Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid.

The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.

PASS-ALL study of paediatric-inspired versus adult chemotherapy regimens on survival of high-risk Philadelphia-negative B-cell acute lymphoblastic leukaemia with allogeneic haematopoietic stem cell transplantation.

This PASS-ALL study was designed to explore the effect of paediatric-inspired versus adult chemotherapy regimens on survival of adolescents and young adults (AYA) with high-risk Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia (HR PH-ve B-cell ALL) eligible for allogeneic haematopoietic stem cell transplantation (allo-HSCT). The PASS-ALL study is a multicentre, observational cohort study, and 143 patients with HR B-cell PH-ve ALL were enrolled from five centres-77 patients allocated in the paediatric-inspired cohort and 66 in the adult cohort with comparable baseline characteristics. Of the 143 patients, 128 cases underwent allo-HSCT. Three-year leukaemia-free survival (LFS) in the paediatric-inspired cohort was 72.2% (95% CI 60.8%-83.6%) compared with 44.6% (95% CI 31.9%-57.3%; p = 0.001). Furthermore, time-to-positive minimal residual disease (TTP-MRD) post-HSCT was marked different, 3-year cumulative incidence of relapse was 25.9% (95% CI 15.8%-37.2%) in paediatric cohort and 45.4% (95% CI 40.0%-57.9%) in adult cohort (p = 0.026). Finally, the 3-year OS rate was 75.3% (95% CI 64.9%-85.7%) for the paediatric-inspired cohort and 64.1% (95% CI 51.8%-76.4%) for the adult cohort (p = 0.074). On a multivariate analysis, paediatric-inspired regimen is a predictive factor for LFS (HR = 2.540, 95% CI 1.327-4.862, p = 0.005). Collectively, our data suggest that paediatric-inspired chemotherapy pre-HSCT results in deeper and durable MRD response reduces relapse post-HSCT and improves survival in HR B-cell PH-ve ALL patients with allo-HSCT.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Dynamics of simplicial SEIRS epidemic model: global asymptotic stability and neural Lyapunov functions.

The transmission of infectious diseases on a particular network is ubiquitous in the physical world. Here, we investigate the transmission mechanism of infectious diseases with an incubation period using a networked compartment model that contains simplicial interactions, a typical high-order structure. We establish a simplicial SEIRS model and find that the proportion of infected individuals in equilibrium increases due to the many-body connections, regardless of the type of connections used. We analyze the dynamics of the established model, including existence and local asymptotic stability, and highlight differences from existing models. Significantly, we demonstrate global asymptotic stability using the neural Lyapunov function, a machine learning technique, with both numerical simulations and rigorous analytical arguments. We believe that our model owns the potential to provide valuable insights into transmission mechanisms of infectious diseases on high-order network structures, and that our approach and theory of using neural Lyapunov functions to validate model asymptotic stability can significantly advance investigations on complex dynamics of infectious disease.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study.

BACKGROUND: The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma. METHODS: This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0-1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60-80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750-800 mg/m2 intravenously on days 1-5] or capecitabine [1000 mg/m2 orally twice daily on days 1-14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442. FINDINGS: Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0-69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6-21·8) in the tislelizumab group and 9·8 months (IQR 5·8-19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8-20·1) and in the placebo group was 10·6 months (9·3-12·1; stratified hazard ratio 0·66 [95% CI 0·54-0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related. INTERPRETATION: Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis. FUNDING: BeiGene.

China special issue on gastrointestinal tumors-Improved survival after multidisciplinary team decision for patients with advanced gastrointestinal cancer: A multicenter, noninterventional, controlled study.

