[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.

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.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

Preparation of graphene oxide and polymer-like quantum dots and their one- and two-photon induced fluorescence properties.

A simple, effective and green bottom-up method for the synthesis of highly fluorescent N doped graphene oxide quantum dots (GOQDs) and polymer-like quantum dots (PQDs) was developed on the basis of rapid one-step microwave assisted pyrolysis of citric acid (CA) and diethylenetriamine (DETA) in different reaction solvents. Both one-photon-induced and two-photon-induced photoluminescence (PL) properties of the resultant GOQDs and PQDs were characterized and analyzed. The one-photon-induced PL quantum yields (QY) of GOQDs and PQDs reached 39.8 and 74.0%, respectively, which are high enough to exhibit strong photoluminescence (PL) emission even under daylight excitation. The origin of the PL behavior and PL quenching mechanism was explored in terms of the interaction between the functional groups on the surfaces of GOQDs or PQDs and Hg(2+). Furthermore, due to the excellent selectivity and sensitivity of the GOQDs and PQDs to Hg(2+), the quantum dots might be used for quantitative detection of Hg(2+) in aqueous solution.

Radiotherapy and PGEMOX/GELOX regimen improved prognosis in elderly patients with early-stage extranodal NK/T-cell lymphoma.

The optimal treatment strategy for elderly patients with natural killer/T-cell lymphoma (NKTCL) remains to be established. A total of 63 elderly patients with newly diagnosed NKTCL were retrospectively reviewed. Among the patients with stage I-II disease, 58.3 % received radiotherapy (RT) ± chemotherapy, and 41.7 % received chemotherapy alone. Compared with chemotherapy alone, RT ± chemotherapy elicited a significantly higher overall response rate (ORR) (100 vs. 57.1 %, P < 0.001) and substantially prolonged 5-year overall survival (OS) (55.3 vs. 18.0 %, P < 0.001) in patients with stage I-II disease. Compared with other chemotherapeutic regimens, pegaspargase plus gemcitabine and oxaliplatin (PGEMOX)/L-asparaginase plus gemcitabine and oxaliplatin (GELOX) was associated with a significantly higher ORR (92.9 vs. 51.6 %, P = 0.009) and a significantly improved 5-year OS (78.6 vs. 23.9 %, P = 0.010) in patients with stage I-II disease. Nine patients with stage I-II disease who were treated with PGEMOX/GELOX followed by RT had an encouraging outcome (5-year OS 100 %, 5-year progression-free survival (PFS) 85.7 %), which was superior to that of patients receiving other regimens followed by RT. In conclusion, RT played an important role for elderly patients with early-stage NKTCL, and the PGEMOX/GELOX regimen was superior to other regimens. The combination of them may be a promising treatment option.

The extent of local tumor invasion predicts prognosis in stage IE nasal natural killer/T-cell lymphoma: a novel T staging system for risk stratification.

A heterogeneous treatment response and prognosis exists among patients with Ann Arbor stage IE natural killer/T-cell lymphoma (NKTCL), and further risk stratification is required to identify high-risk patients. Here, we assessed the extent of local tumor invasion (LTI) in 185 patients with Ann Arbor stage IE primary nasal NKTCL and proposed a novel four-level T staging system. We found that a more advanced T stage was associated with a significantly lower rate of complete remission (CR) after chemotherapy and a marginally lower rate of CR after radiotherapy. While patients with no LTI (T1) or mild LTI (T2) presented with similar 5-year overall survival (OS; 83.6 % vs. 86.0 %, P = 0.990), those with moderately or highly advanced local disease (T3 or T4) had significantly worse survival (5-year OS was 63.3 % and 35.1 %, respectively). A more advanced T stage (T3 or T4) was an independent prognostic factor for both OS and progression-free survival (PFS) in the Cox regression model. In addition, patients with T3 or T4 disease experienced locoregional failure more frequently than those with T1 or T2 disease, and patients with T4 disease had a significantly higher risk of distant failure. Our data demonstrated that the T staging system, based on the extent of LTI, could serve as an effective clinical parameter for further risk stratification among patients with primary nasal Ann Arbor stage IE NKTCL.

Treatment outcome of patients with advanced stage natural killer/T-cell lymphoma: elucidating the effects of asparaginase and postchemotherapeutic radiotherapy.

