BRAFV600E mutation does not predict lymph node metastases and recurrence in Chinese papillary thyroid microcarcinoma patients.

OBJECT: Previous studies suggest BRAFV600E mutation is a marker for poor prognosis in papillary thyroid cancer, however, its ability to further risk stratify papillary thyroid microcarcinoma (PTMC) remains controversial. We aimed to explore the association between BRAFV600E mutation and the clinicopathological features and recurrence in Chinese PTMC patients. METHODS: We retrospectively reviewed 2094 PTMC patients who underwent surgery and had a valid BRAFV600E mutation test result. Among them, 1292 patients had complete follow-up data. The mutation incidence was determined. Moreover, the clinicopathological characteristics, disease-free survival (DFS), and response to therapy distribution were compared between the mutation and non-mutation groups. RESULTS: BRAFV600E mutation was observed in 90.6 % of all patients and 89.2 % of patients with complete follow-up data. No significant difference was observed in lymph node metastases (LNM) number categories between the mutation and non-mutation groups among all patients (P = 0.329) and 1292 patients (P = 0.408). Neither the 3-year DFS (97.9 % vs. 98.0 %, P = 0.832) nor the response to therapy distribution (P > 0.05) indicated a significant difference between the mutation and non-mutation groups. The 3-year DFS differs among patients having different LNM number categories (99.8 % vs. 98.5 % vs. 77.3 %, P < 0.001). Multivariate analysis revealed that high-volume (over 5) LNM (Total thyroidectomy (TT): OR = 4.000, 95 % CI 2.390-6.694, P < 0.001; Unilateral thyroidectomy (UT): OR = 4.183, 95 % CI 1.565-11.190, P = 0.004), rather than BRAFV600E mutation (P > 0.05), was an independent risk factor of response to therapy. CONCLUSIONS: Our results suggested that BRAFV600E mutation could not accurately predict LNM or the recurrence of Chinese PTMC patients. Moreover, high-volume LNM is significantly associated with PTMC prognosis.

Flavonoid extracts of Citrus aurantium L. var. amara Engl. Promote browning of white adipose tissue in high-fat diet-induced mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Obesity has become a public burden worldwide due to its booming incidence and various complications, and browning of white adipose tissue (WAT) is recognized as a hopeful strategy to combat it. Blossom of Citrus aurantium L. var. amara Engl. (CAVA) is a popular folk medicine and dietary supplement used for relieving dyspepsia, which is recorded in the Chinese Materia Medica. Our previous study showed that blossom of CAVA had anti-obesity potential, while its role in browning of WAT was still unclear. AIM OF THE STUDY: This study aimed to characterize the constituents in flavonoids from blossom of CAVA (CAVAF) and to clarify the anti-obesity capacities especially the effects on browning of WAT. MATERIALS AND METHODS: Gradient ethanol eluents from blossom of CAVA were obtained by AB-8 macroporous resin. 3T3-L1 cells and pancreatic lipase inhibition assay were employed to investigate the potential anti-obesity effects in vitro. HPLC and UPLC/MS assays were performed to characterize the chemical profiles of different eluents. Network pharmacology and molecular docking assays were used to reveal potential anti-obesity targets. Furthermore, high-fat diet (HFD)-induced mice were constructed to explore the anti-obesity actions and mechanisms in vivo. RESULTS: 30% ethanol eluents with high flavonoid content and great inhibition on proliferation of 3T3-L1 preadipocytes and pancreatic lipase activity were regarded as CAVAF. 19 compounds were identified in CAVAF. Network pharmacology analysis demonstrated that AMPK and PPARα were potential targets for CAVAF in alleviating obesity. Animal studies demonstrated that CAVAF intervention significantly decreased the body weight, WAT weight, serum TG, TC and LDL-C levels in HFD-fed obese mice. HFD-induced insulin resistance and morphological changes in WAT and brown adipose tissue were also markedly attenuated by CAVAF treatment. CAVAF supplementation potently inhibited iWAT inflammation by regulating IL-6, IL-1ß, TNF-α and IL-10 mRNA expression in iWAT of mice. Furthermore, the gene expression levels of thermogenic markers including Cyto C, ATP synthesis, Cidea, Cox8b and especially UCP1 in iWAT of mice were significantly up-regulated by CAVAF administration. CAVAF intervention also markedly increased the expression levels of PRDM16, PGC-1α, SIRT1, AMPK-α1, PPARα and PPARγ mRNA in iWAT of mice. CONCLUSION: CAVAF treatment significantly promoted browning of WAT in HFD-fed mice. These results suggested that flavonoid extracts from blossom of CAVA were probably promising candidates for the treatment of obesity.

Chemical Composition and Antibacterial and Antiulcerative Colitis Activities of Essential Oil from Pruni Semen.