Formal multidisciplinary team (MDT) discussions in clinical practice require time and space but have unclear survival benefits for advanced gastrointestinal cancer patients. Our study aimed to investigate the long-term survival of patients with advanced gastrointestinal cancer after MDT decision. From June 2017 to June 2019, continuous MDT discussions on advanced gastrointestinal cancer were conducted in 13 medical centers in China. MDT decisions and actual treatment received by patients were prospectively recorded. The primary endpoint was the difference in overall survival (OS) between patients in the MDT decision implementation and nonimplementation groups. The secondary endpoints included the implementation rate of MDT decisions and subgroup survival analysis. A total of 461 MDT decisions of 455 patients were included in our study. The implementation rate of MDT decisions was 85.7%. Previous treatment had an impact on MDT decision-making. The OS was 24.0 months and 17.0 months in the implementation and nonimplementation groups, respectively. The implementation of MDT decisions significantly reduced the risk of death in multivariate analyses (hazard ratio = 0.518; 95% confidence interval: 0.304-0.884, P = .016). Subgroup analysis showed a significant difference in survival of patients with colorectal cancer, but not in survival of patients with gastric cancer. The rate of secondary MDT discussion was only 5.6% among patients who the MDT decisions were discontinued due to changes in their condition. MDT discussion can prolong the OS of patients with advanced gastrointestinal cancer, especially those with colorectal cancer. Timely scheduling of the subsequent MDT discussion is necessary when the disease condition changes.

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric, gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis.

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Synthesis and Structure of a Two-Dimensional Palladium Oxide Network on Reduced Graphene Oxide.

New nanostructures often reflect new and exciting properties. Here, we present an two-dimensional, hitherto unreported PdO square network with lateral dimensions up to hundreds of nanometers growing on reduced graphene oxide (rGO), forming a hybrid nanofilm. An intermediate state of dissolved Pd(0) in the bacterium S. oneidensis MR-1 is pivotal in the biosynthesis and inspires an abiotic synthesis. The PdO network shows a lattice spacing of 0.5 nm and a thickness of 1.8 nm on both sides of an rGO layer and is proposed to be cubic or tetragonal crystal, as confirmed by structural simulations. A 2D silver oxide analog with a similar structure is also obtained using an analogous abiotic synthesis. Our study thus opens a simple route to a whole new class of 2D metal oxides on rGO as promising candidates for graphene superlattices with unexplored properties and potential applications for example in electronics, sensing, and energy conversion.

Characteristics of and antibiotic resistance in urinary tract pathogens isolated from patients with upper urinary tract stones.

To investigate the distribution characteristics and antibiotic resistance patterns of uropathogens in patients with upper urinary calculi and urinary tract infections, data on sex, age, positive midstream urine culture results and drug sensitivity results were collected. The statistical program SPSS 26.0 was used for statistical analysis. Among the 1414 positive urine samples, the most common pathogens were Escherichia coli (36.4%), Enterococcus faecalis (13.8%), Staphylococcus epidermidis (7.5%), Klebsiella pneumoniae (5.0%), Streptococcus agalactiae (3.4%) and Enterococcus faecium (3.3%). The incidences of E. coli (48.6%), K. pneumoniae (6.3%) and Proteus mirabilis (4.2%) were higher in female patients than in male patients (23.2%, 3.5%, 0.6%, respectively; P<0.05). E. faecalis was detected more frequently in the young group (16.0%) than in the elderly group (11.2%; P<0.01). Most of the isolates were resistant to levofloxacin and ciprofloxacin, while few were resistant to imipenem, meropenem, cefoperazone/sulbactam, piperacillin/tazobactam and amikacin. The bacterial spectra in patients with urinary stones varied by sex and age, which should be taken into consideration during treatment. The proportion of E. faecium showed an upward trend, while those of S. epidermidis and S. agalactiae demonstrated downward trends in the study period. Regardless, carbapenems, cefoperazone/sulbactam, piperacillin/tazobactam and amikacin are good choices for serious cases.

Cellular distribution of C-C motif chemokine ligand 2 like immunoreactivities in frontal cortex and corpus callosum of normal and lipopolysaccharide treated animal.

