The Value of Percutaneous Contrast-Enhanced Ultrasound in Sentinel Lymph Node Identification, Metastatic Status and Burden Diagnosis in Early Breast Cancer.

OBJECTIVE: The aim of this study was to evaluate the value of percutaneous contrast-enhanced ultrasound (PCEUS) in the identification and characterization of sentinel lymph node (SLN). METHODS: A total of 102 breast cancer patients were collected and underwent preoperative PCEUS, which was used to identify SLN and lymphatic drainage. SLNs were classified into 4 enhancement patterns, including 6 subtypes: homogeneous (I), featured inhomogeneous (II) including inhomogeneous hypoenhancement (IIa) and annular or semi-annular enhancement (IIb), focal filling defect (III) including filling defect area < 50% (IIIa) and filling defect area ≥ 50% (IIIb), and no enhancement (IV). The enhancement patterns of SLNs were compared with the final pathological diagnosis. RESULTS: The identification rate of SLNs using PCEUS was 100% (102/102); the rate of identification of LCs was 100% (102/102), and the coincidence rate was 98.0% (100/102). Four lymphatic drainage patterns (LDPs) including 5 subtypes were found: single LC/single SLN(74.5%), multiple LCs/ single SLN (13.7%) including 2 subtypes:2 LCs/1 SLN and 3 LCs/1 SLN, single LC/multiple SLNs (7.8%), and multiple LCs/multiple SLNs (3.9%). A total of 86.3% (44/51) of patients without axillary metastasis could be safely selected for types I, IIa, and IIb, while the axillary metastasis rates of types III and IV were 74.4% and 87.5%, respectively (P < .001). Compared with grayscale US, the PCEUS significant improvement in diagnosing metastatic SLNs (.794 versus .579, P < .001). For the SLN metastatic burden, Types I, IIa, IIb, and IIIa had ≤2 SLNs metastases, with a pathological coincidence rate of (64/67, 95.5%), and types IIIb and IV had >2 SLNs metastases, with a pathological coincidence rate of (25/35, 71.4%) (P < .001). The AUC of PCEUS for the diagnosis of SLN metastatic status and burden was .794 and .879, respectively (P < .001). CONCLUSION: PCEUS has a high identification rate for SLN and has good potential for diagnosing SLN metastatic status and burden by enhancement patterns.

Exosomal miR-19a decreases insulin production by targeting Neurod1 in pancreatic cancer associated diabetes.

BACKGROUND: New onset diabetes mellitus demonstrates a roughly correlation with pancreatic cancer (PaC), which is unique in PaC and was named as PaC-induced DM, but the inner mechanism remains unclear. Exosomes mediate intercellular communication and bearing microRNAs might be direct constituent of effect in target cells. METHODS AND RESULTS: The isolated exosomes from PaC cells were used to treat pancreatic ß cells or the primary mice islets, and the glucose stimulated insulin secretions were measured. We validated the exosomal miR-19a from PaC cells to be an important mediator in the down regulation of insulin secretion by targeting Neurod1, the validated gene involved in insulin secretion, by using the quantitative real-time PCR, western blot, and promoter luciferase activity. The relative insulin, cAMP and Ca2+ expressions were also assayed to verify the inverse correlation between cancerous miR-19a and pancreatic islets Neurod1. CONCLUSIONS: Our study indicated that signal changes between cancer cells and ß cells via exosomes might be important in the pathogenesis of PaC-induced DM and supplemented the pathogenesis of PaC-induced DM and provide a possible access of PaC screening strategy.

Identification and Comparison of Constituents of Aurantii Fructus and Aurantii Fructus Immaturus by UFLC-DAD-Triple TOF-MS/MS.

Although Aurantii Fructus (AF) and Aurantii Fructus Immaturus (AFI) are both the fruits of the same rutaceae plant at different stages of growth, they exert similar yet distinct clinical effects. The chemical composition is crucial for quality control as well as therapeutic application. To address this concern, it is significant to evaluate the similarities and differences of the constituents in both AF and AFI. The extract of AF and AFI were comprehensively analyzed by ultra fast liquid chromatography-photodiode array detector-triple-time of flight-tandem mass spectrometry (UFLC-DAD-Triple TOF-MS/MS). Among the 40 compounds detected, 19 metabolites were detected in both the AF and AFI; whereas 13 compounds were only detected in AF and five constituents were exclusively detected in AFI. In particular, even in AFI, three compounds were only identified in AFI (Citrus aurantium' L. and its cultivar). Among the 18 compounds confirmed by standard database, 13 compounds were reported in AF and AFI for the first time. Furthermore, the distinction was also revealed by the content of naringin, hesperidin, neohesperidin, and synephrine. The study directly contributed to the similarities and differences of AF and AFI. Herein, similarities and the differences in chemical profiles of AF and AFI could explain the current clinical applications.

MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1.

Intestinal inflammation is characterized by epithelial disruption, leading to the loss of barrier function, recruitment of immune cells, and host immune responses to gut microbiota. PepT1, a di/tripeptide transporter that uptakes bacterial products, is up-regulated in inflamed colon tissue, which implies its role in bacterium-associated intestinal inflammation. Although microRNA (miRNA)-mediated gene regulation has been found to be involved in various processes of inflammatory bowel disease (IBD), the biological function of miRNAs in the pathogenesis of IBD remains to be explored. In this study we detected miRNA expression patterns in colon tissues during colitis and investigated the mechanism underlying the regulation of colonic PepT1 by miRNAs. We observed an inverse correlation between PepT1 and miR-193a-3p in inflamed colon tissues with active ulcerative colitis, and we further demonstrated that miR-193a-3p reduced PepT1 expression and activity as a target gene and subsequently suppressed the NF-κB pathway. Intracolonic delivery of miR-193a-3p significantly ameliorated dextran sodium sulfate-induced colitis, whereas the overexpression of colonic PepT1 via PepT1 3'-untranslated region mutant lentivirus vector abolished the anti-inflammatory effect of miR-193a-3p. Furthermore, antibiotic treatment eliminated the difference in the dextran sodium sulfate-induced inflammation between the presence and absence of miR-193a-3p. These findings suggest that miR-193a-3p regulation of PepT1 mediates the uptake of bacterial products and is a potent mechanism during the colonic inflammation process. Overall, we believe miR-193a-3p may be a potent regulator of colonic PepT1 for maintaining intestinal homeostasis.

Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAF) are a major constituent of the pancreatic cancer microenvironment and that the meaning is as intended. Pancreatic cancer cells can induce normal fibroblasts to convert into CAF and, reciprocally, CAF promote tumor invasions and proliferations. The mechanism of the conversion from normal fibroblasts (NF) to CAF remains unclear. MicroRNA are short non-coding RNA involved in the post-transcription gene regulation, which have been defined as an imperative controller in tumor invasions, proliferations and colony formations. Microvesicles (MV) have been proved to be an important mediator of intercellular communication and can selectively transport secreted microRNA from a donor cell into a recipient cell. In this study, we isolated primary pancreatic fibroblasts from wild type C57 mice and co-cultured them with pancreatic cancer cell lines, BxPC-3 and SW1990, and observed the conversion from NF to CAF, or at least CAF-like cells. This phenomenon could also be replicated in primary fibroblasts treated with MV separated from a cancer cell media. We identified that miR-155 was upregulated in PaC-derived MV and we confirmed that normal fibroblasts could convert into CAF after MV containing miR-155 had been taken up. TP53INP1 is a target of miR-155 in fibroblasts and a downregulation of TP53INP1 protein levels could contribute to the fibroblasts' activation. These results indicated that pancreatic cancer cells might reprogram normal adjacent fibroblasts into CAF by means of secreted MV containing miR-155. Targeting the circulating microRNA might be a potential therapy for malignant tumors.

Predictive value for axillary lymph node metastases in early breast cancer: Based on contrast-enhanced ultrasound characteristics of the primary lesion and sentinel lymph node.

