Multifunctional Au Modified Ti3C2-MXene for Photothermal/Enzyme Dynamic/Immune Synergistic Therapy.

Ti3C2-MXene-based composites provide multifunctional interfaces in diagnosis and treatment of tumors. Herein, we proposed a multifunctional nanoplatform based on Ti3C2-MXene-Au nanocomposites, which combines photothermal properties and peroxidase-like activity, accomplishing synergistic photothermal therapy (PTT) and enzyme dynamic therapy (EDT) accompanied by photoacoustic (PA) and thermal dual-mode imaging in vivo. Furthermore, PTT induces immunogenic cell death, and EDT promotes cell apoptosis, facilitating dendritic cell (DC) maturation and T cell infiltration into the tumor. On this basis, the antibody OX40 (αOX40) was utilized to further contribute immune therapy for reversing the immunosuppressive tumor microenvironment by activating CD4+ and CD8+ T cells. In summary, a triune of PTT/EDT/antitumor immune therapy is achieved by combining Ti3C2-MXene-Au nanocomposites and αOX40, which possesses several strong features of good biocompatibility, NIR-controlled targeting, significant cancer cell killing, and satisfactory biosafety in vitro and in vivo. Our work might highlight the promising application of MXene-based nanoplatforms for cancer therapy.

A meta-analysis examined the effect of topical nursing application of antimicrobial as a prophylaxis for the stoppage of surgical wound infection in colorectal surgery.

To assess the impact of topical antimicrobial (TA) as a prophylaxis for the stoppage of surgical wound infection (SWI) in colorectal surgery (CS), we lead a meta-analysis. 9160 participants with CS were enrolled in the chosen studies; 4719 of them used TA, while 4441 served as controls. To assess the effectiveness of TA application in lowering SWIs following CS, odds ratios (OR) with 95% confidence intervals (CIs) were computed with a dichotomous technique with a fixed- or random-effect model. Significantly lower SWIs post CS for TA as whole (OR, 0.50; 95% CI, 0.38-0.64; P < .001), gentamicin collagen sponge and beads (OR, 0.52; 95% CI, 0.32-0.86; P = .01), triclosan impregnated fascial suture (OR, 0.57; 95% CI, 0.38-0.84; P = .005), antibiotic powder, ointment, lavage, or injection for the abdominal wound (OR, 0.35; 95% CI, 0.21-0.59; P < .001), and ionised silver dressing on the closed abdominal wound (OR, 0.45; 95% CI, 0.27-0.77; P = .003) compared to control. Significantly lower SWIs post CS for TA as a whole, gentamicin collagen sponge and beads, triclosan impregnated fascial sutures, antibiotic powder, ointment, lavage, or injection for the abdominal wound, and ionised silver dressing on the closed abdominal wound compared with control. The low sample size of 8 out of the 39 included studies in this meta-analysis calls for precaution when analysing the outcomes.

Induction and application of ferroptosis in cancer therapy.

At present, more than one cell death pathways have been found, one of which is ferroptosis. Ferroptosis was discovered in 2012 and described as an iron-dependent and lipid peroxidation-driven regulated cell death pathway. In the past few years, ferroptosis has been shown to induce tumor cell death, providing new ideas for tumor treatment. In this article, we summarize the latest advances in ferroptosis-induced tumor therapy at the intersection of tumor biology, molecular biology, redox biology, and materials chemistry. First, we state the characteristics of ferroptosis in cells, then introduce the key molecular mechanism of ferroptosis, and describes the relationship between ferroptosis and oxidative stress signaling pathways. Finally, we focused on several types of ferroptosis inducers discovered by scholars, and the application of ferroptosis in systemic chemotherapy, radiotherapy, immunotherapy and nanomedicine, in the hope that ferroptosis can exert its potential in the treatment of tumors.

Manipulating Liver Bile Acid Signaling by Nanodelivery of Bile Acid Receptor Modulators for Liver Cancer Immunotherapy.

Gut bacteria and their metabolites influence the immune microenvironment of liver through the gut-liver axis, thus representing emerging therapeutic targets for liver cancer therapy. However, directly manipulating gut microbiota or their metabolites is not practical in clinic since the safety concerns and the complicated mechanism of action. Considering the dysregulated bile acid profiles associated with liver cancer, here we propose a strategy that directly manipulates the primary and secondary bile acid receptors through nanoapproach as an alternative and more precise way for liver cancer therapy. We show that nanodelivery of bile acid receptor modulators elicited robust antitumor immune responses and significantly changed the immune microenvironment in the murine hepatic tumor. In addition, ex vivo stimulation on both murine and patient hepatic tumor tissues suggests the observation here may be meaningful for clinical practice. This study elucidates a novel and precise strategy for liver cancer immunotherapy.

Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells.

Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, play an indispensable role in cancer initiation, progression, metastasis, and metabolism. The limitations of traditional treatments can be partly attributed to the lack of understanding of the role of the tumor stroma. For this reason, CAF targeting is gradually gaining attention, and many studies are trying to overcome the limitations of tumor treatment with CAF as a breakthrough. Glutamine (GLN) has been called a "nitrogen reservoir" for cancer cells because of its role in supporting anabolic processes such as fuel proliferation and nucleotide synthesis, but ammonia is a byproduct of the metabolism of GLN and other nitrogenous compounds. Moreover, in some studies, GLN has been reported as a fundamental nitrogen source that can support tumor biomass. In this review, we discuss the latest findings on the role of GLN and ammonia in the crosstalk between CAFs and cancer cells as well as the potential therapeutic implications of nitrogen metabolism.

The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial.

BACKGROUND: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. METHODS: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. DISCUSSION: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. TRIAL REGISTRATION: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

Serum albumin guided plasmonic nanoassemblies with opposite chiralities.

Chiral assemblies by combining natural biomolecules with plasmonic nanostructures hold great promise for plasmonic enhanced sensing, imaging, and catalytic applications. Herein, we demonstrate that human serum albumin (HSA) and porcine serum albumin (PSA) can guide the chiral assembly of gold nanorods (GNRs) with left-handed chiroptical responses opposite to those by a series of other homologous animal serum albumins (SAs) due to the difference of their surface charge distributions. Under physiological pH conditions, the assembly of HSA or PSA with GNRs yielded left-handed twisted aggregates, while bovine serum albumin (BSA), sheep serum albumin, and equine serum albumin behaved on the contrary. The driving force for the chiral assembly is mainly attributed to electrostatic interaction. The opposite chiroptical signals acquired are correlated with the chiral surface charge distributions of the tertiary structures of SAs. Moreover, the chirality of the assembly induced by both HSA and BSA can be enhanced or reversed by adjusting the pH values. This work provides new insights into the modulation of protein-induced chiral assemblies and promotes their applications.

Regulation of SH3PX1 by dNedd4-long at the Drosophila neuromuscular junction.

Drosophila Nedd4 (dNedd4) is a HECT E3 ubiquitin ligase present in two major isoforms: short (dNedd4S) and long (dNedd4Lo), with the latter containing two unique regions (N terminus and Middle). Although dNedd4S promotes neuromuscular synaptogenesis (NMS), dNedd4Lo inhibits it and impairs larval locomotion. To explain how dNedd4Lo inhibits NMS, MS analysis was performed to find its binding partners and identified SH3PX1, which binds dNedd4Lo unique Middle region. SH3PX1 contains SH3, PX, and BAR domains and is present at neuromuscular junctions, where it regulates active zone ultrastructure and presynaptic neurotransmitter release. Here, we demonstrate direct binding of SH3PX1 to the dNedd4Lo Middle region (which contains a Pro-rich sequence) in vitro and in cells, via the SH3PX1-SH3 domain. In Drosophila S2 cells, dNedd4Lo overexpression reduces SH3PX1 levels at the cell periphery. In vivo overexpression of dNedd4Lo post-synaptically, but not pre-synaptically, reduces SH3PX1 levels at the subsynaptic reticulum and impairs neurotransmitter release. Unexpectedly, larvae that overexpress dNedd4Lo post-synaptically and are heterozygous for a null mutation in SH3PX1 display increased neurotransmission compared with dNedd4Lo or SH3PX1 mutant larvae alone, suggesting a compensatory effect from the remaining SH3PX1 allele. These results suggest a post-synaptic-specific regulation of SH3PX1 by dNedd4Lo.

Ultrasensitive and Selective Determination of Carcinoembryonic Antigen Using Multifunctional Ultrathin Amino-Functionalized Ti3C2-MXene Nanosheets.

Herein, we report on a two-dimensional amino-functionalized Ti3C2-MXene (N-Ti3C2-MXene)-based surface plasmon resonance (SPR) biosensor for detecting carcinoembryonic antigen (CEA) utilizing a sandwich format signal amplification strategy. Our biosensor employs an N-Ti3C2-MXene nanosheet-modified sensing platform and a signal enhancer comprising N-Ti3C2-MXene-hollow gold nanoparticles (HGNPs)-staphylococcal protein A (SPA) complexes. Ultrathin Ti3C2-MXene nanosheets were synthesized and functionalized with aminosilane to provide a hydrophilic-biocompatible nanoplatform for covalent immobilization of the monoclonal anti-CEA capture antibody (Ab1). The N-Ti3C2-MXene/HGNPs nanohybrids were synthesized and further decorated with SPA to immobilize the polyclonal anti-CEA detection antibody (Ab2) and serve as signal enhancers. The capture of CEA followed by the formation of the Ab2-conjugated SPA/HGNPs/N-Ti3C2-MXene sandwiched nanocomplex on the SPR chip results in the generation of a response signal. The fabricated N-Ti3C2-MXene-based SPR biosensor exhibited a linear detection range of 0.001-1000 PM with a detection limit of 0.15 fM. The proposed biosensor showed high sensitivity and specificity for CEA in serum samples, which gives it application potential in the early diagnosis and monitoring of cancer. We believe that this work also opens new avenues for development of MXene-based highly sensitive biosensors for determining various biomolecules.

Peer Support as an Ideal Solution for Racial/Ethnic Disparities in Colorectal Cancer Screening: Evidence from a Systematic Review and Meta-analysis.

BACKGROUND: Low implementation of colorectal cancer screening in ethnic minorities is the main reason for racial and ethnic disparities in colorectal cancer morbidity and mortality. Peer support is widely used for promoting health care in ethnic minorities. However, whether it improves their acceptance to undergo the screening remains controversial. OBJECTIVE: We performed a meta-analysis of the currently available studies to further explore its effectiveness. DATA SOURCES: This meta-analysis was undertaken using PubMed, Embase, Scopus, the Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO for randomized controlled trials. STUDY SELECTION: We included studies that compared peer support interventions among ethnic minorities versus other interventions to promote uptake of colorectal cancer screening. RESULTS: Thirteen studies comprising 8090 participants met the eligibility criteria. Peer support intervention can increase colorectal cancer screening implementation and raise awareness and intention to undergo the screening in ethnic minorities more significantly than fecal occult blood test outreach, print, and usual care. Subgroup analysis showed that peer support intervention achieved great results in Asian Americans and intervention of peer counseling. LIMITATIONS: The results of subgroup analysis had substantial heterogeneity, which may decrease the precision of our estimates. CONCLUSIONS: Peer support can significantly improve the awareness about and the intention for receiving colorectal cancer screening in ethnic minorities and is an ideal choice for promoting the screening among ethnic minorities, particularly in a diverse community. Peer support intervention is recommended to promote the implementation of screening in Asian Americans. Peer counseling is worth promoting; however, church-based peer counseling programs require enhanced management to maintain their fidelity.

O-GlcNAcylation of ITGA5 facilitates the occurrence and development of colorectal cancer.

BACKGROUND/OBJECTIVE: Integrin α5 (ITGA5) as one member of integrins family, plays an important role in promoting cancer cell metastasis and invasion through inducing the communications among different cells or cells with extracellular matrix (ECM). However, the mechanisms underlying ITGA5 in colorectal cancer (CRC) progression need to be explored, especially for its O-GlcNAcylation. To this end, the current study was performed to explore the effects of O-GlcNAcylation on ITGA5 expression, as well as to probe the effects of ITGA5 O-GlcNAcylation on CRC progression. METHODS: The expression profiles of ITGA5, OGT and O-GlcNAc in CRC tissues and cells were detected by immunohistochemistry (IHC), RT-PCR and western blotting. CCK-8, flow cytometry and xenotransplantation assays were used to assess cell growth, apoptosis and tumorigenesis. Immunoprecipitation (IP), in vitro O-GlcNAcylation of ITGA5 and enzymatic labelling of O-GlcNAc assays were used to detect the O-GlcNAcylation of ITGA5 protein. RESULTS: The expression of ITGA5, OGT and O-GlcNAc were all elevated in CRC tissues and cells compared with the normal tissues and cells. Up-regulation of ITGA5 in CRC RKO cells enhanced cell growth and tumorigenesis while decreased cell apoptosis, while down-regulation of ITGA5 in CRC SW620 cells decreased cell growth and tumorigenesis and induced cell apoptosis. Besides, PUGNAc, GlcN or PUGNAc + GlcNAc treatment increased ITGA5 protein expression in RKO and SW620 cells, as well as increased its protein stability via enhancing its O-GlcNAcylation. CONCLUSION: Collectively, the present study makes clear that ITGA5 overexpression accelerates the progression of CRC, which is closely associated to its enhanced O-GlcNAcylation.

LncRNA-UCA1 modulates progression of colon cancer through regulating the miR-28-5p/HOXB3 axis.

Emerging evidence has shown that the long noncoding RNA urothelial carcinoma-associated 1 (UCA1) plays a tumor-promoting role in colorectal cancer, while miR-28-5p shows tumor-inhibitory activity in several tumor types. However, the mechanisms both of these in colon cancer progression are still unknown. In this work, the detailed roles and mechanisms of UCA1 and its target genes in colon cancer were studied. The results showed that UCA1 was upregulated in colon cancer tissues when compared with the adjacent nonhumorous tissues, as well as in the various colon cancer cell lines, but the expression of miR-28-5p showed an opposite trend. Furthermore, a high UCA1 level in colon cancer tissues is positively associated with the tumor size and advanced tumor stages. Functional assays revealed that both UCA1 knockdown and miR-28-5p overexpression could inhibit colon cancer cell growth and migration. Further mechanistic studies indicated that UCA1 knockdown played tumor suppressive roles in SW480 and HT116 cells through binding with miR-28-5p. We also, for the first time, identified HOXB3 as the target gene of miR-28-5p and that HOXB3 overexpression could mediate the functions of UCA1 in cell proliferation and migration of colon cancer cells. In conclusion, our data provided evidence for the regulatory network of UCA1/miR-28-5p/HOXB3 in colon cancer, suggesting that UCA1, miR-28-5p, and HOXB3 are the potential targets for colon cancer therapy.

Peer support interventions for breast cancer patients: a systematic review.

PURPOSE: Due to the clear efficacy of peer support as a means of improving emotional well-being and healthy behaviors in a highly cost-effective manner, this program is widely used. Controversy remains, however, with regard to its efficacy in breast cancer patients. Given the heterogeneity of peer support interventions, this review aimed to categorize, assess, and synthesize the existing evidence from randomized controlled trials (RCTs) to clarify the effects of different types of peer support on breast cancer patients. METHODS: We searched Pubmed, EMBase, CENTRAL, CINAHL, PsychINFO, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Data for English and Chinese language RCTs. The Cochrane Collaboration 'risk of bias' tool for systematic reviews was used to assess the methodological quality of each RCT. RESULTS: Of the 1494 studies screened, 15 studies met eligibility criteria for inclusion, comprising 1695 breast cancer patients. Overall, there were more positive effects than invalid or negative effects across peer interventions, with notable exceptions: unmoderated and unstructured group peer support interventions as well as Internet-based models without peer training had no effect or adverse effects on proximal and distal outcomes. However, adding other peer roles to the peer support structure or using one-on-one models could significantly improve the patients' negative emotions. Peer education showed promising effects on stress management, quality of life, and healthy behaviors. CONCLUSIONS: This systematic review found that different types of peer support have different effects on outcomes for breast cancer patients. Web-based group peer support without peer training must be avoided or used with caution in the future. Peer education is recommended for breast cancer patient support models, given its excellent results and cost-effectiveness.

Fos-like antigen 2 (FOSL2) promotes metastasis in colon cancer.

Among different cancers, incidence and mortality of colorectal cancer (CRC) is one of the highest. KRAS mutation is one of the underlying features in the pathogenesis of CRC with CRC tumors harboring mutant KRAS exhibiting a more aggressive behavior compared to CRC tumors with wild type KRAS. We had earlier shown that the microRNA-143 (miR-143) replenishment not only chemosensitizers CRC cell line with mutant KRAS instead of wild-type KRAS gene, to paclitaxel-mediated cytotoxicity, but also inhibits cell migration and invasion ability. Hence, the study aimed to determine how miR-143 replenishment is inhibiting pre-metastatic behavior in CRC cells with mutant KRAS. Top ten mRNA targets of miR-143 as predicted by TargetScan were evaluated by qRT-PCR in LoVo cells which were performed mock transfection or miR-143 mimic transfection. Evaluation of the changes in cognate mRNA target(s) was done in 30 paired CRC tissue and tumor adjacent normal tissue specimens and in LoVo cells by western blot. Effect of the mRNA target on pro-metastatic behavior was assayed by gain- and loss-of-function studies using a combination of western blotting and in vitro cell proliferation and transwell migration/invasion assay in LoVo cells and in the normal colonic epithelium cell line FHC. In vivo effect of the cognate mRNA target on CRC metastasis was assayed by xenograft assay. Of the 10 predicted mRNA targets, FOSL2 (P < 0.05) and IGFBP5 (P > 0.05) was down regulated in LoVo cells transfected with the miR-143 mimic. FOSL2 mRNA levels were significantly downregulated in CRC tissue specimens compared with adjacent normal tissue (P < 0.05). Immunoblot analysis showed that FOSL2, but not IGFBP5, protein expression is down regulated in LoVo cells after the miR-143 mimic transfection. FOSL2 overexpression in the normal colonic epithelial cell line FHC or siRNA-mediated silencing in LoVo cells induced and repressed, respectively, pro-mesenchymal cell features. Whereas manipulation of FOSL2 expression did not have any effect on cell proliferation rates, silencing its expression inhibited cell migration and invasion ability in vitro. In addition, silencing of FOSL2 expression in the LoVo cells can significantly inhibited invasion of hepatic, while no effect was found for tumorigenic potential. Our results suggest that FOSL2 is a critical regulator of CRC metastasis and might be an important marker for prognostic in CRC patients.

Knockdown of CEMIP suppresses proliferation and induces apoptosis in colorectal cancer cells: downregulation of GRP78 and attenuation of unfolded protein response.

It has been suggested that cell migration inducing hyaluronan binding protein (CEMIP) contributes to the carcinogenesis of colorectal cancer (CRC). Cancer cells can adapt to endoplasmic reticulum (ER) stress by initiating an unfolded protein response (UPR). This study aimed to investigate whether CEMIP affects the UPR of CRC cells, with a focus on 78 kDa glucose-regulated protein (GRP78, a major ER chaperone). We found that knockdown of CEMIP inhibited cell proliferation and induced a G1 arrest in SW480 CRC cells. The levels of cyclin D1 and cyclin E1 and phospho-retinoblastoma, which are known to promote the cell cycle progression from G0 or G1 into S phase, were decreased in CEMIP-silenced cells. CEMIP shRNA induced apoptosis and inhibited GRP78 expression in SW480 and Colo205 cells. The basal UPR of cancer cells was attenuated by CEMIP shRNA, as evidenced by the decreased expression of UPR sensors, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Furthermore, CEMIP silencing sensitized CRC cells to thapsigargin-induced apoptosis. Our study demonstrates that the in-vitro anti-proliferative and pro-apoptotic effects in CRC cells that were induced by silencing CEMIP may be associated with GRP78 repression and UPR attenuation.

Progress in the treatment of advanced gastric cancer.

Gastric cancer is one of the most common malignant tumors in the digestive system. Surgery is currently considered to be the only radical treatment. As surgical techniques improve and progress is made in traditional radiotherapy, chemotherapy, and the implementation of neoadjuvant therapy, the 5-year survival rate of early gastric cancer can reach >95%. However, the low rate of early diagnosis means that most patients have advanced-stage disease at diagnosis and so the best surgical window is missed. Therefore, the main treatment for advanced gastric cancer is the combination of neoadjuvant chemoradiotherapy, molecular-targeted therapy, and immunotherapy. In this article, we summarize several common methods used to treat advanced gastric cancer and discuss the progress made in the treatment of gastric cancer in detail. Only clinical practice and clinical research will allow us to prolong the survival time of patients and allow the patients to truly benefit by paying attention to the individual patient characteristics, drug choice, and developing a reasonable and comprehensive treatment plan.

MicroRNA-143 replenishment re-sensitizes colorectal cancer cells harboring mutant, but not wild-type, KRAS to paclitaxel treatment.

Colorectal cancer (CRC) global incidence is one of the highest among cancers. The KRAS gene has been shown as a robust biomarker for poor prognosis and drug resistance. MicroRNA-143 (miR-143) and let-7 are families of tumor suppressor microRNAs that are often downregulated in CRC, especially with coexistent KRAS mutations. In order to evaluate if miR-143 and/or let-7b replenishment would re-sensitize CRC cells to paclitaxel treatment, we investigated in effect of miR-143 and let-7b replenishments on sensitivity to paclitaxel treatment in KRAS mutant LoVo and wild-type SW48 CRC cell lines. Our results showed that miR-143, but not let-7b, increased sensitization of KRAS mutant tumor cells to paclitaxel. Furthermore, transfection of miR-143, but not let-7b, mimic negatively regulated the expression of mutant but not wild-type KRAS. Combination of miR-143 mimic and paclitaxel induced the onset of apoptosis, and reverted in vitro metastatic properties (migration and invasion) in KRAS mutant tumor cells. MiR-143 thus can be used as a chemosensitizer for the treatment of KRAS mutant tumors and warrants further investigations in in vitro and pre-clinical in vivo models.

Overexpression of miR-203 sensitizes paclitaxel (Taxol)-resistant colorectal cancer cells through targeting the salt-inducible kinase 2 (SIK2).

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR-203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts. We report miR-203 is correlated with Taxol sensitivity: overexpression of miR-203 sensitizes colon cancer cells and the Taxol-resistant cells display downregulated miR-203 compared with Taxol-sensitive cells. We identify SIK2 as a direct target of miR-203 in colorectal cancer cells. Overexpression of miR-203 complementary pairs to the 3' untranslated region (UTR) of SIK2, leading to the sensitization of Taxol resistant cells. In addition, miR-203 and the salt-inducible kinase 2 (SIK2) are reverse expressed in human colorectal tumors. Finally, we demonstrate recovery of SIK2 by overexpression of SIK2-desensitized Taxol-resistant cells, supporting the miR-203-mediated sensitization to Taxol, is through the inhibition of SIK2. In general, our study will provide mechanisms of the microRNA-based anti-tumor therapy to develop anti-chemoresistance drugs.

Therapeutic effects of sequential chemoradiotherapy with pemetrexed and cisplatin on locally advanced laryngeal cancer.

OBJECTIVE: To explore the therapeutic effects of sequential chemoradiotherapy with pemetrexed and cisplatin on locally advanced laryngeal cancer (LALC). METHODS: Fifty LALC patients who were treated in our hospital between January 2010 and January 2012 were selected and randomly divided into an observation group and a control group (n=25). The two groups were given conventional radiotherapy in the same manner, before which two cycles of chemotherapy were performed. The observation group intravenously infused with 500 mg/m2 pemetrexed on d1 and 25 mg/m2 cisplatin on d1-3, with 28 days as a cycle. The control group was intravenously infused with 25 mg/m2 cisplatin on d1-3 and 400 mg/m2 fluorouracil, with 28 days as a cycle. The short-term effects and adverse reactions of both groups were observed after treatment, and their survival was observed by follow-up for five years. RESULTS: The response rate was 84% (21/25) in the observation group and 64% (16/25) in the control group, between which the difference was statistically significant (P<0.05). The differences in the incidence rates of short-term adverse reactions such as grade III-IV gastrointestinal reactions and bone marrow suppression were not statistically significant between PC regimen (pemetrexed combined with cisplatin) and PF regimen (cisplatin combined with fluorouracil) (P>0.05). The incidence of long-term adverse reactions such as grade III-IV laryngeal edemas, laryngeal cartilage inflammation and laryngeal cartilage necrosis showed no significant differences between the two groups (P>0.05). The median survival was 3.3 years after PC chemotherapy and 2.8 years after PF chemotherapy, between which the difference was not statistically significant (P>0.05). The levels of serum tumor markers significantly decreased after PC and PF treatments compared with those before (P<0.05). CONCLUSION: Combining PC chemotherapy with radiotherapy has satisfactory short-term therapeutic effects on LALC, and the resulting adverse effects can be tolerated. Therefore, this strategy is worthy of promotion and application in clinical practice.

p38MAPK Signaling Enhances Glycolysis Through the Up-Regulation of the Glucose Transporter GLUT-4 in Gastric Cancer Cells.

BACKGROUND/AIMS: Previous studies have shown that p38MAPK is involved in gastric cancer, yet the underlying mechanism remains unclear. METHODS: q-PCR, Western blot and immunohistochemistry were used to explore the expression of PP2A and the phosphorylation of p38MAPK in gastric cancer tissues and normal gastric tissues. Activated p38MAPK in the gastric cancer cell line MKN45 using activator, then q-PCR, glucose uptake assay and colony formation assay were performed to determine whether p38MAPK promotes gastric cancer through the enhancement of glycolysis. After transfection of p38MAPK dominant negative mutation (p38DN) into MKN45 cells or MKN45 cells treated with an inhibitor of p38MAPK, Western blot was performed to detect the expression of GLUT-4. The knock down of MEF2α in MKN45 cells by siRNA was followed by Western blot and luciferase reporter assay to investigate the underlying mechanism of the role of p38MAPK in the promotion of gastric cancer. Finally, q-PCR, Western blot and immunohistochemistry were performed to examine GLUT-4 expression in gastric cancer tissues and normal gastric tissues. RESULTS: We found that p38MAPK activation significantly increases GLUT-4 expression and promotes glucose uptake and cell growth in gastric cancer cells. Inhibition of p38MAPK abrogates the up-regulation of GLUT-4. MEF2α knockdown abolishes p38MAPK-mediated GLUT-4 up-regulation. PP2A, an inhibitor of p38MAPK, is down-regulated in gastric cancer tissues, which might contribute to the activation of p38MAPK. CONCLUSIONS: Our data indicate that the abnormal activation of p38MAPK promotes glycolysis within gastric cancer cells through the upregulation of GLUT-4 in a MEF2a-dependent manner.