Pain nursing for gynecologic cancer patients.

Gynecological malignancy remains a prevalent cause of mortality among women. Chronic cancer pain, as a severe complication of malignancy and its therapies, accounts for a substantial burden of physical and psychological distress in affected patients. Accordingly, early identification, assessment, and standardized management of such pain are crucial in the prevention or delay of its progression. In the present review, we provide a comprehensive overview of the pathological factors that contribute to pain in patients with gynecological malignancy while highlighting the underlying mechanisms of pain in this population. In addition, we summarize several treatment modalities targeting pain management in gynecologic cancer patients, including surgery, radiotherapy, and chemotherapy. These interventions are crucial for tumor elimination and patient survival. Chronic cancer pain exerts a significant impact on wellbeing and quality of life for patients with gynecologic cancer. Therefore, our review emphasizes the importance of addressing this pain and its psychological sequelae and advocates for a multidisciplinary approach that encompasses nursing and psychological support. In summary, this review offers valuable insights into the pathological factors underlying pain, reviews pain management modalities, and stresses the critical role of early intervention and comprehensive care in enhancing the quality of life of these patients.

CircRNA-CIRH1A Promotes the Development of Osteosarcoma by Regulating PI3K/AKT and JAK2/STAT3 Signaling Pathways.

Osteogenic sarcoma (OS), one of the mesenchymal tumors with a high degree of malignancy, mainly occurs in the metaphysis of the long bones and around the knee joints in children and adolescents. The poor diagnosis in patients with OS can be attributed to the lack of early clinical symptoms, although the growth of tumor mass gradually results in severe pain and systemic symptoms. The mechanisms underlying the pathogenesis of OS are not fully understood. Thus, identifying early diagnostic biomarkers and novel targets involved in the progression of OS is of critical significance in the management of OS. CircRNA is a class of non-coding RNAs characterized by the close-loop structure and increased stability, which are implicated in the regulation of cell proliferation, differentiation, migration, and apoptosis. Moreover, circRNAs also play significant roles in aging and chronic disorders, such as cancer and cardiovascular diseases. Accordingly, we reported the upregulation of circRNA-CIRH1A in OS tissues and cell lines. Silencing circRNA-CIRH1A in OS cell lines (U2OS, HOS, Saos-2, and MG-63) could inhibit the cell proliferation, invasion, migration, and apoptosis, which was also validated in xenograft tumorigenesis mouse model. We further demonstrated that circRNA-CIRH1A sponged miR-1276, which subsequently disrupted the effect of miR-1276 on PI3K/AKT and JAK2/STAT3 signaling pathways. Together, our study revealed the oncogenic role of circRNA-CIRH1A in OS, and identified miR-1276/ PI3K-AKT and JAK2-STAT3 signaling axis as the key downstream mediators of circRNA-CIRH1A.

Enhanced recovery of postoperative nursing for single-port thoracoscopic surgery in lung cancer patients.

Lung cancer is a common clinical malignant tumor, and the number of new lung cancer patients is increasing year by year. With the advancement of thoracoscopy technology and equipment, the scope of application of minimally invasive surgery has expanded to almost all types of lung cancer resection, making it the mainstream lung cancer resection surgery. Single-port thoracoscopic surgery provides evident advantages in terms of postoperative incision pain since only a single incision is required, and the surgical effect is similar to those of multi-hole thoracoscopic surgery and traditional thoracotomy. Although thoracoscopic surgery can effectively remove tumors, it nevertheless induces variable degrees of stress in lung cancer patients, which eventually limit lung function recovery. Rapid rehabilitation surgery can actively improve the prognosis of patients with different types of cancer and promote early recovery. This article reviews the research progress on rapid rehabilitation nursing in single-port thoracoscopic lung cancer surgery.

PD-1 blockade and lenalidomide combination therapy for chronic active Epstein-Barr virus infection.

OBJECTIVES: Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T-or NK-cell lymphoproliferative diseases. It is a disease with poor outcome. Almost all current therapies are ineffective except of allogeneic hematopoietic stem cell transplantation. METHODS: We investigated the efficacy and safety of programmed death 1 (PD-1) blockade (Sintilimab), combined with lenalidomide, which is an immunomodulatory drug, in an open-label, single-center, prospective study involving CAEBV patients. PD1 blockade 2mg/kg was given every two weeks by intravenous infusion on day 1, and lenalidomide 5mg (age<18 years)/10mg (age ≥ 18 years) was given orally once a day on day 1-14. RESULTS: As of Nov 15, 2020, 34 patients were enrolled. As of the Feb 1, 2021 analysis cut-off date, 24 cases completed at least 3 courses and were assessed for efficacy. The overall response rate is 54.2% (13/24, 45.8% complete response; 8.3% partial response). EBV-DNA copies in PBMC decreased significantly (p = 0.002). The proportion of CD8+T cells in lymphocytes increased (p = 0.007). The comparative analysis between response group and non-response group showed the proportion of Effector Memory CD8+ T cells and cytokines of CTLs activation (IFN-γ, CD27, CD30, MIG, IP-10) increased significantly in Response-group after treatment. Whole-exome sequencing generated from peripheral blood and saliva samples reveal that Non-Response group had a higher somatic mutational load of copy number variation in background. With a median follow-up time of 17.8 months, 22 of 24 patients were alive with an estimated survival probability of 91.3% at 1 year. All 34 patients were assessed for safety evaluation. The possible drug-related adverse events were reported in 17 (50%) patients. CONCLUSIONS: PD-1 blockade combined with lenalidomide was an effective and safe therapy for CAEBV patients. The significant therapeutic effect and the different characteristics between response and non-response group, provides a possible predictive value for CAEBV treatment option.

Application and clinical efficacy of Sufu medical chitosan hydrogel dressing in radiation skin damage caused by radiotherapy for cervical cancer.

Objectives: To investigate the benefits of Sufu medical chitosan hydrogel dressing(Sufu) in the prevention and control of radiation skin damage during radiotherapy for cervical cancer as a combined modality. Methods: Ninety-seven cervical cancer patients who underwent radiotherapy at the Cancer Hospital of China Medical University between May 2017 and November 2018 were recruited according to given inclusion and exclusion criteria. The patients were assigned to a control group (n=48, washing the perineal area with normal saline) and an observation group (n=49, application of Sufu onto the site of radiotherapy in addition to washing the perineal area with normal saline). The treatment regimens for the two groups continued until the end of radiotherapy. A comparison of the RTOG (Radiation Therapy Oncology Group) grading of acute radiation-induced skin reactions (ARISRs), pain intensity (measured by the verbal rating scale (VRS)) and post-treatment wound healing was drawn between the two groups. Results: In the observation group, 81.6% (40/49) of the patients had radiation dermatitis, which was significantly lower than the incidence rate (95.8%, 46/48) in the control group (P <0.05). The observation group was at higher risk of radiation dermatitis when given a high radiation dose, while the control group was more likely to have radiation dermatitis when administered with a moderate radiation dose (P <0.05). The median time of occurrence of pain and the median time of onset of skin reactions were significantly later in the observation group as compared with the control group (P <0.05, respectively). In the observation group, the pain relief rate was 92.50% at Day-3, and the wound healing rate was 95.0% at Day-7, significantly higher than in the control group (73.9% and 80.4%) (P <0.05, respectively). Conclusions: During radiotherapy for cervical cancer, Sufu can effectively prevent and control radiation-induced skin and mucous membrane damage, delay the onset of radiation dermatitis and substantially reduce the incidence rate, relieve radiation dermatitis and pain and promote wound healing.

Rs420137, rs386360 and rs7763726 polymorphisms in fibronectin type III domain containing 1 are associated with susceptibility to coronary heart disease: Analysis in the Han population.

Background: Numerous genetic studies have shown that genes are related to the pathogenesis of coronary heart disease (CHD). The main aim of this study was to confirm whether fibronectin type III domain containing 1 (FNDC1) polymorphisms correlate with the risk of CHD. Methods: In this study, in order to assess the association between three FNDC1 single nucleotide polymorphisms (SNPs) and the risk of CHD, we conducted a case-control study involving 630 patients with CHD and 568 healthy controls using Agena MassARRAY (Agena Bioscience, San Diego, CA, USA). Genotype distribution in case and control groups was analyzed by Chi square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression models adjusted for age, sex, smoking, and alcohol consumption to assess the correlation between SNPs and CHD risk. Results: Our results indicated that FNDC1-rs420137, -rs386360, and -rs7763726 played important roles in enhancing the risk of CHD. Subgroup analysis revealed that rs420137 increased the susceptibility to CHD in males, smokers, and patients aged ≤62 years. Rs360 had an increased risk of CHD in males, patients at aged ≤62 years, smokers, and non-drinkers. Furthermore, the association of rs7763726 with increased CHD risk was also observed in males, patients aged ≤62 years, smokers, and drinkers. Last but not least, these three SNPs we selected were protective factors against hypertension in CHD individuals. Conclusion: Our research suggest that FNDC1-rs420137, -rs386360, and -rs7763726 variants may be regarded as novel biomarkers for predicting CHD risk and other specific mechanisms of action of CHD need to be further studied.

A meta-analysis of the prognostic value of circulating tumor cells in ovarian cancer.

OBJECTIVE: To evaluate the prognostic value of circulating tumor cells (CTCs) in ovarian cancer. METHODS: Chinese databases (Wanfang, Cqvip, CNKI) and English databases (PubMed, Web of Science, Embase, SinoMed, Cochrane Library) were retrieved to collect relevant studies on CTCs evaluation of ovarian cancer prognosis. Data were extracted to analyze the effect of CTCs on the overall survival (OS) and progression-free survival (PFS) of patients, and a meta-analysis was performed using Stata 15 software. RESULTS: Nineteen studies were included in this meta-analysis. The results showed that ovarian cancer patients with positive CTCs had a shorter OS and higher death rate, (HR=1.57, 95% CI: 1.30, 1.84), a shorter PFS and an increased risk of disease progression (HR=1.29, 95% CI: 1.04, 1.54) compared with patients with negative CTCs. Subgroup analysis showed that the HRs for death and disease progression were higher in CTCs-positive patients after treatment than those patients with negative CTCs (P<0.05). CONCLUSION: CTCs detection has a high application value in the prognosis assessment of ovarian cancer.

Utility of cooling patches to prevent hand-foot syndrome caused by pegylated liposomal doxorubicin in breast cancer patients.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) uses the hydrophilic layer of liposomes to reach the sweat on the skin surface or accumulate in the sweat glands, producing toxic free radicals and oxidative damage, resulting in hand-foot syndrome (HFS). Regional cooling can induce vasoconstriction to reduce the release of drugs in the limbs and reduce the accumulation of drugs in sweat glands; thus, decreasing the incidence and severity of HFS. AIM: To study the efficacy of cooling patches to prevent HFS caused by PLD in the short-term. METHODS: This is a retrospective cohort study. Female breast cancer patients (n = 101) who were treated with PLD in two breast wards at our department from February 2020 to February 2021 were enrolled in the study and were randomly divided into the cooling group (51 patients) and the control group (50 patients). Patients in the control group only received routine care, while the patients in the cooling group applied cooling patches, based on routine care, to the palm and back of the hands 15 min before chemotherapy infusion for 10 h. All patients took a corresponding dose of dexamethasone orally one day before chemotherapy, on the day of chemotherapy, and one day after chemotherapy. SPSS23.0 version was used to analyze the data in this study. The occurrence and severity of HFS was analyzed by the Mann-Whitney U test, and scores were analyzed by the Student's t test or Wilcoxon rank-sum test. A P value < 0.05 was regarded as statistically significant. RESULTS: In this study, neither group of patients developed Grade 3 HFS. In the control group, the incidence of Grade 1 HFS and Grade 2 HFS was 38% and 2%, respectively. However, in the cooling group, only one person developed Grade 1 HFS (2%), and none of the patients developed Grade 2 HFS. These findings showed that cooling patches can effectively reduce the frequency and severity of HFS (P < 0.0001) in the short-term. Before the fourth chemotherapy cycle, although general self-efficacy scale scores in the cooling group were low, they were still significantly higher than those in the control group (17.22 ± 5.16 vs 19.63 ± 6.42, P = 0.041). Compared with the control group, the mean Hand-Foot Skin Reaction and Quality of Life Questionnaire score in the cooling group was significantly lower (18.08 ± 7.01 vs 14.20 ± 7.39, P = 0.008). CONCLUSION: Cooling patches can effectively reduce the frequency and severity of HFS caused by PLD in the short-term. In addition, it may help delay the decline in patients' self-efficacy.

Evaluation of the Postoperative Nursing Effect of Thoracic Surgery Assisted by Artificial Intelligence Robot.

In order to evaluate the postoperative nursing effect of artificial intelligence robot-assisted thoracic surgery, this study proposed the Da Vinci robot-assisted pulmonary lobotomy, from January to December 2014; 42 patients (15 males and 27 females, aged 33-69 years old) underwent lobectomy with the Da Vinci robot system in the chest hospital. A series of postoperative nursing was carried out. The surgical results showed that 42 patients with Da Vinci robot-assisted lobectomy had operation time of 62-225 min and blood loss of 70-300 mL. There was no intraoperative blood transfusion, the intraoperative central rate was maintained at 60-100 times/min, and the blood pressure was maintained at 90-140/60-90 mmHg. No patient was transferred to thoracotomy, and 2 patients were performed robotic wedge resection first, and then, robotic lobectomy was performed after malignant tumor was confirmed by freezing results, with relatively light postoperative pain, no infection, beautiful wound, and smooth recovery and discharge. Robot-assisted lobectomy is a new technique with advantages of less trauma, less pain, faster recovery, and safer and more thorough lymph node dissection.

The effects of the quality nursing mode intervention on the psychological moods, postoperative complications, and nursing satisfaction of breast cancer surgery patients.

OBJECTIVE: To evaluate the influence of high-quality care on the psychological well-being, the postoperative complications, and patient satisfaction following a radical mastectomy. METHODS: One hundred and eighteen breast cancer patients who underwent radical mastectomies from February, 2017 to May, 2019 in the Cancer Hospital of China Medical University were enrolled. Among them, 56 patients treated with regular care were included in the regular group, while the other 62 patients who underwent high-quality care were included in the high-quality group. The postoperative recoveries and complications were compared between the two groups. The visual analogue scale (VAS), the disabilities of the arm, shoulder and hand (DASH) questionnaire, the self-rating anxiety scale (SAS), the self-rating depression scale (SDS), the quality of life (QOL) assessment scale, and a patient satisfaction questionnaire were used to evaluate the degrees of pain, the upper limb recovery, the negative emotions, the QOL, the patient satisfaction and the two-year survival rate, respectively. RESULTS: The ambulation times, the regression times of upper limb swelling, and the hospital stays in the high-quality group were remarkably shorter than they were in the regular group (P<0.05). The postoperative complications were less frequent in the high-quality group (P<0.05). The VAS scores in the high-quality group were lower than they were in the regular group at 1, 3, and 5 days after surgery, and the DASH scores in the high-quality group were lower at 1 month after discharge (P<0.05). The high-quality group showed lower SAS and SDS scores and higher QOL and patient satisfaction than the regular group (all P<0.05). There was no difference in the two-year survival rates between the two groups after the intervention (P>0.05). CONCLUSION: High-quality care following a radical mastectomy contributes to postoperative recovery, the relief of negative emotions, the reduction of complications, as well as the enhancement of QOL and patient satisfaction, so it is worthy of clinical promotion.

Overexpression of Short Variant Form of New Kelch Family Protein Leads to Erythroid and Megakaryocyte Dysplasia by Targeting Megakaryocyte-Erythroid Progenitors.

Nd1-S is the nuclear-localizing short variant form of Nd1 (Ivns1abp) encoding a Kelch family transcription factor. While the function of Nd1 has been investigated in the context of metastasis and doxorubicin-induced cardiotoxicity, little is known about its role in hematopoiesis. In this study, we investigated the function of Nd1-S in hematopoiesis by transplanting the Nd1-S-overexpressing murine hematopoietic stem and progenitor cells (HSPCs) into recipient mice (Nd1-S mice). Enforced expression of Nd1-S led to erythroid and megakaryocyte dysplasia, demonstrated by dramatically decreased red blood cells and platelets, and megakaryocytes in the peripheral blood and bone marrow of the Nd1-S mice. Moreover, phenotypic megakaryocyte-erythroid progenitors (MEPs) accumulated in these Nd1-S mice with aberrant morphology and defective colony-forming capability. Furthermore, these phenotypic MEPs showed impaired pathways regulating erythroid differentiation and megakaryocyte development. Therefore, our study provides de novo evidence that overexpression of Nd1-S in HSPCs leads to erythroid and megakaryocyte dysplasia in vivo by targeting MEPs.

Co-delivery of doxorubicin and itraconazole by Pluronic® P123 coated liposomes to enhance the anticancer effect in breast cancers.

