Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance.

The metastasis is a multistep process in which a small proportion of cancer cells are detached from the colony to enter into blood cells for obtaining a new place for metastasis and proliferation. The metastasis and cell plasticity are considered major causes of cancer-related deaths since they improve the malignancy of cancer cells and provide poor prognosis for patients. Furthermore, enhancement in the aggressiveness of cancer cells has been related to the development of drug resistance. Metastasis of pancreatic cancer (PC) cells has been considered one of the major causes of death in patients and their undesirable prognosis. PC is among the most malignant tumors of the gastrointestinal tract and in addition to lifestyle, smoking, and other factors, genomic changes play a key role in its progression. The stimulation of EMT in PC cells occurs as a result of changes in molecular interaction, and in addition to increasing metastasis, EMT participates in the development of chemoresistance. The epithelial, mesenchymal, and acinar cell plasticity can occur and determines the progression of PC. The major molecular pathways including STAT3, PTEN, PI3K/Akt, and Wnt participate in regulating the metastasis of PC cells. The communication in tumor microenvironment can provide by exosomes in determining PC metastasis. The components of tumor microenvironment including macrophages, neutrophils, and cancer-associated fibroblasts can modulate PC progression and the response of cancer cells to chemotherapy.

Molecular panorama of therapy resistance in prostate cancer: a pre-clinical and bioinformatics analysis for clinical translation.

Prostate cancer (PCa) is a malignant disorder of prostate gland being asymptomatic in early stages and high metastatic potential in advanced stages. The chemotherapy and surgical resection have provided favourable prognosis of PCa patients, but advanced and aggressive forms of PCa including CRPC and AVPC lack response to therapy properly, and therefore, prognosis of patients is deteriorated. At the advanced stages, PCa cells do not respond to chemotherapy and radiotherapy in a satisfactory level, and therefore, therapy resistance is emerged. Molecular profile analysis of PCa cells reveals the apoptosis suppression, pro-survival autophagy induction, and EMT induction as factors in escalating malignant of cancer cells and development of therapy resistance. The dysregulation in molecular profile of PCa including upregulation of STAT3 and PI3K/Akt, downregulation of STAT3, and aberrant expression of non-coding RNAs are determining factor for response of cancer cells to chemotherapy. Because of prevalence of drug resistance in PCa, combination therapy including co-utilization of anti-cancer drugs and nanotherapeutic approaches has been suggested in PCa therapy. As a result of increase in DNA damage repair, PCa cells induce radioresistance and RelB overexpression prevents irradiation-mediated cell death. Similar to chemotherapy, nanomaterials are promising for promoting radiosensitivity through delivery of cargo, improving accumulation in PCa cells, and targeting survival-related pathways. In respect to emergence of immunotherapy as a new tool in PCa suppression, tumour cells are able to increase PD-L1 expression and inactivate NK cells in mediating immune evasion. The bioinformatics analysis for evaluation of drug resistance-related genes has been performed.

Acquired and intrinsic gemcitabine resistance in pancreatic cancer therapy: Environmental factors, molecular profile and drug/nanotherapeutic approaches.

