Impact of annual trend volume of low-dose computed tomography for lung cancer screening on overdiagnosis, overmanagement, and gender disparities.

BACKGROUND: With the increasing prevalence of nonsmoking-related lung cancer in Asia, Asian countries have increasingly adopted low-dose computed tomography (LDCT) for lung cancer screening, particularly in private screening programs. This study examined how annual LDCT volume affects lung cancer stage distribution, overdiagnosis, and gender disparities using a hospital-based lung cancer database. METHODS: This study analyzed the annual utilized LDCT volume, clinical characteristics of lung cancer, stage shift distribution, and potential overdiagnosis. At the individual level, this study also investigated the relationship between stage 0 lung cancer (potential strict definition regarding overdiagnosis) and the clinical characteristics of lung cancer. RESULTS: This study reviewed the annual trend of 4971 confirmed lung cancer cases from 2008 to 2021 and conducted a link analysis with an LDCT imaging examination database over these years. As the volume of lung cancer screenings has increased over the years, the number and proportion of stage 0 lung cancers have increased proportionally. Our study revealed that the incidence of stage 0 lung cancer increased with increasing LDCT scan volume, particularly during the peak growth period from 2017 to 2020. Conversely, stage 4 lung cancer cases remained consistent across different time intervals. Furthermore, the increase in the lung cancer screening volume had a more pronounced effect on the increase in stage 0 lung cancer cases among females than it had among males. The estimated potential for overdiagnosis brought about by the screening process, compared to non-participating individuals, ranged from an odds ratio of 7.617 to one of 17.114. Both strict and lenient definitions of overdiagnosis (evaluating cases of stage 0 lung cancer and stages 0 to 1 lung cancer) were employed. CONCLUSIONS: These results provide population-level evidence of potential lung cancer overdiagnosis in the Taiwanese population due to the growing use of LDCT screening, particularly concerning the strict definition of stage 0 lung cancer. The impact was greater in the female population than in the male population, especially among females younger than 40 years. To improve lung cancer screening in Asian populations, creating risk-based prediction models for smokers and nonsmokers, along with gender-specific strategies, is vital for ensuring survival benefits and minimizing overdiagnosis.

CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

Current Situation and Influencing Factors of Delay in Seeking Medical Treatment Among Residents in Rural Areas of Sichuan Province / 中国医学科学院学报

Objective To understand the current situation and explore the influencing factors of delay in seeking medical treatment for common symptoms of residents in the rural areas of Sichuan province. Methods In July 2019,multi-stage random sampling was carried out in Zigong city,Sichuan province,and the data were collected by face-to-face questionnaire interview.The residents who had lived at hometown for more than half a year in the past year and had seen a doctor in the most recent month were surveyed.Logistic regression was adopted to predict the influencing factors of delay in seeking medical treatment. Results A total of 342 subjects were enrolled,and the incidence of delay in seeking medical treatment was 13.45%(46/342).Compared with the young and middle-aged(<65 years)people,the elderly(≥65 years)people were more likely to have delay in seeking medical treatment (OR=2.187,95%CI=1.074-4.457,P=0.031).The rural residents who gave higher score of the overall quality of township health centers were less likely to have delay in seeking medical treatment (OR=0.854,95%CI=0.735-0.992,P=0.039). Conclusions The occurrence of delay in seeking medical treatment for common symptoms of rural residents in Sichuan province is low.Age and the overall quality evaluation of township health centers affect the occurrence of delay in medical treatment among the rural residents in Sichuan province.Efforts should be made to improve the awareness of disease prevention among the elderly in rural areas.The investment in health resources in township health centers should be increased to strengthen the introduction and training of talents.These measures can improve the health services in township health centers,guide residents to make timely use of health resources,and reduce the occurrence of delay in seeking medical treatment.

