Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.

Electroacupuncture relieves chronic pain by promoting microglia M2 polarization in lumbar disc herniation rats.

Electroacupuncture has an effective analgesia on chronic pain caused by lumbar disc herniation (LDH) clinically, however, the underlying mechanism is unclear. In this study, we investigated whether electroacupuncture alleviated pain in LDH model rats by inducing spinal microglia M2 polarization. We established a noncompression LDH rat model by implanting autologous caudal nucleus pulposus into L5/L6 nerve root. Electroacupuncture (30 min/day) treatment on the ipsilateral side was started on the 8th postoperative day, once a day for consecutive 7 days. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were tested for pain behavior. Western blotting was used to detect the protein expression in lumbar enlargement (L5/L6). Immunofluorescence was used to detect iNOS+/Iba-1+ and Arg-1+/Iba-1+ and CB2R+/Iba-1+ in lumbar enlargement (L5/L6). We show that PWT and PWL decreased in the LDH group while Iba-1, iNOS, and TNF-α expression increased significantly in lumbar spinal dorsal horn (SDH) after LDH surgery, and revealing that microglia were activated and polarized towards proinflammatory M1 phenotype. Electroacupuncture treatment significantly increased PWT and PWL while reducing Iba-1, iNOS, and TNF-α expression, interestingly, Arg-1 and IL-10 expression were significantly increased. Moreover, electroacupuncture treatment led to CB2 receptors on microglia upregulation, while NF-κB and p-NF-κB expression in lumbar SDH downregulation. Our study indicated that electroacupuncture may reduce nociceptive hyperalgesia by inhibiting microglia activation and microglia M1 polarization and promoting microglia M2 polarization in lumbar SDH of LDH rats, which may be caused by the activation of CB2 receptors on microglia and inhibition of NF-κB pathway in lumbar SDH.

Effect of Probiotic Yogurt Supplementation(Bifidobacterium animalis ssp. lactis BB-12) on Gut Microbiota of Female Taekwondo Athletes and Its Relationship with Exercise-Related Psychological Fatigue.

OBJECTIVE: The gut microbiota plays a critical role in regulating human health and athletic performance. Probiotic supplementation has been shown to modulate gut microbiota composition and improve exercise performance. This study aimed to investigate the effect of probiotic yogurt supplementation on gut microbiota and its relationship with exercise-related psychological fatigue in female taekwondo athletes. METHODS: Twenty female taekwondo athletes were randomly assigned to either a dietary intervention group (DK) or a control group (CK). The athletes' exercise-related psychological fatigue was measured using the Athlete Burnout Questionnaire (ABQ) before and after an 8-week intervention. High-throughput sequencing was used to profile the gut microbiota, and functional prediction of the microbial community was performed. The effect of the dietary intervention on the athletes' exercise-related psychological fatigue clearance rate and its relationship with the gut microbiota were explored. RESULTS: (1) The probiotic supplementation of Bifidobacterium animalis ssp. lactis BB-12 for 8 weeks significantly increased the ABQ scores of the DK group compared to the CK group (p < 0.05). (2) The abundances of Bifidobacterium, Bacteroides, Lachnospiraceae, family _Lactobacillaceae, and genus _Lactobacillus were significantly higher in the DK group than in the CK group after probiotic supplementation, while Escherichia coli was significantly lower in the DK group than in the CK group. (3) The ABQa scores were positively correlated with Proteus; ABQb scores were positively correlated with Streptococcus and Enterococcus; and ABQc scores were positively correlated with Klebsiella, Bacteroides, and Streptomyces. (4) The DK group had significantly higher levels of L-arginine biosynthesis I (via L-ornithine), fatty acid biosynthesis and oxidation, and L-isoleucine biosynthesis III pathways compared to the CK group. Tyrosine degradation I (via 2,3-dihydroxyphenylpropionate) was significantly lower in the DK group than in the CK group. CONCLUSIONS: Probiotic yogurt supplementation of Bifidobacterium animalis ssp. lactis can promote the clearance of exercise-related psychological fatigue in female taekwondo athletes by upregulating beneficial gut microbiota, inhibiting harmful gut microbiota, and regulating relevant metabolic pathways.