A high number of cancer patients around the world rely on gemcitabine (GEM) for chemotherapy. During local metastasis of cancers, surgery is beneficial for therapy, but dissemination in distant organs leads to using chemotherapy alone or in combination with surgery to prevent cancer recurrence. Therapy failure can be observed as a result of GEM resistance, threatening life of pancreatic cancer (PC) patients. The mortality and morbidity of PC in contrast to other tumors are increasing. GEM chemotherapy is widely utilized for PC suppression, but resistance has encountered its therapeutic impacts. The purpose of current review is to bring a broad concept about role of biological mechanisms and pathways in the development of GEM resistance in PC and then, therapeutic strategies based on using drugs or nanostructures for overcoming chemoresistance. Dysregulation of the epigenetic factors especially non-coding RNA transcripts can cause development of GEM resistance in PC and miRNA transfection or using genetic tools such as siRNA for modulating expression level of these factors for changing GEM resistance are suggested. The overexpression of anti-apoptotic proteins and survival genes can contribute to GEM resistance in PC. Moreover, supportive autophagy inhibits apoptosis and stimulates GEM resistance in PC cells. Increase in metabolism, glycolysis induction and epithelial-mesenchymal transition (EMT) stimulation are considered as other factors participating in GEM resistance in PC. Drugs can suppress tumorigenesis in PC and inhibit survival factors and pathways in increasing GEM sensitivity in PC. More importantly, nanoparticles can increase pharmacokinetic profile of GEM and promote its blood circulation and accumulation in cancer site. Nanoparticles mediate delivery of GEM with genes and drugs to suppress tumorigenesis in PC and increase drug sensitivity. The basic research displays significant connection among dysregulated pathways and GEM resistance, but the lack of clinical application is a drawback that can be responded in future.

Rod-shaped mesoporous silica nanoparticles reduce bufalin cardiotoxicity and inhibit colon cancer by blocking lipophagy.

BACKGROUND: Bufalin (BA) is a potent traditional Chinese medicine derived from toad venom. It has shown significant antitumor activity, but its use is limited by cardiotoxicity, which necessitates innovative delivery methods, such as rod-shaped mesoporous silica nanoparticles (rMSNs). rMSNs have been extensively employed for reducing drug toxicity and for controlled or targeted drug delivery in tumor therapy. However, their potential in delivering BA has not been completely elucidated. Therefore, in this study, BA-loaded rMSNs (BA-rMSNs) were developed to investigate their potential and mechanism in impairing colon cancer cells. METHODS: rMSNs were developed via the sol‒gel method. Drug encapsulation efficiency and loading capacity were determined to investigate the advantages of the rMSN in loading BA. The antiproliferative activities of the BA-rMSNs were investigated via 5-ethynyl-2'-deoxyuridine and CCK-8. To evaluate cell death, Annexin V-APC/PI apoptotic and calcein-AM/PI double staining were performed. Western blotting, oil red O staining, and Nile red solution were employed to determine the ability of BA-rMSNs to regulate lipophagy. RESULTS: The diameter of the BA-rMSNs was approximately 60 nm. In vitro studies demonstrated that BA-rMSNs markedly inhibited HCT 116 and HT-29 cell proliferation and induced cell death. In vivo studies revealed that BA-rMSNs reduced BA-mediated cardiotoxicity and enhanced BA tumor targeting. Mechanistic studies revealed that BA-rMSNs blocked lipophagy. CONCLUSIONS: rMSNs reduced BA-mediated cardiotoxicity and impaired the growth of colon cancer cells. Mechanistically, antitumor activity depends on lipophagy.

Cell membrane-camouflaged bufalin targets NOD2 and overcomes multidrug resistance in pancreatic cancer.

AIMS: Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer. METHODS: The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo. RESULTS: CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX. Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells. CONCLUSIONS: Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.

Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma.

BACKGROUND: Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m6A regulators in hepatocellular carcinoma (HCC). METHODS: Pan-cancer genomic analysis of the crosstalk between 5mC and m6A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m6A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications. RESULTS: 5mC and m6A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients' clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m6A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME. CONCLUSIONS: Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m6A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape.

A bioinformatics analysis, pre-clinical and clinical conception of autophagy in pancreatic cancer: Complexity and simplicity in crosstalk.

Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The genomic profile alterations and dysregulated biological mechanisms commonly occur in PC. Macroautophagy/autophagy is a cell death process that is maintained at a basal level in physiological conditions, whereas its level often changes during tumorigenesis. The function of autophagy in human cancers is dual and can be oncogenic and onco-suppressor. Autophagy is a potent controller of tumorigenesis in PC. The supportive autophagy in PC escalates the growth rate of PC cells and its suppression can mediate cell death. Autophagy also determines the metastasis of PC cells, and it can control the EMT in affecting migration. Moreover, starvation and hypoxia can stimulate glycolysis, and glycolysis induction can be mediated by autophagy in enhancing tumorigenesis in PC. Furthermore, protective autophagy stimulates drug resistance and gemcitabine resistance in PC cells, and its inhibition can enhance radiosensitivity. Autophagy can degrade MHC-I to mediate immune evasion and also regulates polarization of macrophages in the tumor microenvironment. Modulation of autophagy activity is provided by silibinin, ursolic acid, chrysin and huaier in the treatment of PC. Non-coding RNAs are also controllers of autophagy in PC and its inhibition can improve therapy response in patients. Moreover, mitophagy shows dysregulation in PC, which can enhance the proliferation of PC cells. Therefore, a bioinformatics analysis demonstrates the dysregulation of autophagy-related proteins and genes in PC as biomarkers.

CXCR4 expression is elevated in TNBC patient derived samples and Z-guggulsterone abrogates tumor progression by targeting CXCL12/CXCR4 signaling axis in preclinical breast cancer model.

Environmental factors such as exposure to ionizing radiations, certain environmental pollutants, and toxic chemicals are considered as risk factors in the development of breast cancer. Triple-negative breast cancer (TNBC) is a molecular variant of breast cancer that lacks therapeutic targets such as progesterone receptor, estrogen receptor, and human epidermal growth factor receptor-2 which makes the targeted therapy ineffective in TNBC patients. Therefore, identification of new therapeutic targets for the treatment of TNBC and the discovery of new therapeutic agents is the need of the hour. In this study, CXCR4 was found to be highly expressed in majority of breast cancer tissues and metastatic lymph nodes derived from TNBC patients. CXCR4 expression is positively correlated with breast cancer metastasis and poor prognosis of TNBC patients suggesting that suppression of CXCR4 expression could be a good strategy in the treatment of TNBC patients. Therefore, the effect of Z-guggulsterone (ZGA) on the expression of CXCR4 in TNBC cells was examined. ZGA downregulated protein and mRNA expression of CXCR4 in TNBC cells and proteasome inhibition or lysosomal stabilization had no effect on the ZGA-induced CXCR4 reduction. CXCR4 is under the transcriptional control of NF-κB, whereas ZGA was found to downregulate transcriptional activity of NF-κB. Functionally, ZGA downmodulated the CXCL12-driven migration/invasion in TNBC cells. Additionally, the effect of ZGA on growth of tumor was investigated in the orthotopic TNBC mice model. ZGA presented good inhibition of tumor growth and liver/lung metastasis in this model. Western blotting and immunohistochemical analysis indicated a reduction of CXCR4, NF-κB, and Ki67 in tumor tissues. Computational analysis suggested PXR agonism and FXR antagonism as targets of ZGA. In conclusion, CXCR4 was found to be overexpressed in majority of patient-derived TNBC tissues and ZGA abrogated the growth of TNBC tumors by partly targeting the CXCL12/CXCR4 signaling axis.

Identification of a New m6A Regulator-Related Methylation Signature for Predicting the Prognosis and Immune Microenvironment of Patients with Pancreatic Cancer.

