Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study).

Background: The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA. Methods/Design: This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence. Discussion: We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients. Trial registration: https://www.clinicaltrials.gov, identifier NCT05494060.

Protective effects of irigenin against 1-methyl-4-phenylpyridinium-induced neurotoxicity through regulating the Keap1/Nrf2 pathway.

The rhizome of Belamcanda chinensis possesses antiinflammatory and antioxidant activities. However, the effect of irigenin, isolated from the rhizome of B. chinensis, on 1-methyl-4-phenylpyridinium (MPP+ )-induced neurotoxicity is unknown. MTT assay showed that MPP+ exposure dose dependently inhibited the viability of mouse microglia BV-2 cells, whereas irigenin suppressed MPP+ -induced viability reduction. The production of nitric oxide, prostaglandin E2, tumor necrosis factor-α and interleukin-6 were increased by MPP+ treatment, which were abolished by irigenin treatment. Irigenin-attenuated MPP+ -induced increase of malondialdehyde content and activities of superoxide dismutase, catalase and glutathione peroxidase in BV-2 cells. Irigenin treatment also repressed apoptosis, caspase-3/7 activity and Cytochrome C expression in MPP+ -challenged BV-2 cells. Interestingly, irigenin activated the Keap1/Nrf2 pathway in MPP+ -induced BV-2 cells. Nrf2 knockdown attenuated the effects of irigenin on MPP+ -induced viability reduction, inflammation, oxidative stress and apoptosis in BV-2 cells. In conclusion, irigenin alleviated MPP+ -induced neurotoxicity in BV-2 cells through regulating the Keap1/Nrf2 pathway.

How sulfate-rich mine drainage affected aquatic ecosystem degradation in northeastern China, and potential ecological risk.

Mining activity is an increasingly important stressor for freshwater ecosystems. However, the mechanism on how sulfate-rich mine drainage affects freshwater ecosystems is largely unknown, and its potential ecological risk has not been assessed so far. During 2009-2016, water and macroinvertebrate samples from 405 sample sites were collected along the mine drainage gradient from circum-neutral to alkaline waters in Hun-Tai River, Northeastern China. Results of linear regressions showed that sulfate-rich mine drainage was significantly positively correlated with the constituents typically derived from rock weathering (Ca2+, Mg2+ and HCO3-+CO32-); the diversity of intolerant stream macroinvertebrates exhibited a steep decline along the gradient of sulfate-rich mine drainage. Meanwhile, stressor-response relationships between sulfate-rich mine drainage and macroinvertebrate communities were explored by two complementary statistical approaches in tandem (Threshold Indicator Taxa Analysis and the field-based method developed by USEPA). Results revealed that once stream sulfate concentrations in mine drainage exceeded 35mg/L, significant decline in the abundance of intolerant macroinvertebrate taxa occurred. An assessment of ecological risk posed by sulfate-rich mine drainage was conducted based on a tiered approach consisting of simple deterministic method (Hazard Quotient, HQ) to probabilistic method (Joint Probability Curve, JPC). Results indicated that sulfate-rich mine drainage posed a potential risk, and 64.62-84.88% of surface waters in Hun-Tai River exist serious risk while 5% threshold (HC05) and 1% threshold (HC01) were set up to protect macroinvertebrates, respectively. This study provided us a better understanding on the impacts of sulfate-rich mine drainage on freshwater ecosystems, and it would be helpful for future catchment management to protect streams from mining activity.

Evaluation of potential factors affecting deriving conductivity benchmark by utilizing weighting methods in Hun-Tai River Basin, Northeastern China.

