Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Impact of early heparin therapy on outcomes in patients with solid malignancy associated sepsis: a marginal structural model causal analyse.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear. Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables. Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41-0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26-0.68); hospital mortality HR 0.70, 95% CI 0.50-0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34-0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26-0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50-0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16-0.69). Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

[Heterocyclic compounds and phenolic glycosides from flowers of Dendrobium officinale].

Eight heterocyclic compounds and twelve phenolic glycosides were separated from the water extract of Dendrobium officinale flowers through chromatographic techniques, such as Diaion HP-20 macroporous adsorption resin column chromatography(CC), silica gel CC, ODS CC, Sephadex LH-20 CC, and preparative high performance liquid chromatography(PHPLC). According to the spectroscopic analyses(MS, ~1H-NMR, and ~(13)C-NMR) and optical rotation data, the compounds were identified as dendrofurfural A(1), 2'-deoxyadenosine(2), 4-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoic acid(3), 4-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl] butanoic acid(4), 1-(2-hydroxyethyl)-5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde(5), 5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde(6), methyl 5-(hydroxymethyl)-furan-2-carboxylate(7),(S)-5-hydroxymethyl-5H-furan-2-one(8), 2-methoxyphenyl-1-O-ß-D-glucopyranoside(9), arbutin(10), isotachioside(11), 2,6-dimethoxy-4-hydroxyphenol-1-O-ß-D-glucopyranoside(12), orcinol glucoside(13), tachioside(14), gastrodin(15), 4-O-ß-D-glucopyranosylvanillyl alcohol(16), 2,6-dimethoxy-4-hydroxymethylphenol-1-O-ß-D-glucopyranoside(17), icariside D_2(18), 4-formylphenyl-ß-D-glucopyranoside(19), and vanillin-4-O-ß-D-glucopyranoside(20). Among them, compound 1 is a new furfural benzyl alcohol condensate, with the skeleton first found in Dendrobium. Compounds 2-9, 11, 13, and 19 are reported from Dendrobium for the first time, and compounds 14 and 18 are reported for the first time from D. officinale. Compounds 11 and 14 showed moderate DPPH radical scavenging capacity, and compounds 11-14 demonstrated potent ABTS radical scavenging capacity, possessing antioxidant activity.

Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy.

Background: This study aimed to investigate whether early unfractionated heparin (UFH) administration provides a survival advantage for patients with sepsis-induced coagulopathy (SIC). Methods: Patients hospitalized with sepsis-induced coagulopathy from the Medical Information Mart for Intensive Care (MIMIC)-IV database were identified. Patients were divided into two groups, who received unfractionated heparin (UFH) subcutaneously within 24 h after intensive care unit (ICU) admission, and the control group, who received not. The primary endpoint was intensive care unit mortality, the secondary outcomes were 7, 14, and 28-day and hospital mortality. Propensity score matching (PSM) the marginal structural Cox model (MSCM) and E-value analysis were used to account for baseline differences, time-varying and unmeasured confounding factors. Results: A total of 3,377 patients with sepsis-induced coagulopathy were enrolled in the study, of which 815 in unfractionated heparin group and 2,562 in control group. There was significant effect on primary and secondary outcomes with unfractionated heparin after propensity score matching (intensive care unit mortality, hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.52-0.92; 7-day, HR 0.70, 95% CI 0.49-0.99; 14-day, HR 0.68.95% CI 0.50-0.92; 28-day, HR 0.72, 95% CI 0.54-0.96; hospital mortality, HR 0.74, 95% CI 0.57-0.96), marginal structural Cox model manifested unfractionated heparin associated with decreased intensive care unit mortality in all populations (HR 0.64, 95% CI 0.49-0.84), and stratification with the marginal structural Cox model indicated analysis further indicated the survival advantage only among patients with an sepsis-induced coagulopathy score of 4 (HR 0.56, 95% CI 0.38-0.81). Further analysis showed that treatment with 6,250-13750 IU/day of unfractionated heparin associated with a decreased risk of intensive care unit mortality. Similar results were replicated in subgroup analysis with propensity score matching only for patients with an sepsis-induced coagulopathy score of 4 (intensive care unit mortality, HR 0.51, 95% CI 0.34-0.76). Conclusion: This study found early unfractionated heparin therapy to patients with sepsis-induced coagulopathy appears to be associated with improved outcomes. Subgroup analysis further demonstrates heparin therapy decreased intensive care unit mortality primarily in patients only with SIC score of 4.

Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis.

Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening. Tubastatin A directly bonded to GPX4 and inhibited GPX4 enzymatic activity through biotin-linked Tubastatin A putdown and LC/MS analysis, which is independent of its inhibition of HDAC6. In addition, our results showed that radiotherapy not only activated Nrf2-mediated GPX4 transcription but also inhibited lysosome-mediated GPX4 degradation, subsequently inducing ferroptosis tolerance and radioresistance in cancer cells. Tubastatin A overcame ferroptosis resistance and radioresistance of cancer cells by inhibiting GPX4 enzymatic activity. More importantly, Tubastatin A has excellent bioavailability, as demonstrated by its ability to significantly promote radiotherapy-induced lipid peroxidation and tumour suppression in a mouse xenograft model. Our findings identify a novel druggable ferroptosis inducer, Tubastatin A, which enhances radiotherapy-mediated antitumor effects. This work provides a compelling rationale for the clinical evaluation of Tubastatin A, especially in combination with radiotherapy.

Role of the extracellular matrix in COVID-19.

An outbreak of coronavirus disease 2019 (COVID-19) has spread globally, with over 500 million cases and 6 million deaths to date. COVID-19 is associated with a systemic inflammatory response and abnormalities of the extracellular matrix (ECM), which is also involved in inflammatory storms. Upon viral infection, ECM proteins are involved in the recruitment of inflammatory cells and interference with target organ metabolism, including in the lungs. Additionally, serum biomarkers of ECM turnover are associated with the severity of COVID-19 and may serve as potential targets. Consequently, understanding the expression and function of ECM, particularly of the lung, during severe acute respiratory syndrome of the coronavirus 2 infection would provide valuable insights into the mechanisms of COVID-19 progression. In this review, we summarize the current findings on ECM, such as hyaluronic acid, matrix metalloproteinases, and collagen, which are linked to the severity and inflammation of COVID-19. Some drugs targeting the extracellular surface have been effective. In the future, these ECM findings could provide novel perspectives on the pathogenesis and treatment of COVID-19.

Impact of early heparin therapy on mortality in critically ill patients with sepsis associated acute kidney injury: a retrospective study from the MIMIC-IV database.

Background: Inflammatory-coagulation dysfunction plays an increasingly important role in sepsis associated acute kidney injury (SAKI). This study aimed to investigate whether early heparin therapy improves survival in patients with SAKI. Methods: Patients with SAKI were identified from the Medical Information Mart for Intensive Care-IV database. The patients were divided into two groups: those who received heparin subcutaneously within 48 h after intensive care unit (ICU) admission and the control group, who received no heparin. The primary endpoint was ICU mortality, the secondary outcomes were 7-day, 14-day, 28-day, and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), and E-value analyses were performed. Results: The study included 5623 individuals with SAKI, 2410 of whom received heparin and 3213 of whom did not. There were significant effects on ICU and 28-day mortality in the overall population with PSM. MSCM further reinforces the efficacy of heparin administration reduces ICU mortality in the general population. Stratification analysis with MSCM showed that heparin administration was associated with decreased ICU mortality at various AKI stages. Heparin use was also associated with reduced 28-day mortality in patients with only female, age >60 years, and AKI stage 3, with HRs of 0.79, 0.77, and 0.60, respectively (p < 0.05). E-value analysis suggests robustness to unmeasured confounding. Conclusion: Early heparin therapy for patients with SAKI decreased ICU mortality. Further analysis demonstrated that heparin therapy was associated with reduced 28-day mortality rate in patients only among female, age > 60 years and AKI stage 3.

Impact of early empirical antifungal therapy on prognosis of sepsis patients with positive yeast culture: A retrospective study from the MIMIC-IV database.

