HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity.

YAP/TAZ transcriptional co-activators play pivotal roles in tumorigenesis. In the Hippo pathway, diverse signals activate the MST-LATS kinase cascade that leads to YAP/TAZ phosphorylation, and subsequent ubiquitination and proteasomal degradation by SCFß-TrCP . When the MST-LATS kinase cascade is inactive, unphosphorylated or dephosphorylated YAP/TAZ translocate into the nucleus to mediate TEAD-dependent gene transcription. Hippo signaling-independent YAP/TAZ activation in human malignancies has also been observed, yet the mechanism remains largely elusive. Here, we report that the ubiquitin E3 ligase HERC3 can promote YAP/TAZ activation independently of its enzymatic activity. HERC3 directly binds to ß-TrCP, blocks its interaction with YAP/TAZ, and thus prevents YAP/TAZ ubiquitination and degradation. Expression levels of HERC3 correlate with YAP/TAZ protein levels and expression of YAP/TAZ target genes in breast tumor cells and tissues. Accordingly, knockdown of HERC3 expression ameliorates tumorigenesis of breast cancer cells. Our results establish HERC3 as a critical regulator of the YAP/TAZ stability and a potential therapeutic target for breast cancer.

Nogo-B receptor increases the resistance to tamoxifen in estrogen receptor-positive breast cancer cells.

BACKGROUNDS: Tamoxifen is typically used to treat patients with estrogen receptor alpha (ERα)-positive breast cancer. However, 30% of these patients gain acquired resistance to tamoxifen during or after tamoxifen treatment. As a Ras modulator, Nogo-B receptor (NgBR) is required for tumorigenesis through the signaling crosstalk with epidermal growth factor (EGF) receptor (EGFR)-mediated pathways. NgBR is highly expressed in many types of cancer cells and regulates the sensitivity of hepatocellular carcinoma to chemotherapy. In this study, we found the expression of NgBR is increased in tamoxifen-resistant ERα-positive breast cancer cells. METHODS: Tamoxifen-resistant ERα-positive MCF-7 and T47D breast cancer cell lines were established by culturing with gradually increased concentration of 4-hydroxytamoxifen (4-OHT). The effects of NgBR on tamoxifen resistance was determined by depleting NgBR in these cell lines using previously validated small interfering RNA (siRNA). The effects of 4-OHT on cell viability and apoptosis were determined using well-accepted methods such as clonogenic survival assay and Annexin V/propidium iodide staining. The alteration of EGF-stimulated signaling and gene expression was determined by western blot analysis and real-time PCR, respectively. RESULTS: NgBR knockdown with siRNA attenuates EGF-induced phosphorylation of ERα and restores the sensitivity to tamoxifen in ERα-positive breast cancer cells. Mechanistically, our data demonstrated that NgBR knockdown increases the protein levels of p53 and decreases survivin, which is an apoptosis inhibitor. CONCLUSIONS: These results suggested that NgBR is a potential therapeutic target for increasing the sensitivity of ERα-positive breast cancer to tamoxifen.

A near-infrared xanthene fluorescence probe for monitoring peroxynitrite in living cells and mouse inflammation model.

Peroxynitrite (ONOO-) plays important roles in the regulation of many physiological and pathological processes, and an increase in its levels is related to numerous diseases. Thus, accurate detection of ONOO- in physiological conditions is imperative for elucidating its functions. However, studies on high signal-to-noise-ratio (SNR) fluorescence imaging of ONOO-in vivo for its detection are currently lacking. Thus, a novel NIR xanthene fluorescence probe (NOF2) for the endogenous detection of ONOO- is designed and synthesized. The fluorescence of the NOF2 probe is pre-quenched by the hydroxyl protection group of diphenyl phosphinate. Additionally, the NOF2 probe exhibits good selectivity and sensitivity for ONOO- with a low detection limit of 0.40 µM. Importantly, the NOF2 probe displays good performances for the detection of endogenous ONOO- not only in living cells but also in a mouse inflammation model. This demonstrates its great potential for applications involving the detection of ONOO- both in vitro and in vivo to explore the roles of ONOO- in different physiological systems.

A new tetraphenylethylene based AIE sensor with light-up and tunable measuring range for adenosine triphosphate in aqueous solution and in living cells.