Specific conductivity is an increasingly important stressor for freshwater ecosystems. Interacting with other environmental factors, it may lead to habitat degradation and biodiversity loss. However, it is still poorly understood how the effect of specific conductivity on freshwater organisms is confounded by other environmental factors. In this study, a weight-of-evidence method was applied to evaluate the potential environmental factors that may confound the effect of specific conductivity on macroinvertebrate structure communities and identify the confounders affecting deriving conductivity benchmark in Hun-Tai River Basin, China. A total of seven potential environmental factors were assessed by six types of evidence (i.e., correlation of cause and confounder, correlation of effect and confounder, the contingency of high level cause and confounder, the removal of confounder, levels of confounder known to cause effects, and multivariate statistics for confounding). Results showed that effects of dissolved oxygen (DO), fecal coliform, habitat score, total phosphorus (TP), pH, and temperature on the relationship between sensitive genera loss and specific conductivity were minimal and manageable. NH3-N was identified as a confounder affecting deriving conductivity benchmark for macroinvertebrate. The potential confounding by high NH3-N was minimized by removing sites with NH3-N > 2.0 mg/L from the data set. Our study tailored the weighting method previously developed by USEPA to use field data to develop causal relationships for basin-scale applications and may provide useful information for pollution remediation and natural resource management.

Paradigms of mangroves in treatment of anthropogenic wastewater pollution.

Mangroves have been increasingly recognized for treating wastewater from aquaculture, sewage and other sources with the overwhelming urbanization trend. This study clarified the three paradigms of mangroves in disposing wastewater contaminants: natural mangroves, constructed wetlands (including free water surface and subsurface flow) and mangrove-aquaculture coupling systems. Plant uptake is the common major mechanism for nutrient removal in all the paradigms as mangroves are generally nitrogen and phosphorus limited. Besides, sediments accrete and provide substrates for microbial activities, thereby removing organic matter and nutrients from wastewater in natural mangroves and constructed wetlands. Among the paradigms, the mangrove-aquaculture coupling system was determined to be the optimal alternative for aquaculture wastewater treatment by multi-criterion decision making. Sensitivity analysis shows variability of alternative ranking but underpins the coupling system as the most environment-friendly and cost-efficient option. Mangrove restoration is expected to be achievable if aquaculture ponds are planted with mangrove seedlings, creating the coupling system.

[Effect of supplementing qi, blood-activating and kidney-nourishing therapy on postoperative recovery in patients with lumber disc herniation].

OBJECTIVE: To investigate the effect of supplementing qi, activating blood circulation and tonifying kidney therapy on the postoperative outcomes of patients undergoing lumber intervertebral disc herniation. METHODS: From January 2010 to May 2012, 120 patients with lumbar intervertebral disc herniation undergoing surgical treatment in Nanfang hospital were randomized into two equal groups to receive routine therapy (control group) and additional treatment with Yiqi Houxue Bushen Decoction (treatment group). The effect of the interventions was evaluated by assessing the Visual Analogue Scale(VAS), Japanese Orthopedic Association Scores (JOA), WHO Quality of Life-BREF (WHOQOL-BREF), length of hospital stay and adverse event. RESULTS: All the 120 patients were followed up and analyzed. Significant differences were found between the treatment and control groups in VAS, JOA Scores, and WHOQOL-BREF (P<0.01) at 2, 4, and 8 week and at 6 and 12 months after the surgery. At 6 and 12 months postoperatively, the JOA Scores (P<0.01), but not the VAS and WHOQOL-BREF, differed significantly between the two groups. CONCLUSION: Blood-activating and kidney-nourishing therapy is effective in promoting postoperative recovery and helps reduce the clinical symptoms and minimize the adverse events in patients undergoing surgery for lumber intervertebral disc herniation.