Factors Associated With Coronary Heart Disease Among Adult Residents in Jinjiang District,Chengdu City / 中国医学科学院学报

Objective To analyze the prevalence of coronary heart disease among community residents over 18 years old in Jinjiang district of Chengdu city,Sichuan province,and explore its associated factors,so as to provide a reference for the prevention and control of coronary heart disease in communities.Methods From October 15 to November 10 in 2021,a total of 5220 adult residents from 33 communities in Jinjiang were selected by multi-stage stratified random sampling for face-to-face questionnaire survey,physical examination,and laboratory blood test.Binary Logistic regression was employed to predict the factors associated with coronary heart disease among adult residents in Jinjiang.Results The crude and standard prevalence rates of coronary heart disease among 5220 adult residents were 3.39% and 2.11%,respectively.Logistic regression analysis showed that age (OR=1.068,95%CI=1.051-1.086,P<0.001),depressive symptoms (OR=1.639,95%CI=1.037-2.591,P=0.034),regular exercise (OR=0.584,95%CI=0.378-0.902,P=0.015),elevated blood pressure (OR=3.529,95%CI=2.344-5.312,P<0.001),dyslipidemia (OR=2.152,95%CI=1.291-3.587,P=0.003),and core knowledge score of chronic diseases (OR=1.144,95%CI=1.066-1.228,P<0.001) were associated with coronary heart disease among adult residents in Jinjiang.Conclusions The prevalence of coronary heart disease is high among adult residents in Jinjiang district of Chengdu.The urban residents who are older,have depressive symptoms,lack of exercise,elevated blood pressure,dyslipidemia,and score higher on core knowledge of chronic diseases are prone to coronary heart disease.

Relationship Between Maternal Negative Emotions and Feeding Patterns of Infants Aged 0-6 Months in Remote Rural Areas of Sichuan Province / 中国医学科学院学报

Objective To investigate the status of exclusive breastfeeding and bottle feeding in remote rural areas of Sichuan province and explore the relationship between negative emotions of mothers and feeding patterns of infants.Methods Multistage cluster sampling was employed to select the infants aged 0-6 months and their mothers in remote rural areas of Sichuan province.A self-designed questionnaire was used to collect the demographic characteristics of mothers and infants and the basic family information.The Chinese version of Depression Anxiety Stress scale was used to evaluate mothers' negative emotions,and the Breastfeeding Self-efficacy scale to assess the confidence level of mothers' behavior of adhering to exclusive breastfeeding.Results Totally 723 pairs of infants and their mothers were included.The exclusive breastfeeding and bottle feeding rates were 34.16% (247/723) and 57.54% (416/723),respectively.Mothers with depression tendency were less likely to adopt exclusive breastfeeding (OR=0.532,95%CI=0.291-0.974,P=0.041) and more likely to adopt bottle feeding (OR=1.877,95%CI=1.054-3.344,P=0.033).Further subgroup analysis of breastfeeding self-efficacy showed that in the group of low self-efficacy,the mothers with depression tendency were less likely to adopt exclusive breastfeeding (OR=0.461,95%CI=0.236-0.902,P=0.024) and more likely to adopt bottle feeding (OR=1.968,95%CI=1.047-3.701,P=0.036) than the mothers without depression tendency.In the group of high self-efficacy,mothers' depression,anxiety,and stress tendency had no significant correlation with infant feeding patterns (all P>0.05).Conclusions The mothers in the remote rural areas of Sichuan province are more likely to employ bottle feeding than exclusive breastfeeding.The mothers with stronger depression tendency demonstrate lower possibility of exclusive breastfeeding and higher possibility of bottle feeding.Breastfeeding self-efficacy may affect the association between maternal depression and infant feeding patterns.

A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma.