Huo Xiang Zheng Qi Oral Liquid Combined with 5-HT3 Receptor Antagonists and Dexamethasone Can Prevent Chemotherapy-Induced Nausea and Vomiting for Patients Receiving Multiday Cisplatin-Based Regimen: A Multicenter Trial.

Background: Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects associated with deterioration in the quality of life. This study aimed to assess the clinical value of Huoxiang Zhengqi (HXZQ) oral liquid, a Chinese patent medicine, in combination with 5-HT3 receptor antagonists (RAs) and dexamethasone, in preventing CINV in patients receiving multiday cisplatin-based chemotherapy. Methods: In this multicenter, exploratory randomized clinical trial, the authors compared the efficacy of HXZQ oral liquid against a control group receiving a placebo, in combination with 5-HT3 RAs and dexamethasone, in preventing CINV in chemotherapy-naive patients receiving a multiday cisplatin-based regimen between January 2021 and September 2021. The primary endpoint was the complete response (CR) rate. The secondary endpoints included days with no CINV, the incidence of CINV, and life function. Results: Sixty patients were randomized into two groups and included in the study. The CR rate was significantly improved by HXZQ oral liquid in acute CINV (63.33% vs. 33.33%, p = 0.020) and CINV beyond the risk phase (96.67% vs. 46.67%, p = 0.000). The number of days with no CINV was significantly more in the HXZQ group compared with the control group in the overall phase (18.10 ± 3.64 vs. 12.13 ± 7.63, p = 0.002). Significantly higher Functional Living Index-Emesis total and domain scores were observed in the HXZQ group. Conclusions: HXZQ oral liquid combined with 5-HT3 RAs and dexamethasone is a feasible and safe approach to prevent CINV in patients receiving multiday cisplatin-based chemotherapy who cannot use neurokinin 1 RAs. Clinical Trial Registration: ChiCTR2000040123.

Influence of Psychological Factors in Primary Dysmenorrhea Patients on De qi: a Secondary Analysis of a Randomized Controlled Trial.

Background: De qi , the needling sensation, is important in acupuncture treatment. Almost all studies believe that deep needling and manipulation could achieve a significant de qi sensation. However, relatively few studies have examined the effect of psychological factors on de qi, and those that did often reached different conclusions. Objectives: To explore the influence of psychologic factors on de qi in patients with primary dysmenorrhea (PD). Methods: Sixty-eight PD patients with cold and dampness stagnation were randomly allocated to de qi (deep insertion using thick needles, with manipulation, n=17) and non-de qi groups (shallow insertion using thin needles, without manipulation, n=51). Both groups received bilateral needling at Sanyinjiao (SP6) for 30 min. De qi was assessed using the Acupuncture De qi Clinical Assessment Scale (ADCAS). The patients' acupuncture-related anxiety and their expectations of the relationship between needle sensation and curative effect were evaluated using a five-point and four-point scale, respectively. Results: Within the de qi group, all patients experienced the de qi sensation, although anxiety levels were unrelated to de qi. Patients' expectations correlated negatively with de qi timing, and positively with electric sensation. Within the non-de qi group, 59.5% of patients experienced de qi. Between those who experienced it and those who did not, no significant differences were found in anxiety levels, although patients' expectations differed significantly. Among patients who experienced de qi sensations in the non-de qi group, anxiety and throbbing were positively correlated. Additionally, patients' expectations correlated positively with de qi intensity, as well as coldness, and numbness. Conclusion: Psychological factors should be considered when studying de qi since PD patients' expectations could influence the de qi sensation at SP6.

Cancer CRC: A Comprehensive Cancer Core Transcriptional Regulatory Circuit Resource and Analysis Platform.

