Unbiasedly decoding the tumor microenvironment with single-cell multiomics analysis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. Research on the tumor microenvironment (TME) of PDAC has propelled the development of immunotherapeutic and targeted therapeutic strategies with a promising future. The emergence of single-cell sequencing and mass spectrometry technologies, coupled with spatial omics, has collectively revealed the heterogeneity of the TME from a multiomics perspective, outlined the development trajectories of cell lineages, and revealed important functions of previously underrated myeloid cells and tumor stroma cells. Concurrently, these findings necessitated more refined annotations of biological functions at the cell cluster or single-cell level. Precise identification of all cell clusters is urgently needed to determine whether they have been investigated adequately and to identify target cell clusters with antitumor potential, design compatible treatment strategies, and determine treatment resistance. Here, we summarize recent research on the PDAC TME at the single-cell multiomics level, with an unbiased focus on the functions and potential classification bases of every cellular component within the TME, and look forward to the prospects of integrating single-cell multiomics data and retrospectively reusing bulk sequencing data, hoping to provide new insights into the PDAC TME.

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. Here, we identified FBXO32 as an oncogenic driver in PDAC. FBXO32 was aberrantly upregulated in PDAC, and high FBXO32 expression was significantly associated with an unfavorable prognosis in PDAC patients. FRG1 deficiency promoted FBXO32 upregulation in PDAC. FBXO32 promoted cell migration and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, FBXO32 directly interacted with eEF1A1 and promoted its polyubiquitination at the K273 site, leading to enhanced activity of eEF1A1 and increased protein synthesis in PDAC cells. Moreover, FBXO32-catalyzed eEF1A1 ubiquitination boosted the translation of ITGB5 mRNA and activated FAK signaling, thereby facilitating focal adhesion assembly and driving PDAC progression. Importantly, interfering with the FBXO32-eEF1A1 axis or pharmaceutical inhibition of FAK by defactinib, an FDA-approved FAK inhibitor, substantially inhibited PDAC growth and metastasis driven by aberrantly activated FBXO32-eEF1A1 signaling. Overall, this study uncovers a mechanism by which PDAC cells rely on FBXO32-mediated eEF1A1 activation to drive progression and metastasis. FBXO32 may serve as a promising biomarker for selecting eligible PDAC patients for treatment with defactinib.

E3 ubiquitin ligase RBCK1 confers ferroptosis resistance in pancreatic cancer by facilitating MFN2 degradation.

Ferroptosis, a novel form of iron-dependent non-apoptotic cell death, plays an active role in the pathogenesis of diverse diseases, including cancer. However, the mechanism through which ferroptosis is regulated in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, our study, via combining bioinformatic analysis with experimental validation, showed that ferroptosis is inhibited in PDAC. Genome-wide sequencing further revealed that the ferroptosis activator imidazole ketone erastin (IKE) induced upregulation of the E3 ubiquitin ligase RBCK1 in PDAC cells at the transcriptional or translational level. RBCK1 depletion or knockdown rendered PDAC cells more vulnerable to IKE-induced ferroptotic death in vitro. In a mouse xenograft model, genetic depletion of RBCK1 increased the killing effects of ferroptosis inducer on PDAC cells. Mechanistically, RBCK1 interacts with and polyubiquitylates mitofusin 2 (MFN2), a key regulator of mitochondrial dynamics, to facilitate its proteasomal degradation under ferroptotic stress, leading to decreased mitochondrial reactive oxygen species (ROS) production and lipid peroxidation. These findings not only provide new insights into the defense mechanisms of PDAC cells against ferroptotic death but also indicate that targeting the RBCK1-MFN2 axis may be a promising option for treating patients with PDAC.

The NF-κB/NUAK2 signaling axis regulates pancreatic cancer progression by targeting SMAD2/3.

