infants; however, there are some records of contaminants in food, such as mycotoxins, which may be transferred from maternal blood to milk. In this study, we investigated the toxic effects of breast milk on folliculogenesis in offspring following maternal ZEN exposure. Our results showed that maternal ZEN exposure significantly inhibited the process of primordial follicle (PF) assembly and reduced the number of PFs in suckled offspring's ovaries. In addition, RNA-seq analysis showed that RIG-I-like receptor (RLRs) signaling pathways were activated after exposed to ZEN, which increased the expression levels of DNA damage (γ-H2AX, RAD51, and PARP1) and apoptosis related protein (BAX/BCL2 and Caspase-3). Finally, ZEN exposure interfered with follicular development, as evidenced by the reduced percentages of oocyte maturation and embryonic development when the offspring grew to adolescence. It is worth noting that maternal ZEN exposure disrupted the tri-methylation levels of H3K4, H3K9, and H3K27 in the offspring's oocytes. Our results indicated that maternal ZEN exposure affected ovarian development in offspring through the breast milk, which may be detrimental to their reproductive capability in adult life.

To observe the effect of moxibustion on cognitive function in patients with cognitive decline of type 2 diabetes mellitus (T2DM).A total of 47 patients with cognitive decline of T2DM were randomized into an observation group (24 cases, 4 cases dropped off ) and a control group (23 cases, 3 cases dropped off ). Conventional hypoglycemic intervention was adopted in the control group. On the basis of the treatment in the control group,After treatment, the scores of immediate memory and delayed memory of AVLT in the observation group were higher than those before treatment and those in the control group (

Natural and synthetic environmental estrogens (EEs), interfering with the physiological functions of the body's estrogens, are widespread and are rising much concern for their possible deleterious effects on human and animal health, in particular on reproduction. In fact, increasing evidence indicate that EEs can be responsible for a variety of disfunctions of the reproductive system especially in females such as premature ovarian insufficiency (POI). Because of their great structural diversity, the modes of action of EEs are controversial. One important way through which EEs exert their effects on reproduction is the induction of apoptosis in the ovary. In general, EEs can exert pro-and anti-apoptotic effects by agonizing or antagonizing numerous estrogen-dependent signaling pathways. In the present work, results concerning apoptotic pathways and diseases induced by representative EEs (such as zearalenone, bisphenol A and di-2-ethylhexyl phthalate), in ovaries throughout development are presented into an integrated network. By reviewing and elaborating these studies, we propose inflammatory factors, centered on the production of tumor necrosis factor (TNF), as a major cause of the induction of apoptosis by EEs in the mammalian ovary. As a consequence, potential strategies to prevent such EE effect are suggested.

Regulatory T (Treg) cells maintain immune homeostasis by inhibiting abnormal/overactive immune responses to both autogenic and nonautogenic antigens. Treg cells play an important role in immune tolerance, autoimmune diseases, infectious diseases, organ transplantation, and tumor diseases. Treg cells have two functional characteristics: T cell anergy and immunosuppression. Treg cells remain immune unresponsive to high concentrations of interleukin-2 and anti-CD3 monoclonal antibodies. In addition, the activation of Treg cells after TCR-mediated signal stimulation inhibits the activation and proliferation of effector T cells. In the process of tumor development, Treg cells accumulate locally in the tumor and lead to tumor escape by inducing anergy and immunosuppression. It is believed that targeted elimination of Treg cells can activate tumor-specific effector T cells and improve the efficiency of cancer immunotherapy. Therefore, inhibition/clearance of Treg cells is a promising strategy for enhancing antitumor immunity. Here, we review studies of cancer immunotherapies targeting Treg cells.

Insect-microbial symbioses have vast biochemical diversity, which is beneficial to produce bioactive secondary metabolites. In this study, chemical examination of a Streptomyces sp. associated with a mud dauber wasp led to the isolation of fourteen compounds. Their structures were determined by spectroscopic methods and comparison with literature data. Among the isolates, compounds 1,2,3-benzotriazin-4(1H)-one and 4-(2-aminoethyl)phenyl acetate were first reported from this species. Bioactivities of the isolated compounds were assayed for the first time against hexokinase II. 4-(2-Aminoethyl)phenyl acetate, germicidin B, phenylacetic acid, isogermicidin A and germicidin C displayed significant inhibitory activity against hexokinase II, with the IC50 values of 5.11, 7.11, 7.15, 8.45 and 8.78 μM, respectively.