This study was sought to investigate the chemical composition and antibacterial and antiulcerative colitis (UC) effects of essential oil from Pruni Semen (PSEO). A GC-MS assay showed that the major compounds in PSEO were products of amygdalin hydrolysis, which possessed great antibacterial and anti-inflammatory potential. In vitro antibacterial experiments demonstrated that PSEO treatment inhibited activity of four kinds of intestinal pathogens probably by disrupting the cell wall. Further in vivo studies showed that PSEO administration significantly improved physiological indexes, attenuated histopathological characteristics, and inhibited proinflammatory cytokine production in dextran sulfate sodium (DSS)-induced UC mice. Network pharmacology and molecular docking results predicted that PSEO might prevent UC via regulating the PI3K/AKT pathway. Western blotting and immunofluorescence assays were further conducted for verification, and the results evidenced that PSEO intervention significantly regulated the PI3K/AKT pathway and the expression of its downstream proteins in DSS-induced mice. PSEO might provide a new dietary strategy for UC treatment.

Association between hepatitis B or hepatitis C virus infection and risk of pancreatic cancer: a systematic review and meta-analysis of cohort studies.

Background and aim: With conflicting data from previous observational studies on the relationship between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and pancreatic cancer (PC), we decided to conduct a systematic review and meta-analysis in order to evaluate any potential association. Design: This is a systematic review and meta-analysis. Methods: We conducted a search of three databases (PubMed, Embase, and Web of Science) from the time of their creation up to June 2023. The summary results, including hazard ratio (HR) with 95% confidence interval (CI), were pooled using a generic inverse variance method and a random-effects model. Furthermore, subgroup and sensitivity analyses were conducted. Results: In this meta-analysis, 22 cohort studies with a total of 10,572,865 participants were analyzed. Meta-analysis from 15 cohort studies revealed that HBV infection was correlated with an increased risk of PC (HR = 1.53, 95% CI: 1.40-1.68, p < 0.00001) with no heterogeneity (I2 = 0%, p = 0.49). Meta-analysis from 14 cohort studies showed that HCV infection was associated with an increased risk of PC (HR = 1.82, 95% CI: 1.51-2.21, p < 0.00001). Most of our subgroup analyses yielded similar results. Meta-analysis from four cohort studies indicated that co-infection with HBV and HCV was linked to an increased risk of PC (HR = 2.32, 95% CI: 1.40-3.85, p = 0.001) with no heterogeneity observed (I2 = 0%, p = 0.60). The results of sensitivity analyses were robust. Conclusion: Our meta-analysis showed that HBV/HCV infection or co-infection with HBV and HCV was associated with an increased risk of PC. Future prospective cohort studies need to take into account various ethnicities and any confounding factors, as well as investigate the potential mechanisms of PC development in those with HBV/HCV. Trial registration: Open Science Framework registries (No: osf.io/n64ua).

Isolation and characterization of ZK002, a novel dual function snake venom protein from Deinagkistrodon acutus with anti-angiogenic and anti-inflammatory properties.

Introduction: Pathological angiogenesis, the abnormal or excessive generation of blood vessels, plays an important role in many diseases including cancer, diabetic retinopathy, psoriasis, and arthritis. Additionally, increasing evidence supports the close linkage between angiogenesis and inflammation. Snake venoms are a rich natural source of biologically active molecules and carry rich potential for the discovery of anti-angiogenic and anti-inflammatory modulators. Methods: Here, we isolated and purified a novel protein, ZK002, from the venom of the snake Deinagkistrodon acutus, and investigated its anti-angiogenic and anti-inflammatory activities and mechanisms. Results: ZK002 was identified as a 30 kDa heterodimeric protein of α and ß chains, which exhibited anti-angiogenic activity in various in vitro assays. Mechanistically, ZK002 inhibited activation of VEGF signaling and related mediators including eNOS, p38, LIMK, and HSP27. ZK002 also upregulated the metalloproteinase inhibitor TIMP3 and inhibited components of the VEGF-induced signaling cascade, PPP3R2 and SH2D2A. The anti-angiogenic activity of ZK002 was confirmed in multiple in vivo models. ZK002 could also inhibit the in vitro expression of pro-inflammatory cytokines, as well as in vivo inflammation in the carrageenin-induced edema rat model. Conclusion: Our findings highlight the potential for further development of ZK002 as a dual function therapeutic against diseases with involvement of pathogenic angiogenesis and chronic inflammation.

p-Synephrine ameliorates alloxan-induced diabetes mellitus through inhibiting oxidative stress and inflammation via suppressing the NF-kappa B and MAPK pathways.