OBJECTIVE: To evaluate the value of contrast-enhanced ultrasound (CEUS) characteristics based on primary lesion combined with lymphatic contrast-enhanced ultrasound (LCEUS) patterns of SLN in predicting axillary lymph node metastasis (ALNM) with T1-2N0 breast cancer. METHODS: A retrospective study was conducted in 118 patients with clinically confirmed T1-2N0 breast cancer. Conventional ultrasound (CUS) and CEUS characteristics of the primary lesion and enhancement patterns of SLN were recorded. The risk factors associated with ALNM were selected by univariate and binary logistic regression analysis, and the receiver operating characteristic (ROC) curve was drawn for the evaluation of predictive ALNM metastasis performance. RESULTS: Univariate analysis showed that age, HER-2 status, tumor size, nutrient vessels, extended range of enhancement lesion, and the enhancement patterns of SLN were significant predictive features of ALNM. Further binary logistic regression analysis indicated that the extended range of enhancement lesion (p <  0.001) and the enhancement patterns of SLN (p <  0.001) were independent risk factors for ALNM. ROC analysis showed that the AUC of the combination of these two indicators for predicting ALNM was 0.931 (95% CI: 0.887-0.976, sensitivity: 75.0%, specificity: 99.8%). CONCLUSION: The CEUS characteristics of primary lesion combined with enhancement patterns of SLN are highly valuable in predicting ALNM and can guide clinical axillary surgery decision-making in early breast cancer.

Inhibition of DNMT1 attenuates experimental food allergy.

BACKGROUND: The treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1). METHODS: Ovalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35+ regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches. RESULTS: FA mice had a lower frequency of IL-35+ Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA. CONCLUSIONS: The elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1.

Interaction Between Belonolaimus longicaudatus and Helicotylenchus pseudorobustus on Bermudagrass and Seashore Paspalum Hosts.

Belonolaimus longicaudatus and Helicotylenchus pseudorobustus are among the most common nematode parasites of turfgrasses in Florida. Bermudagrass (Cynodon dactylon × C. transvaalensis) and seashore paspalum (Paspalum vaginatum) are the two turf species most commonly used on Florida golf courses. This paper explores the interactions between B. longicaudatus and H. pseudorobustus on bermudagrass and seashore paspalum hosts. Data collected from thousands of nematode samples submitted to the Florida Nematode Assay Lab over a 8-yr period revealed a negative relationship between B. longicaudatus and H. pseudorobustus on bermudagrass, but not seashore paspalum. In a multi-year field plot experiment using multiple cultivars of bermudagrass, and seashore paspalum B. longicaudatus and H. pseudorobustus were negatively related on both turf species. Greenhouse trials where multiple cultivars of both turf species were inoculated with different combinations of B. longicaudatus and H. pseudorobustus found that each nematode species was inhibitory to the other on both host species. Belonolaimus longicaudatus and H. pseudorobustus clearly impact each other on turfgrass hosts, although the mechanism of the nematode-nematode interactions is unknown.

MSMFN: An Ultrasound Based Multi-Step Modality Fusion Network for Identifying the Histologic Subtypes of Metastatic Cervical Lymphadenopathy.

Identifying squamous cell carcinoma and adenocarcinoma subtypes of metastatic cervical lymphadenopathy (CLA) is critical for localizing the primary lesion and initiating timely therapy. B-mode ultrasound (BUS), color Doppler flow imaging (CDFI), ultrasound elastography (UE) and dynamic contrast-enhanced ultrasound provide effective tools for identification but synthesis of modality information is a challenge for clinicians. Therefore, based on deep learning, rationally fusing these modalities with clinical information to personalize the classification of metastatic CLA requires new explorations. In this paper, we propose Multi-step Modality Fusion Network (MSMFN) for multi-modal ultrasound fusion to identify histological subtypes of metastatic CLA. MSMFN can mine the unique features of each modality and fuse them in a hierarchical three-step process. Specifically, first, under the guidance of high-level BUS semantic feature maps, information in CDFI and UE is extracted by modality interaction, and the static imaging feature vector is obtained. Then, a self-supervised feature orthogonalization loss is introduced to help learn modality heterogeneity features while maintaining maximal task-consistent category distinguishability of modalities. Finally, six encoded clinical information are utilized to avoid prediction bias and improve prediction ability further. Our three-fold cross-validation experiments demonstrate that our method surpasses clinicians and other multi-modal fusion methods with an accuracy of 80.06%, a true-positive rate of 81.81%, and a true-negative rate of 80.00%. Our network provides a multi-modal ultrasound fusion framework that considers prior clinical knowledge and modality-specific characteristics. Our code will be available at: https://github.com/RichardSunnyMeng/MSMFN.

