A novel AIE fluorescent probe for the detection and imaging of hydrogen peroxide in living tumor cells and in vivo.

Hydrogen peroxide (H2O2), a key reactive oxygen species (ROS), plays crucial roles in redox signaling pathways and immune responses associated with cell proliferation, differentiation, migration, and disease progression. The selective monitoring of overproduced H2O2 is important for understanding the diagnosis and pathogenesis of diseases such as cardiovascular disease, cancers, diabetes, Parkinson's disease, Alzheimer's disease, and inflammation. In this paper, an AIE fluorescent probe BQM-H2O2 was developed by connecting phenyl borate with the fluorophore BQM-PNH for selective detection of H2O2. In the presence of H2O2 at fw = 99% (pH = 7.4, 1% DMSO), the probe BQM-H2O2 could generate strong fluorescent signals due to the oxidation of the borate ester. The probe exhibited high selectivity and a low detection limit toward H2O2 with the calculated LOD of 112.6 nM. Importantly, it was employed in the detection of exogenous and endogenous hydrogen peroxide in 4T1 cells with low cytotoxicity. This probe has also been successfully applied to imaging of H2O2 in Blab/c mice bearing 4T1 graft tumors.

Exploring Preoperative Experiences and Informational Needs Among Chinese School-Age Children Undergoing Elective Surgery: A Qualitative Study.

AIM: To understand preoperative experiences and information needs of Chinese school-aged children undergoing elective surgery to design standardized preoperative education programs to alleviate preoperative anxiety. METHODS: Semi-structured interviews combined with drawing, writing, and telling techniques were conducted in 12 children. The paintings were interpreted alongside children's verbal expressions. All data were analyzed using thematic analysis. RESULTS: Three themes emerged: Origins of Surgical Knowledge: Proximity-based knowledge, media exposure, past personal medical experiences, ward-mate interactions, healthcare staff education; Pre-Surgery Experiences: Anticipation of pain, post-op sensations and impact on life, fantasizing about the operation, being aware of risks, demonstrating psychological resilience, being curious about anesthesia experience, enjoying a break; Preoperative Informational Needs: 55 identified. CONCLUSIONS: Lack of standardized preoperative education creates a gap between children's knowledge and actual surgical experiences. Developing preoperative education tailored to individualized informational needs and developmental level helps fill their gaps, alleviate preoperative anxiety and improve health outcomes.

A novel fluorescent probe for rapid detection of sulfatase in vitro and in living cells.

Sulfatase participates in a variety of physiological processes in organisms including hormone regulation, cell signaling, and bacterial pathogenesis. Current sulfatase fluorescent probes can be used to track sulfate esterase overexpression in cancer cells for diagnostic purposes and to understand the pathological activity of sulfate esterase. However, some sulfatase fluorescent probes based on the hydrolysis of the sulfate bond were easily disturbed by the catalytic activity of sulfatase. Herein, we developed the fluorescent probe BQM-NH2 for sulfatase detection, which was based on the quinoline-malononitrile. The probe BQM-NH2 showed a fast response to sulfatase within 1 min and satisfactory sensitivity with a calculated LOD of 1.73 U/L. Importantly, it was successfully used to monitor endogenous sulfate in tumor cells, indicating BQM-NH2 has the potential to monitor sulfatase under physiological and pathological conditions.

In situ growth of UiO-66-NH2 in wood-derived cellulose for iodine adsorption.

The capture of radioactive iodine is an inevitable requirement in nuclear industry for environmental protection. Metal-organic frameworks (MOFs) are a new generation of sorbents that have wide applications for iodine adsorption and recovery. Although the loading of MOFs on wood can avoid the drawbacks of the powder form of MOFs in implementation, the dense structure of wood results in the lower loading, even after delignification, which limits the adsorption capacity. Herein, a hierarchically porous UiO-66-NH2 @WCA composite was fabricated by in-situ synthesis of UiO-66-NH2 in wood-derived cellulose aerogel (WCA) that was further removed hemicellulose from delignified wood. UiO-66-NH2 @WCA exhibited a high loading (36 wt%) of UiO-66-NH2 crystals and a high adsorption capacity of 704 mg/g for iodine vapor and 248 mg/g for iodine aqueous solution. The adsorption behavior in iodine aqueous solution was well predicted by the Freundlich isotherm and pseudo-second-order kinetic model. The adsorption capacity of UiO-66-NH2 @WCA was highest in solution when the pH was 6, while the ionic strength had little effect. The hydroxyl groups on the WCA matrix had a charge transfer effect with iodine, providing additional sites for iodine capture. Furthermore, a packed column system was applied to demonstrate the excellent recyclability and potential for practical application.

Individualize management for advanced breast cancer with pyrotinib-based anti-HER2 therapy: a case report.

Background: We report a case of metastatic human epidermal growth factor receptor-2 (HER2) positive breast cancer who achieved encouraging clinical benefits across multiple pyrotinib-based anti-HER2 therapies. Case Description: A 33-year-old woman was diagnosed with hormone receptor (HR) positive, HER2-positive breast cancer in June 2018, and did not receive adjuvant radiotherapy, chemotherapy, or anti-HER2 targeted therapy post-breast conserving surgery. By May 2020, she developed recurrence of the left breast mass with metastases in liver, bone and lymph nodes. She then received pyrotinib plus trastuzumab and nab-paclitaxel as first-line therapy. Both the left breast mass and liver metastases showed noticeable improvement, with the disease evaluated as partial response (PR). Despite this promising result, the patient developed brain metastases after first-line treatment. A combination regimen of pyrotinib retention plus inetetamab and vinorelbine were administered as second-line anti-HER2 therapy, and the brain metastases visibly shrunk, leading to PR, with the extracranial lesions remaining stable. Ultimately, due to brain lesions progression, the treatment was transitioned to trastuzumab deruxtecan. We applied next generation sequencing (NGS) to illustrate the efficacy of anti-HER2 therapy and minimal residual disease (MRD) to detect the disease status. Conclusions: Pyrotinib is a promising antineoplastic agent for HER2-positive advanced breast cancer patients. Under the guidance of precision medicine, it is encouraged to utilize novel diagnostic and therapeutic methods to manage advanced breast cancer patients.

Muscle injuries and recovery training in college sprinters / Lesões musculares e treinamento de recuperação em velocistas universitários / Lesiones musculares y entrenamiento de recuperación en velocistas universitarios

ABSTRACT Introduction The sprint is extremely explosive, and inadequate training methods can cause irreversible muscle damage. Objective Explore the types of sports injuries, the main sites, the main factors affecting the results of physical training, and the main factors affecting recovery from muscle injuries in college and university sprinters, and propose preventive measures. Methods Taking 174 college sprinters as the research object, we analyzed the conditions related to muscle injury and physical training of sprinters, using field investigation, questionnaire survey, and mathematical statistics. The types of sports injuries, the main sites, the main factors affecting the results of physical training, and the main factors affecting college sprinters' recovery from muscle injury were investigated. Results Among the 174 athletes surveyed, 47.7% had sports injuries of different degrees, and 52.3% had no sports injuries. Different physical training methods, training time, training levels, and slack fatigue training can affect physical training results. Conclusion College sprinters should improve their safety awareness, give importance to preparatory activities and flexibility exercises, optimize strength training programs, and use physical and exercise therapy to promote recovery from muscle injuries. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução O velocismo é um esporte extremamente explosivo, e métodos de treinamento inadequados podem causar danos musculares irreversíveis. Objetivo Explorar os tipos de lesões esportivas, os principais locais, os principais fatores que afetam os resultados do treinamento físico e os principais fatores que afetam a recuperação das lesões musculares dos velocistas em faculdades e universidades, propondo medidas preventivas. Métodos Tomando 174 velocistas universitários como objeto de pesquisa, analisou-se as condições relacionadas à lesão muscular e ao treinamento físico dos velocistas, utilizando investigação de campo, levantamento de questionários e estatísticas matemáticas. Pesquisou-se os tipos de lesão esportiva, os principais locais, os principais fatores que afetam os resultados do treinamento físico e os principais fatores que afetam a recuperação da lesão muscular dos velocistas universitários. Resultados Entre os 174 atletas pesquisados, 47,7% apresentaram lesões esportivas de diferentes graus, e 52,3% não tiveram lesões esportivas. Diferentes métodos de treinamento físico, tempo de treinamento, níveis de treinamento e treinamento negligente de fadiga podem afetar os resultados do treinamento físico. Conclusão Os velocistas universitários devem melhorar sua consciência de segurança, dar importância às atividades preparatórias e aos exercícios de flexibilização, otimizar o programa de treinamento de força, usar a fisioterapia e a terapia de exercícios para promover a recuperação de lesões musculares. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción El sprint es un deporte extremadamente explosivo, y métodos de entrenamiento inadecuados pueden causar daños musculares irreversibles. Objetivo Explorar los tipos de lesiones deportivas, las principales localizaciones, los principales factores que afectan a los resultados del entrenamiento físico y los principales factores que afectan a la recuperación de las lesiones musculares en velocistas colegiales y universitarios, proponiendo medidas preventivas. Métodos Tomando como objeto de investigación 174 velocistas universitarios, se analizaron las condiciones relacionadas con las lesiones musculares y el entrenamiento físico de los velocistas mediante investigación de campo, encuesta por cuestionario y estadística matemática. Se investigaron los tipos de lesiones deportivas, las principales localizaciones, los principales factores que afectan a los resultados del entrenamiento físico y los principales factores que afectan a la recuperación de las lesiones musculares de los velocistas universitarios. Resultados De los 174 deportistas encuestados, el 47,7% tenía lesiones deportivas de distinto grado y el 52,3% no tenía lesiones deportivas. Los diferentes métodos de entrenamiento físico, el tiempo de entrenamiento, los niveles de entrenamiento y el entrenamiento descuidado por fatiga pueden afectar a los resultados del entrenamiento físico. Conclusión Los velocistas universitarios deben mejorar su conciencia de seguridad, dar importancia a las actividades preparatorias y a los ejercicios de flexibilidad, optimizar el programa de entrenamiento de fuerza, utilizar la fisioterapia y la terapia de ejercicio para promover la recuperación de las lesiones musculares. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Cardiac Safety in Breast Cancer Patients Receiving Pegylated Liposome Doxorubicin Sequential Anti-HER2 Monoclonal Antibody Therapy.

Background: Cardiotoxicity associated with the sequential use of anthracyclines followed by trastuzumab is common in adjuvant therapy of patients with HER2-positive early breast cancer (eBC). However, the cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) is relatively less studied. Method: Clinical data of patients with HER2-positive eBC treated with PLD and cyclophosphamide (PLD-C) followed by taxanes plus trastuzumab ± pertuzumab (TH or TPH) who then completed standard anti-HER2 treatment for 12 months from June 2012 to August 2021 were retrospectively collected. The primary endpoints were clinical and subclinical cardiotoxicity. Result: In total, 70 eligible patients were enrolled. Among them, 55 patients (78.6%) received PLD-C → TH and 15 patients (21.4%) received PLD-C → TPH. The median follow-up time was 41.8 months. Until August 2021, only two patients had recurrent or metastatic diseases, with 2-year and 5-year disease-free survivals of 98.6% and 96.8%, respectively. Clinical cardiotoxicity occurred in six patients (8.6%), and all of them had an absolute decline of ≥16% from baseline left ventricular ejection fraction (LVEF) but not below the lower limit of normal (LLN = 50%). Subclinical cardiotoxicity events occurred in 17 patients (24.3%), and all of them had absolute declines of ≥10% and <16% from baseline LVEF but not below the LLN. No patients were interrupted from treatment, and all patients completed anti-HER2 treatment for 12 months. The sharpest decrease in LVEF was observed at 18 months after the start of PLD treatment. The cumulative incidences of clinical and subclinical cardiotoxicity were 9.8% and 28.3%, respectively. In the univariate analysis, body mass index, age, left chest wall radiotherapy, and ongoing cardiovascular risk factors were not significantly associated with clinical or subclinical cardiotoxicity (p > 0.05). No patients had congestive heart failure or death caused by PLD or anti-HER2 treatment. Conclusion: The sequential use of PLD and trastuzumab showed a lower incidence of clinical cardiotoxicity, presented as asymptomatic decreased LVEF, compared with the results obtained in previous clinical studies using conventional anthracycline, taxanes and trastuzumab. The study regimen demonstrated good cardiac tolerance and is an alternative strategy for cardioprotection in patients with HER2-positive eBC.

Highly selective fluorescent probe based on AIE for identifying cysteine/homocysteine.

Cysteine (Cys) and homocysteine (Hcy) are involved in maintaining homeostasis in the body and are relevant to various diseases. While the level of Cys and Hcy is much lower than GSH in the living system, which leads to a major challenge to selectively identify Cys/Hcy in the presence of large amounts of GSH. In this paper, an AIE fluorescent probe SQM-NBD was obtained by connecting NBD to the hydroxyl group of the fluorophore SQM-OH for selective detection of Cys/Hcy. Probe SQM-NBD had no fluorescence itself. But, under the disturbance of GSH, the fluorescence signal of probe SQM-NBD could be turned on by Cys/Hcy. The study of the response mechanism showed that probe SQM-NBD could release both SQM-OH and Cys/Hcy-NBD after reacting with Cys/Hcy. While Cys/Hcy continued to quench the fluorescence of SQM-OH through the combination of Michael addition and the ion rich environment, resulting in only the fluorescence signal of Cys/Hcy-NBD being observed. SQM-NBD appeared superior sensitivity to Cys/Hcy, with LOD of 54 nM and 72 nM, respectively. Significantly, probe SQM-NBD realized the application of fluorescence imaging of Cys/Hcy in HeLa cells, indicating that probe SQM-NBD has the potential for Cys/Hcy identification under physiological and pathological conditions.

A novel turn-on type AIE fluorescent probe for highly selective detection of cysteine/homocysteine and its application in living cells.

Biothiols, associated with multiple physiological and pathological processes, have structural similarities. Monitoring Biothiols selectively in organisms is of great significance. Burdened by the aggregation-caused quenching (ACQ) effect, the applications of conventional biothiols fluorescent probes are extremely limited. Herein, we developed a "turn-on" type aggregation-induced emission (AIE) fluorescent probe BQM-NBD, which was composed of a BQM-OH fluorophore molecule with AIE effect and the recognition group 7-nitro-1,2,3-benzoxadiazole (NBD). Non-fluorescent BQM-NBD produces strong fluorescence after the addition of cysteine (Cys) or homocysteine (Hcy). BQM-NBD exhibited excellent linearity for selective detection of Cys (0-100 Μm) and Hcy (0-50 µM) with detection limits of 6.0 × 10-8 M and 8.4 × 10-8 M, respectively. Simultaneously, after treatment with glutathione (GSH), it appeared no fluorescence. The results demonstrated BQM-NBD exhibited good selectivity to Cys/Hcy. Furthermore, BQM-NBD was successfully performed in the imaging of Cys in living cells with low cytotoxicity, which provides a feasible strategy for the selective detection of Cys in the living system.

ADAMTS9-AS1 Constrains Breast Cancer Cell Invasion and Proliferation via Sequestering miR-301b-3p.

Objective: For determination of how ADAMTS9-AS1/miR-301b-3p/TGFBR2/JAK STAT signaling axis modulates progression of breast cancer cells. Methods: Target lncRNA was determined by differential analysis of breast cancer expression data and survival analysis. Differentially expressed miRNAs and target mRNAs that had binding sites with target lncRNA were predicted. GSEA software was used to carry out pathway enrichment analysis for mRNAs. Binding of the researched genes were tested with RNA binding protein immunoprecipitation (RIP). How miR-301b-3p bound TGFBR2 mRNA was tested by dual-luciferase method. Transwell, colony formation, EdU approaches were employed for verification of invasion and proliferation of breast cancer cells in each treatment group. Results: Markedly inactivated ADAMTS9-AS1 in breast cancer pertained to patient's prognosis. MiR-301b-3p was capable of binding TGFBR2/ADAMTS9-AS1. However, overexpression of ADAMTS9-AS1 stimulated miR-301b-3p binding ADAMTS9-AS1 and repressed miR-301b-3p binding TGFBR2 mRNA. ADAMTS9-AS1 interference enhanced cancer proliferation and invasion, facilitated levels of KI67, PCNA, MMP-9 and MMP-2, and activated the JAK STAT signaling pathway. While silencing miR-301b-3p reversed the effect of ADAMTS9-AS1 interference. In addition, TGFBR2 interference or restraining JAK STAT signaling counteracted the effect of ADAMTS9-AS1. Conclusion: ADAMTS9-AS1 could sequester miR-301b-3p to inhibit progression of breast cancer via TGFBR2/JAK STAT pathway. This study supplies a rationale for incremental apprehension of ADAMTS9-AS1 in breast cancer progression.

Ki67 and progesterone receptor status predicts sensitivity to palbociclib: a real-world study.

BACKGROUND: Palbociclib combined with endocrine therapy has been approved as a front-line treatment for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC). A key challenge remains to uncover biomarkers to identify those patients who may benefit from palbociclib treatment. METHODS: We retrospectively analyzed the values of Ki67 and progesterone receptor (PR) as detected by immunohistochemistry in 81 ABC patients with palbociclib and hormone therapy treatment, and evaluated the impact on progression-free survival (PFS). RESULTS: In the total population, women with Ki67 ≥14% had marginally significantly shorter PFS than those with Ki67 <14% (P=0.062). Patients with Ki67 ≥30% had significantly shorter PFS than those with Ki67 <30% (P=0.048). Meanwhile, PR ≥20% was associated with longer PFS. Moreover, the change of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. As for the hormone therapy subgroup, there were significant associations between Ki67 and PR levels and PFS in the aromatase inhibitors (AIs) subgroup. Patients with Ki67 ≥14% or Ki67 ≥30% had shorter PFS than those with Ki67 <14% or Ki67 <30%, respectively (P=0.024, P<0.001). Additionally, the change of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. When both Ki67 and PR were considered, there were significant differences between the different cohorts. Compared with patients with Ki67 ≥14% and PR <20%, those with Ki67 <14% and PR ≥20% had significantly longer PFS. In addition, patients with Ki67 <30% and PR ≥20% had significantly longer PFS than those with Ki67 ≥30% and PR <20%. Furthermore, in the AI cohort, patients with Ki67 <14% and PR ≥20% had significantly longer PFS than those with Ki67 ≥14% and PR <20%. Women with Ki67 <30% and PR ≥20% had significantly longer PFS than those with Ki67 ≥30% and PR <20%. CONCLUSIONS: The present study indicates that both Ki67 and PR have great impacts on palbociclib and hormone therapy and may contribute to selecting more effective partners for palbociclib.

Efficacy of fulvestrant 500 mg in Chinese postmenopausal women with advanced/recurrent breast cancer and factors associated with prolonged time-to-treatment failure: A retrospective case series.

This study was to investigate the efficacy and safety of fulvestrant 500 mg for the treatment of hormone receptor positive advanced postmenopausal women, including ovarian ablation and investigated factors associated with prolonged time-to-treatment failure.Data from 60 women with metastatic breast cancer who were treated at Zhejiang Cancer Hospital. Patients received 500 mg (n = 60) between December 2011 and November 2012 were followed until November 2017. Main outcomes were clinical responses to fulvestrant, including best response, progressive disease, partial response, and stable disease lasting 12 months or more. Time to progression and time to progression-free-survival were also analyzed.Among the included 60 patients (mean age 47.18 years), 51 (85.0%) had received prior adjuvant therapy. During follow-up after fulvestrant treatment, the median PFS for the best response was derived as 7.0 months (inter-quartile = 4, 13.8 months). The observed median progression-free-survival time for best response was represented longer when fulvestrant was first-line treatment than when patients received prior endocrine and/or chemotherapy. Univariate analysis revealed that receiving either endocrine therapy only or endocrine therapy plus chemotherapy prior to fulvestrant treatment may be associated with median progression-free survival time to best response (P = .002, .026, .007, respectively).Fulvestrant treatment is safe and well-tolerated in women with hormone-sensitive advanced breast cancer, and first-line fulvestrant therapy increases progression-free-survival time, especially in patients without prior adjuvant treatment.

In vitro testicular organogenesis from human fetal gonads produces fertilization-competent spermatids.

Unlike most organs that mature during the fetal period, the male reproductive system reaches maturity only at puberty with the commencement of spermatogenesis. Robust modelling of human testicular organogenesis in vitro would facilitate research into mechanisms of and factors affecting human spermatogenic failure and male fertility preservation in prepubertal tumor patients. Here, we report successful recapitulation of human testicular organogenesis in vitro from fetal gonadal ridge. Our model displayed the formation of mature seminiferous epithelium and self-renewing spermatogonia. Remarkably, in vitro-derived haploid spermatids have undergone meiotic recombination, and showed increased genetic diversity as indicated by genetic analysis. Moreover, these spermatids were able to fertilize oocytes and support subsequent blastocyst formation. The in vitro testicular organogenesis system described here will play an important role in elucidating the regulation of human testis development and maintaining male fertility in prepubertal cancer patients.

Risk evaluation of splenic hilar or splenic artery lymph node metastasis and survival analysis for patients with proximal gastric cancer after curative gastrectomy: a retrospective study.

BACKGROUND: As splenectomy and spleen-preserving lymphadenectomy are performed only in some proximal gastric cancer patients, it is difficult to identify patients who have undergone radical gastrectomy with or without splenic hilar (No.10) or splenic artery (No.11) lymph node metastases. We aimed to determine the risk factors for No.10 and No.11 lymph node metastases and evaluate the survival significance of No.10 and No.11 lymph node dissection in advanced proximal gastric cancer patients. METHODS: A total of 873 advanced proximal gastric cancer patients who underwent curative gastrectomy with or without splenectomy or pancreaticosplenectomy were analyzed retrospectively. The clinicopathological characteristics of 152 patients who underwent splenectomy or pancreaticosplenectomy were analyzed to determine the risk factors for No.10 and No.11 lymph node metastases. The survival difference between patients with No.10 and No.11 lymph node dissections and those who did not undergo these dissections were compared. RESULTS: Patients with No.10 and No.11 lymph node metastases had very poor prognoses. Tumor invasion of the greater curvature and No.2 and No.4 lymph node metastases were independent risk factors for No.10 and No.11 lymph node metastases. No survival differences were evident between patients with No.10 and No.11 lymph node metastases who underwent No.10 and No.11 lymph node dissections and those who did not undergo these dissections but were at high risks of No.10 and No.11 lymph node metastases. CONCLUSIONS: Splenic hilar or splenic artery lymph node dissection was not associated with increased survival, in proximal gastric cancer patients without direct cancer invasion of the spleen and pancreas, regardless of whether splenectomy, pancreaticosplenectomy, or spleen-preserving lymphadenectomy was performed.

circTADA2As suppress breast cancer progression and metastasis via targeting miR-203a-3p/SOCS3 axis.

More and more evidence indicates that circular RNAs (circRNAs) have important roles in several diseases, especially in cancers. However, their involvement remains to be investigated in breast cancer. Through screening circRNA profile, we identified 235 differentially expressed circRNAs in breast cancer. Subsequently, we explored the clinical significance of two circTADA2As in a large cohort of triple-negative breast cancer (TNBC), and performed functional analysis of circTADA2A-E6 in vitro and in vivo to support clinical findings. Finally, we evaluated the effect of circTADA2A-E6 on miR-203a-3p and its target gene SOCS3. We detected two circRNAs, circTADA2A-E6 and circTADA2A-E5/E6, which were among the top five differentially expressed circRNAs in breast cancer. They were consistently and significantly decreased in a large cohort of breast cancer patients, and their downregulation was associated with poor patient survival for TNBC. Especially, circTADA2A-E6 suppressed in vitro cell proliferation, migration, invasion, and clonogenicity and possessed tumor-suppressor capability. circTADA2A-E6 preferentially acted as a miR-203a-3p sponge to restore the expression of miRNA target gene SOCS3, resulting in a less aggressive oncogenic phenotype. circTADA2As as promising prognostic biomarkers in TNBC patients, and therapeutic targeting of circTADA2As/miRNA/mRNA network may be a potential strategy for the treatment of breast cancer.

Downregulation of miR­200c­3p contributes to the resistance of breast cancer cells to paclitaxel by targeting SOX2.

Acquisition of resistance to paclitaxel is a major obstacle to successful treatment of breast cancer patients, but the molecular mechanisms underlying the development of drug resistance remain largely unclear. The aim of the present study was to investigate the role and mechanism of action of miR­200c­3p in the resistance of breast cancer to paclitaxel. It was observed that miR­200c­3p expression, as determined by reverse transcription­quantitative polymerase chain reaction analysis, was significantly downregulated in paclitaxel­resistant MCF­7/Tax cells compared with parental MCF­7 cells. Overexpression of miR­200c­3p increased the chemosensitivity to paclitaxel and enhanced apoptosis in MCF­7/Tax cells, whereas the downregulation of miR­200c­3p exerted the opposite effect. In addition, upregulation of miR­200c­3p in MCF­7/Tax cells suppressed the expression of sex­determining region Y­box 2 (SOX2) at the mRNA and protein levels. Dual­luciferase reporter assay demonstrated that SOX2 is a target of miR­200c­3p in MCF­7/Tax cells. Moreover, knockdown of SOX2 expression increased chemosensitivity to paclitaxel and upregulated miR­200c­3p expression in MCF­7/Tax cells. Taken together, the results of the present study indicated that miR­200c­3p plays a key role in the development of paclitaxel resistance in breast cancer, possibly partially through regulating SOX2 expression, suggesting that the miR­200c­3p­SOX2 loop may serve as a potential target for the reversal of paclitaxel resistance in breast cancer.

Bioinformatics identification of dysregulated microRNAs in triple negative breast cancer based on microRNA expression profiling.

Triple negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer cases and is usually more aggressive with a poorer clinical outcome compared with other breast cancer subtypes. Evidence of the involvement of microRNAs (miRNAs) in cancer has provided an opportunity for the development of novel effective therapeutic targets in TNBC. In the present study, the miRNA expression profiles of the human breast cancer cell line, MDA-MB-231, and MCF-7 cells, was evaluated by using miRNA microarray analysis. A total of 107 differentially expressed miRNAs (57 upregulated and 50 downregulated) were identified in MDA-MB-231 cells compared with MCF-7 cells. Five prominently dysregulated miRNAs (miR-200c-3p, miR-221-3p, miR-222-3p, miR-192-5p and miR-146a) were further confirmed by reverse transcription-quantitative polymerase chain reaction. In addition, gene ontology analysis and pathway enrichment analysis revealed that the dysregulated miRNAs and predicted targets were found to be involved in the mitogen-activated protein kinase, Wnt, and transforming growth factor-ß signaling pathways, which were known to contribute to TNBC progression and metastasis. Finally, miRNA gene network analyses suggested that miR-200c may serve as a crucial miRNA in breast cancer. Taken together, these findings may provide a comprehensive view of the function of aberrant miRNAs involved in TNBC, and dysregulated miRNAs hold promise as potential biomarkers and therapeutic targets for patients with TNBC.

