Prognostic significance of platelet­to­albumin ratio in patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy: a retrospective study of 858 cases.

BACKGROUND: Despite evidence supporting the high correlation of the novel platelet-to-albumin ratio (PAR) with survival in diverse malignancies, its prognostic relevance in nasopharyngeal carcinoma (NPC) remains underexplored. This study aimed to examine the link between PAR and overall survival (OS) in NPC and to establish a predictive model based on this biomarker. METHODS: We retrospectively assembled a cohort consisting of 858 NPC patients who underwent concurrent chemoradiotherapy (CCRT). Utilizing the maximally selected log-rank method, we ascertained the optimal cut-off point for the PAR. Subsequently, univariate and multivariate Cox proportional hazards models were employed to discern factors significantly associated with OS and to construct a predictive nomogram. Further, we subjected the nomogram's predictive accuracy to rigorous independent validation. RESULTS: The discriminative optimal PAR threshold was determined to be 4.47, effectively stratifying NPC patients into two prognostically distinct subgroups (hazard ratio [HR] = 0.53; 95% confidence interval [CI]: 0.28-0.98, P = 0.042). A predictive nomogram was formulated using the results from multivariate analysis, which revealed age greater than 45 years, T stage, N stage, and PAR score as independent predictors of OS. The nomogram demonstrated a commendable predictive capability for OS, with a C-index of 0.69 (95% CI: 0.64-0.75), surpassing the performance of the conventional staging system, which had a C-index of 0.56 (95% CI: 0.65-0.74). CONCLUSIONS: In the context of NPC patients undergoing CCRT, the novel nutritional-inflammatory biomarker PAR emerges as a promising, cost-efficient, easily accessible, non-invasive, and potentially valuable predictor of prognosis. The predictive efficacy of the nomogram incorporating the PAR score exceeded that of the conventional staging approach, thereby indicating its potential as an enhanced prognostic tool in this clinical setting.

R2-ISS staging combined with circulating plasma cells improves risk stratification for newly diagnosed multiple myeloma: a single-center real-world study.

We aimed to evaluate if circulating plasma cells (CPC) detected by flow cytometry could add prognostic value of R2-ISS staging. We collected the electronic medical records of 336 newly diagnosed MM patients (NDMM) in our hospital from January 2017 to June 2023. The median overall survival (OS) for patients and R2-ISS stage I-IV were not reached (NR), NR, 58 months and 53 months, respectively. There was no significant difference in OS between patients with stage I and patients with stage II (P = 0.309) or between patients with stage III and patients with stage IV (P = 0.391). All the cases were re-classified according to R2-ISS stage and CPC numbers ≥ 0.05% (CPC high) or<0.05% (CPC low) into four new risk groups: Group 1: R2-ISS stage I + R2-ISS stage II and CPC low, Group 2: R2-ISS stage II and CPC high + R2-ISS stage III and CPC low, Group 3: R2-ISS stage III and CPC high + R2-ISS stage IV and CPC low, Group 4: R2-ISS stage IV and CPC high. The median OS were NR, NR, 57 months and 32 months. OS of Group 1 was significantly longer than that of Group 2 (P = 0.033). OS in Group 2 was significantly longer than that of Group 3 (P = 0.007). OS in Group 3 was significantly longer than that of Group 4 (P = 0.041). R2-ISS staging combined with CPC can improve risk stratification for NDMM patients.

Lignans and [11]-chaetoglobosins from Pseudeurotium bakeri and their immunosuppressive activity.

Two previously unreported lignans (1-2) and four undescribed [11]-chaetoglobosins (3-6) were obtained from the culture extract of an endophytic fungus Pseudeurotium bakeri P1-1-1. Their structures with absolute configurations were determined by spectroscopic data analysis, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, the modified Mosher's method, and Mo2(OAc)4-induced electronic circular dichroism (ICD) experiments. Compounds 5 and 6 showed moderate cytotoxic effects against seven human cancer cell lines. Compounds 2-4 exhibited immunosuppressive activities on concanavalin A-induced T cell proliferation with IC50 values of 3.7, 3.4, and 14.5 µM, and on lipopolysaccharide-induced B cell proliferation with IC50 values of 4.1, 3.9, and 14.2 µM, respectively. Further investigation revealed that 2 and 3 induced apoptosis in activated T cells in a dose-dependent manner.

