The role of smoking in explaining racial/ethnic disparities in bladder cancer incidence in the United States.

INTRODUCTION: Smoking is the most important modifiable risk factor for bladder cancer (BC), with the odds of developing BC among current and former smokers 3 times higher than never-smokers. We hypothesized that the observed disparities in BC incidence may be partially attributable to differences in smoking prevalence. We examined the attributable risk of BC related to smoking according to race/ethnicity and sex. MATERIAL AND METHODS: We used data from SEER and the Behavioral Risk Factor Surveillance System to estimate BC cases that would have been prevented if current and former smokers had never smoked to calculate the Population Attributable Fractions, stratified by sex and race/ethnicity. SDs of BC incidences across racial/ethnic groups before and after smoking elimination were calculated to estimate disparities. RESULTS: A total of 25,747 cases of BC were analyzed from 21 registries in 2018. By removing smoking, 10,176 cases (40%) would have been eliminated. Smoking was associated with a higher proportion of BC cases among males (42%) than females (36%). Across racial/ethnic groups, smoking contributed to the highest proportion of BC cases among American Indian/Alaska Natives (AI/AN) (43%) and Whites (36%) for females, and highest among AI/ANs (47%) and Blacks (44%) for males. Removing smoking, the SD of BC incidence across racial/ethnic groups was reduced for females (39%) and males (44%). CONCLUSION: Approximately 40% of cases of BC in the United States are attributable to smoking, with the highest proportion in AI/ANs for both males and females, and the lowest in Hispanics for females and Asians and Pacific Islanders for males. Smoking contributes to almost half of racial/ethnic disparities in BC incidence in the United States. Accordingly, health policy to encourage smoking cessation among racial-ethnic minorities may substantially reduce inequalities in BC incidence.

BAFF Promotes FLS Activation Through BAFFR-Mediated Non-canonical NF-κB Pathway and the Effects of CP-25.

B cell activating factor (BAFF) has been shown to play a key role in regulating B cell function, but little is known about whether BAFF affects the function of fibroblast-like synoviocyte (FLS), an effector cell of rheumatoid arthritis (RA). CP-25, a new ester derivative of paeoniflorin, could alleviate the arthritis symptoms of collagen-induced arthritis (CIA) mice by inhibiting BAFF-mediated abnormal activation of B cells. In this study, we aimed to understand the mechanism by which BAFF activates FLS and the effect of CP-25 on FLS function. Therefore, the proliferation and migration abilities of FLS and key proteins on the non-canonical NF-κB pathway were examined. The results showed that compared with the FLS of normal rats/OA patients, the expression of BAFF-R, TRAF2, NIK, p-IKKα, P100, and P52 was higher in the FLS of AA rats/RA patients, while the expression of TRAF3 was lower. And, BAFF promotes FLS activation by activating the non-canonical NF-κB signaling pathway. Meanwhile, BAFFR-siRNA inhibited the proliferation of FLS and the activation of non-canonical NF-κB signaling in FLS induced by BAFF. Additionally, CP-25 could inhibit abnormal proliferation and migration of FLS by regulating non-canonical NF-κB signaling. We concluded that BAFF may act as an important role in facilitating the function of FLS through the BAFFR-mediated non-canonical NF-κB pathway, which would be useful for revealing the pathological mechanism of RA. And CP-25 may become a potential new drug for the treatment of RA, providing a scientific basis for the development of new drugs to treat RA.

Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.

BACKGROUND: Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. METHODS: We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer. RESULTS: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis. CONCLUSIONS: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk. IMPACT: Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.

Successful Outcome of Programmed Death 1 Blockade Plus GemOx for Epstein-Barr Virus-Associated Primary Nodal T/NK Cell Lymphoma: A Case Report.