BACKGROUND: C-C motif chemokine ligand 2 (CCL2) is reported to be involved in the pathogenesis of various neurological and/or psychiatric diseases. Tissue or cellular expression of CCL2, in normal or pathological condition, may play an essential role in recruiting monocytes or macrophages into targeted organs, and be involved in a certain pathogenic mechanism. However, few studies focused on tissue and cellular distribution of the CCL2 peptide in brain grey and white matters (GM, WM), and the changes of the GM and WM cellular CCL2 level in septic or endotoxic encephalopathy was not explored. Hence, the CCL2 cellular distribution in the front brain cortex and the corpus callosum (CC) was investigated in the present work by using immunofluorescent staining. RESULTS: (1) CCL2 like immunoreactivity (CCL2-ir) in the CC is evidently higher than the cortex. When the measurement includes ependymal layer attached to the CC, CCL2-ir intensity is significantly higher than cortex. (2) Structures in perivascular areas, most of them are GFAP positive, contribute major CCL2-ir positive profiles in both GM and WM, but apparently more in the CC, where they are bilaterally distributed in the lateral CC between the cingulate cortex and ventricles. (3) The neuron-like CCL2-ir positive cells in cortex are significantly more than in the CC, and that number is significantly increased in the cortex following systemic lipopolysaccharide (LPS), but not in the CC. (4) In addition to CCL2-ir positive perivascular rings, more CCL2-ir filled cashew shape elements are observed, probably inside of microvasculature, especially in the CC following systemic LPS. (5) Few macrophage/microglia marker-Iba-1 and CCL2-ir co-labeled structures especially the soma is found in normal cortex and CC; the co-localizations are significantly augmented following systemic LPS, and co-labeled amoeba like somata are presented. (6) CCL2-ir and astrocyte marker GFAP or Iba-1 double labeled structures are also observed within the ependymal layer. No accumulation of neutrophils was detected. CONCLUSION: There exist differences in the cellular distribution of the CCL2 peptide in frontal cortex GM and subcortical WM-CC, in both the physiological condition and experimental endotoxemia. Which might cause different pathological change in the GM and WM.

Effect of tumour size ratio on liver recurrence-free survival of patients undergoing hepatic resection for colorectal liver metastases.

BACKGROUND: The study aimed to assess the impact of size differences of multiple liver metastases on liver recurrence-free survival (RFS) in patients undergoing hepatic resection for colorectal liver metastases (CRLMs). METHODS: Overall, 147 patients with CRLMs who underwent hepatic resection between January 2010 and December 2016 were retrospectively analysed. Tumour size ratio (TSR) was defined as the maximum diameter of the largest liver lesion over the maximum diameter of the smallest liver lesion. The univariate and multivariate analyses were performed to determine independent prognostic risk factors. The prognostic value of the TSR was further explored in each Tumour Burden Score (TBS) zone. Log-rank survival analyses were used to compare liver RFS in the new clinical score and the Fong clinical score. RESULTS: Based on the TSR, patients were classified into three groups: TSR < 2, 2 ≤ TSR < 4, and TSR ≥ 4. According to the multivariate analysis, TSR of 2-4 (hazard ratio [HR], 2.580; 95% confidence interval [CI] 1.543-4.312; P < 0.001) and TSR < 2 (HR, 4.435; 95% CI 2.499-7.872; P < 0.001) were associated with worse liver RFS. As TSR decreased, liver RFS worsened. TSR could further stratify patients in zones 1 and 2 into different risk groups according to the TBS criteria (zone 1: median liver RFS, 3.2 and 8.9 months for groups 1 and 2, respectively, P = 0.003; zone 2: median liver RFS, 3.5, 5.0, and 10.9 months for groups 1, 2, and 3, respectively, P < 0.05). The predictive ability of the new clinical score, which includes TSR, was superior to that of the Fong clinical score. CONCLUSIONS: TSR, as a prognostic tool, could accurately assess the effect of size differences across multiple liver metastases on liver RFS in patients undergoing hepatectomy for CRLMs. TRIAL REGISTRATION: Retrospectively registered.

Prognostic value of elastic lamina staining in patients with stage III colon cancer.