Background: Mortality and other clinical outcomes of culture-negative and culture-positive among patients with fungal sepsis have not been documented, and whether antifungal therapy prior to fungal culture reports is related to decreased mortality among patients remains largely controversial. This study aimed to determine the mortality and other clinical outcomes of patients with positive yeast cultures and further investigate the effects of initial empiric antifungal therapy. Methods: A retrospective study was conducted among septic patients using the Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients with sepsis were divided into two groups based on first fungal culture status during intensive care unit (ICU) stay, and initial empirical antifungal therapy was prescribed based on physician's experience prior to fungal culture reports within 48 h. The primary outcome was in-hospital all-cause mortality. The secondary outcomes were 30-day all-cause mortality, 60-day all-cause mortality, length of ICU stay and length of hospital stay. Multivariate logistic regression, propensity score matching (PSM), subgroup analyses and survival curve analyses were performed. Results: This study included 18,496 sepsis patients, of whom 3,477 (18.8%) had positive yeast cultures. Patients with positive yeast cultures had higher in-hospital all-cause mortality, 60-day all-cause mortality, and longer lengths of ICU stay and hospital stay than those with negative yeast cultures after PSM (all p < 0.01). Multivariate logistic regression analysis revealed that positive yeast culture was a risk factor for in-hospital mortality in the extended model. Subgroup analyses showed that the results were robust among the respiratory infection, urinary tract infection, gram-positive bacterial infection and bacteria-free culture subgroups. Interestingly, empiric antifungal therapy was not associated with lower in-hospital mortality among patients with positive yeast cultures, mainly manifested in stratification analysis, which showed that antifungal treatment did not improve outcomes in the bloodstream infection (odds ratio, OR 2.12, 95% CI: 1.16-3.91, p = 0.015) or urinary tract infection groups (OR 3.24, 95% CI: 1.48-7.11, p = 0.003). Conclusion: Culture positivity for yeast among sepsis patients was associated with worse clinical outcomes, and empiric antifungal therapy did not lower in-hospital all-cause mortality in the bloodstream infection or urinary tract infection groups in the ICU.

Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database.

Background: Minimal data exist on anticoagulation use and timing and the dose of heparin in patients with sepsis, and whether heparin use improves sepsis survival remains largely unclear. This study was performed to assess whether heparin administration would provide a survival advantage in critically ill patients with sepsis. Methods: A retrospective cohort study of patients with sepsis in the Medical Information Mart for Intensive Care (MIMIC)-IV database was conducted. Cox proportional hazards model and propensity score matching (PSM) were used to evaluate the outcomes of prophylactic anticoagulation with heparin administered by subcutaneous injection within 48 h of intensive care unit (ICU) admission. The primary outcome was in-hospital mortality. Secondary outcomes included 60-day mortality, length of ICU stay, length of hospital stay and incidence of acute kidney injury (AKI) on day 7. E-Value analysis were used for unmeasured confounding. Results: A total of 6646 adult septic patients were included and divided into an early prophylactic heparin group (n = 3211) and a nonheparin group (n = 3435). In-hospital mortality in the heparin therapy group was significantly lower than that in the nonheparin group (prematched 14.7 vs 20.0%, hazard ratio (HR) 0.77, 95% confidence interval (CI) [0.68-0.87], p < 0.001, and postmatched 14.9 vs 18.3%, HR 0.78, 95% CI [0.68-0.89], p < 0.001). Secondary endpoints, including 60-day mortality and length of ICU stay, differed between the heparin and nonheparin groups (p < 0.01). Early prophylactic heparin administration was associated with in-hospital mortality among septic patients in different adjusted covariates (HR 0.71-0.78, p < 0.001), and only administration of five doses of heparin was associated with decreased in-hospital mortality after PSM (HR 0.70, 95% CI 0.56-0.87, p < 0.001). Subgroup analysis showed that heparin use was significantly associated with reduced in-hospital mortality in patients with sepsis-induced coagulopathy, septic shock, sequential organ failure assessment score ≥ 10, AKI, mechanical ventilation, gram-positive bacterial infection and gram-negative bacterial infection, with HRs of 0.74, 0.70, 0.58, 0.74, 0.73, 0.64 and 0.72, respectively (p <0.001). E-Value analysis suggested robustness to unmeasured confounding. Conclusions: This study found an association between early administration prophylactic heparin provided to patients with sepsis and reduced risk-adjusted mortality. A prospective randomized-controlled study should be designed to further assess the relevant findings.

Development and Application of Global Health Events-Mental Stress Scale for Assessment of Medical Staff's Acute Mental Stress Responses.