Pancreatic cancer (PC) is a malignant tumor of the digestive system that has a bad prognosis. N6-methyladenosine (m6A) is involved in a wide variety of biological activities due to the fact that it is the most common form of mRNA modification in mammals. Numerous research has accumulated evidence suggesting that a malfunction in the regulation of m6A RNA modification is associated with various illnesses, including cancers. However, its implications in PC remain poorly characterized. The methylation data, level 3 RNA sequencing data, and clinical information of PC patients were all retrieved from the TCGA datasets. Genes associated with m6A RNA methylation were compiled from the existing body of research and made available for download from the m6Avar database. The LASSO Cox regression method was used to construct a 4-gene methylation signature, which was then used to classify all PC patients included in the TCGA dataset into either a low- or high-risk group. In this study, based on the set criteria of |cor| > 0.4 and p value < 0.05. A total of 3507 gene methylation were identified to be regulated by m6A regulators. Based on the univariate Cox regression analysis and identified 3507 gene methylation, 858 gene methylation was significantly associated with the patient's prognosis. The multivariate Cox regression analysis identified four gene methylation (PCSK6, HSP90AA1, TPM3, and TTLL6) to construct a prognosis model. Survival assays indicated that the patients in the high-risk group tend to have a worse prognosis. ROC curves showed that our prognosis signature had a good prediction ability on patient survival. Immune assays suggested a different immune infiltration pattern in patients with high- and low-risk scores. Moreover, we found that two immune-related genes, CTLA4 and TIGIT, were downregulated in high-risk patients. We generated a unique methylation signature that is related to m6A regulators and is capable of accurately predicting the prognosis for patients with PC. The findings might prove useful for therapeutic customization and the process of making medical decisions.

Percutaneous full endoscopic tumourectomy of a lumbar epidural schwannoma via transforaminal approach: a case report and systematic review of the literature.

STUDY DESIGN: Report of three patients undergoing lumbar epidural schwannoma tumourectomy. Percutaneous endoscopy has been routinely used in the treatment of disk herniation but has not been reported in the management of intraspinal tumours. METHODS: Three patients diagnosed with schwannoma by imaging and pathological examination underwent percutaneous full endoscopic tumourectomy. A 5-mm incision was made, the puncture needle passed through the skin, subcutaneous tissue and the deep fascia and vertebral muscles to the intervertebral foramen area. Next, a working cannula was inserted into the lesion area. Foraminotomy was completed by trephine and microscopic power drill if the foramen was stenosed. Tumour tissue was totally removed piecemeal. After probing the nerve foramen and the nerve root satisfactorily, the working cannula was removed and the incision sutured. RESULTS: Three patients were operated successfully. Symptoms recovered in all cases and no complication or recurrence was found on follow-up. CONCLUSIONS: This case report presents a new technique for non-infiltrating extradural lumbar tumour treatment, demonstrating feasibility and safety of percutaneous full endoscopic lumbar tumourectomy.

Mutational landscape of nasopharyngeal carcinoma based on targeted next-generation sequencing: implications for predicting clinical outcomes.

BACKGROUND: The aim of this study was to draw a comprehensive mutational landscape of nasopharyngeal carcinoma (NPC) tumors and identify the prognostic factors for distant metastasis-free survival (DMFS). METHODS: A total of forty primary nonkeratinizing NPC patients underwent targeted next-generation sequencing of 450 cancer-relevant genes. Analysis of these sequencing and clinical data was performed comprehensively. Univariate Cox regression analysis and multivariate Lasso-Cox regression analyses were performed to identify factors that predict distant metastasis and construct a risk score model, and seventy percent of patients were randomly selected from among the samples as a validation cohort. A receiver operating characteristic (ROC) curve and Harrell's concordance index (C-index) were used to investigate whether the risk score was superior to the TNM stage in predicting the survival of patients. The survival of patients was determined by Kaplan-Meier curves and log-rank tests. RESULTS: The twenty most frequently mutated genes were identified, such as KMT2D, CYLD, and TP53 et al. Their mutation frequencies of them were compared with those of the COSMIC database and cBioPortal database. N stage, tumor mutational burden (TMB), PIK3CA, and SF3B1 were identified as predictors to build the risk score model. The risk score model showed a higher AUC and C-index than the TNM stage model, regardless of the training cohort or validation cohort. Moreover, this study found that patients with tumors harboring PI3K/AKT or RAS pathway mutations have worse DMFS than their wild-type counterparts. CONCLUSIONS: In this study, we drew a mutational landscape of NPC tumors and established a novel four predictor-based prognostic model, which had much better predictive capacity than TNM stage.

Mechanism of the two-dimensional WSeTe/Zr2CO2 direct Z-scheme van der Waals heterojunction as a photocatalyst for water splitting.

The direct Z-scheme van der Waals (vdW) heterojunctions based on biomimetic artificial photosynthesis are a promising strategy for enhancing photocatalytic activity. Therefore, the search for superior direct Z-scheme photocatalysts is an urgent task. Herein, we predicted the WSeTe/Zr2CO2 heterostructure as a potential direct Z-scheme photocatalyst based on density functional theory (DFT). The bands of the WSeTe/Zr2CO2 heterojunction follow a typical Type-II arrangement, where the interlayer band gap is smaller than that of the individual molecular layers, and staggered alignment of the large band-edge creates conditions that allow for a direct Z-scheme. The position of the Fermi energy levels of the two monolayers determines the formation of the built-in electric field pointing from WSeTe to Zr2CO2, promoting the desired interlayer electron-hole (e--h+) recombination and suppressing the undesired carrier recombination. Finally, in-plane biaxial strain can effectively modulate the optoelectronic properties of the catalyst, while compressive strain has a more pronounced effect on the overpotential driving force of the material. Therefore, the WSeTe/Zr2CO2 heterojunction is an effective new photocatalyst satisfying the direct Z-scheme charge transfer mechanism with its specific application.

Age in combination with gender is a valuable parameter in differential diagnosis of solid pseudopapillary tumors and pancreatic neuroendocrine neoplasm.

BACKGROUND: The clinicopathological characteristics of solid pseudopapillary tumor (SPT) and pancreatic neuroendocrine neoplasm (pNEN) are different. We, therefore, systematically investigated the performance of the clinicopathological characteristics in distinguishing SPT from pNEN. METHODS: We collected the cases from the Surveillance, Epidemiology, and End Results Program. The International Classification of Diseases for Oncology, third edition (ICD-O-3) for tumors was used to identify patients with pNEN or patients with SPT. To determine the performance of age in combination with gender in distinguishing SPT from pNEN, a nomogram was developed and the performance of this nomogram was evaluated by the receiver operating characteristic curve and the area under the curve (AUC). RESULTS: In the training cohort, 563 patients with pNENs and 30 patients with SPTs were recruited. The logistic regression and receiver operating characteristic curves suggest that age, gender, T-stage, N-stage, and M-stage could discriminate SPT and pNEN. The AUC of age, gender, T-stage, N-stage, and M-stage was 0.82, 0.75, 0.65, 0.69, and 0.70, respectively. Based on the nomogram, we observed that the AUC of age and gender is significantly high than that of the T-stage, N-stage, and M-stage. CONCLUSIONS: The present study proposes a non-invasive nomogram that could aid in the differential diagnosis of pNEN and SPT. This might help the clinicians to distinguish SPT from pNEN and choose the appropriate treatments for the patients.

The significance of anatomical variation of the inferior mesenteric artery and its branches for laparoscopic radical resection of colorectal cancer: a review.

Currently, high or low ligation of the inferior mesenteric artery (IMA) is a controversial issue in laparoscopic radical surgery for colorectal cancer. High or low ligation of the IMA has both advantages and disadvantages, and the level of ligation during the left colon and/or rectum resection has been a dilemma for surgeons. One important factor influencing the surgeon's decision to ligate the IMA in a high or low position is the anatomical type of the IMA and its branches. Some studies confirm that the anatomy of the IMA and its branches is critical to the anastomotic blood supply and, therefore, influences the choice of surgical approach (level of ligation of the IMA). However, many vascular variations in the anatomy of the IMA and its branches exist. Herein, we have summarized the anatomical types of the IMA and its branches, finding that the classification proposed by Yada et al. in 1997 is presently accepted by most scholars. Based on Yada's classification, we further summarized the characteristics of the IMA's various anatomical types as a guide for high or low ligation in radical colorectal cancer surgery.

The value of tumor deposits in evaluating colorectal cancer survival and metastasis: a population-based retrospective cohort study.

BACKGROUND: The role of tumor deposits (TDs) in TNM staging of colorectal cancer is controversial, especially the relationship with distant metastasis. PURPOSE: This study aimed to determine the effect of TDs on the survival of colorectal cancer and the occurrence of distant metastasis and to determine whether TDs (+) patients behaved similarly to stage IV patients. METHODS: A retrospective analysis of CRC patients from two large independent cohorts from the Surveillance Epidemiology and End Results (SEER) database (n = 58775) and the First Affiliated Hospital of Dalian Medical University (n = 742). RESULTS: Univariate logistic analyses revealed that TDs are an independent predictor of liver metastasis [p < 0.001; odds ratio (OR): 5.738; 95% confidence interval (CI): 3.560-9.248] in the First Affiliated Hospital of Dalian Medical University's patients. Meanwhile, TDs are also an independent predictor of isolated organ metastasis [p <0.001; odds ratio (OR): 3.028; 95% confidence interval (CI): 2.414-3.79; multiple organ metastases [p < 0.001; odds ratio (OR): 4.778; 95% confidence interval (CI): 4.109-5.556]; isolated liver metastasis [p < 0.001; odds ratio (OR): 4.395; 95% confidence interval (CI): 4.099-4.713] and isolated lung metastasis [p < 0.001; odds ratio (OR): 5.738; 95% confidence interval (CI): 3.560-9.248] in the SEER database. Multivariate analyses suggested TDs are an independent poor prognostic factor for distant metastasis (p <0.001). CONCLUSIONS: Our results have shown that compared with patients with negative TDs, CRC patients with positive TDs are more likely to develop distant metastasis. Patients categorized as T4aN2bM0 TDs (+) and T4bN2M0 TDs (+) have a similar prognosis as those with stage IV, and hence these patients should be classified as stage IV.

Pharmaceutical immunoglobulin G impairs anti-carcinoma activity of oxaliplatin in colon cancer cells.

BACKGROUND: Recent evidence proves that intravenous human immunoglobulin G (IgG) can impair cancer cell viability. However, no study evaluated whether IgG application benefits cancer patients receiving chemotherapeutics. METHODS: Influence of pharmaceutical-grade human IgG on the viability of a series of patient-derived colon cancer cell lines with and without chemotherapeutic intervention was determined. Cell death was analysed flow cytometrically. In addition, the influence of oxaliplatin and IgG on the ERK1/2-signalling pathway was evaluated by western blots. RESULTS: We evaluated the effects of pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, in combination with chemotherapeutics. We did not observe any significant effects of IgG on tumour cell viability directly; however, human IgG significantly impaired the anti-tumoral effects of oxaliplatin. Primary cancer cell lines express IgG receptors and accumulate human IgG intracellularly. Moreover, while oxaliplatin induced the activation of ERK1/2, the pharmaceutical IgG inhibited ERK1/2 activity. CONCLUSIONS: The present study demonstrates that pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, can impair the anti-carcinoma activity of oxaliplatin. These data strongly suggest that therapeutic IgG as co-medication might have harmful side effects in cancer patients. The clinical significance of these preclinical observations absolutely advises further preclinical, as well as epidemiological and clinical research.

SRPK1/AKT axis promotes oxaliplatin-induced anti-apoptosis via NF-κB activation in colon cancer.

BACKGROUND: Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown. METHODS: The expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot. RESULTS: We found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p < 0.001). SRPK1 overexpression enhanced the anti-apoptosis ability of colon cancer cells, whereas SRPK1 silencing had the opposite effect under oxaliplatin treatment. Mechanistically, SRPK1 enhances IKK kinase and IκB phosphorylation to promote NF-κB nuclear translocation to confer oxaliplatin resistance. CONCLUSIONS: Our findings suggest that SRPK1 participates in colon cancer progression and enhances the anti-apoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and thus might be a potential pharmaceutically target for colon cancer treatment.