The expansion of polyclonal T regulatory cells (Tregs) offers great promise for the treatment of immune-mediated diseases, such as multiple sclerosis (MS). However, polyclonal Tregs can be non-specifically immunosuppressive. Based on the advancements with chimeric antigen receptor (CAR) therapy in leukemia, we previously engineered Tregs to express a T-cell receptor (TCR) specific for a myelin basic protein (MBP) peptide. These TCR-engineered specific Tregs suppressed the proliferation of MBP-reactive T effector cells and ameliorated myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). Herein, we extend this approach by creating human regulatory T cells expressing functional single-chain chimeric antigen receptors (scFv CAR), targeting either MBP or MOG. These scFv CAR-transduced Tregs retained FoxP3 and Helios, characteristic of Treg cells, after long-term expansion in vitro. Importantly, these engineered CNS targeting CAR-Tregs were able to suppress autoimmune pathology in EAE, demonstrating that these Tregs have the potential to be used as a cellular therapy for MS patients.

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In this study, we screened bacterial strains to identify specific probiotics to treat pig diarrhea caused by Escherichia coli or Salmonella. The potential probiotics were assayed for their survival in gastrointestinal solution, their antimicrobial activity, cell-surface properties, adhesion to Caco-2 cells, and inhibition of pathogen adhesion. Nine out of the 20 strains tested showed high tolerance of a simulated gastrointestinal environment and six strains exerted antagonistic effects against enterohemorrhagic E. coli (EHEC) O157:H7 and Salmonella Typhimurium MQ. Lactobacillus johnsonii pDX1e exhibited a higher potent antibacterial activity. Four strains (pDX1a, pDX1e, pDX3a, and pDX5a) displayed auto-aggregation, hydrophobicity, and adhesion to Caco-2 cells similar to those of the reference strain Lacticaseibacillus rhamnosus GG (LGG). Enterococcus durans pDX5a showed the highest adhesion capacity (13.86%), followed by the reference strain LGG (11.20%). All the tested strains competitively suppressed the attachment of pathogens to Caco-2 cells (by 30.73-55.18%); L. johnsonii pDX1e and Ent. durans pDX5a significantly inhibited the adhesion of pathogens by substitution and exclusion, respectively. Therefore, pDX1e and pDX5a were selected as probiotic strains for further investigation and application.

Background An accurate diagnosis for high-suspicion nodules based on the 2015 American Thyroid Association (ATA) guidelines would reduce unnecessary invasive examinations. Elastography is a useful tool for discriminating benign and malignant thyroid nodules. The aim of this study is to investigate the diagnostic efficiency of elastography for high-suspicion thyroid nodules based on the 2015 ATA guidelines in the Chinese population. Methods Thyroid nodules with high-suspicion characteristics based on the 2015 ATA guidelines were subjected to conventional ultrasound (US) and ultrasound strain elastography (USE) examinations at 12 hospitals from 4 geographic regions across China. Cytology/histology of thyroid nodules was used as a reference method. Receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic performance of the elasticity score (ES) and strain ratio (SR). Logistic regression analysis was used to determine the predictors of malignancy. Results Overall, a total of 1445 thyroid nodules (834 malignant, 611 benign) from 12 centers were included in the final analysis. The areas under the curve of the ES and SR were 0.828 and 0.732, respectively. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the ES were 92.4, 60.7, 79.0, 76.3 and 85.5%, respectively, and those of the SR were 81.1, 50.1, 68.9, 65.9 and 67.9%, respectively. The combination of the Thyroid Imaging Reporting and Data System (TI-RADS) and ES led to a significant increase in the sensitivity and NPV (97.1 and 91.9%, respectively) compared with the TI-RADS alone. Logistic regression analysis showed that microcalcifications (OR = 5.290), taller than wide (OR = 12.710), irregular margins (OR = 10.117), extrathyroidal extension (ETE; OR = 6.412), the ES (OR = 3.741) and the SR (OR = 1.083) were independent predictors of malignant thyroid nodules. The sensitivity, specificity, accuracy, PPV and NPV of the ES were all superior in nodules ≥1 cm than in those Conclusions Elastography combined with the ES is a valuable tool for the assessment of high-suspicion thyroid nodules based on the 2015 ATA guidelines, especially in nodules ≥1 cm.