Background: Medical workers have been increasingly involved in emergent public health events, which can lead to severe stress. However, no standardized, officially recognized, unified tool exists for mental distress measurement in medical workers who experienced the public health events. Purpose: In the present study, we propose the Global Health Events-Mental Stress Scale (GHE-MSS), as a revised version of the Impact of Event Scale-Revision (IES-R), for assessment of medical workers' acute mental stress responses within one month and their chronic mental stress responses within six months after major health events. Patients and methods: The IES-R was slightly modified, developed, and its reliability and validity were tested using the Delphi survey, primary survey with 115 participants, formal survey with 300 participants, and clinical evaluation with 566 participants. Results: Exploratory factor analysis and confirmatory factor analysis confirmed a promising validity of the scale. The values of Cronbach's alpha coefficient, the Spearman-Brown coefficient, and the retested Cronbach's alpha coefficient of the scale applied for the clinical evaluation were 0.88, 0.87, and 0.98, respectively, which confirmed a good internal consistency and stability. The results of the goodness-of-fit test indicated a good adaptation of the model. A correlation analysis was conducted to assess the correlation between the GHE-MSS and the PCL-C, which had a correlation coefficient of 0.68 (P<0.01). Conclusion: GHE-MSS can be applied with a promising reliability and validity for the assessment of the acute mental stress response of medical workers experiencing public health events. This method can also be used for the screening of mental stress-associated disorders.

Novel Signatures Based on the Lymphocyte-to-C-Reactive Protein Ratio Predict the Prognosis of Patients with Early Breast Cancer: A Retrospective Study.

Background: The value of the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) in early breast cancer (BC) is unclear. We explored the correlation between the LCR and survival of patients with early BC and established effective LCR-based prognostic signatures for predicting prognosis. Methods: In this retrospective study, we randomized 623 patients with early-stage BC diagnosed in December 2010 to October 2012 at the Sun Yat-sen University Cancer Center to training and verification datasets. The median follow-up of all patients was 109 months. The survival differences were calculated by Kaplan-Meier method using the Log rank test. For overall survival (OS) and disease-free survival (DFS), the independent factors in the training dataset were identified using univariate and multivariate Cox analyses, in which two-tailed P-values < 0.05 were considered statistically significant. Based on this, we respectively constructed novel signatures for survival prediction and validated the efficiency of signatures through the concordance index (C-index), calibration and receiver operating characteristic (ROC) curves in both datasets. Results: The LCR, lymphatic vessel invasion (LVI), progesterone receptor (PR) status, and Ki67 index were independent prognostic factors of OS. And the LCR and LVI are associated to DFS too. High LCR was associated with better OS and DFS. We constructed the prediction signatures based on those independent prognostic factors and calculated the risk scores. Patients in the training dataset with higher risk scores had significantly worse prognosis (P < 0.001). The signature had excellent discrimination capacity, with an OS C-index of 0.785 [95% confidence interval (CI): 0.713-0.857] and 0.750 (95% CI: 0.669-0.832) in the training and verification datasets, respectively. The time-ROC curves also suggest accurate prediction by the signature. Conclusion: The LCR was a significant prognostic predictor of OS and DFS in early BC. The LCR-based prognostic signatures could be a useful tool for individualized therapeutic guidance.

Early Combination of Albumin With Crystalloid Administration Might Reduce Mortality in Patients With Cardiogenic Shock: An Over 10-Year Intensive Care Survey.

Background: In updated international guidelines, combined albumin resuscitation is recommended for septic shock patients who receive large volumes of crystalloids, but minimal data exist on albumin use and the optimal timing in those with cardiogenic shock (CS). The objective of this study was to evaluate the relationship between resuscitation with a combination of albumin within 24 h and 30-day mortality in CS patients. Methods: We screened patients with CS from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariable Cox proportional hazards models and propensity score matching (PSM) were employed to explore associations between combined albumin resuscitation within 24 h and 30-day mortality in CS. Models adjusted for CS considered potential confounders. E-value analysis suggested for unmeasured confounding. Results: We categorized 1,332 and 254 patients into crystalloid-only and early albumin combination groups, respectively. Patients who received the albumin combination had decreased 30-day and 60-day mortality (21.7 vs. 32.4% and 25.2 vs. 34.2%, respectively, P < 0.001), and the results were robust after PSM (21.3 vs. 44.7% and 24.9 vs. 47.0%, respectively, P < 0.001) and following E-value. Stratified analysis showed that only ≥ 60 years old patients benefited from administration early albumin. In the early albumin combination group, the hazard ratios (HRs) of different adjusted covariates remained significant (HRs of 0.45-0.64, P < 0.05). Subgroup analysis showed that resuscitation with combination albumin was significantly associated with reduced 30-day mortality in patients with maximum sequential organ failure assessment score≥10, with acute myocardial infarction, without an Impella or intra-aortic balloon pump, and with or without furosemide and mechanical ventilation (HRs of 0.49, 0.58, 0.65, 0.40, 0.65 and 0.48, respectively; P < 0.001). Conclusion: This study found, compared with those given crystalloid-only, resuscitation with combination albumin within 24 h is associated with lower 30-day mortality of CS patients aged≥60. The results should be conducted to further assess in randomized controlled trials.