Oxidative stress and inflammation play important roles in the development of diabetes mellitus. p-Synephrine, the primary pharmacologically active protoalkaloid in Citrus species, has been popularly consumed as a dietary supplement for weight loss management. However, the effects of p-synephrine on diabetes mellitus and the action mechanisms have not been clearly elucidated. In this study, the in vitro antioxidant effects of p-synephrine were evaluated. The data showed that p-synephrine treatment exhibited significant scavenging effects against DPPH, ABTS and OH radicals and showed high reducing power. Diabetic mice were developed by alloxan injection, followed by p-synephrine administration to investigate its hypoglycemic effects in vivo. The results showed that p-synephrine intervention significantly prevented alloxan-induced alteration in body weight, organ indexes, serum uric acid content and serum creatinine content. Meanwhile, p-synephrine application significantly improved the lipid profiles, superoxide dismutase (SOD) and catalase (CAT) activities and glutathione (GSH) contents in the serum and kidneys of diabetic mice and reduced the malondialdehyde (MDA) content in the serum of diabetic mice. Further assays suggested that p-synephrine treatment improved alloxan-induced decreases of glucose tolerance and insulin sensitivity. Also, p-synephrine supplementation altered histopathological changes in the kidneys and interscapular brown adipose tissues in diabetic mice. In addition, p-synephrine administration inhibited renal inflammation through suppressing tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) gene expression levels, as well as CD45 expression levels. The anti-inflammatory effects were probably involved in the regulation of nuclear factor-κB (NF-κB) activation and mitogen-activated protein kinase (MAPK) phosphorylation. In conclusion, p-synephrine application significantly ameliorated alloxan-induced diabetes mellitus by inhibiting oxidative stress via suppressing the NF-κB and MAPK pathways.

MdPP2C24/37, Protein Phosphatase Type 2Cs from Apple, Interact with MdPYL2/12 to Negatively Regulate ABA Signaling in Transgenic Arabidopsis.

The phytohormone abscisic acid (ABA) plays an important role in the ability of plants to cope with drought stress. As core members of the ABA signaling pathway, protein phosphatase type 2Cs (PP2Cs) have been reported in many species. However, the functions of MdPP2Cs in apple (Malus domestica) are unclear. In this study, we identified two PP2C-encoding genes, MdPP2C24/37, with conserved PP2C catalytic domains, using sequence alignment. The nucleus-located MdPP2C24/37 genes were induced by ABA or mannitol in apple. Genetic analysis revealed that overexpression of MdPP2C24/37 in Arabidopsis thaliana led to plant insensitivity to ABA or mannitol treatment, in terms of inhibiting seed germination and overall seedling establishment. The expression of stress marker genes was upregulated in MdPP2C24/37 transgenic lines. At the same time, MdPP2C24/37 transgenic lines displayed inhibited ABA-mediated stomatal closure, which led to higher water loss rates. Moreover, when exposed to drought stress, chlorophyll levels decreased and MDA and H2O2 levels accumulated in the MdPP2C24/37 transgenic lines. Further, MdPP2C24/37 interacted with MdPYL2/12 in vitro and vivo. The results indicate that MdPP2C24/37 act as negative regulators in response to ABA-mediated drought resistance.

An immediate postoperative response to therapy assessment can help avoid unnecessary RAI therapy.

Background: Radioiodine (RAI) therapy plays a vital role in the postoperative treatment of differentiated thyroid cancer (DTC) patients underwent total thyroidectomy (TT). However, even in the presence of capsular invasion and lymph node metastasis prognosis can be excellent and a postoperative RAI treatment might not be necessary for all patients. Therefore, this study explored the criteria for avoiding unnecessary RAI therapy in these patients. Method: We applied response to therapy assessment immediately after surgery and prospectively recruited 179 excellent or indeterminate response DTC patients with capsular invasion and/or LNM who underwent TT without RAI therapy. During the follow-up, thyroglobulin (Tg), thyroglobulin antibody (TgAb) levels, and cervical ultrasonography were collected and analyzed. Disease-free survival (DFS) was calculated using the Kaplan-Meier method. In addition, response to therapy assessments was performed on patients during each follow-up. Results: The mean follow-up period was 29.85 ± 17.44 months, and the 3- and 5-year DFS for all the patients was 99.3% in each. At the last follow-up, 165 (92.2%) patients had excellent responses, while 12 (6.7%) had an indeterminate response, and one (0.6%) each had biochemical and incomplete responses. No significant difference was observed in response to therapy between the subgroups of LNM and tumor invasion (P>0.05). For patients with capsular invasion and a number of metastatic lymph nodes ≤5 and >5, the proportions of recorded excellent responses were 95.9%, 91.0%, and 85.7%, respectively. Better responses were observed in females (excellent response: 95.5%, P=0.023), patients with stimulated Tg (s-Tg) ≤1ng/ml (excellent response: 100%, P<0.001), s-Tg ≤ 2ng/ml (excellent response: 98.4%, P<0.001), and excellent response for the immediate postoperative assessment (excellent response: 98.5%, P=0.004). Conclusions: The current study suggested that the response to therapy assessment immediately applied postoperatively could help avoid unnecessary RAI therapy among DTC patients with capsular invasion and/or LNM. Moreover, excellent response patients and patients with indeterminate response and s-Tg ≤ 2ng/ml could be managed without RAI therapy.