Novel neoadjuvant therapy regimens are warranted for oral squamous cell carcinoma (OSCC). In this phase I trial (NCT04393506), 20 patients with locally advanced resectable OSCC receive three cycles of camrelizumab (200 mg, q2w) and apatinib (250 mg, once daily) before surgery. The primary endpoints are safety and major pathological response (MPR, defined as ≤10% residual viable tumour cells). Secondary endpoints include 2-year survival rate and local recurrence rate (not reported due to inadequate follow-up). Exploratory endpoints are the relationships between PD-L1 combined positive score (CPS, defined as the number of PD-L1-stained cells divided by the total number of viable tumour cells, multiplied by 100) and other immunological and genomic biomarkers and response. Neoadjuvant treatment is well-tolerated, and the MPR rate is 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃10 achieve MPR. Post-hoc analysis show 18-month locoregional recurrence and survival rates of 10.5% (95% CI: 0%-24.3%) and 95% (95% CI: 85.4%-100.0%), respectively. Patients achieving MPR show more CD4+ T-cell infiltration than those without MPR (P = 0.02), and decreased CD31 and ɑ-SMA expression levels are observed after neoadjuvant therapy. In conclusion, neoadjuvant camrelizumab and apatinib is safe and yields a promising MPR rate for OSCC.

[Experimental investigation of vincristine on chemosensitivity through Stathmin regulation in oral squamous cell carcinoma].

PURPOSE: Our previous studies have found that Stathmin, a microtubule depolymerizing protein, is a potential biomarker to guide locally advanced oral squamous cell carcinoma (OSCC) induction chemotherapy. This study further explored the regulatory effect of vincristine on Stathmin and its potention as an alternative chemotherapy drug. METHODS: Stathmin overexpressed and knockdown stable cell lines were constructed. Cell proliferation, q-PCR, Western blot, subcutaneous xenograft and other experimental methods were used to value the regulatory effect of vincristine on Stathmin. The differences were statistically analyzed with SPSS 23.0 software package. RESULTS: Vincristine inhibited the expression of Stathmin in OSCC cell lines. The sensitivity to vincristine was increased in Stathmin overexpressed OSCC cell lines. Vincristine had potent anti-tumor effect for OSCC cell line xenografts with higher Stathmin expression. CONCLUSIONS: Vincristine is a potential alternative chemotherapeutic agent for OSCC with higher Stathmin expression.

Anti-Inflammatory Effects of Gynura procumbens on RAW264.7 Cells via Regulation of the PI3K/Akt and MAPK Signaling Pathways.

Gynura procumbens is a traditional herb and food extensively cultivated in China and Southeast Asian countries. In this work, the crude extract (CE) of G. procumbens was purified with macroporous resin to obtain the refined fraction, and its anti-inflammatory activity was compared with that of CE. Moreover, the detailed mechanisms of anti-inflammatory activity were also investigated for the first time. The results indicated that CE was more effective in anti-inflammatory activity and it could reduce the secretion of NO, TNF-α, and PGE2 via decreasing the iNOS, TNF-α, and COX-2 genes transcription and related proteins translation, which were associated with the inhibition of AP-1 and NF-κB nuclear translocation and downregulation of PI3K/Akt and MAPK signaling pathways. In conclusion, the extract of G. procumbens has a promising potential in inflammation-related disorders alleviation, and these findings could provide the basis for the comprehensive utilization of G. procumbens and the new functional food development.

A base-mediated aerobic oxidative synthesis of cyclopent-2-enol derivatives from doubly activated cyclopropanes and substituted acetonitriles.

We report here that polysubstituted cyclopent-2-enols can be constructed by the one-pot reaction of doubly activated cyclopropanes and α-EWG substituted acetonitriles under mild basic conditions via a domino-ring-opening-cyclization/deacylation/oxidation sequence. Moreover, the synthetic applications of these cyclopent-2-enols have been demonstrated in the late-stage derivatization into functionalized cyclopentapyrimidin-4-ones and 2-hydroxy cyclopentanones with good yields.

Sudden cardiac death in heart failure with preserved ejection fraction: an updated review

Despite the advances in medical and device therapies for heart failure (HF), sudden cardiac death (SCD) remains a tremendous global burden in patients with HF. Among the risk factors for SCD, HF has the greatest impact. Previous studies focusing on patients with systolic dysfunction have found several predictive factors associated with SCD, lead‑ ing to the subsequent development of strategies of primary prevention, like placement of implantable cardioverterdefibrillator (ICD) in high-risk patients. Although patients with HF with preserved ejection fraction (HFpEF) were less prone to SCD compared to patients with HF with reduced ejection fraction (HFrEF), patients with HFpEF did account for a significant proportion of all HF patients who encountered SCD. The cutoff value of left ventricular ejection frac‑ tion (LVEF) to define the subset of HF did not reach consensus until 2016 when the European Society of Cardiology proposed a new classification system by LVEF. There is a great unmet need in the field of SCD in HFpEF regarding risk stratification and appropriate device therapy with ICD implantation. In this article, we will approach SCD in HFpEF from HFrEF subsets. We also aim at clarifying the mechanisms, risk factors, and prevention of SCD in HFpEF.

Evaluation of Accuracy and Influencing Factors for Diagnosis of Two Chronic Diseases by Primary Healthcare Providers in Sichuan Rural Areas Based on Standardized Patients / 中国医学科学院学报

Objective We used standardized patients to evaluate the accuracy and explore the influencing factors of the diagnosis of unstable angina pectoris and type 2 diabetes by primary healthcare providers in Sichuan rural areas,aiming to provide a scientific basis for improving the diagnosis accuracy of primary healthcare providers for the two chronic diseases. Methods A multi-stage stratified random cluster sampling method was adopted to select 100 villages from 50 townships in 5 districts/counties in Zigong city,Sichuan province. General and internal medicine practioners who were on duty on the survey day were enrolled in the survey.Two rounds of data collection were conducted.In the first round,the basic information of providers from township health centers and village clinics was collected.One month after the the first survey,standardized patients were used to collect the information related to the diagnosis of unstable angina pectoris and type 2 diabetes by rural primary providers.Logistic regression was carried out to analyze the factors influencing the diagnosis accuracy. Results A total of 172 rural primary healthcare providers were enrolled in the survey,who completed 186 standardized patient visits and showed the correct diagnosis rate of 48.39%.Specifically,the correct diagnosis rates of unstable angina pectoris and type 2 diabetes were 18.68%(17/91) and 76.84%(73/95),respectively.The providers with medical practitioner qualifications were more likely to make correct diagnosis(OR=4.857,95%CI=1.076-21.933, P=0.040).The providers who involved more necessary consultation and examination items in the diagnosis process had higher probability of correct diagnosis(OR=1.627,95%CI=1.065-2.485, P=0.024).Additionally,the providers were more likely to make a correct diagnosis for type 2 diabetes than for unstable angina pectoris(OR=6.306,95%CI=3.611-11.013, P<0.001). Conclusions The overall diagnosis accuracy of unstable angina pectoris and type 2 diabetes was relatively low among primary healthcare providers in Sichuan rural areas.The training of diagnosis process can be taken as a key for improving providers' practice ability so as to increase the diagnosis accuracy of chronic diseases.

Association of Dietary Diversity with Growth and Development of Children in Multi-ethnic Rural Areas of Sichuan Province / 中国医学科学院学报

Objective To understand the growth and dietary diversity status of children in multi-ethnic areas of Sichuan province,and to explore the associations of dietary diversity with growth and development indicators. Methods Children of 18-36 months old and their primary caregivers were selected with multi-stage cluster random sampling method from rural areas of Han,Tibetan,and Yi ethnic groups in Sichuan province. The sociodemographic information of children and their caregivers was collected using self-designed questionnaire.The dietary diversity score(DDS)was calculated according to the criteria in the Guidelines for Measuring Household and Individual Dietary Diversity released by the Food and Agriculture Organization of the United Nations.The body height(length)and body weight of each child were measured by standard equipment for anthropological measurement,and the height for age Z score(HAZ),weight for age Z score(WAZ),and weight for height Z score(WHZ) were calculated.Multivariate linear regression was performed to analyze the relationship between dietary diversity and growth indicators of children. Results A total of 1092 children were enrolled in this study,and the prevalence of stunting(HAZ<-2),underweight(WAZ<-2),and wasting(WHZ<-2)was 21.1%,4.9%,and 2.5%,respectively.The children had the mean DDS of 4.8±1.7,and 45.3% of children had poor dietary diversity(DDS≤4).The children of Han ethnic group(5.8±1.4)had higher DDS than those of Tibetan ethnic group(4.9±1.6)and Yi ethnic group(3.9±1.6)(P<0.001).The results of multivariate linear regression indicated that DDS was positively correlated with HAZ(β=0.206,95%CI=0.158-0.254,P<0.001)after adjustment of sex,age,birth weight,preterm birth,and parental body height.After further adjustment of family fixed assets,ethnic group,caregiver's type,and caregiver's education background,the correlation between DDS and HAZ remained significant(β=0.077,95%CI=0.026-0.128, P=0.003). Conclusions The children in the multi-ethnic rural areas of Sichuan province showed troublesome growth and development status and low dietary diversity,which were conspicuously different between ethnic groups,especially in the rural areas of Yi ethnic group.The dietary diversity was positively associated with HAZ.It is recommended to carry out nutrition and health education according to the local dietary characteristics and thus improve the growth and development of children in multi-ethnic rural areas in Sichuan.