A core transcriptional regulatory circuit (CRC) is a group of interconnected auto-regulating transcription factors (TFs) that form loops and can be identified by super-enhancers (SEs). Studies have indicated that CRCs play an important role in defining cellular identity and determining cellular fate. Additionally, core TFs in CRCs are regulators of cell-type-specific transcriptional regulation. However, a global view of CRC properties across various cancer types has not been generated. Thus, we integrated paired cancer ATAC-seq and H3K27ac ChIP-seq data for specific cell lines to develop the Cancer CRC (http://bio.liclab.net/Cancer_crc/index.html). This platform documented 94,108 cancer CRCs, including 325 core TFs. The cancer CRC also provided the "SE active core TFs analysis" and "TF enrichment analysis" tools to identify potentially key TFs in cancer. In addition, we performed a comprehensive analysis of core TFs in various cancer types to reveal conserved and cancer-specific TFs.

Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models.

The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FcεR)-mediated activation of mast cells and basophils, IgG (FcγR)-mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dose-dependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.

Immunodominance of Epitopes and Protective Efficacy of HI Antigen Are Differentially Altered Using Different Adjuvants in a Mouse Model of Staphylococcus aureus Bacteremia.

HI, a fusion protein that consists of the alpha-toxin (Hla) and the N2 domain of iron surface determinant B (IsdB), is one of the antigens in the previously reported S. aureus vaccine rFSAV and has already entered phase II clinical trials. Previous studies revealed that HI is highly immunogenic in both mice and healthy volunteers, and the humoral immune response plays key roles in HI-mediated protection. In this study, we further investigated the protective efficacy of immunization with HI plus four different adjuvants in a mouse bacteremia model. Results showed that HI-mediated protection was altered in response to different adjuvants. Using antisera from immunized mice, we identified seven B-cell immunodominant epitopes on Hla and IsdB, including 6 novel epitopes (Hla1-18, Hla84-101, Hla186-203, IsdB342-359, IsdB366-383, and IsdB384-401). The immunodominance of B-cell epitopes, total IgG titers and the levels of IFN-γ and IL-17A from mice immunized with HI plus different adjuvants were different from each other, which may explain the difference in protective immunity observed in each immunized group. Thus, our results indicate that adjuvants largely affected the immunodominance of epitopes and the protective efficacy of HI, which may guide further adjuvant screening for vaccine development and optimization.

Valproic Acid Induces Autism-Like Synaptic and Behavioral Deficits by Disrupting Histone Acetylation of Prefrontal Cortex ALDH1A1 in Rats.

OBJECTIVES: This study aimed to investigate the impact of valproic acid (VPA) on the histone acetylation of acetaldehyde dehydrogenase 1A1 (ALDH1A1) and the mechanism underlying VPA-induced autism-like behavior. METHODS: Female Sprague-Dawley rats were intraperitoneally injected with VPA during gestation to establish an autism model in their offspring. Some offspring prenatally exposed to VPA were randomly treated with MS-275, one histone deacetylase (HDAC) inhibitor, or retinoic acid (RA) after birth. Behavioral tests were conducted on the offspring 6 weeks after birth. Electrophysiological experiments were performed to investigate long-term potentiation (LTP) in the prefrontal cortex (PFC). The expression levels of AMPA receptors (GluA1 and 2), NMDA receptors (GluN1 and 2), synapsin 1 (SYN1), HDAC, acetylated histone 3 (AcH3), RA receptor alpha (RARα), and ALDH1A1 in the PFC were measured by Western blotting and quantitative polymerase chain reaction. ALDH enzyme activity in PFC tissue was detected using a Micro ALDH Assay Kit. The RA level in the PFC was measured using ultrahigh-performance liquid chromatography/tandem mass spectrometry. A chromatin immunoprecipitation (ChIP) experiment explored the interaction between the ALDH1A1 gene and AcH3. RESULTS: Offspring prenatally exposed to VPA showed autism-like behavior, upregulated the levels of LTP and GluN2A, GluA1, and SYN1 proteins relevant to synaptic plasticity in the PFC. The expression levels of HDAC3 mRNA and protein were increased. On the other hand, there was a significant reduction in the levels of AcH3, RARα, RA, ALDH1A1 mRNA and protein, the level of ALDH activity and AcH3 enrichment in the ALDH1A1 promoter region in VPA-induced offspring. Administration of MS-275 in VPA offspring significantly elevated the levels of AcH3, ALDH1A1 mRNA and protein, ALDH activity, RA, the level of RARα protein and the binding of AcH3 to the ALDH1A1 promoter. In addition, the GluA1 protein level and LTP were reduced, and most behavioral deficits were reversed. After RA supplementation in the VPA-treated offspring, the RA and RARα protein levels were significantly upregulated, GluA1 protein and LTP were downregulated, and most autism-like behavioral deficits were effectively reversed. CONCLUSION: These findings suggest that VPA impairs histoneacetylation of ALDH1A1 and downregulates the RA-RARα pathway. Such epigenetic modification of ALDH1A1 by VPA leads to autism-like synaptic and behavioral deficits.