Anatomical location of metastatic lymph nodes: an indispensable prognostic factor for gastric cancer patients who underwent curative resection.

BACKGROUND: Although the numeric-based lymph node (LN) staging was widely used in the worldwide, it did not represent the anatomical location of metastatic lymph nodes (MLNs) and not reflect extent of LN dissection. Therefore, in the present study, we investigated whether the anatomical location of MLNs was still necessary to evaluate the prognosis of node-positive gastric cancer (GC) patients. METHODS: We reviewed 1451 GC patients who underwent radical gastrectomy in our institution between January 1986 and January 2008. All patients were reclassified into several groups according to the anatomical location of MLNs and the number of MLNs. The prognostic differences between different patient groups were compared and clinicopathologic features were analyzed. RESULTS: In the present study, both anatomical location of MLNs and the number of MLNs were identified as the independent prognostic factors (p < .01). The patients with extraperigastric LN involvement showed a poorer prognosis compared with the perigastric-only group (p < .001). For the N1-N2 stage patients, the prognostic discrepancy was still observed among them when the anatomical location of MLNs was considered (p < .05). For the N3-stage patients, although the anatomical location of MLNs had no significant effect on the prognosis of these patients, the higher number of MLNs in the extraperigastric area was correlated with the unfavorable prognosis (p < .05). CONCLUSION: The anatomical location of MLNs was an important factor influencing the prognostic outcome of GC patients. To provide more accurate prognostic information for GC patients, the anatomical location of MLNs should not be ignored.

Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation.

METTL3 catalyzes the formation of N6-methyl-adenosine (m6A) which has important roles in regulating various biological processes. However, the in vivo function of Mettl3 remains largely unknown in mammals. Here we generated germ cell-specific Mettl3 knockout mice and demonstrated that Mettl3 was essential for male fertility and spermatogenesis. The ablation of Mettl3 in germ cells severely inhibited spermatogonial differentiation and blocked the initiation of meiosis. Transcriptome and m6A profiling analysis revealed that genes functioning in spermatogenesis had altered profiles of expression and alternative splicing. Our findings provide novel insights into the function and regulatory mechanisms of Mettl3-mediated m6A modification in spermatogenesis and reproduction in mammals.

Redox responsive liposomal nanohybrid cerasomes for intracellular drug delivery.

Cerasome is a freshly developped bilayer vehicle that resemble traditional liposome but has higher mophorlogical stability. In this study, a novel redox-responsive cerasome (RRC) was developed for tumor-targeting drug delivery. The cerasome-forming lipid (CFL) that comprise a cleavable disulfide bond as connector unit of the triethoxysilyl head and the hydrophobic alkyl double chain was synthesized and subsequently used to prepare cerasome through ethanol injection method. RRC that has liposome-resembling lipid bilayer structure was proved being outstanding at drug loading capacity as well as morphological stability as compared to conventional liposomes. In addition, in vitro drug release tests of DOX/RRCs showed a redox-responsive drug release profile: accelerated DOX releasing compared to reduction-insensitive cerasomes (RICs) in the presence of 10mM of GSH. Under the same condition, the reduction sensibility of RRC was further proved by increased hydrodynamic diameter and destroying of integrity from DLS and SEM results. RRC showed non-toxic to human embryonic kidney 293 cells, indicating that this material has good biocompatibility. On the other hand, DOX/RRCs showed a resemble IC50 (half inhibitory concentration) value to that of free DOX to human hepatoma SMMC-7721 cells and breast cancer MCF-7 cells. IC50 values at 48h were found to decrease in the following order: DOX/RIC>DOX/RRC>DOX. Taken together, the RRC developped in this study is of great potential to be utilized as a promising platform for intracellular anticancer drug delivery.