Long- and Intermediate-Term Ambient Particulate Pollution Is Associated with Increased Osteoarthritis Risk: A Population-Based Prospective Analysis.

Recent studies found the intrusion and retention of exogenous fine particles into joints, but epidemiological data for long- and intermediate-term exposure associations are scare. Here, all urban working, retired employee, and rural residents (16.78 million) in Beijing from January 1, 2011 to December 31, 2019 were included to investigate the effects of long- and intermediate-term ambient particulate exposure on development of osteoarthritis. We identified 1,742,067 participants as first-visit patients with osteoarthritis. For each interquartile range increase in annual PM2.5 (23.32 µg/m3) and PM10 (23.92 µg/m3) exposure concentration, the pooled hazard ratios were respectively 1.238 (95% CI: 1.228, 1.249) and 1.178 (95% CI: 1.168, 1.189) for first osteoarthritis outpatient visits. Moreover, age at first osteoarthritis outpatient visits significantly decreased by 4.52 (95% CI: 3.45 to 5.40) days per µg/m3 for annual PM2.5 exposure at below 67.85 µg/m3. Finally, among the six constituents analyzed, black carbon appears to be the most important component associated with the association between PM2.5 exposure and the three osteoarthritis-related outcomes.

Fractional picosecond laser treatment of non-acne atrophic scars and scar erythema in Chinese patients.

BACKGROUND: Fractional picosecond lasers (FPL) are reported to be effective and safe for atrophic acne scars and post-acne erythema. However, there is no evidence regarding the effectiveness and safety of FPL treatment for non-acne atrophic scars and scar erythema among Chinese patients. METHODS: In this retrospective study, 12 Chinese patients with non-acne atrophic scars, including nine with scar erythema, were treated with one to three sessions of 1064 nm FPL treatment. Clinical improvement was objectively assessed through blinded evaluations by external physicians. A modified Manchester Scar Scale (mMSS) and the Clinician Erythema Assessment Scale (CEAS) were individually used to evaluate atrophic scars and scar erythema based on photographs. Physician-assessed and subject-assessed Global Aesthetic Improvement Scale (GAIS) were used to assess changes before and after FPL treatment. Patient satisfaction and adverse events were also documented. RESULTS: Total mMSS scores, as well as three parameters (color, distortion, and texture), were significantly decreased after FPL treatment, with a mean reduction of 3.18 ± 1.60 in total scores (p < 0.05). The CEAS scores were significantly reduced from 2.41 ± 0.98 before treatment to 0.41 ± 0.40 at the final visit (p < 0.05). Based on physician-assessed and subject-assessed GAIS scores, 11 (91.7%) patients were improved after FPL treatment. 33.3% of patients were very satisfied, and 41.7% were satisfied. No serious, prolonged (> 3 weeks) adverse events were observed. CONCLUSION: Our study suggests that 1064 nm FPL treatment may be a promising option for non-acne atrophic scars, especially with scar erythema. Further studies are needed to confirm our results.

Assessment of short-term effects of ambient air pollution exposure on osteoarthritis outpatient visits.

The association of short-term ambient air pollution exposure with osteoarthritis (OA) outpatient visits has been unclear and no study has assessed the modifying roles of district-level characteristics in the association between ambient air pollution exposure and OA outpatient visits. We investigated the cumulative associations of ambient air pollution exposure with daily OA outpatient visits and vulnerable factors influencing the associations using data from 16 districts of Beijing, China during 2013-2019. A total of 18,351,795 OA outpatient visits were included in the analyses. An increase of 10 µg/m3 in fine particulate matter (PM2.5), inhalable particulate matter (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), maximum 8-hour moving-average ozone (8 h-O3), and 0.1 mg/m3 in carbon monoxide (CO) at representative lag days were associated with significant increases of 0.31 %, 0.06 %, 0.77 %, 0.87 %, 0.30 %, and 0.48 % in daily OA outpatient visits, respectively. Considerable OA outpatient visits were attributable to short-term ambient air pollution exposure. In addition, low temperature and high humidity aggravated ambient air pollution associated OA outpatient visits. District-level characteristics, such as population density, green coverage rate, and urbanization rate modified the risk of OA outpatient visits associated with air pollution exposure. These findings highlight the significance of controlling ambient air pollution during the urbanization process, which is useful in policy formation and implementation.