To date, the combinational cancer therapy of anticancer and antiangiogenic agents represents a promising strategy to improve antitumor outcomes in clinics. However, combination therapy with drugs having distinct properties, such as solubility, limits the likelihood of simultaneous delivery. In our study, we aimed to develop a codelivery nanoparticulate system of hydrophilic doxorubicin (DOX) and hydrophobic itraconazole (ITZ) using liposomes coated with Pluronic® P123 (ITZ/DOX-PLip). The prepared ITZ/DOX-PLip exhibited a unimodal size distribution and high loading efficiency with sustained release profiles. Furthermore, cytotoxicity against 4T1 murine breast cancer cells and cellular uptake results revealed that the inhibitory effect of ITZ/DOX-Plip on tumor growth was superior to that of free DOX or DOX-loaded liposome (DOX-Lip), which was primarily attributed to the significantly higher intercellular DOX content. Cytotoxicity against HUVEC and wound healing tests confirmed that ITZ and ITZ formulations could inhibit the growth and migration of endothelial cells. In addition, in xenograft 4T1 bearing BALB/c mice, biodistribution experiments revealed that higher drug accumulation in tumors and decreased distribution in heart were observed for ITZ/DOX-PLip as compared to free DOX. Remarkably, ITZ/DOX-PLip significantly reduced tumor volume, tumor weight, liver metastasis and microvessel density in comparison with the same dose of ITZ injection or DOX-Lip. Overall, this Pluronic® P123 modified liposome-based codelivery system represents a promising nano-platform for combination therapy in cancers.

Nerve growth factor regulates CD133 function to promote tumor cell migration and invasion via activating ERK1/2 signaling in pancreatic cancer.

BACKGROUND: Perineural invasion (PNI) is extremely high frequency among the various metastatic routes in pancreatic cancer. Nerve growth factor, secreted by astroglial cells, exerts effects on tumor invasion in some cancer cells, but its function on migration and invasion in pancreatic cancer is still unclear. In the present study, we determined the effects of NGF on modulating tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. METHODS: NGF and CD133 expression were detected in tumor tissues using immunohistochemical analysis and Western blotting analysis. The effects of NGF on the regulation of CD133 expression and the promotion of cancer migration and invasion were investigated using wound healing and matrigel transwell assay. A related mechanism that NGF regulates CD133's function via activating ERK1/2 signaling also was observed. RESULTS: NGF/CD133 is overexpressed in human pancreatic cancer and promotes the migration and invasion of human pancreatic cancer cells through the activation of the ERK/CD133 signaling cascade. NGF/ERK signaling modulates the cancer cell EMT process, migration and invasion through the regulation of CD133 expression and its subcellular localization. CONCLUSIONS: NGF/CD133 signaling initiated the migration and invasion of pancreatic cancer cells. NGF/CD133 might be an effective and potent therapeutic target for pancreatic cancer metastasis, particularly in PNI.

Gastrin regulates ABCG2 to promote the migration, invasion and side populations in pancreatic cancer cells via activation of NF-κB signaling.

Gastrin is absent in most normal adult pancreatic tissues but is highly expressed in pancreatic cancer tissues. Although Gastrin expression was reported to be associated with tumor proliferation in human pancreatic cancer, studies on the relationship between Gastrin and tumor metastasis in pancreatic cancer are rare. In this study, we performed an analysis to determine the effects of Gastrin on modulating the side populations, cell proportion and tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. We indicated that Gastrin and ABCG2 were widely expressed in pancreatic cancer cell lines and overexpressed in cancer tissues. Gastrin induced ABCG2 expression, and this effect was mediated by NF-κB activation. Gastrin regulated the SP proportion of BxPC-3 cells via modulating ABCG2 expression. Through the regulation of the functions of NF-κB/ABCG2, Gastrin functionally promoted the migration and invasion in pancreatic cancer cell. The present study indicated that Gastrin induced ABCG2 expression by activating NF-κB and thereby modulated the SP proportion, tumor cell metastatic potential and invasion activity in pancreatic cancer. Gastrin could serve as an effective therapeutic target for the metastasis of pancreatic cancer.

Hypoxia regulates ABCG2 activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells.