Ultrasound contrast-enhanced patterns of sentinel lymph nodes: predictive value for nodal status and metastatic burden in early breast cancer.

Background: In the post-Z0011 era, sentinel lymph node (SLN) status and metastatic burden determine whether axillary management entails conservative sentinel lymph node biopsy (SLNB) or radical axillary lymph node dissection (ALND) in breast cancer patients. However, SLN status and metastatic burden cannot be evaluated preoperatively in clinical practice. This study explored the predictive value of contrast-enhanced ultrasound (CEUS) patterns of SLN to assess the nodal status and metastatic burden in early breast cancer patients. Methods: A retrospective study was conducted on 88 consecutive patients who were diagnosed with clinical T1-2N0 breast cancer between December 2020 and November 2021 at the Lanzhou University Second Hospital and scheduled for SLNB. Preoperative CEUS was performed to confirm the location and enhancement pattern of the SLN, and the conventional ultrasonic characteristics of the primary breast lesions and SLN were recorded. Intraoperative localized SLN and postoperative pathological results were used as the gold standard for comparison with preoperative ultrasound findings. Results: CEUS successfully identified at least 1 SLN in 88 patients, with a total of 118 SLNs identified in the entire cohort. Univariate analysis showed that lesion size, blood flow grade, SLN longitudinal diameter, cortical thickness, and enhancement pattern were significant predictive features of SLN metastasis. Further multiple regression analysis indicated that the enhancement pattern of the SLN was an independent risk factor for SLN metastasis, with a sensitivity and a specificity of 84.2% (32/38) and 80.0% (40/50), respectively. Meanwhile, the SLN enhancement pattern could predict the lymph node metastasis burden (P<0.001). In patients presenting with a type I (homogeneous enhancement) or type II (heterogeneous enhancement) SLN, 91.5% (65/71) had ≤2 positive SLNs, whereas in patients with a type III (no enhancement) SLN, 70.6% (12/17) had >2 metastatic nodes. Conclusions: The contrast-enhanced pattern of the SLN is an independent risk factor for SLN status. Patients presenting with a type I or type II SLN enhanced pattern are unlikely to have high-burden metastases detected at their final surgical treatment and omission of ALND may be appropriate.

Contrast-enhanced ultrasound demonstrates greater adjuvant potential: past, current status, and future applications in Hepatocellular carcinoma early diagnosis.

Hepatocellular carcinoma (HCC) has an atypical onset of clinical symptoms and a rapid tumor progression. The majority of patients with HCC are already in the late stages of the disease when they are diagnosed, limiting them to the best available treatments. Contrast-enhanced ultrasound (CEUS) has achieved significant advances in the diagnosis of HCC, including the detection of small lesions, the investigation of more beneficial contrast agents, and the use of CEUS-based radiomics. The purpose of this review is to discuss the relevant research and future challenges of CEUS in the early detection of HCC, to advise more accurate therapy.

Variants of a putative baseplate wedge protein extend the host range of Pseudomonas phage K8.

BACKGROUND: Narrow host range is a major limitation for phage applications, but phages can evolve expanded host range through adaptations in the receptor-binding proteins. RESULTS: Here, we report that Pseudomonas phage K8 can evolve broader host range and higher killing efficiency at the cost of virion stability. Phage K8 host range mutant K8-T239A carries a mutant version of the putative baseplate wedge protein GP075, termed GP075m. While phage K8 adsorbs to hosts via the O-specific antigen of bacterial LPS, phage K8-T239A uses GP075m to also bind the bacterial core oligosaccharide, enabling infection of bacterial strains resistant to K8 infection due to modified O-specific antigens. This mutation in GP075 also alters inter-protein interactions among phage proteins, and reduces the stability of phage particles to environmental stressors like heat, acidity, and alkalinity. We find that a variety of mutations in gp075 are widespread in K8 populations, and that the gp075-like genes are widely distributed among the domains of life. CONCLUSION: Our data show that a typical life history tradeoff occurs between the stability and the host range in the evolution of phage K8. Reservoirs of viral gene variants may be widely present in phage communities, allowing phages to rapidly adapt to any emerging environmental stressors. Video Abstract.