[Effects of biochar combined with nitrification/urease inhibitors on soil active nitrogen emissions from subtropical paddy soils]. / ç”Ÿç‰©ç‚­é æ–½ç¡åŒ–/è„²é ¶æŠ‘åˆ¶å‰‚å¯¹äºšçƒ­å¸¦æ°´ç¨»åœŸæ´»æ€§æ°®æ°”ä½“æŽ’æ”¾çš„å½±å“.

We examined the effects of biochar and urease inhibitors/nitrification inhibitors on nitrification process, ammonia and N2O emission in subtropical soil, and determined the best combination of biochar with nitrification and urease inhibitors. This work could provide a theoretical basis for the mitigation of the negative environmental risk caused by reactive nitrogen gas in the application of nitrogen fertilizer. A indoor aerobic culture test was conducted with seven treatments [urea+biochar (NB), urea+nitrification inhibitor (N+NI), urea+urease inhibitor (N+UI), urea+nitrification inhibitor+urease inhibitor (N+NIUI), urea+nitrification inhibitor+biochar (NB+NI), urea+urease inhibitor+biochar (NB+UI), urea+nitrification inhibitor+urease inhibitor+biochar (NB+NIUI)] and urea (N) as the control. The dynamics of soil inorganic nitrogen content, N2O emission and the volatility of ammonia volatilization were observed under combined application of biochar with urease inhibitor (NBPT)/nitrification inhibitor (DMPP). The results showed that:1)Compared to the control (5.11 mg N·kg-1·d-1) during the incubation period, NB treatment significantly increased therate constant of nitrification by 33.9%, and N+NI treatment significantly reduced the nitrification rate constant by 22.9%. NB treatment significantly increased the abundance of ammonia oxidizing bacteria (AOB) by 56.0%. 2) Compared with N treatment, N+NI and NB+NI treatments signi-ficantly enhanced the cumulative emission of NH3 by 49%. The N+UI treatment reduced the cumulative loss of NH3. The inhibition effect of NB+UI treatment was more significant. 3) The emission rate of N2O was highest in the first 10 days after fertilization. The N2O emission under NB treatment was the earliest, and that of N treatment was the highest (5.87 µg·kg-1·h-1). The combined application of DMPP and NBPT performed the best in reducing soil N2O emission. We estimated global warming potential (GWP) of the direct N2O and indirect N2O (NH3) emissions. Compared with N treatments, N+NI and NB+NI treatments increased the GWP by 34.8% and 40.9%, respectively. While the NB and NB+UI treatments significantly reduced the GWP by 45.9% and 60.5%, the combination of biochar and urease inhibitor had the best effect on reduction of GWP of soil active nitrogen emissions.

Combination of Anti-PD-1 Antibody, Anlotinib and Pegaspargase "Sandwich" With Radiotherapy in Localized Natural Killer/T Cell Lymphoma.

Asparaginase/pegaspargase containing regimens combined with radiotherapy are highly effective and considered the cornerstone of localized Natural killer/T-cell lymphoma (NKTL) treatment. However, these chemotherapy regimens inevitably cause relatively high incidence of treatment-related adverse events (TRAEs). Herein we retrospectively evaluated the efficacy and safety of the combined regimen of anti-PD-1 antibody, anlotinib and pegaspargase "sandwich" with radiotherapy in localized NKTL. Anti-PD-1 antibody and pegaspargase at 2500 U/m2 were administered on day 1, while anlotinib (12 mg once a day) was orally administered on days 1-14. The treatment was repeated every 3 weeks. All the eight patients included received 3 cycles of the regimen followed by radiotherapy and an additional 3 cycles. The overall response rate was 100%, and the complete response rate was 87.5%. With a median follow-up time of 35.5 months (range, 34.03-40.90 months), median PFS and OS times were not reached. The 3-year PFS and OS rates were 100% and 100%, respectively. All patients were alive at the last follow-up. No treatment-related death and no grade 4 TRAE was reported. No grade 3/4 hematological toxicity was detected, and half of the patients didn't report any hematological toxicity. This study indicates that anti-PD-1 antibody combined with anlotinib and pegaspargase is a promising chemoradiotherapy regimen for localized NTKL, with mild toxicity and good tolerance.