Novel recombinant human thyroid-stimulating hormone in aiding postoperative assessment of patients with differentiated thyroid cancer-phase I/II study.

PURPOSE: Thyroid hormone withdrawal (THW) inevitably induced hypothyroidism in patients with differentiated thyroid cancer (DTC), and we aimed to evaluate the safety and efficacy of a novel recombinant human thyroid-stimulating hormone (rhTSH, ZGrhTSH) as an alternative of THW in China. METHODS: Totally, 64 DTC patients were enrolled with 24 in the dose-escalation cohort equally grouped into 0.9 mg × 1 day, 0.9 mg × 2 day, 1.8 mg × 1 day, and 1.8 mg × 2 day dosage, and 40 further enrolled into 0.9 mg × 2 day dose-expansion cohort. All patients underwent both ZGrhTSH phase and levothyroxine (L-T4) withdrawal phase for self-comparison in terms of TSH levels, the radioactive iodine (RAI) uptake, stimulated thyroglobulin level, and the quality of life (QoL). RESULTS: In ZGrhTSH phase, no major serious adverse events were observed, and mild symptoms of headache were observed in 6.3%, lethargy in 4.7%, and asthenia in 3.1% of the patients, and mostly resolved spontaneously within 2 days. Concordant RAI uptake was noticed in 89.1% (57/64) of the patients between ZGrhTSH and L-T4 withdrawal phases. The concordant thyroglobulin level with a cut-off of 1 µg/L was noticed in 84.7% (50/59) of the patients without the interference of anti-thyroglobulin antibody. The QoL was far better during ZGrhTSH phase than L-T4 withdrawal phase, with lower Billewicz (- 51.30 ± 4.70 vs. - 39.10 ± 16.61, P < 0.001) and POMS (91.70 ± 16.70 vs. 100.40 ± 22.11, P = 0.011) scores which indicate the lower the better. Serum TSH level rose from basal 0.11 ± 0.12 mU/L to a peak of 122.11 ± 42.44 mU/L 24 h after the last dose of ZGrhTSH. In L-T4 withdrawal phase, a median of 23 days after L-T4 withdrawal was needed, with the mean TSH level of 82.20 ± 31.37 mU/L. The half-life for ZGrhTSH clearance was about 20 h. CONCLUSION: The ZGrhTSH held the promise to be a safe and effective modality in facilitating RAI uptake and serum thyroglobulin stimulation, with better QoL of patients with DTC compared with L-T4 withdrawal.

LINC00094/miR-19a-3p/CYP19A1 axis affects the sensitivity of ER positive breast cancer cells to Letrozole through EMT pathway.

The endocrine therapy resistance of breast cancer is the difficulty and challenge to be urgently solved in the current treatment. In this study, we examined the effects of noncoding RNA LINC00094 and miR-19a-3p on breast cancer in vivo and in vitro by RT-QPCR, Western Blot, luciferase assay, immunofluorescence and drug sensitivity tests. The plasma level of CYP19A1 in patients with breast cancer resistance was lower than that in drug sensitive patients. Compared with normal subjects, miR-19a-3p was highly expressed in plasma of patients with breast cancer. miR-19a-3p is highly expressed in estrogen receptor positive breast cancer cells. The expression of miR-19a-3p promoted the migration and EMT of breast cancer cells and reduced the sensitivity of breast cancer to Letrozole. LINC00094 sponge adsorbed miR-19a-3p. LINC00094 promotes the expression of CYP19A1, the target gene of miR-19a-3p, and inhibits the EMT process of breast cancer, ultimately promoting the sensitivity of ER-positive breast cancer cells to Letrozole. This study found a new mechanism of Letrozole sensitivity in ER positive breast cancer.

Anfibatide alleviates inflammation and apoptosis via inhibiting NF-kappaB/NLRP3 axis in ischemic stroke.

