Immunosuppressive regulatory cells in cancer immunotherapy: restrain or modulate?

Immunosuppressive regulatory cells (IRCs) play important roles in negatively regulating immune response, and are mainly divided into myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Large numbers of preclinical and clinical studies have shown that inhibition or reduction of IRCs could effectively elevate antitumor immune responses. However, several studies also reported that excessive inhibition of IRCs function is one of the main reasons causing the side effects of cancer immunotherapy. Therefore, the reasonable regulation of IRCs is crucial for improving the safety and efficiency of cancer immunotherapy. In this review, we summarised the recent research advances in the cancer immunotherapy by regulating the proportion of IRCs, and discussed the roles of IRCs in regulating tumour immune evasion and drug resistance to immunotherapies. Furthermore, we also discussed how to balance the potential opportunities and challenges of using IRCs to improve the safety of cancer immunotherapies.

The association between cataract and incidence of cognitive impairment in older adults: A systematic review and meta-analysis.

BACKGROUND: Cataract has been shown to be associated with an increased risk of cognitive impairment. However, the results of previous studies have been inconsistent. This systematic review and meta-analysis aimed to investigate the association between cataract and the incidence of cognitive impairment in older adults. METHODS: A comprehensive search of electronic databases from inception to January 2023 was performed to identify relevant studies. Data were extracted from eligible studies and a meta-analysis was performed to calculate the pooled hazard ratio (HR) and 95% confidence interval (CI). RESULTS: We included 13 studies with 25 study arms involving a total of 798,694 participants. Compared with participants without cataract, those with cataract had a higher risk of developing all-cause dementia (pooled HR: 1.22; 95 % CI: 1.08-1.38; I2 =86 %; 9 studies), Alzheimer's disease dementia (pooled HR: 1.18; 95 % CI: 1.07-1.30; I2 =0 %; 9 studies), vascular dementia (pooled HR: 1.21; 95 % CI: 1.02-1.43; I2 =77 %;3 studies) and mild cognitive impairment (pooled HR: 1.30; 95% CI: 1.13-1.50; I2 =0%;2 studies). There was no significant association between cataract and mixed dementia (pooled HR: 1.03; 95 % CI: 0.52-2.04; I2 =78 %;2 studies). We assessed the risk of bias of the included studies using the Newcastle-Ottawa Scale and found that most of them had a low or moderate risk of bias. The number of studies in each meta-analysis ranged from two to nine, with more studies available for all-cause dementia and Alzheimer's disease dementia than for vascular dementia and mixed dementia. CONCLUSIONS: The findings suggest that cataract may be associated with cognitive impairment in older adults. However, the causal relationship between cataract and cognition remains unclear and requires further investigation.

Cell Adhesion Molecule CD99 in Cancer Immunotherapy.

The CD99 antigen is a transmembrane protein expressed in a broad variety of tissues, particularly in hematopoietic cells, thymus, endothelial cells, etc. It participates in several crucial biological processes, including cell adhesion, migration, death, differentiation, and inflammation. CD99 has shown oncogenic or tumor suppressor roles in different types of cancer. Therefore, it has been used as a biomarker and therapeutic target for several types of cancer. Moreover, it has also been reported to be involved in several critical immune processes, such as T cell activation and differentiation, dendritic cell differentiation, and so on. Hence, CD99 may have potential values in cancer immunotherapy. Anti-CD99 antibodies have shown therapeutic effects on certain types of cancer, especially on Ewing sarcoma and T cell acute lymphoblastic leukemia (ALL). This review summarizes the recent progress of CD99 in cancer research and targeting therapies, especially in cancer immunotherapy, which may help researchers understand the crucial roles of CD99 in cancer development and design new therapeutic strategies.

Combination of a Novel Fusion Protein CD3εζ28 and Bispecific T Cell Engager Enhances the Persistance and Anti-Cancer Effects of T Cells.

Bi-specific T cell engager (BiTE), an artificial bi-functional fusion protein, has shown promising therapeutic potential in preclinical and clinical studies. However, T cells cannot be sufficiently activated by BiTE, most likely due to lacking co-stimulatory signal. We reasoned that incorporating co-stimulatory signal might have the potential to enhance the T cell activation mediated by BiTE. We, therefore, designed a chimeric fusion protein, named as CD3εζ28, which consists of the CD3ε extracellular region, the CD28 costimulatory signal and the intracellular region of CD3ζ in tandem. T cells genetically modified to express both CD3εζ28 and GFP (T-CD3εζ28-GFP) were generated by retroviral transduction. The results from in vitro experiments showed that T-CD3εζCD28-GFP cells had superior cytotoxic effects on tumor cells in presence of BiTE compared with control T cells, as evidenced by IL-2 and IFN-γ production, T cell proliferation and sequential killing assay. In vivo, T-CD3εζCD28-GFP cells showed superior anti-tumor effects in Hela-BiTE. EGFRvIII xenograft tumor model, as evaluated by tumor growth rate and T cell persistence in comparison with control T cells. In order to further confirm these findings, we generated T cells modified to express both CD3εζCD28 on cell surface and BiTE.CD19 by autocrine manner (T-CD3εζCD28-BiTE.19). The superior anti-tumor effects of T-CD3εζCD28-BiTE.19 cells could also be evidenced by the similar in vitro and in vivo experiments; thus, incorporating co-stimulatory signal may be an effective approach to improve the effector function of T cells mediated by BiTE.