Phase II Study of Gemcitabine, Peg-Asparaginase, Dexamethasone and Methotrexate Regimen for Newly Diagnosed Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Final Analysis With Long-Term Follow-Up and Rational Research for the Combination.

Patients with extranodal natural killer/T-cell lymphoma (ENKTL), nasal type are benefit from peg-asparaginase, gemcitabine, and methotrexate. Therefore, we conducted a prospective phase II trial using a combination of these drugs as GAD-M regimen in naïve ENKTL patients, simultaneously, explored the combinational mechanism. The GAD-M regimen was administered for 6 cycles sandwiched by radiotherapy for stage I/II and 6 cycles for stage III/IV patients. After 6 cycles, the overall response rate of 36 patients was 91.6%, and the complete remission rate increased to 83.3%. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 74.8% and 77.8%, respectively. The 5-year PFS and OS were 68.3% and 77.8%. No patient suffered from the central nervous system (CNS) relapse. Most patients experienced recoverable liver dysfunction and anemia in this study. The plasma MTX concentration ratio at 12 to 24 hr during the first cycle could be an early predictor of outcomes in ENKTL (PFS, P=0.005; OS, P=0.002). Additionally, we found that high dose MTX (HD-MTX) and gemcitabine had the synergistic effect of ENKTL cell in vitro. Mechanistically, we demonstrated that the combination could lead to obviously apoptosis in ENKTL cell with extremely release of reactive oxygen spices (ROS), which mediated by endoplasmic reticulum stress. In conclusion, the GAD-M regimen could be a new choice to newly diagnosed ENKTL, especially for stage I/II patients. Furthermore, our results showed the synergy effect of HD-MTX with gemcitabine in ENKTL. CLINICAL TRIAL REGISTRATION: This trial was registered at www.clinicaltrials.gov as #NCT01991158.

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002).

PURPOSE: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. PATIENTS AND METHODS: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. RESULTS: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. CONCLUSIONS: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

Mimotope-Based Immunoassays for the Rapid Analysis of Mycotoxin: A Review.

Mycotoxins are toxic contaminants in foods and feeds that are naturally occurring and largely unavoidable. Determining their contents in these products is essential to protect humans from harm. Immunoassays of mycotoxins have been well-established because they are fast, sensitive, simple, and cost-effective. However, a major limitation of immunoassays is the requirement of toxic mycotoxins as competing antigens, standards, or competing tracers. Mimotopes are peptides or proteins that can specifically bind to antibodies and compete with analytes for binding sites by mimicking antigenic epitopes. They can be employed as substitutes for competing antigens, standards, or competing tracers to avoid use of mycotoxins. This review summarizes the production and functionalization of the two main kinds of mimotopes, mimic peptides and anti-idiotypic antibodies (Ab2), and their applications in rapid analysis of mycotoxins.

Establishment and Validation of Nomogram Based on Combination of Pretreatment C-Reactive Protein/Albumin Ratio-EBV DNA Grade in Nasopharyngeal Carcinoma Patients Who Received Concurrent Chemoradiotherapy.

BACKGROUND: A higher ratio of pretreatment C-reactive protein/albumin ratio (CAR) is associated with poor prognosis in nasopharyngeal carcinoma (NPC), and Epstein-Barr virus (EBV) DNA level is known to not only participate in the occurrence of nasopharyngeal carcinoma but also affect the development and prognosis of the disease. Herein, we proposed that a combination of both these markers could improve the predictive prognostic ability. METHODS: In all, 842 NPC patients who received concurrent chemoradiotherapy (CCRT) were entered in this study. We collected all patients' blood samples and EBV DNA copy numbers within one week before any treatment. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off. We employed the Kaplan-Meier method for survival analyses and the univariate and multivariate analyses (Cox proportional hazards regression model) for statistical analysis. A nomogram was constructed based on multivariate analyses results of the validation set. The model was internally validated using 1000 bootstrap samples to avoid overfitting. Another validation of 10-fold cross-validation was also applied. Calibration curves and concordance index (C-index) were calculated to determine predictive and discriminatory capacity. RESULTS: In the whole cohort, we observed that higher CAR, EBV DNA level, and CAR-EBV DNA (C-E) grade were associated with shorter overall survival (OS) and distant metastasis-free survival (DMFS) (all P<0.05). In univariate and multivariate analyses, C-E grade was an independent prognostic factor (all P<0.05). In the training set, we gained the similar results with the whole set. According to multivariate analyses of the training set, we constructed a nomogram. The results of bootstrap samples and 10-fold cross-validation showed favorable predictive efficacy. And calibration curves of the model provided credibility to its predictive capability. CONCLUSION: C-E grade was confirmed as an independent prognostic predictor in patients with NPC who received CCRT. Higher level of pretreatment C-E grade could signify a higher risk of metastasis and shorter OS. The prognostic nomogram based on C-E grade was dependable in nasopharyngeal carcinoma patients.