OBJECTIVE: The objectives of this study were to analyze the difference between the preoperative radiological and postoperative pathological stages of colorectal cancer (CRC) and explore the feasibility of elastic lamina invasion (ELI) as a prognostic marker for patients with stage III colon cancer. METHODS: A total of 105 consecutive patients underwent radical surgery (R0 resection) for stage III colon cancer at the Cancer Hospital of China Medical University between January 2015 and December 2017. Clinicopathological features, including radiological stage and elastic lamina staining, were analyzed for prognostic significance in stage III colon cancer. RESULTS: A total of 105 patients with stage III colon cancer who met the criteria and had complete data available were included. The median follow-up period of survivors was 41 months. During the follow-up period, 33 (31.4%) patients experienced recurrence after radical resection, and the 3-year disease-free survival (DFS) rate was 64.8%. The consistency between preoperative radiological and postoperative pathological staging was poor (κ = 0.232, P < 0.001). The accuracy of ≤ T2 stage diagnoses was 97.1% (102/105), that of T3 stage was 60.9% (64/105), that of T4a stage was 68.6% (72/105) and that of T4b stage was 91.4% (96/105). The DFS rate of T3 ELI (+) patients was significantly lower than that of both T3 ELI (-) patients (P = 0.000) and pT4a patients (P = 0.013). The DFS rate of T3 ELI (-) patients was significantly higher than that of pT4b patients (P=0.018). T3 ELI (+) (HR (Hazard ratio), 8.444 [95% CI, 1.736-41.067]; P = 0.008), T4b (HR, 57.727[95% CI, 5.547-600.754]; P = 0.001), N2 stage (HR, 10.629 [95% CI, 3.858-29.286]; P < 0.001), stage III (HR, 0.136 [95% CI, 0.31-0.589]; P = 0.008) and perineural invasion (PNI) (HR, 8.393 [95% CI, 2.094-33.637]; P = 0.003) were independent risk factors for postoperative recurrence of stage III colon cancer. CONCLUSIONS: The consistency between preoperative radiological and postoperative pathological staging was poor, especially for tumors located in the ascending colon and descending colon. Elastic lamina staining is expected to become a stratified indicator of recurrence risk for patients with stage III colon cancer and a guide for individualized adjuvant chemotherapy, thus improving patient prognosis.

Significant higher-level C-C motif chemokine ligand 2/3 and chemotactic power in cerebral white matter than grey matter in rat and human.

Recent observations indicate that cerebral white matter (WM) exhibits a higher chemoattractant capability for immune cells. The C-C motif chemokine ligands 2 and 3 (CCL2, CCL3) are key chemokines for monocytes and T cells. However, tissue differential of these chemokines is unclear, although the higher CCL2/3 mRNA levels were found in rodent WM. It has been shown that more immune cells infiltrated to WM than to grey matter (GM) in multiple sclerosis (MS) and human/simian immunodeficiency virus (HIV/SIV)-infected brains. More nodular lesions have also been identified in the WM of patients with MS or HIV/SIV encephalitis. We hypothesize that higher levels of CCL2/3 in the WM may associate with neuropathogenesis. To test this hypothesis, we compared CCL2 and CCL3 peptide levels in WM and GM of rat and human, and found both were significantly higher in the WM. Next, we tested the effect of CCL2 on primary rat microglia migration and observed a dose-dependent migratory pattern. Then, we assessed effects of WM and GM homogenates on microglia chemotaxis and observed significant stronger effects of WM than GM in a concentration-dependent manner. The concentration-dependent pattern of tissue homogenates on chemotaxis was similar to the effect of CCL2. Finally, we found the chemoattractant effects of WM on microglia were significantly attenuated by addition of a CCL2 receptor blocker to culture medium and a neutralizing antibody against CCL3 functional motif in the WM homogenate. Taking together, these results suggest that CCL2/3 played significant roles in the microglia chemotaxis toward WM homogenate.

Near-Infrared Light-Induced Self-Powered Aptasensing Platform for Aflatoxin B1 Based on Upconversion Nanoparticles-Doped Bi2S3 Nanorods.

A light source plays a pivotal role in a photofuel cell (PFC)-based self-powered biosensor. Although a visible light source has been extensively employed to drive a PFC, it still has some drawbacks for biosensing due to its relatively high energy. Herein we constructed a PFC-based aptasensor using near-infrared (NIR) light as the irradiation source. To achieve an efficient absorption of the NIR light, NaYF4:Yb,Er upconversion nanoparticles (UCNPs) that could convert low-energy incident light into high-energy radiation were combined with Bi2S3 nanorods (UCNPs/Bi2S3) to serve as the photoactive materials. The PFC was comprised of a UCNPs/Bi2S3 photoanode and a Pt cathode, which could generate electrical output under NIR light irradiation to provide the self-powered sensing signal without the supply from an external power source. The aflatoxin B1 (AFB1) binding aptamer was immobilized on the photoanode to serve as the recognition element. The detection of AFB1 was based on the competition between the interaction of aptamer with AFB1 analyte and the hybridization of aptamer with Au nanoparticles-labeled DNA sequence (AuNPs-cDNA). Under optimum conditions, the proposed aptasensor presented good sensitivity and high specificity for AFB1 detection in the concentration range from 0.01 to 100 ng·mL-1, with a detection limit of 7.9 pg·mL-1. Moreover, the developed sensor was applied to an assay of AFB1 in flour samples with a desirable accuracy and precision.

Minocycline attenuation of rat corpus callosum abnormality mediated by low-dose lipopolysaccharide-induced microglia activation.

BACKGROUND: Microglia are resident innate immune cells in the brain, and activation of these myeloid cells results in secretion of a variety of pro-inflammatory molecules, leading to the development of neurodegenerative disorders. Lipopolysaccharide (LPS) is a widely used experimental stimulant in microglia activation. We have previously shown that LPS produced microglia activation and evoked detectable functional abnormalities in rat corpus callosum (CC) in vitro. Here, we further validated the effects of low-dose LPS-induced microglia activation and resultant white matter abnormality in the CC in an animal model and examined its attenuation by an anti-inflammatory agent minocycline. METHODS: Twenty-four SD rats were divided randomly into three groups and intra-peritoneally injected daily with saline, LPS, and LPS + minocycline, respectively. All animals were subject to MRI tests 6 days post-injection. The animals were then sacrificed to harvest the CC tissues for electrophysiology, western blotting, and immunocytochemistry. One-way ANOVA with Tukey's post-test of all pair of columns was employed statistical analyses. RESULTS: Systemic administration of LPS produced microglial activation in the CC as illustrated by Iba-1 immunofluorescent staining. We observed that a large number of Iba-1-positive microglial cells were hyper-ramified with hypertrophic somata or even amoeba like in the LPS-treated animals, and such changes were significantly reduced by co-administration of minocycline. Electrophysiological recordings of axonal compound action potential (CAP) in the brain slices contained the CC revealed an impairment on the CC functionality as detected by a reduction in CAP magnitude. Such an impairment was supported by a reduction of fast axonal transportation evidenced by ß-amyloid precursor protein accumulation. These alterations were attenuated by minocycline, demonstrating minocycline reduction of microglia-mediated interruption of white matter integrity and function in the CC. CONCLUSIONS: Systemic administration of LPS produced microglia activation in the CC and resultant functional abnormalities that were attenuated by an anti-inflammatory agent minocycline.

Starch Capped Atomically Thin CuS Nanocrystals for Efficient Photothermal Therapy.

Photothermal therapy requires efficient plasmonic nanomaterials with small size, good water dispersibility, and biocompatibility. This work reports a one-pot, 2-min synthesis strategy for ultrathin CuS nanocrystals (NCs) with precisely tunable size and localized surface plasmon resonance (LSPR), where a single-starch-layer coating leads to a high LSPR absorption at the near-IR wavelength 980 nm. The CuS NC diameter increases from 4.7 (1 nm height along [101]) to 28.6 nm (4.9 nm height along [001]) accompanied by LSPR redshift from 978 to 1200 nm, as the precursor ratio decreases from 1 to 0.125. Photothermal temperature increases by 38.6 °C in 50 mg L-1 CuS NC solution under laser illumination (980 nm, 1.44 W cm-2 ). Notably, 98.4% of human prostate cancer PC-3/Luc+ cells are killed by as little as 5 mg L-1 starch-coated CuS NCs with 3-min laser treatment, whereas CuS NCs without starch cause insignificant cell death. LSPR modeling discloses that the starch layer enhances the photothermal effect by significantly increasing the free carrier density and blue-shifting the LSPR toward 980 nm. This study not only presents a new type of photothermally highly efficient ultrathin CuS NCs, but also offers in-depth LSPR modeling investigations useful for other photothermal nanomaterial designs.

Key role of CCR2-expressing macrophages in a mouse model of low back pain and radiculopathy.