Neferine Protects against Hypoxic-Ischemic Brain Damage in Neonatal Rats by Suppressing NLRP3-Mediated Inflammasome Activation.

Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. Given the prevalence of HIE and the associated fatality, further studies on its pathogenesis are warranted. Oxidative stress and neuroinflammatory injury are two important factors leading to brain tissue injury and nerve cell loss in HIE. Neferine, an alkaloid extracted from lotus seed embryo, exerts considerable effects against several diseases such as cancers and myocardial injury. In this study, we demonstrated the neuroprotective effect of neferine on HIE and hypothesized that it involves the inhibition of neuronal pyroptosis, thereby ameliorating neurological inflammation and oxidative stress. We demonstrated that the mRNA levels of proteins associated with pyroptosis including caspase-1, the caspase adaptor ASC, gasdermin D, interleukin- (IL-) 18, IL-1ß, and some inflammatory factors were significantly increased in neonatal HIBD model rats compared to those in the control group. The increase in these factors was significantly suppressed by treatment with neferine. We stimulated PC12 cells with CoCl2 to induce neuronal HIBD in vitro and investigated the relationship between neferine and pyroptosis by altering the expression of the NLRP3 inflammasome. The overexpression of NLRP3 partially reversed the neuroprotective effect of neferine on HIBD, whereas NLRP3 knockdown further inhibited caspase-1 activation and IL-1ß and IL18 expression. In addition, simultaneous alteration of NLRP3 expression induced changes in intracellular oxidative stress levels after HIBD. These findings indicate that neferine ameliorates neuroinflammation and oxidative stress injury by inhibiting pyroptosis after HIBD. Our study provides valuable information for future studies on neferine with respect to neuroinflammation and pyroptosis.

A weekly vitamin A supplementary program alleviates social impairment in Chinese children with autism spectrum disorders and vitamin A deficiency.

BACKGROUND: Children in China with Autism Spectrum Disorders (ASD) are prone to vitamin A deficiency (VAD). The present study compared two vitamin A supplements (VAS) in two groups of children with ASD and VAD to explore a better VAS program for children with ASD. METHOD: A total of 138 3-8-year-old children with ASD (118 males and 20 females) were enrolled in this 6-month study. Of these 138 children, 82 who had VAD (ASD-VAD) were divided into two VAS groups that received the recommended VAS program (RNI-VAS) or a weekly dose of VAS (WD-VAS). The 56 children who had normal vitamin A levels (ASD-VAN) served as a control group. The Social Responsiveness Scale (SRS) was used to assess the severity of social impairment before and after the interventions. Their serum retinol (VA) and oxytocin (OXT) concentrations, the mRNA expression of retinoic acid receptors (RARs), and CD38 gene in peripheral blood was measured before and after the 6-month intervention. RESULTS: The WD-VAS program increased VA levels better than the RNI-VAS program did (P < 0.01), and it significantly decreased SRS scores (P < 0.05). In addition, the change in VA was positively correlated with the change in mRNA levels in RARß (r = 0.2441, P = 0.0092), the CD38 in PBMC (r = 0.2729, P = 0.0033), and the change in OXT concentration in serum (r = 0.3735, P < 0.0001). VA was also negatively correlated with changes in SRS scores across the three groups (r = -0.2615, P = 0.0026). CONCLUSION: The WD-VAS might be more suitable for children with ASD and VAD than other interventions to improve both VA and social functioning, which may be mediated through the RARß-CD38-OXT axis.

Maternal vitamin A deficiency impairs cholinergic and nitrergic neurons, leading to gastrointestinal dysfunction in rat offspring via RARß.

AIMS: Many gastrointestinal (GI) disorders are developmental in origin and are caused by abnormal enteric nervous system (ENS) formation. Maternal vitamin A deficiency (VAD) during pregnancy affects multiple central nervous system developmental processes during embryogenesis and fetal life. Here, we evaluated whether maternal diet-induced VAD during pregnancy alone can cause changes in the ENS that lead to GI dysfunction in rat offspring. MAIN METHODS: Rats were selected to construct animal models of normal VA, VA deficiency and VA supplementation. The fecal water content, total gastrointestinal transmission time and colonic motility were measured to evaluate gastrointestinal function of eight-week-old offspring rats. The expression levels of RARß, SOX10, cholinergic (ChAT) and nitrergic (nNOS) enteric neurons in colon tissues were detected through western blot and immunofluorescence. Primary enteric neurospheres were treated with retinoic acid (RA), infection with Ad-RARß and siRARß adenovirus, respectively. KEY FINDINGS: Our data revealed marked reductions in the mean densities of cholinergic and nitrergic enteric neurons in the colon and GI dysfunction evidenced by mild intestinal flatulence, increased fecal water content, prolonged total GI transit time and reduced colon motility in adult offspring of the VAD group. Interestingly, maternal VA supplementation (VAS) during pregnancy rescued these changes. In addition, in vitro experiments demonstrated that exposure to appropriate doses of RA promoted enteric neurosphere differentiation into cholinergic and nitrergic neurons, possibly by upregulating RARß expression, leading to enhanced SOX10 expression. SIGNIFICANCE: Maternal VAD during pregnancy is an environmental risk factor for GI dysfunction in rat offspring.

Therapeutic potential of targeting MKK3-p38 axis with Capsaicin for Nasopharyngeal Carcinoma.

Background: Capsaicin is an active compound found in plants of the Capsicum genus; it has a range of therapeutic benefits, including anti-tumor effects. Here we aimed to delineate the inhibitory effects of capsaicin on nasopharyngeal carcinoma (NPC). Methods: The anti-cancer effects of capsaicin were confirmed in NPC cell lines and xenograft mouse models, using CCK-8, clonogenic, wound-healing, transwell migration and invasion assays. Co-immunoprecipitation, western blotting and pull-down assays were used to determine the effects of capsaicin on the MKK3-p38 axis. Cell proliferation and EMT marker expression were monitored in MKK3 knockdown (KD) or over-expression NPC cell lines treated with or without capsaicin. Finally, immunohistochemistry was performed on NPC specimens from NPC patients (n = 132) and the clinical relevance was analyzed. Results: Capsaicin inhibited cell proliferation, mobility and promoted apoptosis in NPC cells. Then we found that capsaicin directly targets p38 for dephosphorylation. As such, MKK3-induced p38 activation was inhibited by capsaicin. Furthermore, we found that capsaicin-induced inhibition of cell motility was mediated by fucokinase. Xenograft models demonstrated the inhibitory effects of capsaicin treatment on NPC tumor growth in vivo, and analysis of clinical NPC samples confirmed that MKK3 phosphorylation was associated with NPC tumor growth and lymphoid node metastasis. Conclusions: The MKK3-p38 axis represents a potential therapeutic target for capsaicin. MKK3 phosphorylation might serve as a biomarker to identify NPC patients most likely to benefit from adjunctive capsaicin treatment.