Mechanism of sensitivity to cisplatin, docetaxel, and 5-fluorouracil chemoagents and potential erbB2 alternatives in oral cancer with growth differentiation factor 15 overexpression.

The aim of this study was to: (a) explore the potential mechanism of cancer cell sensitivity to cisplatin, docetaxel, and 5-fluorouracil (TPF) in oral squamous cell carcinoma (OSCC) patients overexpressing growth differentiation factor 15 (GDF15); and (b) identify potential alternative agents for patients who might not benefit from inductive TPF chemotherapy. The results indicated that OSCC cells overexpressing GDF15 were sensitive to TPF through a caspase-9-dependent pathway both in vitro and in vivo. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential GDF15-binding protein, which was verified by coimmunoprecipitation. Growth differentiation factor 15 overexpression promoted OSCC cell proliferation through erbB2 phosphorylation, as well as downstream AKT and Erk signaling pathways. When GDF15 expression was blocked, the phosphorylation of both the erbB2 and AKT/Erk pathways was downregulated. When OSCC cells with GDF15 overexpression were treated with the erbB2 phosphorylation inhibitor, CI-1033, cell proliferation and xenograft growth colony formation were significantly blocked (P < .05). Thus, GDF15-overexpressing OSCC tumors are sensitive to TPF chemoagents through caspase-9-dependent pathways. Growth differentiation factor 15 overexpression promotes OSCC proliferation through erbB2 phosphorylation. Thus, ErbB2 inhibitors could represent potential targeted drugs or an alternative therapy for OSCC patients with GDF15 overexpression.

Effects of Monoammonium Glycyrrhizinate on Stem Cell-like Characteristics, Oxidative Stress and Mitochondrial Function of Acute Promyelocytic Leukemia NB4 Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of monoammonium glycyrrhizinate on the stem cell-like characteristics, oxidative stress and mitochondrial function of acute promyelocytic leukemia cells NB4.@*METHODS@#CCK-8 method was used to detect the viability of acute promyelocytic leukemia cells NB4, and the appropriate dose was screened; Cloning method was used to detect the proliferation rate of NB4 cell; Western blot was used to detect the expression of cell cycle-related protein; flow cytometry was used to detect cell apoptosis and sort NB4 stem cells positive (CD133+); Stem cell markers (Oct4, ABCG2, Dclk1) were detected by RT-PCR; ROS was detected by fluorescence; The kit was used to detect the level of oxidative stress markers (MDA); The flow cytometry was used to detect the change of mitochondrial membrane potential; Western blot was used to detect the expression of mitochondrial damage index-related proteins (Bax/BCL-2).@*RESULTS@#Compared with the control group, if the concentration of MAG was less than 5 μmol/L, the cell NB4 viability showed no significant difference; if the concentration was higher than 5 μmol/L, the inhibitory effect on the growth of cell NB4 increased and showed significant difference (P<0.05), according to the results of CCK-8 experiment, four groups were set based on the concentration of MAG 0 μmol/L, MAG 5 μmol/L, MAG 10 μmol/L, and MAG 20 μmol/L; compared with the control group (MAG 0 μmol/L), the cells in MAG 5 μmol/L group showed no significant difference, while the proliferation rate, cyclin expression, mitochondrial membrane potential, stem cell CD133+ ratio, and marker mRNA level ( Oct4, ABCG2, Dclk1) of NB4 cell were significantly reduced (P<0.05); the apoptosis rate, reactive oxygen species, MDA content and Bax/BCL-2 expression of NB4 cell significantly increased (P<0.05).@*CONCLUSION@#Monoammonium glycyrrhizinate has a significant inhibitory effect on acute promyelocytic leukemia cells NB4, which may be related to the regulation of stem cell-like characteristics, oxidative stress and mitochondrial function.

Targeting ERK combined with apatinib may be a promising therapeutic strategy for treating oral squamous cell carcinoma.

Apatinib is an oral tyrosine kinase inhibitor that targets VEGFR2 signaling and shows potent antitumor effects in various cancers. In this study, we explored the efficacy of apatinib against oral squamous cell carcinoma (OSCC). The relationships between VEGFR2 protein expression and clinical variables were investigated in OSCC patients. OSCC tissues had higher VEGFR2 levels than paracancerous tissues. Compared to patients with low VEGFR2 expression, patients with high VEGFR2 expression had poorer overall survival (OS) and disease-free survival (DFS). Apatinib significantly induced G0/G1 phase arrest and apoptosis, inhibited cell growth and colony formation ability, and blocked autophagic flux by downregulating p-AKT and p-mTOR signaling via the VEGFR2/AKT/mTOR pathway in vitro. Moreover, the inhibition of ERK phosphorylation increased apatinib-induced apoptosis in vitro and in vivo. Apatinib synergized with SCH772984 to achieve a more significant suppression of tumor growth than individual treatment, suggesting the combination of apatinib and SCH772984 as a potent OSCC therapy.

A therapeutic approach with combination of interferon-gamma and autophagy inhibitor for oral squamous cell carcinoma.

Former clinical trials and experimental research have indicated that Interferon-gamma therapy does not achieve an ideal effect in solid tumors. Autophagy has been associated with tumor chemoresistance. The aim of this study was to explore the efficacy of Interferon-gamma and autophagy inhibitor in the combination treatment of oral squamous cell carcinoma. Interferon-gamma-induced apoptosis was evaluated by the expression of relative proteins (cleaved-PARP and caspase-3) and flow cytometry. Interferon-gamma induced autophagy was assessed by the expression of Beclin1, LC3B, and P62. The synergistic effect of interferon-gamma and autophagy inhibitor (chloroquine) was evaluated in vitro and in vivo. Interferon-gamma induced anti-proliferation, apoptosis, and autophagy in oral squamous cell carcinoma cells. Autophagy-related protein 5 was a key feature in Interferon-gamma-induced autophagy flux. Interferon-gamma and chloroquine had obvious synergistic effects on cellular growth inhibition and apoptosis promotion in oral squamous cell carcinoma cells and xenograft models. Our findings suggest that Interferon-gamma-induced autophagy plays a cellular protective role, and blocking autophagy flux can promote Interferon-gamma mediated oral squamous cell carcinoma cell apoptosis. The combination of Interferon-gamma and autophagy inhibitors represents a novel strategy for oral squamous cell carcinoma therapy.

Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma.

BACKGROUND: Smart nanoscale drug delivery systems that target acidic tumor microenvironments (TME) could offer controlled release of drugs and modulate the hypoxic TME to enhance cancer therapy. The majority of previously reported MnO2 nanostructures are nanoparticles, nanosheets, or nanocomposites incorporated with other types of nanoparticles, which may not offer the most effective method for drug loading or for the controlled release of therapeutic payloads. Previous studies have designed MnO2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO2 nanoshells on metastatic cancer is still uncertain. RESULT: Here, intelligent "theranostic" platforms were synthesized based on hollow mesoporous MnO2 (H-MnO2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (H2O2) decomposition. In vitro experiments showed that compared with the control group, the proliferation, colony formation and migration ability of CAL27 and SCC7 cells were significantly reduced in H-MnO2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO2-PEG/TP treatment group, HE staining showed that most of the tumor cells were severely damaged, and TUNEL assay showed cell apoptosis was up-regulated. He staining of renal and liver sections showed no obvious fibrosis, necrosis or hypertrophy, indicating good biosafety. Fluorescence staining showed that HIF-1α expression was decreased, suggesting that the accumulation of MnO2 in the tumor caused the decomposition of H2O2 into O2 and alleviated the hypoxia of the tumor. CONCLUSION: In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions.