Accuracy and clinical characteristics of robot-assisted cervical spine surgery: a systematic review and meta-analysis.

PURPOSE: To evaluate the accuracy and feasibility of robot-assisted cervical screw placement and factors that may affect the accuracy. METHODS: A comprehensive search was made on PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Wanfang Med for the selection of potential eligible literature. The outcomes were evaluated in terms of the relative risk (RR) or standardized mean difference (MD) and corresponding 95% confidence interval (CI). Subgroup analyses of the accuracy of screw placement at different cervical segments and with different screw placement approaches were performed. A comparison was made between robotic navigation and conventional freehand cervical screw placement. RESULTS: Six comparative cohort studies and five case series studies with 337 patients and 1342 cervical screws were included in this study. The perfect accuracy was 86% (95% CI, 82-89%) and the clinically acceptable rate was 98% (95% CI, 95-99%) in robot-assisted cervical screw placement. The perfect accuracy of robot-assisted C1 lateral mass screw placement was the highest (96%), followed by C6-7 pedicle screw placement (93%) and C2 pedicle screw placement (86%), and the lowest was C3-5 pedicle screw placement (75%). The open approach had a higher perfect accuracy than the percutaneous/intermuscular approach (91% vs 83%). Compared with conventional freehand cervical screw placement, robot-assisted cervical screw placement had a higher accuracy, a lower incidence of perioperative complications, and less intraoperative blood loss. CONCLUSION: With good collaboration between the operator and the robot, robot-assisted cervical screw placement is accurate and feasible. Robot-assisted cervical screw placement has a promising prospect.

Rosemary: Unrevealing an old aromatic crop as a new source of promising functional food additive-A review.

Rosemary (Rosmarinus officinalis L.) is one of the most famous spice plants belonging to the Lamiaceae family as a remarkably beautiful horticultural plant and economically agricultural crop. The essential oil of rosemary has been enthusiastically welcome in the whole world for hundreds of years. Now, it is wildly prevailing as a promising functional food additive for human health. More importantly, due to its significant aroma, food, and nutritional value, rosemary also plays an essential role in the food/feed additive and food packaging industries. Modern industrial development and fundamental scientific research have extensively revealed its unique phytochemical constituents with biologically meaningful activities, which closely related to diverse human health functions. In this review, we provide a comprehensively systematic perspective on rosemary by summarizing the structures of various pharmacological and nutritional components, biologically functional activities and their molecular regulatory networks required in food developments, and the recent advances in their applications in the food industry. Finally, the temporary limitations and future research trends regarding the development of rosemary components are also discussed and prospected. Hence, the review covering the fundamental research advances and developing prospects of rosemary is a desirable demand to facilitate their better understanding, and it will also serve as a reference to provide many insights for the future promotion of the research and development of functional foods related to rosemary.

Integrative Analysis of Bioinformatics and Machine Learning Algorithms Identifies a Novel Diagnostic Model Based on Costimulatory Molecule for Predicting Immune Microenvironment Status in Lung Adenocarcinoma.