The prognosis of advanced stage natural killer/T-cell lymphoma (NKTCL) remains relatively disappointing, and the optimal treatment strategy for this disease has yet to be discovered. Seventy-three patients with Ann Arbor stage III or IV NKTCL were retrospectively reviewed. The treatment efficacies of asparaginase-containing and asparaginase-absent chemotherapy regimens were compared, and the effects of postchemotherapeutic radiotherapy were explored. The overall response rate (ORR) of the asparaginase-containing regimens was marginally higher than that of the asparaginase-absent regimens (56.5 vs 32.6 %, P = 0.057). However, no significant difference was observed in 2-year overall survival (OS) (38.3 vs 22.7 %, P = 0.418) or 2-year progression-free survival (PFS) (25.4 vs 14.9 %, P = 0.134) between the asparaginase-containing and asparaginase-absent groups. Postchemotherapeutic radiotherapy was associated with a significantly prolonged survival (2-year OS 57.5 vs 14.5 %, P < 0.001; 2-year PFS 46.3 vs 8.4 %, P < 0.001) and was an independent predictor of both OS and PFS. Radiotherapy significantly improved the prognosis among the patients who exhibited complete or partial remission after initial chemotherapy (2-year OS 81.5 vs 40.2 %, P = 0.002; 2-year PFS 65.6 vs 23.4 %, P = 0.008) but failed to provide a significant survival advantage among those who experienced stable or progressive disease after initial chemotherapy. In conclusion, the use of asparaginase did not significantly improve survival for the treatment of patients with stage III/IV NKTCL. Postchemotherapeutic radiotherapy provided additional prognostic benefits to patients who responded well to the initial chemotherapy, which requires further validation in future prospective studies using larger sample sizes.

High APRIL but not BAFF serum levels are associated with poor outcome in patients with follicular lymphoma.

Elevated B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serum levels have been reported to correlate with worse prognosis in B cell-derived malignancies. However, limited information exists regarding the prognostic significance of BAFF and APRIL serum levels in follicular lymphoma (FL). We measured BAFF and APRIL serum levels for 81 patients with newly diagnosed FL and 12 healthy controls. The mean ± standard deviation (SD) BAFF serum level (1,193.86 ± 1,126.51 pg/ml) was higher in patients with FL than that in the controls (477.16 ± 155.55 pg/ml; P < 0.001). No significant difference in the mean ± SD serum level of APRIL was found between patients and healthy controls (14.39 ± 43.33 vs 5.07 ± 2.52 ng/ml; P = 0.193). When the patients were divided into low- and high-BAFF and low- and high-APRIL groups based on the median value of the BAFF and APRIL serum levels (855.14 pg/ml and 6.35 ng/ml, respectively), a high APRIL, but not a high BAFF, serum level significantly correlated with low complete response rate to initial therapy, high relapse/progression rate, and inferior progression-free survival (PFS; P = 0.019) and overall survival (OS; P = 0.008) rates. A high APRIL serum level was also significantly associated with decreased PFS and OS in patients treated with non-rituximab regimens but not in patients treated with rituximab-containing regimens. The APRIL serum level remained an independent predictor for PFS and OS in multivariate analysis. APRIL may be an important prognostic predictor with potential significance as a therapeutic target in FL.

Expression of BAFF-R, but not BAFF, is an independent prognostic factor in diffuse large B-cell lymphoma patients treated with R-CHOP.

B-cell activating factor (BAFF) and BAFF-receptor (BAFF-R) play crucial roles in the progression of malignant B-cells. The aim of the present study was to evaluate the expression profiles and the clinical significance of BAFF and BAFF-R in diffuse large B-cell lymphoma (DLBCL). Paraffin-embedded specimens from 136 patients with newly diagnosed DLBCL, treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP), were examined for BAFF and BAFF-R expression by immunohistochemistry. BAFF and BAFF-R were expressed in 72.1 % (98/136) and 47.1 % (64/136) of the DLBCL tissues, respectively. Negative BAFF-R expression was significantly correlated with elevated serum lactate dehydrogenase (LDH) levels (P = 0.036), an International Prognostic Index (IPI) score of 2 or higher (P < 0.001), and a poor revised IPI (R-IPI) risk score (P = 0.043). The complete response rate after R-CHOP was higher in patients with positive BAFF-R expression than in those with negative BAFF-R expression (73.4 vs. 56.9 %, P = 0.045). Negative expression of BAFF-R, but not of BAFF, was significantly associated with inferior progression-free survival (PFS; P = 0.020) and overall survival (OS; P = 0.028). Only negative BAFF-R expression was correlated with inferior PFS and OS in multivariate analysis (P = 0.049 and 0.040, respectively). Taken together, our results showed that the majority and approximate one-half of patients with DLBCL were positive for BAFF and BAFF-R, respectively. Negative expression of BAFF-R, but not of BAFF, could be an independent risk factor for PFS and OS in patients with DLBCL treated with standard R-CHOP.

Prognostic values of interim and post-therapy 18F-FDG PET/CT scanning in adult patients with Burkitt's lymphoma.