Vitamin A deficiency exacerbates autism-like behaviors and abnormalities of the enteric nervous system in a valproic acid-induced rat model of autism.

The manifestations of autism spectrum disorder (ASD) are highly heterogeneous. As many individuals with ASD have gastrointestinal (GI) comorbidities, ASD with GI problems is considered to be a subtype of ASD. Vitamin A (VA) plays an important role in the development of both the central and peripheral nervous system. However, the relationship between VA deficiency (VAD) and ASD with GI comorbidities is still unclear. We established rat models with different VA levels based on the valproic acid-induced autism model. Compared to autism model rats with VA normal (VAN), autism model rats with gestational VAD showed more severe autism-like behavior, increased GI transit time, and impairment of the enteric nervous system (ENS). Besides, the expression levels of retinoic acid receptor α (RARα) and Ret in autism model rats with VAD were decreased compared with those in rats with VAN. Supplementation with VA was found to effectively ameliorate autism-like behaviors and impairments of GI motility and the ENS in autism model rats with VAD. Chromatin immunoprecipitation results suggested that RARa can bind to the promoter region of the Ret gene and regulate the Ret signaling pathway. We speculate that VAD in autism might lead to impairments of both the brain and ENS. VAD might be a factor that causes individuals to be more susceptible to ASD-related risk factors and aggravates a subtype of ASD with GI comorbidities.

Prognosis of limited-stage small cell lung cancer with comprehensive treatment including radical resection.

BACKGROUND: The NCCN (National Comprehensive Cancer Network) Clinical Practice Guidelines in Oncology (NCCN guidelines) recommend radical resection for T1-2N0M0 patients with limited-stage small cell lung cancer (LS-SCLC). However, only about 5% of patients with small cell cancer (SCLC) were initially diagnosed as T1-2N0M0. The purpose of our study was to analyze and compare the effects of the comprehensive treatment including radical surgery and concurrent chemoradiotherapy on the prognosis of patients with LS-SCLC. METHODS: We comprehensively reviewed the medical data of patients with SCLC diagnosed by pathology in our hospital from January 2011 to April 2018. The Ethics Committee of West China Hospital of Sichuan University approved the study. Finally, 50 patients with good follow-up and complete medical data were selected as the surgical group (S group). According to the clinical characteristics of the patients in the S group, 102 LS-SCLC patients who received concurrent chemoradiotherapy in the same period were included in the CCRT group (concurrent chemoradiotherapy group) as the control group. Then according to the orders of the adjuvant treatments, the patients in the S group were divided into the SA group (radical surgery + adjuvant chemotherapy + adjuvant radiotherapy group, 30 cases in total) and the NS group (neoadjuvant chemotherapy + radical surgery + adjuvant chemotherapy ± adjuvant radiotherapy group, 20 cases in total) for subgroup analysis. The SPSS 23.0 software was used for statistical analysis, and the t test was used for group comparison; Kaplan-Meier was used for survival analysis. P < 0.05 demonstrates a statistically significant difference. RESULTS: The median progress-free survival (PFS) in the S group (73 months) was significantly better than that in the CCRT group (10.5 months, P < 0.0001), and the median overall survival (OS) in the S group (79 months) was also significantly better than that in the CCRT group (23 months, P < 0.0001). Subgroup analysis showed that there was no significant difference between the NS group and the SA group. CONCLUSIONS: For LS-SCLC patients, the comprehensive treatment including radical surgery (radical surgery + adjuvant chemotherapy ± adjuvant radiotherapy/neoadjuvant chemotherapy + radical surgery + adjuvant chemotherapy ± adjuvant radiotherapy)may be superior to concurrent chemoradiotherapy.