Risk Factors for Esophageal Squamous Cell Carcinoma in Patients with Head and Neck Squamous Cell Carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is a common second primary neoplasia in patients with a history of head and neck squamous cell carcinoma (HNSCC). The aim of this study was to provide further information and novel insights into the risk factors for ESCC in patients with HNSCC. Methods: We retrospectively analyzed 98 HNSCC patients diagnosed from 2007 to 2017, 30 HNSCC patients suffering from ESCC, who had undergone endoscopic examination because of positive imaging examinations or symptoms, and 68 HNSCC patients who had no ESCC occurrence for at least six years post-HNSCC diagnosis. Associated clinicopathological data and lifestyle information of the ESCC group and the without ESCC group were collected, and a case-control study of risk factors was analyzed between the two groups. Results: The majority (83.4%) of the cases with HNSCC esophageal cancers were male patients over 50 years. We established that 93.75% (30/32) of the ESCC occurred within six years after HNSCC diagnosis. HNSCC location, stage, and radiotherapy history had no significant association with the development of ESCC. High Ki67 labeling index (Ki67 LI) (>46) patients tended to be 3.1 times (95% CI = 1.3-7.6) more likely to develop ESCC compared to low Ki67 LI (≤45) patients (P < 0.05). Drinkers with alcohol flushing response were at a 3.3 times higher risk to have ESCC (95% CI = 1.0-10.4) than drinkers without flush response (P < 0.05). Conclusions: HNSCC patients, especially drinkers with an alcohol flushing response, as well as those with high Ki67 LI of HNSCC tissue, were more likely to develop ESCC.

Anti-tumor effects of P-LPK-CPT, a peptide-camptothecin conjugate, in colorectal cancer.

To explore highly selective targeting molecules of colorectal cancer (CRC) is a challenge. We previously identified a twelve-amino acid peptide (LPKTVSSDMSLN, namely P-LPK) by phage display technique which may specifically binds to CRC cells. Here we show that P-LPK selectively bind to a panel of human CRC cell lines and CRC tissues. In vivo, Gallium-68 (68Ga) labeled P-LPK exhibits selective accumulation at tumor sites. Then, we designed a peptide-conjugated drug comprising P-LPK and camptothecin (CPT) (namely P-LPK-CPT), and found P-LPK-CPT significantly inhibits tumor growth with fewer side effects in vitro and in vivo. Furthermore, through co-immunoprecipitation and molecular docking experiment, the glutamine transporter solute carrier 1 family member 5 (SLC1A5) was identified as the possible target of P-LPK. The binding ability of P-LPK and SLC1A5 is verified by surface plasmon resonance and immunofluorescence. Taken together, P-LPK-CPT is highly effective for CRC and deserves further development as a promising anti-tumor therapeutic for CRC, especially SLC1A5-high expression type.

Field Responses of Bermudagrass and Seashore paspalum Cultivars to Sting and Spiral Nematodes.

Belonolaimus longicaudatus and Helicotylenchus spp. are damaging nematode species on bermudagrass (Cynodon spp.) and seashore paspalum (Paspalum vaginatum) in sandy soils of the southeastern United States. Eight bermudagrass and three seashore paspalum cultivars were tested for responses to both nematode species in field plots for two years in Florida. Soil samples were taken every three months and nematode population densities in soil were quantified. Turfgrass aboveground health was evaluated throughout the growing season. Results showed that all bermudagrass cultivars, except TifSport, were good hosts for B. longicaudatus, and all seashore paspalum cultivars were good hosts for H. pseudorobustus. Overall, bermudagrass was a better host for B. longicaudatus while seashore paspalum was a better host for H. pseudorobustus. TifSport bermudagrass and SeaDwarf seashore paspalum cultivars supported the lowest population densities of B. longicaudatus. Seashore paspalum had a higher percent green cover than bermudagrass in the nematode-infested field. Nematode intolerant cultivars were identified.

Characteristics of esophageal cancer in patients with head and neck squamous cell carcinoma.