Pancreatic cancer is a drug resistant hypovascular tumor. Although there are many studies on the mechanism of chemoresistance in pancreatic cancers, studies on the relationship between ABCG2 and chemoresistance during hypoxia of pancreatic cancer are rare. Hypoxia-inducible factor-1 (HIF-1α) is a master regulator of the transcriptional response to oxygen deprivation in cancer cells. The aim of this study was to examine the role of ABCG2 and HIF-1α in mediating chemoresistance during hypoxia in pancreatic cancer. In this study, we detected the expression levels of ABCG2, ERK/phosphorylated-ERK (p-ERK) and HIF-1α by immunohistochemistry in fresh pancreatic cancer and paracarcinoma tissues obtained from 25 patients. The mechanism by which p-ERK1/2 and HIF-1α affect ABCG2s expression was analyzed in the hypoxic cultured human pancreatic cancer cell line Capan-2. ABCG2-mediatedregulation of gemcitabine response under hypoxic conditions in pancreatic cancer cells was observed. It was found that ABCG2, ERK/p-ERK and HIF-1α were overexpressed in cancer tissues. ABCG2, HIF-1α and p-ERK levels were demonstrated to be high during hypoxic conditions in pancreatic cancer cells. Hypoxia induced phosphorylation of ERK1/2 to activate HIF-1α and contribute the ABCG2 expression and mediated gemcitabine chemoresistance in pancreatic cancer cells. Hypoxic conditions induced HIF-1α binding to target gene sequences in the ABCG2 promoter, resulting in increased transcription in pancreatic cancer cells. We demonstrated that hypoxia-induced chemoresistance is due to the regulation of ABCG2 through the activation of ERK1/2/HIF-1α. ABCG2 could serve as a predictor of gemcitabine response and, potentially, as a chemotherapeutic target in pancreatic cancer. Inhibition of ERK1/2 and HIF-1αcould result in increased gemcitabine sensitization in pancreatic cancer with highly expressed ABCG2 cell member protein.

Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response.

Mitochondrion-orientated transportation of smart liposomes has been developed as a promising strategy to deliver anticancer drugs directly to tumor sites, and these have a tremendous potential for killing cancer cells, especially those with multidrug resistance (MDR). Herein we report a novel dual-functional liposome system possessing both extracellular pH response and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of drug-resistant cancer cells. Briefly, peptide D[KLAKLAK]2 (KLA) was modified with 2, 3-dimethylmaleic anhydride (DMA) and combined with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a DSPE-KLA-DMA (DKD) lipid. This dual-functional DKD was then mixed with other commercially available lipids to fabricate liposomes. In vitro anticancer efficacy of this liposome system was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/Taxol cells. At tumor extracellular pH (∼6.8), liposomes could reverse their surface charge (negative to positive), facilitating liposome internalization. After cellular uptake, KLA peptide directed delivery-enabled selective accumulation of these liposomes into mitochondria and favored release of their cargo paclitaxel (PTX) into desired sites. Specifically, enhanced apoptosis of MDR cancer cells through mitochondrial signaling pathways was evidenced by release of cytochrome c and increased activity of caspase-9 and -3. These dual-functional liposomes had the greatest efficacy for treating A549 cells and A549/Taxol cells in vitro, and in treating drug-resistant lung cancer A549/Taxol cells xenografted onto nude mice (tumor growth inhibition 86.7%). In conclusion, dual-functional liposomes provide a novel and versatile approach for overcoming MDR in cancer treatment.

Poly(ethylene glycol)-block-poly(ε-caprolactone)-and phospholipid-based stealth nanoparticles with enhanced therapeutic efficacy on murine breast cancer by improved intracellular drug delivery.