Safety of Thread Embedding Acupuncture Therapy: A Systematic Review.

OBJECTIVE: To evaluate the safety of thread embedding acupuncture therapy (TEAT) and discuss the prevention and treatment of some adverse events (AEs). METHODS: Review of databases, including China National Knowledge Infrastructure (CNKI), CBMdisc, Wanfang, VIP databases and English literature published in PubMed, MEDLINE, EMBASE and Web of Science, were searched from their inception to January 2020, randomized controlled trials (RCTs) and case reports in which AEs with TEAT were included. Cochrane Collaboration's tool and RevMan V.5.3.3 software were used to evaluate the quality of the studies. RESULTS: A total of 61 studies (45 RCTs and 16 case reports) with 620 cases of AEs were included in this review. These studies were published in two countries: China and South Korea. Twenty eight kinds of AEs were summarized. The most common AEs were induration, bleeding and ecchymosis, redness and swelling, fever, and pain. They were accounted for 75.35% (425/564) in the review, and most of them were mild. The rarest AEs were epilepsy, irregular menstruation, skin ulcer, thread malabsorption, and fat liquefaction, with 1 case each. But not all of them had clear causal relationship with TEAT. Most of the AEs were local reactions [with incidence of 9.83% (480/4,882)] and systemic reactions accounted for only 1.27% (62/4,882). Although the included studies showed that AEs were very commonly encountered (11.09%), only 5 cases of severe AEs reported from 2013 to 2017 (0.1%) by using catgut thread, which are rarely seen nowdays with the wide use of new absorbable surgical suture. All of the severe AEs were recovered after symptomatic treatment with no sequelae. CONCLUSIONS: The evidence showed that TEAT is a relatively safe and convenient therapy especially since application of new absorbable surgical suture. Improving practitioner skills, regulating operations, and paying attention to the patients' conditions may reduce the incidence of AEs and improve safety of TEAT.

Association between Procalcitonin and Acute Kidney Injury in Patients with Bacterial Septic Shock.

OBJECTIVE: The objective of this study was to assess the relationship between serum procalcitonin (PCT) and acute kidney injury (AKI) induced by bacterial septic shock. METHODS: A retrospective study was designed which included patients who were admitted to the ICU from January 2015 to October 2018. Multiple logistic regression and receiver operating characteristic (ROC) as well as smooth curve fitting analysis were used to assess the relationship between the PCT level and AKI. RESULTS: Of the 1,631 patients screened, 157 patients were included in the primary analysis in which 84 (53.5%) patients were with AKI. Multiple logistic regression results showed that PCT (odds ratio [OR] = 1.017, 95% confidence interval [CI] 1.009-1.025, p < 0.001) was associated with AKI induced by septic shock. The ROC analysis showed that the cutoff point for PCT to predict AKI development was 14 ng/mL, with a sensitivity of 63% and specificity 67%. Specifically, in multivariate piecewise linear regression, the occurrence of AKI decreased with the elevation of PCT when PCT was between 25 ng/mL and 120 ng/mL (OR 0.963, 95% CI 0.929-0.999; p = 0.042). The AKI increased with the elevation of PCT when PCT was either <25 ng/mL (OR 1.077, 95% CI 1.022-1.136; p = 0.006) or >120 ng/mL (OR 1.042, 95% CI 1.009-1.076; p = 0.013). Moreover, the PCT level was significantly higher in the AKI group only in female patients aged ≤75 years (p = 0.001). CONCLUSIONS: Our data revealed a nonlinear relationship between PCT and AKI in septic shock patients, and PCT could be used as a potential biomarker of AKI in female patients younger than 75 years with bacterial septic shock.