Recent evidence suggests that Nod-like receptor protein-3 (NLRP3) inflammasome is a key mediator of inflammatory response and can induce the activation of apoptosis signaling pathways in ischemic stroke. In this research, we assessed the effects of anfibatide (ANF) on inflammatory and apoptosis in cerebral ischemic injury and the potential mechanisms. Middle cerebral artery occlusion (MCAO) model was established on male Sprague-Dawley rats to induce cerebral ischemia/reperfusion (I/R) injury in vivo. Primary cortical neurons (PCN) cells were exposed to oxygen-glucose deprivation and reintroduction (OGD/R) to mimic cerebral I/R injury in vitro. The results showed that ANF markedly alleviated infarct volume, neurological deficit and neurobehavioral impairment in MCAO/R rats, enhanced cell viability and decreased LDH release in PCN after OGD/R. The number of TUNEL-positive cells, Bax, cleaved-caspase-3, p-IκBα, p-p65, NLRP3, ASC, cleaved caspase-1, IL-ß and IL-18 proteins expression were significantly upregulated in the cortex of MCAO/R rats and PCN exposed to OGD/R, NLRP3 and caspase-1 mRNA levels were also evidently elevated. Bcl-2 protein expression significantly decreased in the cortex of MCAO/R rats. Treatment with ANF obviously inhibited the expression of p-IκBα, p-p65, NLRP3, ASC, cleaved caspase-1, Bax and cleaved-caspase-3, promoted the expression of Bcl-2, then decreased the TUNEL-positive cell number and the level of inflammatory cytokines (IL-ß and IL-18) in cerebral ischemia reperfusion in vito and in vitro. Our findings suggest that ANF exerts effects of alleviating inflammation and apoptosis through inhibiting NF-kappaB/NLRP3 axis. ANF is a potential candidate for treating cerebral I/R injury.

Role of polyphenols from Polygonum multiflorum Caulis in obesity-related disorders.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygoni Multiflori Caulis (PMC) has been widely consumed as folk medicine in China for anti-obesity, sleep-enhancing and many other pharmacological effects. However, the material basis and underlying mechanism of PMC on obesity-related disorders were still not clear. AIM OF THE STUDY: To screen active constituents from PMC and explore their multitarget mechanisms in the treatment of obesity and its associated disorders. MATERIALS AND METHODS: Several major constituents were extracted from PMC and LC-MS assay were used to identify the compounds. The lipase inhibitory activity and lipid accumulation in 3T3-L1 preadipocytes were determined. Furthermore, Caenorhabditis elegans (C. elegans) and high-fat diet (HFD)-induced mice were established to explore the potential pharmacological functions and related mechanisms using kits, RT-qPCR and biochemical analysis. RESULTS: Regarding the lipase inhibitory activity, the inhibition rate of EA and n-Bu extracts at 4 mg/mL reached over 80%. Effects on 3T3-L1 preadipocytes proliferation and differentiation were also obvious, indicating that EA and n-Bu extracts might exert potential anti-obesity functions. LC-MS assay further showed that polyphenols including emodin and physcion comprised majority of EA and n-Bu extracts. EA and n-Bu extracts treatment could significantly modulate the antioxidant response and lipid accumulation in C. elegans, as evidenced by increased SOD and CAT contents, reduced MDA levels, higher TG contents and changes of related mRNA expression levels. In HFD-induced mice, the inhibition ratio of body weight as well as the histological and biochemical indexes of liver, plasma and epididymal adipose tissues were also reversed by EA and n-Bu extracts treatment. Moreover, EA and n-Bu extracts administration increased the microbial diversity, reshaped the microbiota structure and enhanced the relative abundance of Bifidobacterium. CONCLUSIONS: This study demonstrated the multicomponent and multitarget characteristics of PMC in preventing obesity related disorders. The results provided novel insights for the development and utilization of PMC.

Natural bioactive constituents from herbs and nutraceuticals promote browning of white adipose tissue.

Obesity is a significant public health problem worldwide that is characterized by abnormal or excessive fat accumulation. Unfortunately, the application of available weight-loss drugs has been restricted because of their serious adverse effects. Browning of white adipose tissue (WAT), which refers to the transformation of white adipocytes to beige adipocytes under certain stimulations, is regarded as a new strategy to solve the obesity problem. Numerous studies have recently evidenced that traditional Chinese medicine (TCM) could promote browning of WAT with multi-component and multi-target characteristics. This article summarizes natural constituents from TCM with stimulatory effects on browning of WAT in the past two decades. The active ingredients can be generally divided into polyphenols, saponins, alkaloids, terpenoids, phenylpropanoids and others, such as resveratrol, quercetin, curcumin, genistein, capsaicin, epigallocatechin gallate (EGCG), berberine, menthol, emodin and ginsenosides. Simultaneously, the chemical structures, source, model, efficacy and mechanism of these monomeric compounds are also described. And the mechanisms of these active ingredients are mainly involved in the regulation of PRDM16, PGC-1α, PPARγ, SIRT1, AMPK, ß3-adrenergic receptors, TRPV1 and TRPM8 channels, FGF21 and miRNAs. The present article opens opportunities for developing novel drugs or supplements from TCM with wide acceptability to prevent obesity progression and its associated metabolic disorders.

Survival prognostic factors for differentiated thyroid cancer patients with pulmonary metastases: A systematic review and meta-analysis.