Effect of supplementing qi, blood-activating and kidney-nourishing therapy on postoperative recovery in patients with lumber disc herniation / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effect of supplementing qi, activating blood circulation and tonifying kidney therapy on the postoperative outcomes of patients undergoing lumber intervertebral disc herniation.</p><p><b>METHODS</b>From January 2010 to May 2012, 120 patients with lumbar intervertebral disc herniation undergoing surgical treatment in Nanfang hospital were randomized into two equal groups to receive routine therapy (control group) and additional treatment with Yiqi Houxue Bushen Decoction (treatment group). The effect of the interventions was evaluated by assessing the Visual Analogue Scale(VAS), Japanese Orthopedic Association Scores (JOA), WHO Quality of Life-BREF (WHOQOL-BREF), length of hospital stay and adverse event.</p><p><b>RESULTS</b>All the 120 patients were followed up and analyzed. Significant differences were found between the treatment and control groups in VAS, JOA Scores, and WHOQOL-BREF (P<0.01) at 2, 4, and 8 week and at 6 and 12 months after the surgery. At 6 and 12 months postoperatively, the JOA Scores (P<0.01), but not the VAS and WHOQOL-BREF, differed significantly between the two groups.</p><p><b>CONCLUSION</b>Blood-activating and kidney-nourishing therapy is effective in promoting postoperative recovery and helps reduce the clinical symptoms and minimize the adverse events in patients undergoing surgery for lumber intervertebral disc herniation.</p>

[Management and prognostic factors for 119 patients with follicular thyroid carcinoma].

OBJECTIVE: To explore the optimal management and analyze the prognostic factors for follicular thyroid carcinoma. METHODS: The clinicopathological data of 119 patients with well-differentiated follicular thyroid carcinoma treated in our hospital from 1970 to 2008 were retrospectively reviewed. The overall survival (OS) rate was estimated by Kaplan-Meier method. Log rank and Cox regression analyses were used to identify the prognostic factors. RESULTS: The 5- and 10-year OS rates were 81.1% and 66.7%, respectively. The 3- , 5- and 10-year cumulative distant metastasis rates were 27.4%, 29.6% and 35.9%, respectively. The age of ≥ 45 years old was one of the most important factors affecting survival rate (P < 0.05) and an independent factor for distant matastasis. CONCLUSIONS: Follicular thyroid carcinoma has some special features such as diffuse growth and vascular tumors thrombosis and with a relatively poor prognosis. The key measure to improve local control and prognosis is radical resection. Some aggressive management such as total thyroidectomy combined with (13)1I therapy and regular follow-up should be performed to improve the survival rate and to control postoperative distant metastasis for patients ≥ 45 years old.

Management and prognostic factors for 119 patients with follicular thyroid carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the optimal management and analyze the prognostic factors for follicular thyroid carcinoma.</p><p><b>METHODS</b>The clinicopathological data of 119 patients with well-differentiated follicular thyroid carcinoma treated in our hospital from 1970 to 2008 were retrospectively reviewed. The overall survival (OS) rate was estimated by Kaplan-Meier method. Log rank and Cox regression analyses were used to identify the prognostic factors.</p><p><b>RESULTS</b>The 5- and 10-year OS rates were 81.1% and 66.7%, respectively. The 3- , 5- and 10-year cumulative distant metastasis rates were 27.4%, 29.6% and 35.9%, respectively. The age of ≥ 45 years old was one of the most important factors affecting survival rate (P < 0.05) and an independent factor for distant matastasis.</p><p><b>CONCLUSIONS</b>Follicular thyroid carcinoma has some special features such as diffuse growth and vascular tumors thrombosis and with a relatively poor prognosis. The key measure to improve local control and prognosis is radical resection. Some aggressive management such as total thyroidectomy combined with (13)1I therapy and regular follow-up should be performed to improve the survival rate and to control postoperative distant metastasis for patients ≥ 45 years old.</p>

Protective effect of the daming capsule on impaired baroreflexes in STZ-induced diabetic rats with hyperlipoidemia.