Epstein-Barr virus (EBV)-associated lymph nodal T/NK cell lymphoma (nodal TNKL) is a rare and aggressive malignancy with an extremely poor prognosis. Although treatments of extranodal NK/T cell lymphoma are frequently reported, the characteristics and pathogenesis of EBV-associated nodal TNKL are different. However, there is no known effective therapy regimen at present. Here, we reported the clinical efficacy and feasibility of the programmed death 1 (PD-1) blockade therapy regimen in an elderly female patient with EBV-associated nodal TNKL. The patient failed to respond to cyclophosphamide, doxorubicin, vindesine, and prednisone regimen but achieved complete response after three cycles of anti-PD-1 antibody (tislelizumab) combined with gemcitabine and oxaliplatin (GemOx) regimen. The finding indicated that tislelizumab combined with the GemOx regimen may be a potent salvage regimen for EBV-associated nodal TNKL.

Blockade of platelet glycoprotein receptor Ib ameliorates blood-brain barrier disruption following ischemic stroke via Epac pathway.

Glycoprotein (GP) Ib is a platelet membrane receptor complex exposed to vascular injury, proposed as an effective target for stroke therapy. Previously, we have observed that the GPIb antagonist anfibatide (ANF) could mitigate blood-brain barrier (BBB) disruption following cerebral ischemia/reperfusion (CI/R) injury. The current study was designed to investigate whether the amelioration of the BBB by ANF is mediated via the Epac signaling pathway. A murine model of CI/R injury was induced following 90 min of transient middle cerebral artery occlusion (MCAO). ANF (4 µg/kg) was intravenously injected 1 h after reperfusion. Herein, ANF ameliorated BBB disruption, increased the expression of tight junction proteins, suppressed F-actin cytoskeleton rearrangement, decreased the permeability of the ischemic brain tissue, and relieved brain edema. ANF-treated mice had smaller infarct volumes and less severe neurological deficits than the MCAO mice. Moreover, the effects of ANF and Epac1 agonists were very similar in the MCAO mice. Epac activation with a cAMP analog, 8-CPT-2'-O-Me-cAMP, mitigated the breakdown of BBB function and CI/R injury. The Epac specific antagonist, ESI-09, worsened barrier damage and cerebral impairment, antagonizing the protective effects afforded by ANF. In addition, ANF upregulated the expression of Epac1 protein in the ischemic cerebral cortex. Collectively, our results indicate that the protective effect of ANF on the BBB after CI/R could be attributed to the activation of the Epac pathway.

Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival.

BACKGROUND: Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients. METHODS: We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis. RESULTS: Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10-7], 0.86 (0.80-0.93, P = 9.4 × 10-5) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (Ptrend < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes. CONCLUSION: These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes.

Mesenchymal stem cell-derived small extracellular vesicles in the treatment of human diseases: Progress and prospect.

Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells that could differentiate into multiple tissues. MSC-based therapy has become an attractive and promising strategy for treating human diseases through immune regulation and tissue repair. However, accumulating data have indicated that MSC-based therapeutic effects are mainly attributed to the properties of the MSC-sourced secretome, especially small extracellular vesicles (sEVs). sEVs are signaling vehicles in intercellular communication in normal or pathological conditions. sEVs contain natural contents, such as proteins, mRNA, and microRNAs, and transfer these functional contents to adjacent cells or distant cells through the circulatory system. MSC-sEVs have drawn much attention as attractive agents for treating multiple diseases. The properties of MSC-sEVs include stability in circulation, good biocompatibility, and low toxicity and immunogenicity. Moreover, emerging evidence has shown that MSC-sEVs have equal or even better treatment efficacies than MSCs in many kinds of disease. This review summarizes the current research efforts on the use of MSC-sEVs in the treatment of human diseases and the existing challenges in their application from lab to clinical practice that need to be considered.

A Novel Fluorescent Probe Based on Pyrazole-Pyrazoline for Fe (III) Ions Recognition.

Firstly, a novel pyrazole-pyrazoline fluorescent probe was developed and synthesized. The probe can be used to determine Fe3+ ions in a series of cations in tetrahydrofuran aqueous solution with high selectivity and high sensitivity. After the addition of iron ions, the fluorescence intensity is significantly reduced, Its structure was characterized by 1H NMR, 13C NMR and HR-ESI-MS. UV absorption spectra and Fluorescence spectroscopy were used to study the selective recognition of probe M on metal ions. The probe M can selectivity and sensitivity to distinguish the target ion from other ions through different fluorescence phenomena. In addition, the binding modes of M with Fe3+ were proved to be 1:1 stoichiometry in the complexes by Job's plot, IR results. The combination of probe M and iron ions is 1:1, and the detection limit is 3.9 × 10-10 M. The binding mode and sensing mechanism of M with Fe3+ was verified by theoretical calculations using Gaussian 09 based on B3LYP/6-31G(d) basis.

Novel Variants of ELP2 and PIAS1 in the Interferon Gamma Signaling Pathway Are Associated with Non-Small Cell Lung Cancer Survival.

BACKGROUND: IFNγ is a pleiotropic cytokine that plays critical immunomodulatory roles in intercellular communication in innate and adaptive immune responses. Despite recognition of IFNγ signaling effects on host defense against viral infection and its utility in immunotherapy and tumor progression, the roles of genetic variants of the IFNγ signaling pathway genes in survival of patients with cancer remain unknown. METHODS: We used a discovery genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 1,185) and a replication genotyping dataset from the Harvard Lung Cancer Susceptibility Study (n = 984) to evaluate associations between 14,553 genetic variants in 150 IFNγ pathway genes and survival of non-small cell lung cancer (NSCLC). RESULTS: The combined analysis identified two independent potentially functional SNPs, ELP2 rs7242481G>A and PIAS1 rs1049493T>C, to be significantly associated with NSCLC survival, with a combined HR of 0.85 (95% confidence interval, 0.78-0.92; P < 0.0001) and 0.87 (0.81-0.93; P < 0.0001), respectively. Expression quantitative trait loci analyses showed that the survival-associated ELP2 rs7242481A allele was significantly associated with increased mRNA expression levels of elongator acetyltransferase complex subunit 2 (ELP2) in 373 lymphoblastoid cell lines and 369 whole-blood samples. The PIAS1 rs1049493C allele was significantly associated with decreased mRNA expression levels of PIAS1 in 383 normal lung tissues and 369 whole-blood samples. CONCLUSIONS: Genetic variants of IFNγ signaling genes are potential prognostic markers for NSCLC survival, likely through modulating the expression of key genes involved in host immune response. IMPACT: Once validated, these variants could be useful predictors of NSCLC survival.

Novel Genetic Variants of ALG6 and GALNTL4 of the Glycosylation Pathway Predict Cutaneous Melanoma-Specific Survival.

Because aberrant glycosylation is known to play a role in the progression of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with the survival of cutaneous melanoma (CM) patients. To test this hypothesis, we used a Cox proportional hazards regression model in a single-locus analysis to evaluate associations between 34,096 genetic variants of 227 glycosylation pathway genes and CM disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from Harvard University nurse/physician cohorts. In the multivariable Cox regression analysis, we found that two novel single-nucleotide polymorphisms (SNPs) (ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C) predicted CMSS, with an adjusted hazards ratios of 0.60 (95% confidence interval = 0.44-0.83 and p = 0.002) and 0.66 (0.52-0.84 and 0.004), respectively. Subsequent expression quantitative trait loci (eQTL) analysis revealed that ALG6 rs10889417 was associated with mRNA expression levels in the cultured skin fibroblasts and whole blood cells and that GALNTL4 rs12270446 was associated with mRNA expression levels in the skin tissues (all p < 0.05). Our findings suggest that, once validated by other large patient cohorts, these two novel SNPs in the glycosylation pathway genes may be useful prognostic biomarkers for CMSS, likely through modulating their gene expression.

Relationship between ß-amyloid protein 1-42, thyroid hormone levels and the risk of cognitive impairment after ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is not only a common consequence of stroke but also an important factor for adverse prognosis of patients. Biochemical indicators such as blood lipids and blood pressure are affected by many factors, and the ability of evaluating the progress of patients with PSCI is insufficient. Therefore, it is necessary to find sensitive markers for predicting the progress of patients and avoiding PSCI. Recent studies have shown that ß-amyloid protein 1-42 (Aß1-42) and thyroid hormone levels are closely related to PSCI, which may be the influencing factors of PSCI, but there are few related studies. AIM: To investigate the relationship between serum levels of Aß and thyroid hormones in acute stage and PSCI and its predicted value. METHODS: A total of 195 patients with acute cerebral infarction confirmed from June 2016 to January 2018 were enrolled in this study. Baseline data and serological indicators were recorded to assess cognitive function of patients. All patients were followed up for 1 year. Their cognitive functions were evaluated within 1 wk, 3 mo, 6 mo and 1 yr after stroke. At the end of follow-up, the patients were divided into PSCI and non-PSCI according to Montreal cognitive assessment score, and the relationship between biochemical indexes and the progression of PSCI was explored. RESULTS: Compared with patients with non-PSCI, the levels of Aß1-42, triiodothyronine (T3) and free thyroxin were lower in the patients with PSCI. Repeated measures analysis of variance showed that the overall content of Aß1-42 and T3 in PSCI was also lower than that of the non-PSCI patients. Further analysis revealed that Aß1-42 (r = 0.348), T3 (r = 0.273) and free thyroxin (r = 0.214) were positively correlated with disease progression (P < 0.05), suggesting that these indicators have the potential to predict disease progression and outcome. Cox regression analysis showed that Aß1-42 and T3 were important factors of PSCI. Then stratified analysis showed that the lower the Aß1-42 and T3, the higher risk of PSCI in patients who were aged over 70, female and illiterate. CONCLUSION: Aß1-42 and T3 have the ability to predict the progression of PSCI, which is expected to be applied clinically to reduce the incidence of PSCI and improve the quality of life of patients.

Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.

The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.

Two new species of Yunnanomonticola Telnov (Coleoptera, Anthicidae) from China.

Two new species of the genus Yunnanomonticola Telnov, 2002 are described based on the specimens collected in China. Yunnanomonticolalatissima sp. n. is collected from Yunnan and Y.tenuipenis sp. n. is from Guizhou. Photographes of the new species are provided, with a key to the three species of Yunnanomonticola.

Layer-Structured Design and Fabrication of Cyanate Ester Nanocomposites for Excellent Electromagnetic Shielding with Absorption-Dominated Characteristic.

In this work, we propose novel layer-structured polymer composites (PCs) for manipulating the electromagnetic (EM) wave transport, which holds unique electromagnetic interference (EMI) shielding features. The as-prepared PCs with a multilayered structure exhibits significant improvement in overall EMI shielding effectiveness (EMI SE) by adjusting the contents and distribution of electrical and magnetic loss fillers. The layer-structured PCs with low nanofiller content (5 wt % graphene nanosheets (GNSs) and 15 wt % Fe3O4) and a thickness of only 2 mm exhibited ultrahigh electrical conductivity and excellent EMI SE, reaching up to 2000 S/m and 45.7 dB in the X-band, respectively. The increased EMI SE of the layer-structured PCs was mainly based on the improved absorption rather than the reflection of electromagnetic waves, which was attributed to the "absorb-reflect-reabsorb" process for the incident electromagnetic waves. This work may provide a simple and effective approach to achieve new EMI shielding materials, especially for absorption-dominated EMI shielding.

Sericin regulates proliferation of human gastric cancer MKN45 cells through autophagic pathway / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effect of sericin on the proliferation of human gastric cancer MKN45 cells and explore the underlying molecular mechanism.</p><p><b>METHODS</b>MKN45 cells were transfected by LC3 double fluorescent autophagic virus, and the positive cells screened by puromycin were divided into blank group, sericin group and sericin∓3-MA group. After incubation with sericin for 48 h, the cells were examined for proliferation, apoptosis and cell cycle using CCK-8 assay and flow cytometry. Cell autophagy was detected by transmission electron microscopy (TEM) and fluorescent inverted microscope, and the autophagy-related markers including LC3, p62 and Beclin proteins were detected with Western blotting. Nude mice bearing gastric cancer xenograft were treated with normal saline or sericin injections (n=5) and the changes in the tumor volume and weight were measured.</p><p><b>RESULTS</b>Compared with the blank group, MKN45 cells with sericin treatment showed significantly inhibited proliferation both in vitro and in nude mice. Autophagosomes were observed in sericin-treated cells under TEM and fluorescent inverted microscope. Sericin treatment of the cells significantly increased the cell apoptosis (P<0.01), caused obvious cell cycle arrest in G/M phase (P<0.01), up-regulated the expressions of both LC3-2 and Beclin, and down-regulated the expression of p62. The autophagy inhibitor 3-MA obviously antagonized the effects of sericin on cell apoptosis, cell cycle and autophagic protein expressions.</p><p><b>CONCLUSION</b>Sericin can inhibit the proliferation of human gastric cancer MKN45 cells by regulating cell autophagy to serve as potential anti-tumor agent.</p>

Reduced blood loss after intra-articular tranexamic acid injection during total knee arthroplasty: a meta-analysis of the literature.

PURPOSE: The purpose of the study is to conduct a meta-analysis of randomized, controlled trials evaluating the efficacy and safety of intra-articular injection of tranexamic acid (TXA) for reducing blood loss and transfusion in patients undergoing total knee arthroplasty (TKA). METHODS: A meta-analysis was conducted of RCTs published before March 2013, identified from the PubMed, EMBase, Cochrane library, ScienceDirect, and other databases. Two independent reviewers assessed the methodological quality of the studies and performed data extraction. Mean difference in blood loss and blood transfusions, risk ratios of transfusion rates, and deep vein thrombosis (DVT) incidence in the TXA-treated group versus placebo group were pooled from the included studies. Data were analysed using Stata 11.0 software. RESULTS: Six studies were included, with a total sample size of 647 patients. The use of TXA significantly reduced total blood loss (mean difference: -344.96; 95% confidence interval (CI) -401.20 to -239.68; P < 0.01) and the proportion of patients requiring blood transfusions (risk ratios, 0.28; 95% CI: 0.19-0.42; P < 0.01). There were no significant differences in the incidence of DVT, pulmonary embolism, or other complications between the study groups. CONCLUSIONS: The present meta-analysis indicated that intra-articular injection of TXA in patients undergoing TKA may reduce total blood loss and the need for blood transfusions, particularly when a high dosage of TXA is used (≥30 mg/ml), without any increase in the risk of post-operative DVT. LEVEL OF EVIDENCE: II.

HIF-1α-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia.

Novel therapeutic strategies are needed to address and to solve the emerging problem of hypoxia-induced resistance to anticancer drugs. N-(4-Hydroxyphenyl)retinamide (4-HPR) exhibits potent anticancer and chemopreventive activities, but its inefficiency under hypoxia, through undetermined mechanisms, may contribute to its lack of activity in clinical trials. In this study, we showed that under normoxia, 4-HPR resulted in apoptosis and ultimate cell death; in contrast, under hypoxia, autophagy was preferentially induced by 4-HPR at an equivalent concentration, accompanied by microtubule associated protein light-chain 3 (LC3) conversion and acidic vesicular organelle formation. Under hypoxia, autophagy inhibition by 3-methyladenine or chloroquine significantly enhanced apoptosis and decreased cell viability in 4-HPR-exposed cells, indicating that autophagy prevents cancer cell death and presumably leads to hypoxia-induced resistance to 4-HPR. Importantly, knockdown of hypoxia-inducible factor-1α (HIF-1α) inhibited autophagy but promoted 4-HPR-induced apoptosis under hypoxia, demonstrating its critical role as a mediator of this protective autophagy. The present study provides the first evidence supporting the hypothesis that autophagy and apoptosis can be differentially induced by 4-HPR under different oxygen conditions; mediated by HIF-1α, 4-HPR-induced autophagy under hypoxia confers a survival advantage to HeLa cells, protects them from 4-HPR-induced death signals, and thus contributes to their hypoxia-induced resistance to this agent. Our data suggest that autophagy inhibition is a potential alternative strategy to overcome hypoxia-induced resistance to 4-HPR and enhance the anticancer activities of this agent.