Background: The prognostic factors for differentiated thyroid cancer (DTC) patients with pulmonary metastases (PM) remain scantly identified and analyzed. Therefore, this systematic review and meta-analysis were performed to identify and summarize the prognostic factors in adult DTC patients with PM to help distinguish patients with different prognoses and inform the rational treatment regimens. Method: We performed a comprehensive search of the relevant studies published in the Cochrane Library, PubMed, Scopus, Embase, Wanfang database, VIP database, China National Knowledge Infrastructure, and Google Scholar from their inception until February 2021. The pooled hazard ratios (HR) for overall survival and/or progression-free survival (PFS) with 95% confidence intervals were applied to evaluate and identify the potential prognostic factors. Pooled OS at different time points were also calculated for the available data. A random-effects model was used in the meta-analysis. Results: The review and meta-analysis included 21 studies comprising 2722 DTC patients with PM. The prognostic factors for poor OS were: age over 40 years (HR=7.21, 95% confidence interval [CI] 1.52-34.10, P=0.01, N=788), age over 45 years (HR=2.18, 95% CI 1.26-3.77, P<0.01, N=601), male gender (HR=1.01, 95% CI 1.01-1.19, P=0.03, N=1396), follicular subtype of thyroid cancer (HR=1.63, 95% CI 1.36-1.96, P<0.01, N=2110), iodine non-avidity (HR=3.10, 95% CI 1.79-5.37, P<0.01, N=646), and metastases to other organs (HR=3.18, 95% CI 2.43-4.16, P<0.01, N=1713). Factors associated with poor PFS included age over 45 years (HR=3.85, 95% CI 1.29-11.47, P<0.01, N=306), male gender (HR=1.36, 95% CI 1.06-1.75, P=0.02, N=546), iodine non-avidity (HR=2.93, 95% CI 2.18-3.95, P<0.01, N=395), pulmonary metastatic nodule size over 10mm (HR=2.56, 95% CI 2.02-3.24, P<0.01, N=513), and extra-thyroidal invasion (HR=2.05, 95% CI 1.15-3.67, P=0.02, N=271). The pooled 1, 3, 5, 10, 15, and 20-years OS were 95.24%, 88.46%, 78.36%, 64.86%, 56.57%, and 51.03%, respectively. Conclusions: This review and meta-analysis identified the prognostic factors of DTC patients with PM. Notably, FTC, metastases to other organs, and iodine non-avidity were particularly associated with poor prognosis. The identified prognostic factors will help guide the clinical management of DTC patients with PM. Systematic review registration: https://inplasy.com/inplasy-2022-2-0026/, identifier (INPLASY202220026).

Inhibitory effect of chloroform extracts from Citrus aurantium L. var. amara Engl. on fat accumulation.

BACKGROUND: Excess lipid accumulation can accelerate the development of various metabolic diseases. Blossoms of Citrus aurantium L. var. amara Engl. (CAVA) have been reported to possess inhibitory capacities on lipid deposition. However, the constituents responsible for the observed bioactivity and the underlying mechanisms are still not clearly understood. PURPOSE: To screen constituents from blossoms of CAVA with inhibitory effects on lipid accumulation and to explore the action mechanism. METHODS: The chloroform (CHL) extracts are prepared from blossoms of CAVA by fractional extraction and are characterized using LC-MS assay. 3T3-L1 preadipocytes are induced with differentiation medium (DMI) and treated with CHL extracts. High fat diet (HFD)-induced obese mice are further established and administrated with CHL extracts for 12 weeks. Hematoxylin and eosin (HE) staining, Oil Red O staining, ELISA, RT-qPCR, western blot and 16S rRNA gene sequence methods are employed. RESULTS: 14 compounds are identified in CHL extracts and trigonelline hydrochloride, nobiletin and 7-demethylsuberosin are most abundant. CHL extracts treatment significantly inhibit differentiation of 3T3-L1 cells by regulating expression of preadipocyte factor-1 (Pref-1), fatty acid synthase (FAS) and CCAAT/enhancer binding protein α (C/EBPα). CHL extracts intervention also significantly attenuate features of obesity and improved plasma biochemical profiles in HFD-fed mice. HFD-triggered hepatic steatosis and epididymal adipose tissues (EATs) hypertrophy are also reversed by CHL extracts administration through enhancing antioxidant responses and modulating lipogenesis and energy expenditure-related genes and proteins. 16S rRNA gene sequence data further show that CHL extracts enhance the diversity of gut microbiota. CHL extracts at lower concentrations reduce the ratio of Firmicutes to Bacteroidetes and the abundance of Erysipelotrichaceae. CHL extracts at higher doses markedly increase the abundance of Lachnospiraceae. CONCLUSION: These findings suggest that CHL extracts probably suppress lipid accumulation through inhibiting differentiation of 3T3-L1 cells and attenuating metabolic syndromes in HFD-fed mice.

Efficacy, Safety, and Tolerability of a Novel Cyclosporine, a Formulation for Dry Eye Disease: A Multicenter Phase II Clinical Study.