Optical Vaginal Biopsy Using Optical Coherence Tomography.

OBJECTIVE: Optical coherence tomography is a noninvasive technology that visualizes tissue microstructure with high spatial resolution. We designed a novel vaginal system that demonstrates a clear distinction between vaginal tissues planes. In this study, we sought to compare vaginal tomographic images of premenopausal, perimenopausal, and postmenopausal women, demonstrate feasibility of tracking vaginal tissue changes after treatment with fractional-pixel CO2 laser therapy, and obtain a histologic correlation of these findings. METHODS: Enrolled subjects underwent imaging and were divided into 3 groups based on menopausal status. Women with genitourinary syndrome of menopause who received fractional-pixel CO2 laser therapy were assessed before and after treatment. A cadaveric vagina was used to obtain tomographic and histologic images to assess for accuracy. Our primary outcome was mean vaginal epithelial thickness. Statistical analysis was performed using analysis of variance and t tests, respectively. RESULTS: Among 6 women, the mean vaginal epithelial thickness decreased with menopause (P < 0.01). Although change in epithelial thickness after fractional-pixel CO2 laser treatment varied between the 2 subjects evaluated, it increased significantly for the subject who reported improvement of vaginal symptoms (P < 0.01). Using a cadaveric specimen, optical biopsy was correlated to an hematoxylin and eosin-stained biopsy of the same vaginal site. CONCLUSIONS: This study establishes feasibility of optical coherence tomography in providing an optical biopsy of the vaginal epithelium and lamina propria. In addition, it demonstrates vaginal changes as women enter menopause. This report is the initial phase of a longitudinal cohort study to evaluate changes in vaginal microstructure after energy-based treatment.

Maternal folic acid and micronutrient supplementation is associated with vitamin levels and symptoms in children with autism spectrum disorders.

To explore possible associations between maternal use of micronutrient supplements and the subsequent vitamin levels and symptoms in offspring with autism spectrum disorder (ASD), a total of 416 children with ASD and 201 typically developing (TD) children were enrolled. The children born to mothers without folic acid (FA) and micronutrient supplementation during pregnancy had more severe social cognition impairments, social communication impairments, autism behaviour mannerisms, developmental delays in adaptive and gross motor behaviour and gastrointestinal problems than children born to mothers who used FA and micronutrient supplements (P＜0.05). Interestingly, there was an association between maternal micronutrient supplementation and vitamin A (VA), vitamin D (VD) and folate levels in the ASD children (P<0.05), and levels of these vitamins also were associated with symptoms of ASD. Maternal FA and/or micronutrient supplementation may potentially moderate the symptoms of ASD. Interrupting the chain of micronutrient deficiencies between pregnant mothers and children may be beneficial in improving symptoms of ASD.

Effect of Xiao-Ai-Ping injection on paclitaxel pharmacokinetics in rats by LC-MS/MS method.

Xiao-Ai-Ping injection (XAP) has been shown to be clinically effective in treatment of gastric carcinoma, liver cancer and lung cancer, when it was combined with anticancer drug paclitaxel (PTX). To analyze the effect of XAP on the pharmacokinetics of PTX, a liquid chromatography-tandem mass spectroscopy (LCMS/MS) assay method was developed and validated to quantify PTX simultaneously and its main metabolite 3'-p-hydroxypaclitaxel (C3'-OHP) in rat plasma. PTX and C3'-OHP were quantified using positive MRM mode. The analysis method was validated for specificity, recovery, carry-over, accuracy, precision, sample stability and dilution integrity under various storage conditions. The pharmacokinetic parameters were determined in rats after tail intravenous administration of 6 mg/mL PTX in the absence (control group) or presence of intraperitoneal administration of 10 mL/kg、20 mL/kg XAP (study groups). Compared to control group, the area under the plasma concentration-time curve (AUC) of PTX and C3'-OHP in study groups increased significantly following consecutive administration with XAP for 10 days. In conclusion, pretreatment with XAP enhanced the exposure of PTX and C3'-OHP. There would be herb-drug interaction happening between XAP and PTX in rats.