BACKGROUND: Effective anticancer drug delivery to the tumor site without rapid body clearance is a prerequisite for successful chemotherapy. 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-N-(methoxy[polyethyleneglycol]-2000) (DSPE-PEG2000) has been widely used in the preparation of stealth liposomes. Although PEG chains can efficiently preserve liposomes from rapid clearance by the reticuloendothelial system (RES), its application has been hindered by poor cellular uptake and unsatisfactory therapeutic effect. METHODS: To address the dilemma, we presented a facile approach to fabricate novel stealth nanoparticles generated by poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL), soybean phosphatidylcholine (SPC), and cholesterol, namely LPPs (L represented lipid and PP represented PEG-b-PCL), for the delivery of anticancer drug paclitaxel (PTX). LPPs were prepared using the thin film hydration method. Two PEG-b-PCL polymers with different molecular weights (MW; PEG2000-b-PCL2000, MW: 4,000 Da and PEG5000-b-PCL5000, MW: 10,000 Da) were used to fabricate stealth nanoparticles. Conventional PEGylated liposome (LDP2000, L represented lipid and DP2000 represented DSPE-PEG2000) composed of SPC, cholesterol, and DSPE-PEG2000 was used as the control. The physical properties, cellular uptake, endocytosis pathway, cytotoxicity, pharmacokinetics, tumor accumulation, and anticancer efficacy of free PTX, PTX-loaded LPPs, and LDP2000 were systemically investigated after injection into 4T1 breast tumor-bearing mice. RESULTS: LPPs were vesicles around 100 nm in size with negative zeta potential. With enhanced stability, LPPs achieved sustainable release of cancer therapeutics. The cellular uptake level was closely related to the PEG chain length of PEG-b-PCL; a shorter PEG chain resulted in higher cellular uptake. Moreover, the cellular internalization of LPP2000 modified by PEG2000-b-PCL2000 on 4T1 cells was 2.1-fold higher than LDP2000 due to the improved stability of LPP2000. The cytotoxicity of PTX-loaded LPP2000 was also higher than that of LDP2000 and LPP5000 as observed using a WST-8 assay, while blank LPPs showed negligible toxicity. Consistent with the results of the in vitro study, in vivo experiments showed that LPPs allowed significantly improved bioavailability and prolonged T1/2ß as compared to free PTX injection. More importantly, LPPs mainly accumulated at the tumor site, probably due to the enhanced permeation and retention effect (EPR effect). As a nanomedicine, LPP2000 (tumor inhibition rate of 75.1%) significantly enhanced the therapeutic effect of PTX in 4T1 breast tumor-bearing mice by inhibiting tumor growth compared to LDP2000 and LPP5000 (tumor inhibition rates of 56.3% and 49.5%, respectively). CONCLUSION: Modification of liposomes with PEG2000-b-PCL2000 can simultaneously improve drug accumulation at the target tumor site and tumor cells, showing great promise for utilization as a PEG modification tool in the fabrication of stealth nanoparticles for cancer chemotherapy.

Tenascin-C induces resistance to apoptosis in pancreatic cancer cell through activation of ERK/NF-κB pathway.

As a glycol-protein located in extracellular matrix (ECM), tenascin-C (TNC) is absent in most normal adult tissues but is highly expressed in the majority of malignant solid tumors. Pancreatic cancer is characterized by an abundant fibrous tissue rich in TNC. Although it was reported that TNC's expression increased in the progression from low-grade precursor lesions to invasive cancer and was associated with tumor differentiation in human pancreatic cancer, studies on the relations between TNC and tumor progression in pancreatic cancer were rare. In this study, we performed an analysis to determine the effects of TNC on modulating cell apoptosis and chemo-resistance and explored its mechanisms involving activation in pancreatic cancer cell. The expressions of TNC, ERK1/2/p-ERK1/2, Bcl-xL and Bcl-2 were detected by immunohistochemistry and western blotting. Then the effects of exogenous and endogenous TNC on the regulation of tumor proliferation, apoptosis and gemcitabine cytotoxicity were investigated. The associations among the TNC knockdown, TNC stimulation and expressions of ERK1/2/NF-κB/p65 and apoptotic regulatory proteins were also analyzed in cell lines. The mechanism of TNC on modulating cancer cell apoptosis and drug resistant through activation of ERK1/2/NF-κB/p65 signals was evaluated. The effect of TNC on regulating cell cycle distribution was also tested. TNC, ERK1/2/p-ERK1/2, and apoptotic regulatory proteins Bcl-xL and Bcl-2 were highly expressed in human pancreatic cancer tissues. In vitro, exogenous TNC promoted pancreatic cancer cell growth also mediates basal as well as starved and drug-induced apoptosis in pancreatic cancer cells. The effects of TNC on anti-apoptosis were induced by the activation state of ERK1/2/NF-κB/p65 signals in pancreatic cell. TNC phosphorylate ERK1/2 to induce NF-κB/p65 nucleus translocation. The latter contributes to promote Bcl-xL, Bcl-2 protein expressions and reduce caspase activity, which inhibit cell apoptotic processes. TNC mediated gemcitabine chemo-resistance via modulating cell apoptosis in pancreatic cancer. TNC resulted in the enrichment of pancreatic cancer cells in S-phase with a concomitant decrease in number of cells in G1 phase. The present study indicated TNC in cellular matrix induces an activation of ERK1/2/NF-κB/p65 signaling cascade and thereby mediates resistance to apoptosis in pancreatic cancer. TNC could serve as a diagnostic marker and predictor of gemcitabine response and potentially as a target for chemotherapy of pancreatic cancer.