PURPOSE: The purpose of this study was to explore the efficacy, safety, and tolerability of a novel cyclosporine formulation for dry eye disease (DED). METHODS: This is an exploratory, multicenter, single-blind, randomized, positive-controlled Phase II clinical trial between cyclosporine ophthalmic gel (CyclAGel) and an open-label comparator (Restasis, positive control). A total of 240 eligible patients with moderate to severe DED were randomized to 4 study groups: CyclAGel 0.05%/once daily (QD) (n = 59), CyclAGel 0.05%/BID (n = 60), CyclAGel 0.1%/QD (n = 60), and Restasis 0.05%/BID (n = 61). After receiving BID dosing of hypromellose eye drops during a 2-week run-in period, patients were randomized to the respective treatment group and dosed QD or BID for 12 weeks. Efficacy was assessed based on a number of sign and symptom end points, including eye dryness score (visual analog scale), 6 other parameters of symptoms for dryness (burning/stinging, itching, foreign body sensation, discomfort, sensitivity to light, and pain), and corneal fluorescein staining. The Schirmer test was used to assess dry eye symptoms (visual analog scale severity) at visit 3 (week 2), visit 4 (week 6), and visit 5 (week 12). FINDINGS: CyclAGel showed a consistent improvement in eye dryness score and the 6 other parameters of symptoms for dryness, corneal fluorescein staining, breakup time, and Schirmer test scores compared with Restasis over the 12-week treatment period. However, there were no statistically significant differences between CyclAGel and Restasis after baseline corrections were made, and the results of the full analysis set remained consistent with those of the per-protocol set (P > 0.05). Moreover, each CyclAGel-treated group (0.05%/QD, 0.05%/BID, and 0.1%/QD) exerted better effects than the Restasis group, and CyclAGel 0.05%/QD showed the most significant improvement. The number of ocular-related treatment-emergent adverse events was low in all treatment groups, with no serious drug-related treatment-emergent adverse events. IMPLICATIONS: CyclAGel showed excellent safety, tolerability, and comfort profiles at 2 concentrations and frequency in moderate to severe DED.

Anfibatide Preserves Blood-Brain Barrier Integrity by Inhibiting TLR4/RhoA/ROCK Pathway After Cerebral Ischemia/Reperfusion Injury in Rat.

The disruption of the blood-brain barrier (BBB) and the consequent brain edema are major contributors to the pathogenesis of cerebral ischemia/reperfusion injury. RhoA is generally thought to play a crucial role in the process of BBB disruption and participate in the signaling pathways emanating from TLR4. However, it remains unverified the regulatory role of TLR4 in the RhoA/ROCK pathway in cerebral I/R injury and its effects on the BBB as well. The present study probes into the protective effect of ANF on the BBB after cerebral I/R injury and the possible mechanisms. Focal cerebral ischemia was induced by 120 min of transient middle cerebral artery occlusion (MCAO). ANF (1, 2, 4 µg/kg) was achieved by intravenous injection after 120 min of MCAO followed by 1, 24, 48, and 72 h reperfusion. Evans blue extravasation, brain water content, RhoA activity, and the expressions of TLR4, ROCK1/2, p-MLC2, MMP-2/9, ZO-1, occludin, and claudin-5 protein in rat brain were evaluated 72 h after reperfusion. ANF could significantly reduce the Evans blue extravasation and water content in the ipsilateral hemisphere and obviously increase the occludin, claudin-5, and ZO-1 expression after cerebral I/R injury. Furthermore, cerebral I/R injury induced apparently increased expression of TLR4, RhoA-GTP, ROCK1/2, p-MLC2, and MMMP-2/9, which, however, could be remarkably alleviated by ANF intervention. Taken together, the TLR4/RhoA/ROCK signaling pathway is implicated in BBB breakdown after cerebral I/R injury, and ANF preserves BBB integrity, probably via inhibiting the TLR4/RhoA/ROCK signaling pathway.

Pathological evaluation of neoadjuvant chemotherapy in advanced gastric cancer.

BACKGROUND: Although pathological evaluation has been considered an effective evaluation method, some problems still exist in practice. Therefore, we explored whether there are more reasonable and practical pathological evaluation criteria for neoadjuvant chemotherapy in patients with advanced gastric cancer. Here, we aim to determine pathological judgment criteria for neoadjuvant chemotherapy in patients with advanced gastric cancer. METHODS: Eighty-seven patients with cT2-4 or cN+ were enrolled in this study. Pathological factors for overall survival (OS) were investigated using univariate and multivariate analyses, and the pathological criteria for neoadjuvant chemotherapy were then determined. RESULTS: A total of 87 patients underwent 3-4 cycles of neoadjuvant chemotherapy, with 67 (77.0%), 15 (17.2%), and 5 (5.8%) receiving Folfox6, Xelox, and SOX regimens, respectively. All patients showed different levels of graded histological regression (GHR) of the primary tumor, with a ≥ 50% regression rate of 50.6%. The univariate analysis showed that GHR ≥ 50% (p = 0.022), 66.7% (p = 0.013), and 90% (p = 0.028) were significantly correlated with OS. The multivariate analysis demonstrated that ypTNM (II/III) stage was significantly associated with OS compared with ypTNM (0+I) stage [HR = 3.553, 95% CI 1.886-6.617; HR = 3.576, 95% CI 1.908-6.703, respectively] and that the Lauren classification of diffuse type was also an independent risk factor for OS compared with the intestinal type (HR = 3.843, 95% CI 1.443-10.237). CONCLUSIONS: The Lauren classification and ypTNM stage after neoadjuvant chemotherapy are independent prognostic factors in advanced gastric cancer. A GHR ≥ 50%/< 50% can be used as the primary criterion for advanced gastric cancer after neoadjuvant chemotherapy to determine postoperative adjuvant chemotherapy regimens.

A Fast Dense Feature-Matching Model for Cross-Track Pushbroom Satellite Imagery.

Feature-based matching can provide high robust correspondences and it is usually invariant to image scale and rotation. Nevertheless, in remote sensing, the robust feature-matching algorithms often require costly computations for matching dense features extracted from high-resolution satellite images due to that the computational complexity of conventional feature-matching model is O ( N 2 ) . For replacing the conventional feature-matching model, a fast dense (FD) feature-matching model is proposed in this paper. The FD model reduces the computational complexity to linear by splitting the global one-to-one matching into a set of local matchings based on a classic frame-based rectification method. To investigate the possibility of applying the classic frame-based method on cross-track pushbroom images, a feasibility study is given by testing the frame-based method on 2.1 million independent experiments provided by a pushbroom based feature-correspondences simulation platform. Moreover, to improve the stability of the frame-based method, a correspondence-direction-constraint algorithm is proposed for providing the most favourable seed-matches/control-points. The performances of the FD and the conventional models are evaluated on both an automatic feature-matching evaluation platform and real satellite images. The evaluation results show that, for the feature-matching algorithms which have high computational complexity, their running time for matching dense features reduces from hours level to minutes level when they are operated on the FD model. Meanwhile, based the FD method, feature-matching algorithms can achieve comparable matching results as they achieved based on the conventional model.

Antimicrobial resistance and pathogen distribution in hospitalized burn patients: A multicenter study in Southeast China.

Burn infections pose a serious obstacle to recovery. To investigate and analyze the antimicrobial resistance and distribution of pathogenic bacteria among hospitalized burn patients. A 3-year retrospective study was conducted in the southeast of China.The electronic medical records system was used to collect all clinical data on 1449 hospitalized patients from Fujian Medical University Union Hospital, the 180th Hospital of Chinese People's Liberation Army (PLA), the 92nd Hospital of PLA, and the First Hospital of Longyan City.A total of 1891 strains of pathogenic bacteria were detected from 3835 clinical specimens, and the total detection rate was 49.3% (1891/3835). The main pathogens were gram-negative bacteria (1089 strains; 57.6%), followed by gram-positive bacteria (689 strains; 36.4%), and fungi (113 strains; 6.0%). The predominant five bacteria were Staphylococcus aureus (19.0%), Acinetobacter baumannii (17.6%), Pseudomonas aeruginosa (16.7%), Klebsiella pneumoniae (7.4%), and Enterococcus faecalis (4.5%). Methicillin-resistant Staphylococcus aureus (MRSA) accounted for 74.1% (265/359) of S aureus isolates. Staphylococcus epidermidis accounted for 40.6% (69/170) of coagulase-negative staphylococcal isolates, 72.5% (50/69) of which were methicillin-resistant Staphylococcus epidermidis (MRSE). Both MRSA and MRSE were 100% resistant to penicillin and ampicillin. A baumannii was the most commonly isolated strain of gram-negative bacteria with 100% resistance to ampicillin, amoxicillin, amoxicillin/clavulanic acid, and aztreonam. More than 80% of K pneumoniae isolates were resistant to ampicillin, amoxicillin and cefazolin. More than 80% of Escherichia coli isolates were resistant to ampicillin, piperacillin, cefazolin, amoxicillin, tetracycline, and sulfamethoxazole trimethoprim. The detection rates of extended-spectrum ß-lactamases (ESBL) among K pneumoniae and E coli isolates were 44.6% (62/139) and 67.2% (41/61), respectively. Low-resistance antibiotics included teicoplanin, tigecycline, vancomycin, and linezolid.The pathogens presented high resistance to antimicrobial agents, especially MRSA and A baumannii. Monitoring of bacterial population dynamics should be established to inhibit the progression of bacterial resistance.