BACKGROUND: We investigated the clinicopathological features of esophageal cancer in patients with a history of head and neck squamous cell carcinoma (HNSCC) with the intention of providing information regarding the characteristics of these patients. METHODS: A retrospective study was performed in 32 cases of esophageal cancer with HNSCC who were diagnosed using upper gastrointestinal endoscopy between 2007 to 2017. Synchronous carcinoma (SC) group and metachronous carcinoma (MC) group was established based on whether esophageal cancer was diagnosed within 6 months after HNSCC diagnosis. The clinicopathological features of esophageal cancer and HNSCC, as well as follow-up treatment and survival, were analyzed in esophageal cancer patients in both groups. RESULTS: There were 8 cases of 8 patients (7 males and 1 female) in the SC group and 24 cases of 22 patients (21 males and 1 female) in the MC group. The majority of esophageal cancer of HNSCC were male patients aged 50-69 years. The average interval time between diagnosis of esophageal cancer and HNSCC was 36.0±39.2 months (3.25±2.19 months for the SC group and 46.90±39.73 months for the MC group). Ninety-three-point-seven-five percent (30/32) of the patients had esophageal cancer within 6 years after HNSCC. The proportion of early esophageal cancer and successful surgical treatment in the SC group was significantly higher compared to the MC group (P<0.05). CONCLUSIONS: Detection of esophageal cancer should be prioritized in HNSCC patients.

YTHDC1-mediated augmentation of miR-30d in repressing pancreatic tumorigenesis via attenuation of RUNX1-induced transcriptional activation of Warburg effect.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a malnourished environment; however, little is known about the mechanisms by which PDAC cells actively promote aerobic glycolysis to maintain their metabolic needs. Gene Expression Omnibus (GEO) was used to identify differentially expressed miRNAs. The expression pattern of miR-30d in normal and PDAC tissues was studied by in situ hybridization. The role of miR-30d/RUNX1 in vitro and in vivo was evaluated by CCK8 assay and clonogenic formation as well as transwell experiment, subcutaneous xenograft model and liver metastasis model, respectively. Glucose uptake, ATP and lactate production were tested to study the regulatory effect of miR-30d/RUNX1 on aerobic glycolysis in PDAC cells. Quantitative real-time PCR, western blot, Chip assay, promoter luciferase activity, RIP, MeRIP, and RNA stability assay were used to explore the molecular mechanism of YTHDC1/miR-30d/RUNX1 in PDAC. Here, we discover that miR-30d expression was remarkably decreased in PDAC tissues and associated with good prognosis, contributed to the suppression of tumor growth and metastasis, and attenuation of Warburg effect. Mechanistically, the m6A reader YTHDC1 facilitated the biogenesis of mature miR-30d via m6A-mediated regulation of mRNA stability. Then, miR-30d inhibited aerobic glycolysis through regulating SLC2A1 and HK1 expression by directly targeting the transcription factor RUNX1, which bound to the promoters of the SLC2A1 and HK1 genes. Moreover, miR-30d was clinically inversely correlated with RUNX1, SLC2A1 and HK1, which function as adverse prognosis factors for overall survival in PDAC tissues. Overall, we demonstrated that miR-30d is a functional and clinical tumor-suppressive gene in PDAC. Our findings further uncover that miR-30d is a novel target for YTHDC1 through m6A modification, and miR-30d represses pancreatic tumorigenesis via suppressing aerobic glycolysis.

Pancreatic cancer-derived exosomal microRNA-19a induces ß-cell dysfunction by targeting ADCY1 and EPAC2.

New-onset diabetes mellitus has a rough correlation with pancreatic cancer (PaC), but the underlying mechanism remains unclear. This study aimed to explore the exosomal microRNAs and their potential role in PaC-induced ß-cell dysfunction. The pancreatic ß cells were treated with isolated exosomes from PaC cell lines, SW1990 and BxPC-3, before measuring the glucose-stimulated insulin secretion (GSIS), validating that SW1990 and BxPC-3 might disrupt GSIS of both ß cell line MIN6 and primary mouse pancreatic islets. The difference in expression profiles between exosomes and exosome-free medium of PaC cell lines was further defined, revealing that miR-19a secreted by PaC cells might be an important signaling molecule in this process. Furthermore, adenylyl cyclase 1 (Adcy1) and exchange protein directly activated by cAMP 2 (Epac2) were verified as the direct targets of exogenous miR-19a, which was involved in insulin secretion. These results indicated that exosomes might be an important mediator in the pathogenesis of PaC-DM, and miR-19a might be the effector molecule. The findings shed light on the pathogenesis of PaC-DM.

Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2.

WHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in OS patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What's more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.

Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway.

Exploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway.