Inosine enhances the efficacy of immune-checkpoint inhibitors in advanced solid tumors: A randomized, controlled, Phase 2 study.

BACKGROUND: This study aimed to evaluate whether inosine enhances the efficacy of immune-checkpoint inhibitors in human malignant solid tumors. METHODS: This single-center, prospective, randomized, open-label study was conducted, from January 2021 to December 2022, in Beijing Friendship Hospital, Capital Medical University, and participants were randomly assigned (1:1) to either the inosine (trial) or non-inosine (control) group that received inosine (dosage: 0.2 g, three times/day) + PD-1/PD-L1 inhibitor or only PD-1/PD-L1 inhibitor ± targeted ± chemotherapy, respectively. Efficacy was assessed every 6 weeks (i.e., after every two-three treatment cycles). The primary endpoint was the objective response rate (ORR); the secondary endpoints were disease control rate, overall survival (OS), and progression-free survival (PFS). The trial was registered at ClinicalTrials.gov (NCT05809336). RESULTS: Among the 172 participants with advanced malignant solid tumors, 86 each were assigned to the inosine and non-inosine groups, wherein the median PFS (95% CI) was 7.00 (5.31-8.69) and 4.40 (3.10-5.70) months, respectively (hazard ratio [HR] 0.63; 95% CI 0.44-0.90, p = 0.011), and the ORR was 26.7% and 15.1%, respectively (p = 0.061). In the inosine and non-inosine groups, the median OS was not reached and was 29.67 (95% CI 17.40-41.94) months, respectively (HR 1.05 [95% CI 0.59-1.84], p = 0.874). Compared with the non-inosine group, the median PFS and ORR of the inosine group were significantly prolonged and improved in the multiple exploratory subgroup analyses. The safety analysis showed that Grades 3 and 4 adverse reactions occurred in 25 (29%) and 31 (36%) patients in the inosine and non-inosine groups, respectively, and tended to decrease in the inosine group compared with the non-inosine group. CONCLUSION: Inosine had a tendency to enhance the efficacy of immune-checkpoint inhibitors and reduced immunotherapy-related adverse reactions.

Insights into the antineoplastic activity and mechanisms of action of coumarin-coordinated 8-hydroxyquinoline ruthenium(II/III) compounds.

Ruthenium(II/III) coordination compounds have gained widespread attention as chemotherapy drugs, photosensitizers, and photodynamic therapy reagents. Herein, a family of 11 novel coumarin-coordinated 8-hydroxyquinoline ruthenium(II/III) compounds, i.e., [RuII2(µ2-Cl)2(QL1a)2(DMSO)4] (YNU-4a = Yulin Normal University-4a), [RuII2(µ2-Cl)2(QL1b)2(DMSO)4] (YNU-4b), [RuII2(µ2-Cl)2(QL1c)2(DMSO)4] (YNU-4c), [RuII2(µ2-Cl)2(QL1d)2(DMSO)4]⋅2CH3OH (YNU-4d), [RuII(QL1e)2(DMSO)2] (YNU-4e), [RuIII(QL1e)2(QL3a)] (YNU-4f), [RuIII(QL1e)2(QL3b)] (YNU-4g), [RuIII(QL1e)2(QL3c)] (YNU-4h), [RuIICl2(H-QL3a)2(DMSO)2] (YNU-4i), [RuIICl2(H-QL3b)2(DMSO)2] (YNU-4j), and [RuIICl2(H-QL3c)2(DMSO)2] (YNU-4k), featuring the coligands 5,7-diiodo-8-hydroxyquinoline (H-QL1a), 5,7-dichloro-8-quinolinol (H-QL1b), 5-chloro-7-iodo-8-hydroxyquinolin (H-QL1c), 5,7-dibromo-8-hydroxyquinoline (H-QL1d), and 5,7-dichloro-8-hydroxy-2-methylquinoline (H-QL1e) and the main ligands 6,7-dichloro-3-pyridin-2-yl-chromen-2-one (H-QL3a), 6-bromo-3-pyridin-2-yl-chromen-2-one (H-QL3b), and 6-chloro-3-pyridin-2-yl-chromen-2-one (H-QL3c), respectively. The structure of compounds YNU-4a-YNU-4k was fully confirmed by conducting various spectroscopic analyses. The anticancer activity of YNU-4a-YNU-4k was evaluated in cisplatin-resistant A549/DDP lung cancer cells (LC549) versus normal embryonic kidney (HEK293) cells. Notably, compound YNU-4f bearing QL1e and QL3a ligands showed a more pronounced antiproliferative effect against LC549 cells (IC50 = 1.75 ± 0.09 µM) with high intrinsic selectivity toward LC549 cancer cells than YNU-4a-YNU-4e, H-QL1a-H-QL1e, cisplatin (PDD), YNU-4g-YNU-4k, and H-QL3a-H-QL3c. Additionally, a colocalization assay analysis of YNU-4e and YNU-4f showed that these two ruthenium(II/III) compounds were subcellularly accumulated in the mitochondria and other regions of the cytoplasm, where they induce mitophagy, adenosine triphosphate (ATP) reduction, mitochondrial respiratory chain complex I/IV(RC1/RC4) inhibition, and mitochondrial dysfunction. Accordingly, compounds YNU-4a-YNU-4k can be regarded as mitophagy inductors for the eradication of cisplatin-resistant LC549 cancer cells.