Costimulatory molecules are an indispensable signal for activating immune cells. However, the features of many costimulatory molecule genes (CMGs) in lung adenocarcinoma (LUAD) are poorly understood. This study systematically explored expression patterns of CMGs in the tumor immune microenvironment (TIME) status of patients with LUAD. Their expression profiles were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Two robust TIME subtypes ("hot" and "cold") were classified by K-means clustering and estimation of stromal and immune cells in malignant tumor tissues using expression data. The "hot" subtype presented higher infiltration in activated immune cells and enrichments in the immune cell receptor signaling pathway and adaptive immune response. Three CMGs (CD80, LTB, and TNFSF8) were screened as final diagnostic markers by means of Least Absolute Shrinkage Selection Operator and Support Vector Machine-Recursive Feature Elimination algorithms. Accordingly, the diagnostic nomogram for predicting individualized TIME status showed satisfactory diagnostic accuracy in The Cancer Genome Atlas training cohort as well as GSE31210 and GSE180347 validation cohorts. Immunohistochemistry staining of 16 specimens revealed an apparently positive correlation between the expression of CMG biomarkers and pathologic response to immunotherapy. Thus, this diagnostic nomogram provided individualized predictions in TIME status of LUAD patients with good predictive accuracy, which could serve as a potential tool for identifying ideal candidates for immunotherapy.

Lactate and Lactylation in the Brain: Current Progress and Perspectives.

As the final product of glycolysis, lactate features not only as an energy substrate, a metabolite, and a signaling molecule in a variety of diseases-such as cancer, inflammation, and sepsis-but also as a regulator of protein lactylation; this is a newly proposed epigenetic modification that is considered to be crucial for energy metabolism and signaling in brain tissues under both physiological and pathological conditions. In this review, evidence on lactylation from studies on lactate metabolism and disease has been summarized, revealing the function of lactate and its receptors in the regulation of brain function and summarizing the levels of lactylation expression in various brain diseases. Finally, the function of lactate and lactylation in the brain and the potential mechanisms of intervention in brain diseases are presented and discussed, providing optimal perspectives for future research on the role of lactylation in the brain.

Low H3K27 acetylation of SF1 in PBMC: a biomarker for prenatal dexamethasone exposure-caused adrenal insufficiency of steroid synthesis in male offspring.

Dexamethasone is widely used to treat pregnancy disorders related to premature delivery. However, lots of researches have confirmed that prenatal dexamethasone exposure (PDE) could increase the risk of offspring multiple diseases. This study was designed to elucidate the epigenetic mechanism of adrenal developmental programming and explore its early warning marker in peripheral blood mononuclear cells (PBMC). We found the adrenal morphological and functional changes of PDE male offspring rats before and after birth, which were mainly performed as the decreased serum corticosterone concentration, steroidogenic acute regulatory (StAR) protein expression, and histone 3 lysine 27 acetylation (H3K27ac) level of steroidogenic factor 1 (SF1) promoter region and its expression. Simultaneously, the expressions of glucocorticoid receptor (GR) and histone acetylation enzyme 5 (HDAC5) in the PDE male fetal rats were increased. In vitro, dexamethasone reduced the expression of SF1, StAR, and cortisol production and still increased the expression of GR and HDAC5, the binding between GR and SF1 promoter region, and protein interaction between GR and HDAC5. GR siRNA or HDAC5 siRNA was able to reverse the above roles of dexamethasone. Furthermore, in vivo, we confirmed that H3K27ac levels of SF1 promoter region and its expression in PBMC of the PDE group were decreased before and after birth, showing a positive correlation with the same indexes in adrenal. Meanwhile, in clinical trials, we confirmed that prenatal dexamethasone application decreased H3K27ac of SF1 promoter region and its expression in neonatal PBMC. In conclusion, PDE-caused adrenal insufficiency of male offspring rats was related to adrenal GR activated by dexamethasone in uterus. The activated GR, on the one hand, increased its direct binding to SF1 promoter region to inhibit its expression, on the other hand, upregulated and recruited HDAC5 to decrease H3K27ac level of SF1 promoter region, and strengthened the inhibition of SF1 and subsequent StAR expression.

Global burden and trends of transport injuries from 1990 to 2019: an observational trend study.