Application of Elastin-like Polypeptide in Tumor Therapy.

Elastin-like polypeptides (ELPs) are stimulus-responsive artificially designed proteins synthesized from the core amino acid sequence of human tropoelastin. ELPs have good biocompatibility and biodegradability and do not systemically induce adverse immune responses, making them a suitable module for drug delivery. Design strategies can equip ELPs with the ability to respond to changes in temperature and pH or the capacity to self-assemble into nanoparticles. These unique tunable biophysicochemical properties make ELPs among the most widely studied biopolymers employed in protein purification, drug delivery, tissue engineering and even in tumor therapy. As a module for drug delivery and as a carrier to target tumor cells, the combination of ELPs with therapeutic drugs, antibodies and photo-oxidation molecules has been shown to result in improved pharmacokinetic properties (prolonged half-life, drug targeting, cell penetration and controlled release) while restricting the cytotoxicity of the drug to a confined infected site. In this review, we summarize the latest developments in the application methods of ELP employed in tumor therapy, with a focus on its conjugation with peptide drugs, antibodies and photosensitizers.

Antitumor activity of recombinant oncolytic vaccinia virus with human IL2.

The tumor microenvironment is highly immunosuppressive. The genetically modified oncolytic vaccinia virus (OVV) is a promising vector for cancer immunotherapy. The aim of the present study was to assess the antitumor effects of human interleukin-2 (hIL2)-armed OVV in vitro. The hIL2 gene was inserted into a thymidine kinase and the viral growth factor double deleted oncolytic VV (VVDD) to generate recombinant hIL2-armed OVV (rVVDD-hIL2). Viral replication capacity in A549 cells was quantified by plaque titration on CV-1 cells. Production of hIL2 in cancer cells infected by rVVDD-hIL2 was measured by enzyme-linked immunosorbent assay. Finally, 3-(4,5-dimethylthiazol-2-yl)-5-(3-arboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay was performed to assess the antitumor effects of rVVDD-hIL2. The results showed that rVVDD-hIL2 viral particles expressed increasing levels of hIL2 in human and murine cancer cell lines with growing multiplicities of infection (MOIs). The insertion of the hIL2 gene did not impair the replication capacity of VV, and the rVVDD-hIL2 virus killed cancer cells efficaciously. The lytic effects of the recombinant oncolytic virus on tumor cells increased with the growing MOIs. In conclusion, these findings suggest that hIL2-armed VVDD effectively infects and lyses tumor cells, with high expression of hIL2.

Activation-induced cell death in CAR-T cell therapy.

Engineered T cells expressing chimeric antigen receptors (CARs) with tumor specificity have shown remarkable therapeutic effects on hematologic malignancies. However, CAR-T cells are less effective on solid tumors mainly due to the weak persistence of CAR-T cells, which might be caused by T cell death. Significant activation-induced cell death (AICD) of CAR-T cells was triggered by repeated antigen stimulation. AICD of T cell is characterized by the upregulation of death receptors and low persistence of T cells. Understanding the mechanism of AICD is crucial to improve the anti-tumor effect of CAR-T cells against solid tumors. Many approaches have been applied in CAR-T cell modification to enhance their anti-apoptosis ability. In this review, we summarized the molecular mechanisms of AICD in CAR-T cells and the progresses of anti-AICD in CAR-T cells therapy.

The application of oncolytic viruses in cancer therapy.

Oncolytic therapy is a treatment method used to directly combat tumor cells by modifying the genes of naturally occurring low pathogenic viruses to form "rhizobia" virus. By taking the advantage of abnormal signal pathways in cancer cells, it selectively replicates in tumor cells leading to tumor cell lysis and death. At present, clinical studies widely employ biomolecular technology to transform oncolytic viruses to exert stronger oncolytic effects and reduce their adverse reactions. This review summarizes the current progresses and the molecular mechanism of oncolytic viruses towards tumor treatment and management.

Multi-organ metastasis as destination for breast cancer cells guided by biomechanical architecture.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against ß-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of ß-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.

Corrigendum to "Trend of HIV-1 drug resistance in China: A systematic review and meta-analysis of data accumulated over 17 years (2001-2017)" [EClinicalMedicine 18 (2020) 100238].

[This corrects the article DOI: 10.1016/j.eclinm.2019.100238.].

Development of chimeric antigen receptor-modified T cells for the treatment of esophageal cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an overexpressed antigen in esophageal squamous cell carcinomas (ESCCs) but with limited expression levels in normal esophageal tissues. Therefore, employing the adoptive transfer of T cells genetically modified to express chimeric antigen receptor (CAR) targeting HER2 could be a promising therapeutic strategy against ESCC. METHODS: Two different second-generation CAR-T cells expressing antibodies for HER2 and CD19 antigens were developed using retroviral vector transduction. The expression of HER2 antigen in ESCC tissue and cell lines was examined by immunohistochemistry and flow cytometry, respectively. The tumor killing efficacy of the CAR-T cells in mice model and ESCC cell lines and its potential for the treatment of ESCC was evaluated by determining tumor size in mice xenograft, and by crystal violet staining, MTS assay, and cytokine release. RESULTS: In vitro, HER2.CAR-T cells efficiently recognized and killed HER2-positive tumor cells as evidenced by the secretion of proinflammatory cytokines, interferon-γ, and interleukin 2 and by cytotoxicity assays. In vivo, intratumor injection of HER2.CAR-T cells resulted in a significant suppression of established ESCCs in a subcutaneous xenograft BALB/c nude mouse model. In contrast, the injection of CD19.CAR-T cells did not affect the tumor growth pattern. CONCLUSIONS: An effective HER2 CAR targeting ESCC was developed successfully. The HER2.CAR-T cell showed promising immunotherapeutic potential for the treatment of HER2-positive esophageal cancer.

Cryptotanshinone decreases granulosa cell apoptosis and restores ovarian function in mice with premature ovarian failure.

With the increasing incidence of premature ovarian failure (POF) seriously threaten the women's health. Whether cryptotanshinone decreased the granulosa cell apoptosis to improve the POF would be explored. POF mice were conducted with intraperitoneal injection of cyclophosphamide and then treated with cryptotanshinone. The body weight and ovarian weight were recorded. The estrus was detected by vaginal smears. The pathological changes of ovarian were observed with hematoxylin and eosin staining. ELISA assay analyzed the levels of LH, FSH, AMH, E2 and AzpAB in mice serum. The expression of Bcl-2, Bax, KI67 and PCNA in ovarian tissues was detected by Western blot analysis and KI67 expression was also determined by immunohistochemistry. The body weight and ovarian weight were decreased and the pathological results of ovarian were worsen in POF mice. The estrus was decreased in POF mice. The levels of LH, FSH and AzpAB were increased and the levels of AMH and E2 were decreased in POF mice serum. The expression of Bcl-2, KI67 and PCNA was decreased and Bax expression was increased in ovarian tissues of POF mice. Those changes affected by cyclophosphamide could be reversed by cryptotanshinone. Cryptotanshinone could decrease the granulosa cell apoptosis to restore ovarian function.

Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis.

To demonstrate multifaceted contribution of aspartate ß-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's ß-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

Trend of HIV-1 drug resistance in China: A systematic review and meta-analysis of data accumulated over 17 years (2001-2017).

BACKGROUND: The emergence and spread of HIV-1 drug resistance may compromise HIV control globally. In response to HIV/AIDS epidemic, China launched national HIV/AIDS treatment program in 2003, and started to accumulate drug resistance data since 2001. In this study we aimed to assess the level, trend and distribution of HIV-1 drug resistance during a period of 17 years from 2001 to 2017, and to characterize crucial drug resistance mutations. METHODS: We systematically reviewed 4737 studies published between January 1, 2001 and March 31, 2019 in PubMed, Embase, China National Knowledge Infrastructure (CNKI), WanFang Database, Web of Science, conference abstracts from the Chinese Medical Association and the Chinese AIDS Academic Conferences, and selected 170 studies that met our study criteria. To assess the prevalence of drug resistance in whole country or a local region, we performed pooled analyses of raw data. The transformed proportions were pooled using the inverse variance fixed effects methods or the DerSimonian-Laired random effects methods. The temporal trend of transmitted drug resistance (TDR) was determined using generalized additive model implemented in the Mgcv version 1.8 package. HIV-1 genotypic resistance was analyzed using the Stanford HIVdb algorithm. FINDINGS: We assembled 218 datasets from 170 selected studies (129 in Chinese and 41 in English), covering 21,451 ART-naïve and 30,475 ART-treated individuals with HIV-1 infection. The pooled prevalence of TDR was 3.0% (95%CI: 2.8-3.2), including 0.7% (95%CI: 0.4-1.0), 1.4% (95%CI: 1.3-1.6) and 0.5% (95%CI: 0.4-0.6) for nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI) and protease inhibitor (PI) resistance, respectively. The acquired drug resistance (ADR) prevalence was 44.7% (95%CI: 39.3-50.2), including 31.4% (95%CI: 28.2-34.6), 39.5% (95%CI: 35.6-43.5) and 1.0% (95%CI: 0.8-1.2) for NRTI, NNRTI and PI resistance, respectively. TDR and ADR prevalence had characteristic regional patterns. The worst prevalence of drug resistance occurred in Central China, and higher ADR prevalence occurred in South China than North China. TDR in whole country has risen since 2012, and this rise was driven mainly by NNRTI resistance. One NRTI-associated (M184V/I) and three NNRTI-associated (K103N/S, Y181C/I and G190A/S) mutations had high percentages in ART-naïve and ART-treated individuals, and these mutations conferred high-level resistance to 3TC, EFV and/or NVP. INTERPRETATION: These findings suggest that the current available first-line ART regimens containing 3TC and/or EFV or NVP need to be revised. In addition, scale-up of multiple viral load measurements per year and drug resistance testing prior to ART initiation are recommended. Furthermore, implementation of pre-treatment education and counseling to improve patient adherence to ART is encouraged. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (81672033, U1302224, and 81271888) and Open Research Fund Program of the State Key Laboratory of Virology of China (2019IOV002).

ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis.

BACKGROUND: Aspartate ß-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. METHODS: Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. RESULTS: Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH's ß-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. CONCLUSIONS: ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH's pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.

Genotypic Methods for HIV Drug Resistance Monitoring: The Opportunities and Challenges Faced by China.

AIDS is a globalized infectious disease. In 2014, UNAIDS launched a global project of "90-90-90" to end the HIV epidemic by 2030. The second and third 90 require 90% of HIV-1 infected individuals receiving antiretroviral therapy (ART) and durable virological suppression. However, wide use of ART will greatly increase the emergence and spreading of HIV drug resistance and current HIV drug resistance test (DRT) assays in China are seriously lagging behind, hindering to achieve virological suppression. Therefore, recommending an appropriate HIV DRT method is critical for HIV routine surveillance and prevention in China. In this review, we summarized the current existing HIV drug resistance genotypic testing methods around the world and discussed the advantages and disadvantages of these methods.

Aspartate ß-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway.

BACKGROUND: Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate ß-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. METHODS: To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's ß-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. RESULTS: ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). CONCLUSION: Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

Stress resistance and lifespan extension of Caenorhabditis elegans enhanced by peptides from mussel (Mytilus edulis) protein hydrolyzate.

Bioactive peptides derived from mussels have multiple healthcare functions. Herein, we aimed to examine the effects of mussel peptide preparation on lifespan, stress resistance, apoptosis and aging in Caenorhabditis elegans. Lifespan was determined by counting the number of surviving nematodes daily. ROS level and lipofuscin were measured using a fluorescent microscope. The mussel protein was prepared and hydrolyzed, and then fractionated by ultrafiltration. The fraction (<3 kDa) was purified by gel filtration to obtain the bioactive peptides, and the peptide sequences included in the fractions were identified, which were mostly composed of peptides with <20 amino acid residues. Mussel peptides treatment was found to significantly increase oxidative stress resistance and extend the lifespan of C. elegans. Moreover, this treatment also reduced endogenous ROS level and aging pigments accumulation in C. elegans as well as apoptosis. Collectively, these findings demonstrated that mussel peptides could contribute to healthspan extension of C. elegans through regulating mRNA expression of daf-2 and daf-16. These results highlighted the important role of mussel peptides for food and pharmaceutical industries to develop new nutraceuticals and functional foods.

PPARδ promotes tumor progression via activation of Glut1 and SLC1-A5 transcription.

Malignant cancer cell uncontrolled growth depends on the persistent nutrient availability such as glucose and amino acids, which is required for cancer cell energetic and biosynthetic pathways. As a nuclear hormone receptor, peroxisome-proliferator-activated receptor δ (PPARδ) plays a critical role in inflammation and cancer, however, it is still unclear the regulatory mechanism of PPARδ on cancer cell metabolism. Here, we found that PPARδ directly regulated neutral amino acid transporter SLC1-A5 (solute carrier family 1 member 5) and glucose transporter-1 (Glut1) gene transcription, leading to uptake of glucose and amino acid, activation of mTOR signaling, and tumor progression. In contrast, silence of PPARδ or its antagonist inhibited this event. More importantly, PPARδ promoted cancer cell metabolic reprogramming resulting in chemoresistance, which was alleviated by PPARδ antagonist. These findings revealed a novel mechanism of PPARδ-mediated tumor progression, which provided a potential strategy for cancer treatment.