In-Plane Radiation of Surface Plasmon Polaritons Excited by Free Electrons.

Surface plasmon polaritons (SPPs) have become a research hotspot due to their high intensity and subwavelength localization. Through free-electron excitation, a portion of the momentum of moving electrons can be converted into SPPs. Converting highly localized SPPs into a radiated field is an approach with the potential to aid in the development of a light radiation source. Reducing losses of SPPs is currently a critical challenge that needs to be addressed. The lifetime of SPPs in metal films is longer than that in metal blocks. Traditional optical gratings can transform SPPs into radiation to avoid the decay of SPPs in metal; however, they are created by etching metal films, so they tend to alter the dispersion characteristics of these films and will emit radiation in the direction perpendicular to the metal surface. This paper proposes an approach to converting the SPPs of a metal film excited by free electrons into a radiation field via lateral grating and obtaining in-plane radiation. We investigate the properties of SPP lateral radiation. The study of lateral radiation from metal films holds significant importance for SPP radiation sources and SPP on-chip circuit development.

Cost-effectiveness of different intervention strategies of HIV in Zhejiang, China.

OBJECTIVE: Mass screening for HIV and preexposure prophylaxis (PrEP) may be effective measures for reducing the probability of HIV transmission. Our study aimed to determine the cost-effectiveness of preliminary screening in the general population, PrEP for HIV-negative spouses in serodiscordant couples, or both approaches in Zhejiang Province. DESIGN: From a policy-maker's perspective, a Markov model was constructed to compare four strategies over a 30-year horizon. METHODS: In the Markov model, the implementation intensities of the strategies varied from 50 to 100%. Different strategies were evaluated by the reduction of unfavorable clinical outcomes, saved life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). RESULTS: The PrEP-screening strategy reduced the most unfavorable clinical outcomes and saved the most life-years and QALYs from 2023 to 2052. It always gained the maximum QALYs and NMB, while its ICER was always lower than the willingness-to-pay (WTP). The NMB of the PrEP-screening strategy gradually increased as the implementation intensity increased. CONCLUSION: With adequate manpower and policies, we suggest implementing the PrEP-screening strategy in Zhejiang Province, suggesting that the broader the population coverage of the strategy, the better. In addition, the PrEP strategy is an alternative.

PD-1/PD-L1 axis is involved in the interaction between microglial polarization and glioma.