BACKGROUND: Transport injuries (TIs) are a major cause of global disability-adjusted life-years (DALYs) and mortality. In this study, we aimed to assess the global burden and trends of TIs from 1990 to 2019. METHODS: We assessed the annual age-standardised incidence rate (ASIR) and age-standardised DALYs rate of TIs by sex, age, Social Development Index (SDI) and geographical region from 1990 to 2019 from the Global Burden of Disease Study 2019. The changing trends were described by estimated annual percentage changes (EAPCs). RESULTS: Globally, in 2019, the ASIR and age-standardised DALYs rates of TIs were 134 6.06/100 000 (95% UI 11 42.6/100 000-157 5.57/100 000) and 97 7.91/100 000 (86 8.91/100 000-107 6.81/100 000), respectively. From 1990 to 2019, the global ASIR of TIs presented significant upwards trends with the EAPC (0.25%, 95% CI 0.19% to 0.31%), and it was significantly increased in the age groups of 15-49 (0.37%, 95% CI 0.29% to 0.45%), 50-69 (0.40%, 95% CI 0.36% to 0.44%) and 70+ (0.22%, 95% CI 0.17% to 0.28%). Prominent increases in ASIR were detected in middle-SDI areas (0.72%, 95% CI 0.57% to 0.87%), low-middle SDI areas (0.66%, 95% CI 0.59% to 0.72%) and low-SDI areas (0.21%, 95% CI 0.17% to 0.26%). The global age-standardised DALYs rate presented downwards trends with the EAPC (-1.27%, 95% CI -1.35% to -1.2%), and it was significantly decreased in all age groups and SDI areas. CONCLUSION: Globally, TIs still cause a serious burden, and the incidence has significantly increased, especially in people above the age of 14 and in middle-SDI and low-SDI areas, thus necessitating more attention and health interventions.

In vivo and molecular docking studies of the pathological mechanism underlying adriamycin cardiotoxicity.

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These findings will help develop effective treatment strategies to combat ADR-induced cardiotoxicity and broaden the application of ADR for clinical practice.

Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis.

Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.

Prevalence of preoperative deep vein thrombosis in long bone fractures of lower limbs: a systematic review and meta-analysis.

BACKGROUND: There is a paucity of data regarding the prevalence of preoperative deep vein thrombosis (DVT) in patients with long bone (including femur, tibia and fibula) fractures of the lower limbs. We performed a meta-analysis to address the issue. METHODS: Electronic databases, including PubMed, EMBASE, the Web of Science, the Cochrane Library, the VIP database, CNKI, and the Wanfang database, were systematic searched for original articles that reported the prevalence of preoperative DVT in long bone fractures of the lower limbs from January 2016 to September 2021. The prevalence of preoperative DVT was pooled using random-effects models, and subgroups were established according to study type, detection method, sample size and fracture site. RESULTS: Twenty-three articles reporting on 18,119 patients were eligible. The overall pooled preoperative DVT prevalence was 24.1% (95% CI 19.3-28.8%). In different subgroups, the preoperative DVT prevalences were 18.2-27.3%, 15.2-28.6%, 23.1-24.9%, 18.2-26.0% and 23.2-23.4% for different study designs, sample sizes, age groups, detection methods and fracture sites, respectively. CONCLUSIONS: Despite the heterogeneity among studies, this systematic review suggests that the prevalence of preoperative DVT, which may seriously affect the prognosis of patients, is high. Therefore, greater efforts should be devoted to the improvement of screening and prevention strategies for preoperative DVT in lower-extremity long bone fractures. LEVEL OF EVIDENCE: Level III. Trial Registration The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database with the registration number CRD42022324706.

Anlotinib plus etoposide and cisplatin/carboplatin as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC): a single-arm, phase II study.

Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high relapse rates and poor prognosis. Anlotinib monotherapy has shown promising efficacy for patients with ES-SCLC and has a non-overlapping toxicity profile with chemotherapy. Therefore, the study aims to assess the efficacy and safety of the addition of anlotinib to platinum-chemotherapy as first-line therapy for patients with ES-SCLC. ES-SCLC patients without systemic chemotherapy and immunotherapy were recruited. Eligible patients received anlotinib (12 mg/day, on day 1-14) of a 21-day cycle, with concomitant etoposide (100 mg/m2, on day 1-3) plus cisplatin (75 mg/m2, on day 1) or carboplatin (AUC = 4-5, on day 1) for 4-6 cycles, followed by indefinite anlotinib maintenance therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Between Jan 15, 2019 and Dec 31, 2020, 25 patients were enrolled. At the data cut-off time (November 3, 2021), the median follow-up was 14.3 months. Median PFS was 10.3 months (95% CI: 6.0-14.5) and median OS was 17.1 months (95% CI: 11.1-19.3). The ORR and DCR were 90% and 100%, respectively. The most common grade 3 or worse treatment-related adverse events were neutropenia (50%), leukopenia (35%), thrombocytopenia (25%), fatigue (10%), nausea (10%), hyponatremia (10%), anemia (10%). One patient discontinued treatment due to treatment-related adverse events. No treatment-related death occurred. Anlotinib plus platinum-chemotherapy as first-line therapy for ES-SCLC has anti-tumor activity, and showed acceptable tolerability. These results provide a basis for future randomized controlled trials.

The efficacy of human epidermal growth factor receptor 2 (HER2) blockade switching mode in refractory patients with HER2-positive metastatic breast cancer: a phase II, multicenter, single-arm study (SYSUCC-005).

BACKGROUND: Despite significant survival improvement in human epidermal growth factor receptor 2 (HER2) blockade for HER2-positive breast cancer, resistance to anti-HER2 remains inevitable. Subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable with limited efficacy when other anti-HER2 treatment is unavailable. This single-arm, phase II study (SYSUCC-005) aimed to explore the efficacy of switching mode for HER2-positive refractory metastatic breast cancer. METHODS: Patients with HER2-positive metastatic breast cancer rapidly progressing during pre-trastuzumab from six hospitals in China were designed to switch to lapatinib 1,250 mg orally once per day continuously plus capecitabine (1,000 mg/m2 orally twice per day on days 1-14) or vinorelbine (25 mg/m2 intravenously once per day on days 1 and 8) of each 21-day cycle. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 5, 2015 and May 31, 2020, 159 patients were eligible in this study. The median follow-up was 33.1 months, a median PFS of 8.5 months was achieved. Brain metastases (hazard ratio [HR] = 1.582, 95% confidence interval [CI] 1.019- 2.453, P = 0.041) and ≥ 2 metastatic sites (HR = 1.679, 95% CI 1.151-2.450, P = 0.007) were independent prognostic factors for PFS. The most common grade ≥ 3 adverse events were diarrhea (3.8%) and hand-foot syndrome (9.4%). CONCLUSION: The switching mode showed predominant efficacy, which might be a prior therapeutic option over continuing mode in subsequent anti-HER2 therapy for patients with HER2-positive refractory metastatic breast cancer. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov ( NCT02362958 ) on 13/02/2015.

Resorcylic acid lactones from a Podospora sp. that induce apoptosis in activated T cells through MAPKs/AKT pathway.

Podomycins A-L (1-12), 12 undescribed hypothemycin-type resorcylic acid lactones (RALs), were characterized from Podospora sp. G214, an endophyte harbored in the roots of Sanguisorba officinalis L. Their structures were addressed by spectroscopic data, X-ray crystallography, the modified Mosher's method, together with Mo2(OAc)4- and Rh2(OCOCF3)4-induced electronic circular dichroism (ICD) experiments. Podomycins A-C (1-3) represent the first class of natural RALs with a 13-membered macrolactone ring, while 4-12 are rearranged methoxycarbonyl substituted RALs. Biologically, compounds 2, 6, 8, 10, and 12 displayed immunosuppressive activities against T cell proliferation with IC50 values of 14.5-21.9 µM, and B cell proliferation with IC50 values of 22.3-36.5 µM, respectively. Further mechanism of action research demonstrated that podomycin F (6) distinctly induced apoptosis in activated T cells via MAPKs/AKT pathway.

[11]-chaetoglobosins with cytotoxic activities from Pseudeurotium bakeri.