Environmental influence is one of the attributing factors for health status. Chronic interaction with electronic display technology and lack of outdoor activities might lead to health issues. Given the concerns about the digital impact on lifestyle and health challenges, we aimed to investigate the daily activity inclination and health complaints among the Malaysian youth. A self-administered questionnaire covering lifestyle and health challenges was completed by 220 youths aged between 16 and 25. There were a total of 22 questions. Seven questions inspected the patterns of indoor and outdoor activities. Fifteen questions focused on the visual and musculoskeletal symptoms linked to both mental and physical health. The total time spent indoors (15.0 ± 5.4 hours/day) was significantly higher than that spent outdoors (2.5 ± 2.6 hours/day) (t = 39.01, p < 0.05 ). Total time engrossed in sedentary activities (13.0 ± 4.5 hours/day) was significantly higher than that in nonsedentary activities (4.5 ± 3.8 hours/day) comprised of indoor sports and any outdoor engagements (t = 27.10, p < 0.05 ). The total time spent on electronic related activities (9.5 ± 3.7 hours/day) was were higher than time spent on printed materials (3.4 ± 1.6 hours/day) (t = 26.01, p < 0.05 ). The association of sedentary activities was positive in relation to tired eyes (χ2 = 17.58, p < 0.05 ), sensitivity to bright light (χ2 = 12.10, p < 0.05 ), and neck pain (χ2 = 17.27, p < 0.05 ) but negative in relation to lower back pain (χ2 = 8.81, p < 0.05 ). Our youth spent more time in building and engaged in sedentary activities, predominantly electronic usage. The health-related symptoms, both visual and musculoskeletal symptoms, displayed a positive association with a sedentary lifestyle and a negative association with in-building time.

To observe the effects of acupuncture on resting-state functional connectivity (rs-FC) in patients with refractory peripheral facial paralysis, and to preliminarily explore the central mechanism of acupuncture for this disease.Twenty patients with refractory peripheral facial paralysis were selected as subject and treated with acupuncture at Qianzheng (EX-HN 16), Fengchi (GB 20), Cuanzhu (BL 2), Dicang (ST 4), Jiache (ST 6), Shuigou (GV 26), Chengjiang (CV 24), Yifeng (TE 17), Touwei (ST 8), Sibai (ST 2), Yingxiang (LI 20) and Hegu (LI 4), once every other day, three times a week, 15 times as a course of treatment. The 1-course treatment was given. The score of Sunnybrook (Toronto) facial grading system was used to evaluate the clinical efficacy before and after the treatment. In addition, 20 healthy volunteers were selected as control. For patients, the resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment, for healthy volunteers, the scans were performed when they were recruited. The brain magnetic resonance images were analyzed with left primary motor area (LMⅠ) and right primary motor area (RMⅠ) as regions of interest. The differences of rs-FC between patients with refractory peripheral facial paralysis before and after treatment and healthy volunteers were compared.Compared before treatment, the Sunnybrook score was increased after the treatment ((1) Acupuncture could effectively improve the clinical symptoms of refractory peripheral facial paralysis. (2) The brain function of patients with refractory peripheral facial paralysis has been changed before acupuncture, which may be caused by the reactive compensation of the brain. (3) Acupuncture could enhance the functional connection between LMⅠ and left inferior frontal gyrus to promote the compensatory response, which may be one of the central mechanisms of acupuncture for refractory peripheral facial paralysis.

Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this study was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum–DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner. Mol Cancer Ther; 17(2); 474–83. ©2017 AACR.

Precision cancer medicine seeks to target the underlying genetic alterations of cancer; however, it has been challenging to use genetic profiles of individual patients in identifying the most appropriate anti-cancer drugs. This spurred the development of patient avatars; for example, patient-derived xenografts (PDXs) established in mice and used for drug exposure studies. However, PDXs are associated with high cost, long development time and low efficiency of engraftment. Herein we explored the use of microfluidic devices or microchambers as simple and low-cost means of maintaining bladder cancer cells over extended periods of times in order to study patterns of drug responsiveness and resistance. When placed into 75 µm tall microfluidic chambers, cancer cells grew as ellipsoids reaching millimeter-scale dimeters over the course of 30 days in culture. We cultured three PDX and three clinical patient specimens with 100% success rate. The turn-around time for a typical efficacy study using microchambers was less than 10 days. Importantly, PDX-derived ellipsoids in microchambers retained patterns of drug responsiveness and resistance observed in PDX mice and also exhibited in vivo-like heterogeneity of tumor responses. Overall, this study establishes microfluidic cultures of difficult-to-maintain primary cancer cells as a useful tool for precision cancer medicine.