BACKGROUND: The Daming capsule (DMC) is a traditional Chinese medicine used to treat hyperlipoidemia. Both clinic trials and studies on animal models have demonstrated that DMC is beneficial against diabetic symptoms. Impairment of the baroreflex can cause life-threatening arrhythmias and sudden cardiac death in patients with diabetes mellitus (DM). This study was designed to elucidate the effects of DMC on baroreflexes in streptozocin (STZ)-induced diabetic rats with hyperlipoidemia. METHODS: Wistar rats were randomly divided into three groups: untreated controls, rats pretreated STZ and high lipids (a diabetes model or DM rats), and DM rats treated with DMC. The baroreflex sensitivity was examined during intravenous injection of phenylephrine (PE) or sodium nitroprusside (SNP) and quantified by the change in heart rate over the change in mean arterial blood pressure (ΔHR/ΔMABP). Morphological remodeling of baroreceptors was analyzed by transmission electron microscopy (TEM). The mRNA levels and expression of GluR2 and a GABAA receptor subunit were measured by quantitative RT-PCR and Western blotting. RESULTS: Compared to untreated DM rats, DMC significantly elevated the ratio of ΔHR/ΔMABP by enhancing the compensatory reduction in HR (-ΔHR) in response to PE-induced hypertension (+ΔMABP) (P < 0.05). In the presence of SNP, DMC increased the ΔMABP (P < 0.05). In addition, DMC markedly shortened the duration of blood pressure changes elicited by PE or SNP in DM rats compared to the untreated DM group (P < 0.05). Electron microscopy revealed disrupted myelin sheaths, swollen ER, and lysed mitochondria in the nucleus ambiguous (NAm) DM rats. These signs of neuropathology were largely prevented by treatment with DMC for 30 days. Treatment with DMC elevated both mRNA and protein level of GluR2 in the NAm of DM rats, but had no effect on GABAA receptor expression. CONCLUSION: The Daming capsule partially reversed the parasympathetic baroreflex impairment observed in STZ-induced diabetic rats with hyperlipoidemia. Treatment with DMC also prevented the degeneration of neurons and myelinated axons in the brain stem NAm and reversed the down-regulation of GluR2 mRNA. Rescue of NAm function may contribute to the medicinal properties of DMC in diabetic rats.

Cardioprotective effects and underlying mechanisms of oxymatrine against Ischemic myocardial injuries of rats.

Oxymatrine has been demonstrated to have a variety of pharmacological actions. Accumulating evidence indicates that oxymatrine may exert a protective effect on the cardiovascular system. The study was designed to explore the possible role of oxymatrine against myocardial ischemic damage and several related signaling pathways as potential mechanisms. The protective properties of oxymatrine were studied in a rat model of acute myocardial infarction due to permanent ligation of the left anterior descending coronary artery. The results showed that administration of oxymatrine relieved myocardial injuries during ischemia, and this was achieved by protecting cardiomyocytes from apoptotic death. The beneficial effects of oxymatrine were likely mediated by an inhibition of lipid peroxidation (MDA production) and an increase in endogenous antioxidant activity (SOD), activation of the survival signaling molecule (Bcl-2), and a reduction of apoptotic mediator (Fas) and intracellular Ca2+ overload.

Flavonoids from Chinese Viscum coloratum: antiarrhythmic efficacy and ionic mechanisms.

Viscum coloratum flavonoids (VCF) have been demonstrated to produce a variety of biological actions. An accumulating line of evidence supported the view that VCF may exert protective effects on the cardiovascular system. The aim of the study was to assess the antiarrhythmic activity as well as the electrophysiological properties of VCF. The antiarrhythmic effects of VCF were observed in a rat model of arrhythmia induced by aconitine. VCF significantly and dose-dependently increased the dosage of aconitine required to induce the arrhythmia indexes. Electrophysiological experiment revealed that VCF shortened APD through inhibition of ICa-L.

Effects of artemisinin on action potentials from C-type nodose ganglion neurons.