Fourteen new [11]-chaetoglobosins (1-14), along with two known congeners, cytochalasins X and Y (15 and 16), were isolated from the cultures of an endophytic fungus Pseudeurotium bakeri P1-1-1. Their structures incorporating absolute configurations were elucidated based on the comprehensive analyses of one- and two-dimensional NMR data, HRESIMS spectrometry, chemical methods, and single-crystal X-ray diffraction analysis (Cu Kα). All isolates were evaluated for their cytotoxic activities and chaetopseudeurin M (1) displayed significant cytotoxic effects against seven human cancer cell lines, with IC50 values ranging from 5.1 ± 0.9 to 10.8 ± 0.1 µM. Western blot experiments exhibited that compound 1 exerted its cytotoxic effect in MCF-7 cells by inducing G2/M cell cycle arrest and apoptosis via downregulating the expression of cyclin B1 and Cdk1, and activating Bcl-2/caspase-3/PARP pathway, respectively.

Dexmedetomidine exerts its protective effect on cerebral ischemia reperfusion injury in mice by inhibiting ferroptosis. / å³ç¾Žæ‰˜å’ªå®šé€šè¿‡æŠ‘åˆ¶é“æ­»äº¡å‘æŒ¥å¯¹å°é¼ è„‘ç¼ºè¡€å†çŒæ³¨æŸä¼¤çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: Stroke is one of the major diseases that can threaten human life and health. The incidence of ischemic stroke accounts for more than 70% of stroke. The mechanism of ischemia reperfusion (IR) injury caused by ischemic stroke is extremely complex. In recent years, dexmedetomidine has been increasingly studied in anti-cerebral IR injury as a common clinical anesthetic adjunct, but its specific mechanism is not fully understood. Therefore, this study aims to explore the effects and mechanisms of dexmedetomidine on cerebral IR injury in mice. METHODS: The mouse middle cerebral artery occlusion (MCAO) model was prepared by modified suture method. Male ICR mice were randomly divided into a sham group, an IR group, an IR+D1 group (IR+administered 25 µg/kg dexmedetomidine), an IR+D2 group(IR+administered 50 µg/kg dexmedetomidine), an IR+D3 group (IR+administered 100 µg/kg dexmedetomidine), and an IR+D2+ML385 group (IR+administered 50 µg/kg dexmedetomidine and 30 mg/kg ML385). The neurologic behavior of mice was evaluated by Longa's five-point method. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to detect the percentage of cerebral infarct volume in mice. The protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), transferrin receptor 1 (TFR1), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) in the cerebral tissues of mice were detected by Western blotting.Mitochondrial morphology was observed under the transmission electron microscope. The contents of MDA, Fe2+, and GSH in the cerebral tissues of mice were detected. RESULTS: Compared with the sham group, neurobehavioral scores, cerebral infarct volume, the contents of MDA and Fe2+, as well as the protein expression of TFR1 were significantly increased; the contents of GSH and the protein expression of SLC7A11 and GPX4 were significantly reduced (all P<0.05); mitochondria in cerebral tissue were wrinkled, cristae were reduced, and membrane density was increased in the IR group. Compared with the IR group, neurobehavioral scores, cerebral infarction volume, MDA and Fe2+ contents, as well as the protein expression of TFR1 were significantly reduced; the contents of GSH and the protein expression of SLC7A11 and GPX4 were significantly increased (all P<0.05); mitochondrial damage in cerebral tissue was significantly relieved with the pre-treatment of dexmedetomidine. Compared with the IR+D2 group, neurobehavioral scores, cerebral infarction volume, MDA and Fe2+ contents, as well as the protein expression of TFR1 were significantly increased; the contents of GSH and the protein expression of SLC7A11 and GPX4 were significantly reduced (all P<0.05);mitochondria reappeared significantly damaged with the ML385 on the basis of dexmedetomidine pre-treatment. CONCLUSIONS: The protective effect of dexmedetomidine on cerebral IR injury mice is related to its inhibition of ferroptosis, and the mechanism might be related to its regulation of Nrf2 expression.