An AIE based tetraphenylethylene derivative (TPPTPE) was synthesized for light-up sensing of ATP in aqueous solution. The measuring range for ATP can be tuned by varying the concentration of the TPPTPE. A one-step straightforward quantitative analysis of the ATP level in cell lysates can be realized using the TPPTPE. Moreover, the TPPTPE can be used for monitoring apyrase activity in aqueous solution and detecting ATP both in living cancer cell lines and in living normal cell lines.

Renal primitive malignant tumor with endocrine activity.

OBJECTIVE: To report a hypertensive and systematically pigmented female with primitive neuroectodermal tumors. CLINICAL PRESENTATION AND INTERVENTION: A female patient presented with a complaint of right flank pain. She had a right renal space-occupying lesion, underwent right radical nephrectomy, and returned to normotensive postoperatively. The pathological examination identified typical primitive neuroectodermal tumor histology. During a 60-month follow-up period, she remained normotensive and demonstrated normal renal and adrenal functions. CONCLUSION: Early diagnosis and definitive surgery led to the patient's long-term survival.

The effect of folic acid on ovine fetuses in utero during late gestation.

To investigate whether folic acid would have toxic effects on fetal cardiac, hepatic, and renal functions, this was the first in utero fetal study testing acute effects of folic acid at the last third of gestation. Folic acid (5 mg/day) or 0.9% saline as the control was intragastricly administrated into pregnant ewes. Both maternal and fetal blood were analyzed for pH, PO(2), PCO(2), SO(2)%, hemoglobin, hematocrit, glucose, lactic acid, osmolality, Na(+), and K(+) concentrations. Maternal and fetal cardiovascular functions were assessed by examining cardiac enzymes and cardiovascular responses in vivo. Fetal hepatic and renal functions were examined by analysis of biochemistry index and renal excretion. Folic acid did not alter the blood values in both ewes and fetuses. Cardiac enzyme activities remained unchanged, and no alteration in cardiovascular responses was observed. Folic acid did not affect fetal urine volume, urine electrolytes, and osmolality. Enzyme activities related to hepatic and renal functions were not changed. In addition, maternal application of folic acid had no effect on maternal and fetal lipid profile. The results showed that folic acid used (5 mg/day) during the last third of gestation did not cause biochemical changes related to cardiac, hepatic, and renal functions in both maternal and fetal sheep, providing new information for use of folic acid during late pregnancy.

Identification of an immune-related gene pair signature in breast cancer.

Background: Although breast cancer outcome has improved significantly with the recent use of molecularly targeted agents, reliable prognostic signatures are still unavailable because of tumor heterogeneity. Immune processes play an important role in tumor progression. Therefore, the aim of this study was to construct a prognostic signature based on immune-related genes (IRGs). Methods: Clinical information and gene expression of 3,496 patients were extracted from eight public data sets. A total of 2,498 IRGs associated to 17 immune processes were downloaded from the ImmPort database. RNA sequencing (RNAseq) datasets [The Cancer Genome Atlas (TCGA) and GSE96058] were used as the training set (n=2,736) and all microarray datasets were used as validation set (n=760). IRGs related to prognosis were screened out from the training set and used to construct gene pairs. The Cox regression model was used, based on the immune-related gene pairs (IRGPs). The risk score of each patient was calculated and patients were stratified into high- and low-risk groups according to the optimal threshold of the risk score. Immune cell infiltration was evaluated between both groups. Results: Among the 129 prognostic-related immune genes, 8,256 IRGPs were constructed. After screening, 89 IRGPs, including 86 unique IRGs, were used in the prognostic prediction model. Patients in the high-risk group exhibited a significantly poorer overall survival (OS) both in the training set [hazard ratio (HR): 5.9, 95% confidence interval (CI): 4.61-7.54] and validation set (HR: 1.52, 95% CI: 1.16-1.98) compared to the low-risk group. In addition, patients in the high-risk group showed a significantly lower infiltration of CD8+ T cells than patients in the low-risk group. Conclusions: An independent IRGP signature was constructed. Through pairwise comparison of a set of genes, the OS of patients could be predicted. This method avoids the impact of the batch effect caused by different sequencing platforms and has a promising application prospect.

Real-Time Visualization of the Antioxidative Potency of Drugs for the Prevention of Myocardium Ischemia-Reperfusion Injury by a NIR Fluorescent Nanoprobe.