AIM: To investigate the effects of artemisinin (Art) on the action potentials (AP) recorded from identified C-type nodose neurons and study its anti-arrhythmic and anesthetic mechanisms. METHODS: Neonatal and adult rats were selected for the preparation of isolated nodose ganglia neurons (NGN) and nodose ganglion-vagus slice preparation. Somatic AP were recorded from both isolated and slice NGN using whole-cell patch technique. Conduction velocity (CV) was measured using slice preparation. The effects of Art on AP were evaluated with the reference to ketamine. RESULTS: Effects of Art on AP were that: (1) AP depolarizing profiles were inhibited without changing resting membrane potential (RMP). The peak of AP (AP(peak)) and upstroke velocity (UV(APD50) and UV(max)) decreased markedly (P<0.01). (2) The duration of AP at the point of half repolarization (APD(50)) was obviously prolonged (P<0.01). (3) Art also slowed down AP repolarization profiles (downstroke velocity, DV(APD50), and DV(max)) and the peak of after-hyperpolarization (AHP(peak)) was less negative. (4) Total inward and outward currents over the course of AP were significantly reduced in the presence of Art. (5) CV did not changed by Art. (6) The effects of Art on AP were concentration-dependent and resembled with those of ketamine except for CV. CONCLUSION: Art inhibited both depolarization and repolarization of AP, suggesting that the effects of Art were probably, due to the blockade of Na+ and K+ ion channels.

[Structure characteristics of ORF2a gene of potato leafroll virus Chinese isolate].

According to the genomic sequence of foreign four PLRV isolates, three pairs of specific primer were designed and synthesized. The cDNA of the ORF2a gene of PLRV-Ch was synthesized by reverse transcription and followed by Polymerase Chain Reaction amplication. The synthesized 3' and 5' cDNA fragment of the PLRV-Ch ORF2a gene were inserted into pUC19 and cloned in E. coli JM109 and were sequenced respectively. The middle cDNA fragment were directly sequenced. The homology of nucleotide sequence of PLRV-Ch compared with PLRV-S (Scotland, UK), PLRV-N(Netherlands), PLRV-A(Australia) and PLRV-C(Canada) were 98.96%, 98.70%, 94.79%, 97.5%, the homology of putative amino acid sequence are 97.97%, 97.97%, 89.69%, 95.94%. In 3' region of ORF2a gene a slippery sequence for-1 frameshift and its downstream "stem-loop" or "pseudoknot" and upstream nucleotide sequence repeats were found. Authors suggested that the nucleotide repeat sequences characteristic for PLRV could form a tight successively folded complementary double stranded regions and hairpins. This structure possibly has something to do with-1 frameshift. The amino acid sequence of C terminus region of 70 kD protein translated by motif IV has a protease characteristic motif and a helicase motif IV. The amino acid sequence of polypeptide translated by ORF2a gene undergoing frameshift has a single-stranded nucleic acid binding protein-like characteristic motif.

Structure characteristics of ORF2a gene of potato leafroll virus Chinese isolate / 生物工程学报

According to the genomic sequence of foreign four PLRV isolates, three pairs of specific primer were designed and synthesized. The cDNA of the ORF2a gene of PLRV-Ch was synthesized by reverse transcription and followed by Polymerase Chain Reaction amplication. The synthesized 3' and 5' cDNA fragment of the PLRV-Ch ORF2a gene were inserted into pUC19 and cloned in E. coli JM109 and were sequenced respectively. The middle cDNA fragment were directly sequenced. The homology of nucleotide sequence of PLRV-Ch compared with PLRV-S (Scotland, UK), PLRV-N(Netherlands), PLRV-A(Australia) and PLRV-C(Canada) were 98.96%, 98.70%, 94.79%, 97.5%, the homology of putative amino acid sequence are 97.97%, 97.97%, 89.69%, 95.94%. In 3' region of ORF2a gene a slippery sequence for-1 frameshift and its downstream "stem-loop" or "pseudoknot" and upstream nucleotide sequence repeats were found. Authors suggested that the nucleotide repeat sequences characteristic for PLRV could form a tight successively folded complementary double stranded regions and hairpins. This structure possibly has something to do with-1 frameshift. The amino acid sequence of C terminus region of 70 kD protein translated by motif IV has a protease characteristic motif and a helicase motif IV. The amino acid sequence of polypeptide translated by ORF2a gene undergoing frameshift has a single-stranded nucleic acid binding protein-like characteristic motif.