Novel synthesis of fused spiro piperidone-cyclopropanes from cyclopropyl amides and electron-deficient alkenes.

We report here that a series of bridged O,O-ketal fused spiro piperidone-cyclopropane derivatives 3 can be constructed with excellent yields and good diastereoselectivity by the one-pot reaction of 1-acylcyclopropanecarboxamides 1 with electron-deficient alkene 2a (EWG = CHO) via the domino process involving [4 + 2] annulation/intermolecular electrophilic addition/intramolecular cyclization. Furthermore, reactions of 1 with 2b/2c (EWG = CN, COOMe), leading to spiro piperidone-cyclopropane derivatives 4 or 5 by base catalyst selection, were also presented.

Purification of Four Caffeoylquinic Acid Derivatives from the Flowers of Gynura Procumbens by HSCCC.

Four caffeoylquinic acid derivatives from the Gunura procumbens flowers (GPF) were successfully isolated and purified by high-speed counter-current chromatography (HSCCC). Ethyl acetate-methanol-water (3:1:3, v/v/v) was the optimum biphasic solvent system, which was selected by high-performance liquid chromatography (HPLC) and run on a preparative scale where the lower aqueous phase was used as the mobile phase with a head-to-tail elution mode. Chlorogenic acid (3.83 mg), Isochlorogenic acid A (6.51 mg), Isochlorogenic acid B (4.38 mg) and Isochlorogenic acid C (4.47 mg) were obtained for the first time in an one-step HSCCC separation from 800 mg of the crude extracts. The purities of four compounds were determined to be >95% by HPLC. Chemical structures of each isolated compounds were identified by nuclear magnetic resonance and electrospray ionization mass spectrometry methods. It is worth noting that all the four compounds were isolated here for the first time from GPF and this work confirms the effectiveness of HSCCC for the separation of compounds contained in complex samples, and provides a foundation for further exploitation of G. procumbens.

Genome-wide quantitative trait loci mapping on Verticillium wilt resistance in 300 chromosome segment substitution lines from Gossypium hirsutum × Gossypium barbadense.

Cotton Verticillium wilt (VW) is a devastating disease seriously affecting fiber yield and quality, and the most effective and economical prevention measure at present is selection and extension of Gossypium varieties harboring high resistance to VW. However, multiple attempts to improve the VW resistance of the most widely cultivated upland cottons have made little significant progress. The introduction of chromosome segment substitution lines (CSSLs) provide the practical solutions for merging the superior genes related with high yield and wide adaptation from Gossypium hirsutum and VW resistance and the excellent fiber quality from Gossypium barbadense. In this study, 300 CSSLs were chosen from the developed BC5F3:5 CSSLs constructed from CCRI36 (G. hirsutum) and Hai1 (G. barbadense) to conduct quantitative trait locus (QTL) mapping of VW resistance, and a total of 40 QTL relevant to VW disease index (DI) were identified. Phenotypic data were obtained from a 2-year investigation in two fields with two replications per year. All the QTL were distributed on 21 chromosomes, with phenotypic variation of 1.05%-10.52%, and 21 stable QTL were consistent in at least two environments. Based on a meta-analysis, 34 novel QTL were identified, while 6 loci were consistent with previously identified QTL. Meanwhile, 70 QTL hotspot regions were detected, including 44 novel regions. This study concentrates on QTL identification and screening for hotspot regions related with VW in the 300 CSSLs, and the results lay a solid foundation not only for revealing the genetic and molecular mechanisms of VW resistance but also for further fine mapping, gene cloning and molecular designing in breeding programs for resistant cotton varieties.