Influence of the Intensity, Components, and Spreading of the Deqi Sensation on the Analgesic Effect of SP6 Needling in Primary Dysmenorrhea Patients: A Secondary Analysis of a Randomised Controlled Trial.

Although deqi, the phenomenon whereby excitation of Qi in the meridians occurs with needling, is critical to the practice of acupuncture and its efficacy, it is poorly understood. So we investigate the influence of the deqi sensation on the analgesic effects of acupuncture in patients who were enrolled in a randomised controlled trial for the treatment of patients with primary dysmenorrhea, a painful and common condition, and cold and dampness stagnation. Two groups were assessed: a deqi group (undergoing deep needling with thick needles and manipulation, n=17) and a non-deqi group (undergoing shallow needling with thin needles and no manipulation, n=51). The Sanyinjiao (SP6) was needled for 30 min in both groups. Pain scores at baseline, upon needle removal, and at 10, 20, and 30 min after needle removal were evaluated by the Visual Analogue Scale for pain. The deqi sensation was evaluated by the Acupuncture Deqi Clinical Assessment Scale. Patients who experienced a genuine deqi sensation (n=39) were selected for further analysis. Compared with patients in the non-deqi group who experienced deqi (n=25), patients who self-reported deqi in the deqi group (n=14) felt a stronger deqi sensation, experienced soreness and fullness more frequently, felt a greater intensity of soreness, fullness, electric sensation, spreading, and radiating, and experienced larger spreading distances. In those who experienced the deqi sensation in the deqi group, the intensity of the sensation, as well as their degree of soreness and fullness, was negatively correlated with pain reduction. In patients who experienced the deqi sensation in the non-deqi group, deqi intensity was positively correlated with pain reduction, while soreness was negatively correlated with pain reduction. The distance of spreading was not correlated with pain reduction in either group. We found, in SP6 needling of patients with primary dysmenorrhea with cold and dampness stagnation, that a moderate deqi response predicted a prolonged analgesic effect better than a strong deqi response.

Construction of 2D Antimony(III) Selenide Nanosheets for Highly Efficient Photonic Cancer Theranostics.

Photonic cancer hyperthermia has been considered to be one of the most representative noninvasive cancer treatments with high therapeutic efficiency and biosafety. However, it still remains a crucial challenge to develop efficient photothermal nanoagents with satisfactory photothermal performance and biocompatibility, among which two-dimensional (2D) ultrathin nanosheets have recently been regarded as the promising multifunctional theranostic agents for photothermal tumor ablation. In this work, we report, for the first time, on the construction of a novel kind of photothermal agents based on the intriguing 2D antimony(III) selenide (Sb2Se3) nanosheets for highly efficient photoacoustic imaging-guided photonic cancer hyperthermia by near-infrared (NIR) laser activation. These Sb2Se3 nanosheets were easily fabricated by a novel but efficiently combined liquid nitrogen pretreatment and freezing-thawing approach, which were featured with high photothermal-conversion capability (extinction coefficient: 33.2 L g-1 cm-1; photothermal-conversion efficiency: 30.78%). The further surface engineering of these Sb2Se3 ultrathin nanosheets with poly(vinyl pyrrolidone) (PVP) substantially improved the biocompatibility of the nanosheets and their stability in physiological environments, guaranteeing the feasibility in photonic antitumor applications. Importantly, 2D Sb2Se3-PVP nanosheets have been certificated to efficiently eradicate the tumors by NIR-triggered photonic tumor hyperthermia. Especially, the biosafety in vitro and in vivo of these Sb2Se3 ultrathin nanosheets has been evaluated and demonstrated. This work meaningfully expands the biomedical applications of 2D bionanoplatforms with a planar topology through probing into new members (Sb2Se3 in this work) of 2D biomaterials with unique intrinsic physiochemical property and biological effect.