BACKGROUND: The prognostic values of interim and post-therapy fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and PET/computed tomography (CT) scanning have been confirmed in several subtypes of lymphoma. However, its prognostic value in Burkitt's lymphoma has not been clearly defined. The aim of the present study was to assess the prognostic value of PET/CT scanning during different treatment processes of Burkitt's lymphoma. METHODS: A total of 29 adult patients with newly diagnosed Burkitt's lymphoma were retrospectively involved in this study; of them, 23 patients underwent baseline PET/CT, 15 patients underwent mid-therapy PET/CT after 1-4 cycles of chemotherapy, and 17 patients underwent post-therapy PET/CT after all planned first-line chemotherapy cycles. Mid-therapy and post-therapy PET/CT results (positive vs. negative) were visually interpreted according to the criteria of the International Harmonization Project. The reduction in the maximum standardizes uptake values (∆SUVmax) of 25%, 50%, and 75% were regarded as cutoff points. Overall survival (OS) and progression-free survival (PFS) were regarded as the major endpoints. RESULTS: The median OS and PFS were 27.6 months (range 6.5-78.3 months) and 27.2 months (range 3.0-78.3 months), respectively. The median SUVmax of the baseline PET/CT was 18.3 (range 1.6-35.9), whereas the median SUVmax of the mid-therapy and post-therapy PET/CT decreased to 4.0 (range 0-17.6) and 3.0 (range 0-14.5), respectively. The patients' Eastern Cooperative Oncology Group (ECOG) scores (<2 vs. ≥2) were significantly associated with the baseline PET/CT SUVmax. The mid-therapy and post-therapy PET/CT results (positive vs. negative) showed no significant association with OS or PFS. The optimal cutoff ∆SUVmax from the baseline to the post-therapy PET/CT that could predict a change in OS in patients with Burkitt's lymphoma was 50% (P = 0.019). CONCLUSIONS: (18)F-FDG uptake was intense in Burkitt's lymphoma, and there was a significant reduction in SUVmax during the interim and post-therapy PET/CT procedures. A ∆SUVmax of greater than 50% was a favorable cutoff point to predict the OS of Burkitt's lymphoma patients.

Highly luminescent and transparent ZnO quantum dots-epoxy composite used for white light emitting diodes.

By using epoxy silane as a modifier and stabilizer, ZnO quantum dots (QDs) were synthesized by a one-step precipitation approach. The ZnO QDs acquired showed satisfactory redispersibility and exhibited strong and stable photoluminescence in both solution and dry states. When the ZnO QDs content was as high as 8 wt%, the ZnO QDs-epoxy nanocomposite was still highly transparent and luminescent. Accordingly, the ZnO QDs can be used as a luminescent material, and a cool white light emitting diode (WLED) lamp was made by encapsulating a UV chip with the nanocomposite, without traditional tricolor rare earth phosphors. Additionally, the high loading nanocomposite possessed high ultraviolet resistance, which would help to improve the lifetime of the WLED.

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.

Three prognostic factors influence clinical outcomes of primary testicular lymphoma.

The standard treatment of primary testicular lymphoma (PTL) has not been well established. Our study aimed to evaluate the relationship between the prognostic factors and clinical outcomes of PTL. We retrospectively reviewed the clinical records of 43 PTL patients and included the 39 patients who were diagnosed with primary testicular diffuse large B cell lymphoma (DLBCL) for analysis of prognostic factors and assessment of treatment modalities. Cox regression analysis showed that poor ECOG performance status (PS, ≥2), infiltration of adjacent tissues (spermatic cord, epididymis, or scrotum), and bulky disease (tumor mass, >9 cm) were independent predictors of worse overall survival (OS) for primary testicular DLBCL. According to these three factors, the patients were divided into two groups. Rituximab was found to significantly prolong progression-free survival (PFS) in the low-risk group (P = 0.044) but not in the high-risk group (P = 0.748). And the combination therapy for CNS prophylaxis significantly prolonged the survival in the high-risk group (P = 0.005 for OS; P = 0.004 for PFS), but not in the low-risk group (P = 0.092 for OS; P = 0.191 for PFS). ECOG performance status, infiltration of adjacent tissues, and bulky disease are practical prognostic factors of survival in patients with primary testicular DLBCL. The addition of rituximab is more important for the patients without the prognostics factors, and the combination CNS prophylaxis is more significant for the patients with the prognostics factors.

Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL. METHODS: Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis. RESULTS: The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category. CONCLUSION: The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL.

The Glasgow Prognostic Score (GPS) as a novel and significant predictor of extranodal natural killer/T-cell lymphoma, nasal type.

The Glasgow Prognostic Score (GPS), an inflammation-based prognostic score including C-reactive protein and albumin, shows significant prognostic value in several types of solid tumors. The prognostic value of GPS in lymphoma remains unclear. We performed this study to evaluate the prognostic significance of GPS in extranodal natural killer (NK)/T-cell lymphoma (ENKL). We retrospectively analyzed 164 patients with newly diagnosed ENKL. The prognostic value of GPS was evaluated and compared with that of International Prognostic Index (IPI), Prognostic Index for Peripheral T-cell lymphoma unspecified (PIT), and Korean Prognostic Index (KPI). Patients with higher GPS tended to have more adverse clinical characteristics, lower rates of complete remission (P < 0.001), inferior progression-free survival (PFS, P < 0.001), and inferior overall survival (OS, P < 0.001). Multivariate analysis demonstrated that high GPS, age > 60 years, and elevated LDH were independent adverse predictors of OS. GPS was found superior to IPI, PIT, and KPI in discriminating patients with different outcomes in low-risk groups (all P < 0.05). GPS is an independent predictor of survival outcomes in ENKL. Inflammatory response might play an important role in the progression of ENKL and survival of patients with ENKL.

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.

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.

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.

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.

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.