Chronic low back pain is a common condition, with high societal costs and often ineffectual treatments. Communication between macrophages/monocytes (MØ) and sensory neurons has been implicated in various preclinical pain models. However, few studies have examined specific MØ subsets, although distinct subtypes may play opposing roles. This study used a model of low back pain/radiculopathy involving direct local inflammation of the dorsal root ganglia (DRG). Reporter mice were employed that had distinct fluorescent labels for two key MØ subsets: CCR2-expressing (infiltrating pro-inflammatory) MØ, and CX3CR1-expressing (resident) macrophages. We observed that local DRG inflammation induced pain behaviors in mice, including guarding behavior and mechanical hypersensitivity, similar to the previously described rat model. The increase in MØ in the inflamed DRG was dominated by increases in CCR2+ MØ, which persisted for at least 14 days. The primary endogenous ligand for CCR2, CCL2, was upregulated in inflamed DRG. Three different experimental manipulations that reduced the CCR2+ MØ influx also reduced pain behaviors: global CCR2 knockout; systemic injection of INCB3344 (specific CCR2 blocker); and intravenous injection of liposomal clodronate. The latter two treatments when applied around the time of DRG inflammation reduced CCR2+ but not CX3CR1+ MØ in the DRG. Together these experiments suggest a key role for the CCR2/CCL2 system in establishing the pain state in this model of inflammatory low back pain and radiculopathy. Intravenous clodronate given after pain was established had the opposite effect on pain behaviors, suggesting the role of macrophages or their susceptibility to clodronate may change with time.

Total synthesis and biological evaluation of 7-hydroxyneolamellarin A as hypoxia-inducible factor-1α inhibitor for cancer therapy.

7-Hydroxyneolamellarin A (7-OH-Neo A, 1), a natural marine product derived from sponge Dendrilla nigra, was first synthesized with 10% overall yield under the instruction of convergent synthetic strategy. We found that 7-OH-Neo A could attenuate the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein and inhibit vascular epidermal growth factor (VEGF) transcriptional activity, showing well inhibitory effect on HIF-1 signaling pathway. Meantime, 7-OH-Neo A had the well anti-tumor activities, such as inhibiting tumor angiogenesis, proliferation, migration and invasion. More importantly, 7-OH-Neo A exhibited profound anti-tumor effect in mice breast cancer model by suppressing the accumulation of HIF-1α in tumor tissue. Mechanism study demonstrated that 7-OH-Neo A might target the protein with the ability of stabilizing HIF-1α in hypoxia. Due to the excellent water solubility, superior anti-tumor activity and good biocompatibility, 7-OH-Neo A shows the promising potential for being exploited as an anti-tumor agent in near future.

Electronic Spillover from a Metallic Nanoparticle: Can Simple Electrochemical Electron Transfer Processes Be Catalyzed by Electronic Coupling of a Molecular Scale Gold Nanoparticle Simultaneously to the Redox Molecule and the Electrode?

Electrochemical electron transfer (ET) of transition metal complexes or redox metalloproteins can be catalyzed by more than an order of magnitude by molecular scale metallic nanoparticles (NPs), often rationalized by concentration enhancement of the redox molecules in the interfacial region, but collective electronic AuNP array effects have also been forwarded. Using DFT combined with molecular electrochemical ET theory we explore here whether a single molecular scale Au nanocluster (AuC) between a Au (111) surface and the molecular redox probe ferrocene/ferricinium (Fc/Fc+) can trigger an ET rate increase. Computational challenges limit us to AunCs (n up to 147), which are smaller than most electrocatalytic AuCs studied experimentally. AuC-coating thiols are addressed both as adsorption of two S atoms at the structural Au55 bridge sites and as superexchange of variable-size AuCs via a single six-carbon alkanethiyl bridge. Our results are guiding, but enable comparing many AuC surface details (apex, ridge, face, direct vs superexchange ET) with a planar Au(111) surface. The rate-determining electronic transmission coefficients for ET between Fc/Fc+ and AuC are highly sensitive to subtle AuC electronic features. The transmission coefficients mostly compete poorly with direct Fc/Fc+ ET at the Au(111) surface, but Fc/Fc+ 100 face-bound on Au79 and Au147 and ridge bound on Au19 leads to a 2- or 3-fold rate enhancement, in different distance ranges. Single AuCs can thus indeed cause rate enhancement of simple electrochemical ET, but additional, possibly collective AuNC effects, as well as larger clusters and more complete coating layers, also need to be considered.