Nuclear factor kappa B (NF-κB) plays a pivotal role in the development of pancreatic cancer, and its phosphorylation has previously been linked to the regulation of NUAK2. However, the regulatory connection between NF-κB and NUAK2, as well as NUAK2's role in pancreatic cancer, remains unclear. In this study, we observed that inhibiting NUAK2 impeded the proliferation, migration, and invasion of pancreatic cancer cells while triggering apoptosis. NUAK2 overexpression partially resisted apoptosis and reversed the inhibitory effects of the NF-κB inhibitor. NF-κB transcriptionally regulated NUAK2 transcription by binding to the promoter region of NUAK2. Mechanistically, NUAK2 knockdown remarkably reduced the expression levels of p-SMAD2/3 and SMAD2/3, resulting in decreased nuclear translocation of SMAD4. In SMAD4-negative cells, NUAK2 knockdown impacted FAK signaling by downregulating SMAD2/3. Moreover, NUAK2 knockdown heightened the sensitivity of pancreatic cancer cells to gemcitabine, suggesting that NUAK2 inhibitors could be a promising strategy for pancreatic cancer treatment.

Predictive modeling of postpartum blood pressure spikes.

BACKGROUND: Hypertensive disorders of pregnancy are one of the leading causes of maternal morbidity and mortality worldwide. Management of these conditions can pose many clinical dilemmas and can be particularly challenging during the immediate postpartum period. Models for predicting and managing postpartum hypertension are necessary to help address this clinical challenge. OBJECTIVE: This study aimed to evaluate predictive models of blood pressure spikes in the postpartum period and to investigate clinical management strategies to optimize care. STUDY DESIGN: This was a retrospective cohort study of postpartum women who participated in remote blood pressure monitoring. A postpartum blood pressure spike was defined as a blood pressure measurement of ≥140/90 mm Hg while on an antihypertensive medication and a blood pressure measurement of ≥150/100 mm Hg if not on an antihypertensive medication. We identified 3 risk level patient clusters (low, medium, and high) when predicting patient risk for a blood pressure spike on postpartum days 3 to 7. The variables used in defining these clusters were peak systolic blood pressure before discharge, body mass index, patient systolic blood pressure per trimester, heart rate, gestational age, maternal age, chronic hypertension, and gestational hypertension. For each risk cluster, we focused on 2 treatments, namely (1) postpartum length of stay (<3 days or ≥3 days) and (2) discharge with or without blood pressure medications. We evaluated the effectiveness of the treatments in different subgroups of patients by estimating the conditional average treatment effect values in each cluster using a causal forest. Moreover, for all patients, we considered discharge with medication policies depending on different discharge blood pressure thresholds. We used a doubly robust policy evaluation method to compare the effectiveness of the policies. RESULTS: A total of 413 patients were included, and among those, 267 (64.6%) had a postpartum blood pressure spike. The treatments for patients at medium and high risk were considered beneficial. The 95% confidence intervals for constant marginal average treatment effect for antihypertensive use at discharge were -3.482 to 4.840 and - 5.539 to 4.315, respectively; and for a longer stay they were -5.544 to 3.866 and -7.200 to 4.302, respectively. For patients at low risk, the treatments were not critical in preventing a blood pressure spike with 95% confidence intervals for constant marginal average treatment effect of 1.074 to 15.784 and -2.913 to 9.021 for the different treatments. We considered the option to discharge patients with antihypertensive use at different blood pressure thresholds, namely (1) ≥130 mm Hg and/or ≥80 mm Hg, (2) ≥140 mm Hg and/or ≥90 mm Hg, (3) ≥150 mm Hg and/or ≥ 100 mm Hg, or (4) ≥160 mm Hg and/or ≥ 110 mm Hg. We found that policy (2) was the best option with P<.05. CONCLUSION: We identified 3 possible strategies to prevent outpatient blood pressure spikes during the postpartum period, namely (1) medium- and high-risk patients should be considered for a longer postpartum hospital stay or should participate in daily home monitoring, (2) medium- and high-risk patients should be prescribed antihypertensives at discharge, and (3) antihypertensive treatment should be prescribed if patients are discharged with a blood pressure of ≥140/90 mm Hg.

Ribosome profiling: a powerful tool in oncological research.

Neoplastic cells need to adapt their gene expression pattern to survive in an ever-changing or unfavorable tumor microenvironment. Protein synthesis (or mRNA translation), an essential part of gene expression, is dysregulated in cancer. The emergence of distinct translatomic technologies has revolutionized oncological studies to elucidate translational regulatory mechanisms. Ribosome profiling can provide adequate information on diverse aspects of translation by aiding in quantitatively analyzing the intensity of translating ribosome-protected fragments. Here, we review the primary currently used translatomics techniques and highlight their advantages and disadvantages as tools for translatomics studies. Subsequently, we clarified the areas in which ribosome profiling could be applied to better understand translational control. Finally, we summarized the latest advances in cancer studies using ribosome profiling to highlight the extensive application of this powerful and promising translatomic tool.

Epidemiology of pancreatic cancer: New version, new vision.

Pancreatic cancer (PC) is a devastating malignancy with an extremely high mortality rate and poses significant challenges to healthcare systems worldwide. The prevalence of PC risk factors spiked over the years, leading to a global increase in PC incidence rates. The contribution of different risk factors, however, varied from region to region due to genetic predisposition, environmental, social, and political factors underlying disease prevalence in addition to public health strategies. This comprehensive review aims to provide a thorough analysis of the epidemiology of PC, discussing its incidence, risk factors, screening strategies and socioeconomic burden. We compiled a wide range of seminal studies as well as epidemiological investigations to serve this review as a comprehensive guide for researchers, healthcare professionals, and policymakers keen for a more profound understanding of PC epidemiology. This review highlights the essentiality of persistent research efforts, interdisciplinary collaboration, and public health initiatives to address the expanding burden of this malignancy.

Novel strategies optimize immunotherapy by improving the cytotoxic function of T cells for pancreatic cancer treatment.

Pancreatic cancer (PC) is considered highly malignant due to its unsatisfying prognosis and limited response to therapies. Immunotherapy has therefore been developed to harness the antigen-specific properties and cytotoxicity of the immune system, aiming to induce a robust anti-tumor immune response that specifically demolishes PC cells while minimizing lethality in healthy tissue. The activation and augmentation of cytotoxic T cells play a critical role in the initiation and final success of immunotherapy. PC, however, is often immunotherapy resistant due to its intrinsic immunosuppressive tumor microenvironment that consequently hampers effective T cell priming. Emerging therapeutic approaches are orientated to modulate the tumor microenvironment in PC to enhance immune system involvement and heighten T cell efficacy. These novel strategies have shown promising therapeutic effects in the treatment of PC either as standalone approaches or combinatorial with other therapeutic schemes. The objective of this article is to explore innovative approaches to optimize immunotherapy for PC patients through T cell cytotoxic function augmentation.

From basic research to clinical application: targeting fibroblast activation protein for cancer diagnosis and treatment.

PURPOSE: This study aims to review the multifaceted roles of a membrane protein named Fibroblast Activation Protein (FAP) expressed in tumor tissue, including its molecular functionalities, regulatory mechanisms governing its expression, prognostic significance, and its crucial role in cancer diagnosis and treatment. METHODS: Articles that have uncovered the regulatory role of FAP in tumor, as well as its potential utility within clinical realms, spanning diagnosis to therapeutic intervention has been screened for a comprehensive review. RESULTS: Our review reveals that FAP plays a pivotal role in solid tumor progression by undertaking a multitude of enzymatic and nonenzymatic roles within the tumor stroma. The exclusive presence of FAP within tumor tissues highlights its potential as a diagnostic marker and therapeutic target. The review also emphasizes the prognostic significance of FAP in predicting tumor progression and patient outcomes. Furthermore, the emerging strategies involving FAPI inhibitor (FAPI) in cancer research and clinical trials for PET/CT diagnosis are discussed. And targeted therapy utilizing FAP including FAPI, chimeric antigen receptor (CAR) T cell therapy, tumor vaccine, antibody-drug conjugates, bispecific T-cell engagers, FAP cleavable prodrugs, and drug delivery system are also introduced. CONCLUSION: FAP's intricate interactions with tumor cells and the tumor microenvironment make it a promising target for diagnosis and treatment. Promising strategies such as FAPI offer potential avenues for accurate tumor diagnosis, while multiple therapeutic strategies highlight the prospects of FAP targeting treatments which needs further clinical evaluation.

Organoid: Bridging the gap between basic research and clinical practice.

Nowadays, the diagnosis and treatment system of malignant tumors has increasingly tended to be more precise and personalized while the existing tumor models are still unable to fully meet the needs of clinical practice. Notably, the emerging organoid platform has been proven to have huge potential in the field of basic-translational medicine, which is expected to promote a paradigm shift in personalized medicine. Here, given the unique advantages of organoid platform, we mainly explore the prominent role of organoid models in basic research and clinical practice from perspectives of tumor biology, tumorigenic microbes-host interaction, clinical decision-making, and regenerative strategy. In addition, we also put forward some practical suggestions on how to construct a new generation of organoid platform, which is destined to vigorously promote the reform of basic-translational medicine.

PRKRA promotes pancreatic cancer progression by upregulating MMP1 transcription via the NF-κB pathway.

Objective: Pancreatic cancer (PC) is highly malignant, but the underlying mechanisms of cancer progression remain unclear. PRKRA is involved in cellular stress response, but its role in PC was unknown. Methods: The expression of PRKRA between normal and tumor tissues were compared, and the prognostic value of PRKRA was evaluated. SiRNA and plasmids were applied to investigate the effects of PRKRA on PC cells. Organoids and cell lines with knockout and overexpression of PRKRA were established by CRISPR/Cas9 and lentivirus. The effects of PRKRA on PC were evaluated in vivo by cell-derived xenografts. The downstream genes of PRKRA were screened by transcriptome sequencing. The regulation of the target gene was validated by RT-qPCR, western blot, ChIP and dual luciferase reporter assay. Besides, the correlation between PRKRA and gemcitabine sensitivity was investigated by PC organoids. Results: PRKRA was significantly overexpressed in PC tissues and independently associated with poor prognosis. PRKRA promoted the proliferation, migration, and chemoresistance of PC cells. The proliferation of PC organoids was decreased by PRKRA knockout. The growth and chemoresistance of xenografts were increased by PRKRA overexpression. Mechanistically, PRKRA upregulated the transcription of MMP1 via NF-κB pathway. ChIP and dual luciferase reporter assay showed that NF-κB subunit P65 could bind to the promoter of MMP1. The sensitivity of PC organoids to gemcitabine was negatively correlated with the expression of PRKRA and MMP1. Conclusions: Our study indicated that the PRKRA/NF-κB/MMP1 axis promoted the progression of PC and may serve as a potential therapeutic target and prognosis marker.

Genomic analysis and filtration of novel prognostic biomarkers based on metabolic and immune subtypes in pancreatic cancer.

PURPOSE: Patients with pancreatic cancer (PC) can be classified into various molecular subtypes and benefit from some precise therapy. Nevertheless, the interaction between metabolic and immune subtypes in the tumor microenvironment (TME) remains unknown. We hope to identify molecular subtypes related to metabolism and immunity in pancreatic cancer METHODS: Unsupervised consensus clustering and ssGSEA analysis were utilized to construct molecular subtypes related to metabolism and immunity. Diverse metabolic and immune subtypes were characterized by distinct prognoses and TME. Afterward, we filtrated the overlapped genes based on the differentially expressed genes (DEGs) between the metabolic and immune subtypes by lasso regression and Cox regression, and used them to build risk score signature which led to PC patients was categorized into high- and low-risk groups. Nomogram were built to predict the survival rates of each PC patient. RT-PCR, in vitro cell proliferation assay, PC organoid, immunohistochemistry staining were used to identify key oncogenes related to PC RESULTS: High-risk patients have a better response for various chemotherapeutic drugs in the Genomics of Drug Sensitivity in Cancer (GDSC) database. We built a nomogram with the risk group, age, and the number of positive lymph nodes to predict the survival rates of each PC patient with average 1-year, 2-year, and 3-year areas under the curve (AUCs) equal to 0.792, 0.752, and 0.751. FAM83A, KLF5, LIPH, MYEOV were up-regulated in the PC cell line and PC tissues. Knockdown of FAM83A, KLF5, LIPH, MYEOV could reduce the proliferation in the PC cell line and PC organoids CONCLUSION: The risk score signature based on the metabolism and immune molecular subtypes can accurately predict the prognosis and guide treatments of PC, meanwhile, the metabolism-immune biomarkers may provide novel target therapy for PC.

Higher clearance rates of multiple HPV infections may explain their lower risk of HSIL: A retrospective study in Wenzhou, China.

Persistent human papilloma virus (HPV) infection is known to be associated with cervical lesions. The chief object of the study is to investigate if the pathogenicity of multiple HPV infections is different from a single infection. Furthermore, we would like to corroborate the discrepancy with clearance rates. Between August 1, 2020, and September 31, 2021, 5089 women underwent a colposcopy-directed biopsy in our hospital. We divided the 2999 patients who met the criteria into multiple and single HPV infection groups. The HPV genotypes were identified using the flow cytometry fluorescence hybridization technology. Binary logistic regression and survival analysis were used to perform statistics. Among HPV-positive individuals, 34.78% (1043/2999) were positive for 2 or more HPV types. After adjusting for the main factors, compared with single infection, multiple infections were associated with a significantly decreased risk of high squamous intraepithelial lesions (HSIL) (odds ratio [OR]: 0.570; 95% confidence interval [CI]: 0.468-0.694). In the mean time, the clearance rates of multiple infections were significantly higher (OR: 2.240; 95% CI: 1.919-2.614). When analyzing specific types covered by the 9-valent HPV vaccine, consistency between the lower risk of HSIL and the higher clearance rate was found in the most groups. Compared with a single infection, multiple HPV infections have a lower risk of HSIL, which may be related to its higher clearance rate. It suggests that aggressive treatment of multiple HPV infections early in their detection may be beneficial.

Genital HPV Prevalence, Follow-Up and Persistence in Males and HPV Concordance Between Heterosexual Couples in Wenzhou, China.

Purpose: This study aimed to investigate male HPV infection, re-examination rate, clearance rate and relevant influencing factors as well as HPV infection between heterosexual partners in Wenzhou, China. Methods: The study enrolled 2359 men who accepted ≥1 HPV detection in the First Affiliated Hospital of Wenzhou Medical University between June 2014 and June 2020. An outpatient follow-up was carried out for collecting HPV re-test results among males who were tested HPV positive. In addition, we collected female sexual partners' HPV infection state through outpatient information system or telephone call. For males who had not re-tested HPV more than half a year after the first HPV positive result, a telephone follow-up would be provided. Results: Male HPV prevalence was 39.39% (928/2359) at baseline, of which the median age was 38.00 years. The percentage of co-infection and HR HPV infection was 35.24% (327/928) and 61.08% (874/1431). Genotype-specific concordance of HPV infection among heterosexual partners was 61.19% (123/201). The most common types were HPV6, HPV52, HPV16, HPV53, HPV11, HPV43 and HPV58. Percentage of males finishing HPV re-examination was low (40.09%). Infection with HR HPV, discomfort or HPV-related diseases and sexual partners with HPV infection were possible motivator for male HPV re-test. The medium time to male HPV clearance was 300.000 (95% CI=274.845-325.155) days. Infection with HR HPV, sexual partners with HPV infection and growth of age might prolong HPV persistence time included. Conclusion: Males are susceptible population for genital HPV infection as well as females. Whereas, males are generally less aware of HPV and its influence on their couples. The study showed that male HPV testing as well as the role of males in the diagnosis and treatment of HPV-associated cervical diseases for females should be popularized and co-treatment of couples was necessary.

Cancer-specific survival and metastasis in pancreatic mucinous cystadenocarcinoma: A SEER-based cohort study.

Aims: This study aimed to investigate the prognostic value of clinical features for cancer-specific survival (CSS) and metastasis in patients with pancreatic mucinous cystadenocarcinoma (MCAC). We further constructed and validated an effective nomogram to predict CSS. Methods: We screened patients diagnosed with pancreatic MCAC from Surveillance Epidemiology and End Results (SEER) database. Kaplan-Meier curves were used to determine the CSS time. Univariate and multivariate Cox and logistic regression analyses were conducted to identify the prognostic factors for CSS and metastasis. The nomogram was constructed to predict the prognosis of pancreatic MCAC based on the results from the multivariate analysis. We used the concordance index (C-index), the area under the curve (AUC), and the calibration plots to determine the predictive accuracy and discriminability of the nomogram. Results: Multivariate Cox analysis revealed that age, primary site, grade, and radiotherapy were independent prognostic factors associated with CSS. Multivariate logistic regression analysis revealed that surgery and grade were independent risk factors associated with metastasis. The independent risk factors were included to construct a prognosis prediction model for predicting CSS in patients with pancreatic MCAC. The concordance index (C-index), receiver operating characteristic (ROC) curves, and calibration plots of the training cohort and the validation cohort showed that the nomogram had an acceptable predictive performance. Conclusion: We established a nomogram that could determine the 3- and 5-year CSS, which could evaluate individual clinical outcomes and provide individualized clinical decisions.

HIF-1α-regulated stanniocalcin-1 mediates gemcitabine resistance in pancreatic ductal adenocarcinoma via PI3K/AKT signaling pathway.

Pancreatic ductal adenocarcinoma (PDAC) has a poor response to the first-line chemotherapy drug gemcitabine. We previously identified stanniocalcin-1 as a gemcitabine-resistant-related gene, but its specific role and function in pancreatic cancer remain unclear. RT-qPCR and Western blot were used to evaluate differential protein and mRNA expressions. The biological functions of genes were determined using proliferation and drug-resistance experiments. Subcutaneous tumorigenesis experiment was performed on nude mice. Prognostic analysis was performed using public databases and our clinical data. We found HIF-1α-regulated STC1 expression mediated chemoresistance in pancreatic cancer. Deeper, we explored the action mechanism of STC1 and identified PI3K/AKT as the downstream signaling pathway of STC1. Furthermore, we analyzed clinical data and found that STC1 expression was related to the prognosis of gemcitabine-treated patients after surgery. In general, we proved the HIF-1α/STC1/PI3K-AKT axis participated in PDAC progression and chemoresistance, and STC1 may serve as a potential prognostic factor and therapeutic target for PDAC treatment.

Intelligent fault diagnosis of rolling bearings under varying operating conditions based on domain-adversarial neural network and attention mechanism.

As a domain adaptation method, the domain-adversarial neural network (DANN) can utilize the adversarial learning of the feature extractor and domain discriminator to extract the domain-invariant features, thus realizing fault identification of rolling bearings. In the cross-domain diagnosis of rolling bearing faults, how to obtain fault-related discriminative domain-invariant features from the noisy signals is a key to improving the diagnostic result. In response to this, this paper proposes an intelligent diagnosis model based on the DANN and attention mechanism to identify rolling bearing faults. In order to relieve the influence of noisy data on feature extraction and improve the quality of the learned features, the ensemble empirical mode decomposition (EEMD) is first adopted to denoise the raw sample data to weaken the influence of noise on feature extraction. Secondly, a feature extractor composed of three feature extraction modules in series is designed, and each feature extraction module is composed of a convolution layer, an attention mechanism module and a pooling layer. The feature extractor with attention mechanism enables the model to learn and retain key features related to the faults during training process. Meanwhile, the global average pooling layer is used to replace some fully connected layers in the fault classifier and domain discriminator to reduce model parameters and avoid model overfitting. Finally, the analysis using two sets of rolling bearing experimental about the performance of the presented method show that the proposed method has the potential to become a promising tool for the fault diagnosis of rolling bearings.

Targeting hypoxic tumor microenvironment in pancreatic cancer.

Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.