Epidemiologic trends and prognostic risk factors of patients with pancreatic neuroendocrine neoplasms in the US: an updated population-based study.

Background: We aimed to evaluate the incidence, mortality and survival outcome for patients with pancreatic neuroendocrine neoplasms (pNEN). Methods: Patients with pNEN were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Incidence, mortality and average annual percentage change (AAPC) were calculated using SEER stat 8.3.6 and Joinpoint software. Survival outcome was estimated using Kaplan-Meier and Cox proportional hazard model. Results: During 2000-2016, the incidence of pNEN significantly rose from 0.2647 to 1.0618 per 100,000 persons with an AAPC of 9.4; AAPC of mortality was 6.7. Prognostic improvement was revealed in 2010-2016, but not for late-stage pNEN, which had the highest risk of death. Conclusion: Efforts to improve prognosis of pNEN patients must focus on not only early detection, but also on improving therapy for late-stage disease.

Revealing potential lipid biomarkers in clear cell renal cell carcinoma using targeted quantitative lipidomics.

BACKGROUND: The high drug resistance and metabolic reprogramming of clear cell renal cell carcinoma (ccRCC) are considered responsible for poor prognosis. In-depth research at multiple levels is urgently warranted to illustrate the lipid composition, distribution, and metabolic pathways of clinical ccRCC specimens. METHODS: In this project, a leading-edge targeted quantitative lipidomic study was conducted using 10 pairs of cancerous and adjacent normal tissues obtained from ccRCC patients. Accurate lipid quantification was performed according to a linear equation calculated using internal standards. Qualitative and quantitative analyses of lipids were performed with multiple reaction monitoring analysis based on ultra-performance liquid chromatography (UPLC) and mass spectrometry (MS). Additionally, a multivariate statistical analysis was performed using data obtained on lipids. RESULTS: A total of 28 lipid classes were identified. Among them, the most abundant were triacylglycerol (TG), diacylglycerol (DG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). Cholesteryl ester (CE) was the lipid exhibiting the most considerable difference between normal samples and tumor samples. Lipid content, chain length, and chain unsaturation of acylcarnitine (CAR), CE, and DG were found to be significantly increased. Based on screening for variable importance in projection scores ≥1, as well as fold change limits between 0.5 and 2, 160 differentially expressed lipids were identified. CE was found to be the most significantly upregulated lipid, while TG was observed to be the most significantly downregulated lipid. CONCLUSION: Based on the absolute quantitative analysis of lipids in ccRCC specimens, it was observed that the content and change trends varied in different lipid classes. Upregulation of CAR, CE, and DG was observed, and analysis of changes in the distribution helped clarify the causes of lipid accumulation in ccRCC and possible carcinogenic molecular mechanisms. The results and methods described herein provide a comprehensive analysis of ccRCC lipid metabolism and lay a theoretical foundation for cancer treatment.

Tailoring terahertz surface plasmon wave through free-standing multi-walled carbon nanotubes metasurface.

Surface plasmons have a fundamental role in the dynamics of photon-electron interactions and in optical metamaterials. Terahertz (THz) time-domain spectroscopy was used to characterize the complex dielectric constant, index of refraction, and conductivity of super-aligned, free-standing, multi-walled carbon nanotube films over the range 0.2-2.5 THz. These complex parameters were in excellent agreement with Maxwell-Garnett and Drude-Lorentz models. In addition, surface plasmon excitations in engineered, subwavelength, multi-walled carbon nanotube metasurfaces were examined. The observed surface plasmon resonances, reproduced by simulation, could be changed over the THz frequency range by altering the lattice constant of the arrays. The THz transmission was enhanced at the resonance peak. Overall, the results indicate potential applications for THz metasurfaces based on super-aligned, free-standing multi-walled carbon nanotubes.