The tumor microenvironment plays a vital role in glioblastoma growth and invasion. PD-1 and PD-L1 modulate the immunity in the brain tumor microenvironment. However, the underlying mechanisms remain unclear. In the present study, in vivo and in vitro experiments were conducted to reveal the effects of PD-1/PD-L1 on the crosstalk between microglia and glioma. Results showed that glioma cells secreted PD-L1 to the peritumoral areas, particularly microglia containing highly expressed PD-1. In the early stages of glioma, microglia mainly polarized into the pro-inflammatory subtype (M1). Subsequently, the secreted PD-L1 accumulated and bound to PD-1 on microglia, facilitating their polarization toward the microglial anti-inflammatory (M2) subtype primarily via the STAT3 signaling pathway. The role of PD-1/PD-L1 in M2 polarization of microglia was partially due to PD-1/PD-L1 depletion or application of BMS-1166, a novel inhibitor of PD-1/PD-L1. Consistently, co-culturing with microglia promoted glioma cell growth and invasion, and blocking PD-1/PD-L1 significantly suppressed these processes. Our findings reveal that the PD-1/PD-L1 axis engages in the microglial M2 polarization in the glioma microenvironment and promotes tumor growth and invasion.

8-hydroxyquinoline-N-oxide copper(II)- and zinc(II)-phenanthroline and bipyridine coordination compounds: Design, synthesis, structures, and antitumor evaluation.

Fourteen novel tumor-targeting copper(II) and zinc(II) complexes, [Cu(ONQ)(QD1)(NO3)]·CH3OH (NQ3), [Cu(ONQ)(QD2)(NO3)] (NQ2), [Cu(NQ)(QD2)Cl] (NQ3), [Cu(ONQ)(QD1)Cl] (NQ4), [Cu(ONQ)(QD3)](NO3) (NQ5), [Cu(ONQ)(QD3)Cl] (NQ6), [Zn(ONQ)(QD4)Cl] (NQ7), [Zn(ONQ)(QD1)Cl] (NQ8), [Zn(ONQ)(QD5)Cl] (NQ9), [Zn(ONQ)(QD2)Cl] (NQ10), [Zn(ONQ)(QD6)Cl] (NQ11), [Zn(ONQ)(QD7)Cl] (NQ12), and [Zn(ONQ)(QD3)Cl] (NQ13) supported on 8-hydroxyquinoline-N-oxide (H-ONQ), 2,2'-dipyridyl (QD1), 5,5'-dimethyl-2,2'-bipyridyl (QD2), 1,10-phenanthroline (QD3), 4,4'-dimethoxy-2,2'-bipyridyl (QD4), 4,4'-dimethyl-2,2'-bipyridyl (QD5), 5-chloro-1,10-phenanthroline (QD6), and bathophenanthroline (QD7), were first synthesized and characterized using various spectroscopic techniques. Furthermore, NQ1-NQ13 exhibited higher antiproliferative activity and selectivity for cisplatin-resistant SK-OV-3/DDP tumor cells (CiSK3) compared to normal HL-7702 cells based on results obtained from the cell counting Kit-8 (CCK-8) assay. The complexation of copper(II) ion with QD2 and ONQ ligands resulted in an evident increase in the antiproliferation of NQ1-NQ6, with NQ6 exhibiting the highest antitumor potency against CiSK3 cells compared to NQ1-NQ5, H-ONQ, QD1-QD7, and NQ7-NQ13 as well as the reference cisplatin drug with an IC50 value of 0.17 ± 0.05 µM. Mechanistic studies revealed that NQ4 and NQ6 induced apoptosis of CiSK3 cells via mitophagy pathway regulation and adenosine triphosphate (ATP) depletion. Further, the differential induction of mitophagy decreased in the order of NQ6 > NQ4, which can be attributed to the major impact of the QD3 ligand with a large planar geometry and the Cl leaving group within the NQ6 complex. In summary, these results confirmed that the newly synthesized H-ONQ copper(II) and zinc(II) coordination metal compounds NQ1-NQ13 exhibit potential as anticancer drugs for cisplatin-resistant ovarian CiSK3 cancer treatment.

Perioperative Chemotherapy versus Adjuvant Chemotherapy in Patients with Resectable Gastric Cancer: A Systematic Review with meta-analysis.

PURPOSE: The study aimed to investigate the prognosis and safety of perioperative chemotherapy (PC) compared with adjuvant chemotherapy (AC). METHODS: We systematically searched and assessed studies in PubMed, Embase, and the Cochrane Library from inception to 1st September 2022. RESULTS: Eighteen studies were eligible for the analysis, including 4686 patients in total. Our study found that patients with resectable gastric cancer undergoing PC had favorable prognosis on OS (HR 0.77; 95% CI 0.69 to 0.87) and DFS (HR 0.76; 95% CI 0.69 to 0.84) than those who undergoing AC. Addition of neoadjuvant chemotherapy (NAC) to AC provided higher R0 resection rate but did not increase the risk of postoperative complication rate and most of the adverse event rates. CONCLUSION: Our study demonstrated that PC shows better OS and DFS in Asians with resectable gastric cancer compared with AC. PC should be preferred because of its favorable prognosis and similar safety.

Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.

Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.

Pre-treatment of rapamycin transformed M2 microglia alleviates traumatic cervical spinal cord injury via AIM2 signaling pathway in vitro and in vivo.

BACKGROUND: Traumatic spinal cord injury (SCI) is still devastating. It was suggested that the inhibition of mTOR may alleviate neuronal inflammatory injury but its underlying mechanism remained to be elucidated. AIM2 (absent in melanoma 2) recruits ASC (apoptosis-associated speck-like protein containing a CARD) and caspase-1 to form the AIM2 inflammasome, activate caspase-1, and elicit inflammatory responses. We designed this study to elucidate whether pre-treatments of rapamycin could suppress SCI induced neuronal inflammatory injury via AIM2 signaling pathway in vitro and in vivo. METHODS: We performed oxygen and glucose deprivation / re-oxygenation (OGD) treatment and rats clipping model to mimic neuronal injury after SCI in vitro and in vivo. Morphologic changes of injured spinal cord were detected by hematoxylin and eosin staining. The expression of mTOR, p-mTOR, AIM2, ASC, Caspase-1 and et al were analyzed by fluorescent staining, western blotting or qPCR. The polarization phenotype of microglia was identified by flow cytometry or fluorescent staining. RESULTS: We found BV-2 microglia without any pre-treatment cannot alleviate primary cultured neuronal OGD injury. However, pre-treated rapamycin in BV-2 cells could transform microglia to M2 phenotype and protects against neuronal OGD injury via AIM2 signaling pathway. Similarly, pre-treatment of rapamycin could improve the outcome of cervical SCI rats through AIM2 signaling pathway. CONCLUSIONS: It was suggested that resting state microglia pre-treated by rapamycin could protect against neuronal injury via AIM2 signaling pathway in vitro and in vivo. Pre-inhibition of mTOR pathway may improve neuronal protection after SCI.

Comparison of symptomatic vertebrobasilar plaques between patients with and without Diabetes Mellitus using computed tomographic angiography and vessel wall magnetic resonance imaging.

OBJECTIVES: Diabetes mellitus is significantly associated with posterior circulation ischemic stroke. We aimed to compare the characteristics of vertebrobasilar plaques in symptomatic patients with and without diabetes using high-resolution vessel wall magnetic resonance imaging and computed tomographic angiography. METHODS: From April 2017 to May 2021, cases from patients with transient ischemic attack or stroke in the posterior circulation territory who underwent high-resolution vessel wall magnetic resonance imaging and computed tomographic angiography were reviewed. Characteristics of culprit vertebrobasilar plaques were compared between patients with and without diabetes. Multivariate regression analysis was performed to assess the correlation between culprit plaque characteristics and diabetes. RESULTS: A total of 148 patients were included and 75 patients were diagnosed with diabetes mellitus. Patients with diabetes had more intraplaque hemorrhage, calcification, spotty calcification presence, and higher calcification volume (all p < 0.05) compared with those without diabetes. Multivariate analysis demonstrated differences in the presence of intraplaque hemorrhage (p = 0.045) and number of spotty calcifications (p = 0.047) were statistically significant after adjusting for baseline characteristics. CONCLUSIONS: Symptomatic patients with diabetes have a higher incidence of intraplaque hemorrhage and larger calcification burden than those without diabetes, indicating the association of diabetes with more advanced plaque features in the posterior circulation.

Iptakalim improves cerebral microcirculation in mice after ischemic stroke by inhibiting pericyte contraction.

Pericytes are present tight around the intervals of capillaries, play an essential role in stabilizing the blood-brain barrier, regulating blood flow and immunomodulation, and persistent contraction of pericytes eventually leads to impaired blood flow and poor clinical outcomes in ischemic stroke. We previously show that iptakalim, an ATP-sensitive potassium (K-ATP) channel opener, exerts protective effects in neurons, and glia against ischemia-induced injury. In this study we investigated the impacts of iptakalim on pericytes contraction in stroke. Mice were subjected to cerebral artery occlusion (MCAO), then administered iptakalim (10 mg/kg, ip). We showed that iptakalim administration significantly promoted recovery of cerebral blood flow after cerebral ischemia and reperfusion. Furthermore, we found that iptakalim significantly inhibited pericytes contraction, decreased the number of obstructed capillaries, and improved cerebral microcirculation. Using a collagen gel contraction assay, we demonstrated that cultured pericytes subjected to oxygen-glucose deprivation (OGD) consistently contracted from 3 h till 24 h during reoxygenation, whereas iptakalim treatment (10 µM) notably restrained pericyte contraction from 6 h during reoxygenation. We further showed that iptakalim treatment promoted K-ATP channel opening via suppressing SUR2/EPAC1 complex formation. Consequently, it reduced calcium influx and ET-1 release. Taken together, our results demonstrate that iptakalim, targeted K-ATP channels, can improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke. Our work reveals that iptakalim might be developed as a promising pericyte regulator for treatment of stroke.

Cost-Effectiveness of Hepatitis B Mass Screening and Management in High-Prevalent Rural China: A Model Study From 2020 to 2049.

BACKGROUND: Chronic hepatitis B (CHB) is highly prevalent among adults in rural China and better management of those populations is of vital importance for viral hepatitis elimination. Adult immunization has been the subject of much controversy in previous studies. This study estimates the cost-effectiveness of population-based hepatitis B screening, treatment, and immunization strategy (comprehensive strategy) in rural areas with high prevalence under the national policy of sharp-drop drug prices. METHODS: We constructed a Markov model comparing 4 strategies in a 30-year horizon from the healthcare payer perspective: (1) the conventional pattern; (2) screening and treating infected (treatment); (3) screening and immunizing susceptible individuals (immunization); and (4) the comprehensive strategy. Screening intensity ranged from 50% to 100%. Outcomes were measured by costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and clinical outcomes. RESULTS: The costs for the conventional pattern, treatment strategy, immunization strategy, and comprehensive strategy were US$ 341, 351, 318, and 323, respectively. In addition, effects were 17.45, 17.57, 17.46, and 17.58 QALYs, respectively. The ICER of the comprehensive strategy was US$ 35/QALY gained at 50% screening intensity and 420 US$/QALY gained at 100%. The net monetary benefit increased with increasing screening intensity and declined after 90%, with the highest value of US$40 693. All new infections and 52.5% mortality could be avoided from 2020 to 2049 if all patients were properly treated and all susceptible individuals were immunized. The results were stable within a wide range of parameters. CONCLUSION: It was cost-effective to implement the mass hepatitis B screening, treatment, and immunization strategy in areas of rural China with high prevalence, and the strategy gained the most net monetary benefit at a screening intensity of 90%. Although it was impractical to fulfill 100% coverage, efforts should be made to obtain more people screened.

Salvianolic acid B regulates collagen synthesis: Indirect influence on human dermal fibroblasts through the microvascular endothelial cell pathway.

BACKGROUND: Salvianolic acid B (SAB) is one of the main active ingredients of Salvia Miltiorrhiza. It has significant skin anti-aging, whitening, and sun protection properties. AIMS: The study aimed at studying the mechanism underlying the effect of salvianolic acid Bon collagen synthesis, which has good anti-aging efficacy and modulates microcirculation. METHODS: This study employed available public databases, bioinformatics methodologies, and the inverse docking approach to explore the effectiveness of SAB in the regulating collagen synthesis, and then used an human dermal fibroblast (HDF)- Human dermal microvascular endothelial cell (HDMEC) in vitro model to validate the predicted mechanism of SAB in influencing collagen synthesis. RESULTS: The results showed that NO production in SAB-treated HDMEC-conditioned medium was increased compared to that in control media, and the same tendency was also observed for growth factor production. SAB also upregulated HDMEC cellular eNOS and VEGF. When SAB-treated HDMEC conditioned medium was transferred to HDFs, the expression of collagen I, collagen III, and elastin in HDFs was upregulated and MMP-1 was downregulated. CONCLUSIONS: The results show that SAB regulates collagen through the HDMEC-HDF pathway. Furthermore, the mechanisms might be closely related to the microcirculation factors NO and VEGF.

The role of fibrosis index FIB-4 in predicting liver fibrosis stage and clinical prognosis: A diagnostic or screening tool?

This review evaluates the ability of the fibrosis index based on four factors (FIB-4) identifying fibrosis stages, long-time prognosis in chronic liver disease, and short-time outcomes in acute liver injury. FIB-4 was accurate in predicting the absence or presence of advanced fibrosis with cut-offs of 1.0 and 2.65 for viral hepatitis B, 1.45 and 3.25 for viral hepatitis C, 1.30 (<65 years), 2.0 (≥65 years), and 2.67 for non-alcoholic fatty liver disease (NAFLD), respectively, but had a low-to-moderate accuracy in alcoholic liver disease (ALD) and autoimmune hepatitis. It performed better in excluding fibrosis, so we built an algorithm for identifying advanced fibrosis by combined methods and giving work-up and follow-up suggestions. High FIB-4 in viral hepatitis, NAFLD, and ALD was associated with significantly high hepatocellular carcinoma incidence and mortality. Additionally, FIB-4 showed the ability to predict high-risk varices with cut-offs of 2.87 and 3.91 in cirrhosis patients and predict long-term survival in hepatocellular carcinoma patients after hepatectomy. In acute liver injury caused by COVID-19, FIB-4 had a predictive value for mechanical ventilation and 30-day mortality. Finally, FIB-4 may act as a screening tool in the secondary prevention of NAFLD in the high-risk population.

Risk of station 12a lymph node metastasis in patients with lower-third gastric cancer.

BACKGROUND: Controversy over the issue that No. 12a lymph node involvement is distant or regional metastasis remains, and the possible inclusion of 12a lymph nodes in D2 lymphadenectomy is unclear. As reported, gastric cancer (GC) located in the lower third is highly related to the metastasis of station 12a lymph nodes. AIM: To investigate whether the clinicopathological factors and metastasis status of other perigastric nodes can predict station 12a lymph node metastasis and evaluate the prognostic significance of station 12a lymph node dissection in patients with lower-third GC. METHODS: A total of 147 patients with lower-third GC who underwent D2 or D2+ lymphadenectomy, including station 12a lymph node dissection, were included in this retrospective study from June 2003 to March 2011. Survival prognoses were compared between patients with or without station 12a lymph node metastasis. Logistic regression analyses were used to clarify the association between station 12a lymph node metastasis and clinicopathological factors or metastasis status of other perigastric nodes. The metastasis status of each regional lymph node was evaluated to identify the possible predictors of station 12a lymph node metastasis. RESULTS: Metastasis to station 12a lymph nodes was observed in 18 patients with lower-third GC, but not in 129 patients. The incidence of station 12a lymph node involvement was reported as 12.2% in patients with lower-third GC. The overall survival of patients without station 12a lymph node metastasis was significantly better than that of patients with station 12a metastasis (P < 0.001), which could also be seen in patients with or without extranodal soft tissue invasion. Station 12a lymph node metastasis and extranodal soft tissue invasion were identified as independent predictors of poor prognosis in patients with lower-third GC. Advanced pN stage was defined as independent risk factor significantly correlated with station 12a lymph node positivity. Station 3 lymph node staus was also proven to be significantly correlated with station 12a lymph node involvement. CONCLUSION: Metastasis of station 12a lymph nodes could be considered an independent prognosis factor for patients with lower-third GC. The dissection of station 12a lymph nodes may not be ignored in D2 or D2+ lymphadenectomy due to difficulties in predicting station 12a lymph node metastasis.

Oridonin prevents oxidative stress-induced endothelial injury via promoting Nrf-2 pathway in ischaemic stroke.

Oridonin, a natural diterpenoid compound extracted from a Chinese herb, has been proved to exert anti-oxidative stress effects in various disease models. The aim of the present study was to investigate the protective effects of oridonin on oxidative stress-induced endothelial injury in ischaemic stroke. We found oridonin repaired blood-brain barrier (BBB) integrity presented with upregulation of tight junction proteins (TJ proteins) expression, inhibited the infiltration of periphery inflammatory cells and neuroinflammation and thereby reduced infarct volume in ischaemic stroke mice. Furthermore, our results showed that oridonin could protect against oxidative stress-induced endothelial injury via promoting nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf-2). The specific mechanism could be the activation of AKT(Ser473)/GSK3ß(Ser9)/Fyn signalling pathway. Our findings revealed the therapeutic effect and mechanism of oridonin in ischaemic stroke, which provided fundamental evidence for developing the extracted compound of Chinese herbal medicine into an innovative drug for ischaemic stroke treatment.

Expression of TNF­α and IL­ß can be suppressed via the PPAR­Î³/mTOR signaling pathway in BV­2 microglia: A potential anti­inflammation mechanism.

Currently, microglia are considered as crucial factors in suppressing inflammatory reactions, but the specific molecular mechanism remains unknown. To elucidate whether peroxisome proliferator­activated receptor­Î³ (PPAR­Î³) can inhibit neuroinflammatory cytokine expression via the mTOR signal pathway, the BV­2 cell line was incubated with lipopolysaccharide (10 mM/ml) to induce an inflammatory injury. PPAR­Î³ was activated by rosiglitazone, and was inhibited by GW9662. The mTOR signal pathway was activated by phosphatidic acid (P.A.), while it was inhibited by rapamycin. Western blotting and reverse transcription­quantitative PCR were used to evaluate the expression levels of PPAR­Î³/mTOR signal pathway related proteins and neuroinflammatory cytokines, including NF­κB, tumor necrosis factor (TNF)­α and interleukin (IL)­1ß. When treated with P.A., the expression levels of phosphorylated (p)mTOR and p­ribosomal protein S6 kinase (pS6K) were significantly increased and the expression levels of TNF­α and IL­1ß were significantly lower. However, the expression of PPAR­Î³ was similar in P.A. treated cells and cells treated with rapamycin. When PPAR­Î³ was activated, pmTOR and pS6K protein expression levels were significantly decreased, and the mRNA expression levels of TNF­α and IL­1ß were significantly reduced, but this inhibition could be alleviated by administrating GW9662. Collectively, it was indicated that the mTOR signal pathway may be located downstream of PPAR­Î³. Furthermore, neuroinflammatory reactions could be inhibited via the activation of PPAR­Î³ by suppressing the mTOR signal pathway in microglia.

Advances in para-aortic nodal dissection in gastric cancer surgery: A review of research progress over the last decade.

Approximately 17%-40% of para-aortic lymph node (PAN) metastasis occurs in patients with advanced gastric cancer. As the third tier of lymphatic drainage of the stomach and the final station in front of the systemic circulation, PAN infiltration is defined as distant metastasis and plays a key role in the evaluation of the prognosis of advanced gastric cancer. Many clinical factors including tumor size ≥ 5 cm, pT3 or pT4 depth of tumor invasion, pN2 and pN3 stages, the macroscopic type of Borrmann III/IV, and the diffuse/mixed Lauren classification are indicators of PAN metastasis. Whether PAN dissection (PAND) should be performed on patients with or without the macroscopic PAN invasion remains unascertained, regardless of the numerous retrospective comparative studies reported on the improved prognosis over D2 alone. Another paradoxical result from many other studies showed no significant difference in the overall survival between these two lymphadenectomies. A phase II trial launched by the Japan Clinical Oncology Group indicated that two or three courses of S-1 and cisplatin preoperatively followed by radical surgery with D2 + PAND and postoperative S-1 is the current standard strategy for the treatment of patients with extensive lymph node metastasis, and this regimen could be substituted by a promising strategy with effective combination chemotherapy or suitable chemotherapy duration. This review focuses on the advances in radical gastrectomy plus PAND with or without chemotherapy for patients with advanced gastric cancer.

JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25/SP1/MMP2 axis.

BACKGROUND: Gastric cancer (GC) is the most prevalent gastrointestinal tumor with an unfavorable clinical prognosis. GC patients are largely threatened owing to metastasis and drug resistance. Tumor angiogenesis plays an important role in the development of gastric cancer and is a challenge in the treatment of gastric cancer. METHODS: Mouse xenograft models were used for screening of therapeutic peptides on GC growth and metastasis. Routine laboratory experimental methods including conditional cell culture, tube formation assay, qRT-PCR, Western blotting, immunohistochemistry (IHC), ubiquitination assay, and immunofluorescence (IF) were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3/SP1 and TRIM25/MEK1/2. RESULTS: We identified an MMP2-targeted peptide JP3 that plays inhibiting roles in modulating growth and metastasis of GC in vivo and has no observable toxic side effects. JP3 reduced tumor microvessel density (MVD) in vivo and human umbilical vein endothelial cells (HUVECs) tube formation in vitro. Mechanistic studies revealed that JP3 reduces polyubiquitination-mediated degradation of TRIM25 by increasing the stability of TRIM25 through phosphorylating it at Ser12. TRIM25, as an E3 ubiquitin ligase, promoted the ubiquitin of SP1 at K610, further suppressed expression of MMP2 and inhibited angiogenesis in GC. Importantly, the inversely association between TRIM25 and SP1 protein level was further verified in human GC tissues. Decreased TRIM25 expression and increased SP1 expression in tumor tissues were positively correlated with poor prognosis of GC patients. CONCLUSIONS: MMP2-targeted peptide JP3 plays a therapeutic role in GC through anti-angiogenesis by modulating TRIM25/SP1/MMP2.

Effects of dl-3-n-butylphthalide on serum lipoprotein-associated phospholipase A2 and hypersensitive C-reactive protein levels in acute cerebral infarction.

OBJECTIVE: This study aims to explore the curative effect of dl-3-n-butylphthalide (NBP) on patients with acute cerebral infarction (ACI) and its effects on serum lipoprotein-associated phospholipase A2 (Lp-PLA2) and hypersensitive C-reactive protein (hs-CRP) levels. METHODS: A total of 136 ACI patients treated in our hospital, who met the criteria, were selected and randomly divided into two groups: control group (n = 60, including 28 males and 32 females) and treatment group (n = 76, including 32 males and 44 females). Patients in the control group were treated with routine drug therapy, while patients in the treatment group were treated with NBP on this basis. A dose of 100 ml was administered by intravenous injection for 2 times/day, for 14 days. The curative effect was evaluated using the National Institute of Health Stroke Scale (NIHSS) and Barthel index (BI) self-care ability. The levels of the two factors in serum were measured using enzyme-linked immunosorbent assay, and the changes in levels of these two factors in serum at different time points before and after treatment were compared between the two groups. RESULTS: (a) Lp-PLA2 and hs-CRP levels in the treatment group after treatment were significantly lower than those before treatment and those in the control group after treatment (p < .05). (b) The NIHSS and BI scores in the treatment group were significantly lower after treatment than before treatment and those in the control group after treatment (p < .05). CONCLUSION: Dl-3-n-butylphthalide can improve the expression of Lp-PLA2 and hs-CRP in serum in ACI patients. Furthermore, NBP has significant efficacy in inhibiting inflammation and improving neurological symptoms.