The burst of the reactive oxygen species (ROS) is the culprit of myocardial ischemia-reperfusion injury. As direct ROS scavengers, antioxidants are clinically documented drugs for the prevention of reperfusion injury. However, some drugs give disappointing therapeutic performance despite their good in vitro effects. Therefore, in vivo assessments are necessary to screen the antioxidants before clinical trials. However, traditional methods such as histological study require invasive and complicated preprocessing of the biological samples, which may fail to reflect the actual level of the unstable ROS with a very short lifetime. Peroxynitrite (ONOO-) is a characteristic endogenous ROS produced during reperfusion. Here, we modified the ONOO--responsive near-infrared fluorescent probe on a myocardium-targeting silica cross-linked micelle to prepare a nanoprobe for the real-time monitoring of ONOO- during coronary reperfusion. A ROS-stable cyanine dye was co-labeled as an internal reference to achieve ratiometric sensing. The nanoprobe can passively target the infarcted myocardium and monitor the generation of ONOO- during reperfusion in real-time. The antioxidants, carvedilol, atorvastatin, and resveratrol, were used as model drugs to demonstrate the capability of the nanoprobe to evaluate the antioxidative potency in situ. The drugs were either loaded and delivered by the nanoprobe to compare their in vivo efficacy under similar concentrations or administered intraperitoneally as a free drug to take their pharmacokinetics into account. The imaging results revealed that pharmacokinetics might be the determinant factor that influences the efficacy of the antioxidants.

Myocardium-Targeted Micelle Nanomedicine That Salvages the Heart from Ischemia/Reperfusion Injury.

Cardioprotective medication is the common treatment to relieve myocardial ischemia/reperfusion (I/R) injury. However, limited by the low bioavailability of therapeutic drugs, the therapeutic outcome is barely satisfactory. Because the I/R injury can enhance the permeability of the vasculature and allow the extravasation of nanoparticles into the surrounding tissue, herein we formulate the cardiotonic drug olprinone (Olp) in cross-linked micelles as the nanomedicine to achieve myocardium-targeted delivery after systematic administration. As a result, the local concentration of Olp in the injured myocardium is raised by orders of magnitude with prolonged drug duration time. The treatment successfully preserves the pumping efficiency of the heart, alleviates ventricular remodeling, and thus stops the positive feedback loop for the deteriorated cardiac function. Consequently, the myocardium-targeted nanomedicine significantly salvages the heart from I/R injury before irreversible pathological changes take place.

STAT5 confers lactogenic properties in breast tumorigenesis and restricts metastatic potential.

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5aca) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5aca reduced the migratory and invasive ability of human breast cancer cell lines in vitro. Furthermore, we demonstrated that STAT5aca overexpression in human breast cancer cells lowered their metastatic burden in xenografted mice. Moreover, RPPA, Western blotting, and studies of ChIPseq data identified several EMT drivers regulated by STAT5. In addition, bioinformatic studies detected a correlation between STAT5 activity and better prognosis of breast cancer patients. Together, we conclude that STAT5 activation during mammary tumorigenesis specifies a tumor phenotype of lactogenic differentiation, suppresses EMT, and diminishes potential for subsequent metastasis.

Clinical features and prognosis of a unilateral fibroadenoma of the breast in a 16-month-old female.

Fibroadenoma of the breast is a common benign disease, occurring mainly in females younger than 30 years of age. Infant fibroadenoma is extremely rare. Here, we report on a 16-month-old female with a 6 month history of unilateral progressive breast enlargement. Upon clinical evaluation, a palpable mass was observed in the upper and outer quarter of the right breast. The single tumor was solid and well circumscribed. Various clinical examinations were performed, including determination of hormone levels, ultrasound, mammography, magnetic resonance imaging, as well as the collection of a fine needle aspiration. The results showed that the sex hormones were present at normal levels. The size of the tumor was approximately 3 × 3 × 3 cm. Enlarged lymph nodes were not detected in the axillary region or any other regions. The tumor was removed surgically and fibroadenoma was diagnosed post-operatively. The patient was followed up for 38 months and no tumor recurrence was observed.

Hard antler extract inhibits invasion and epithelial-mesenchymal transition of triple-negative and Her-2+ breast cancer cells by attenuating nuclear factor-κB signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Hard antler extract (HAE) is a traditional Chinese medicine and has potent antitumor, antioxidative, anti-inflammatory, and immunomodulatory activities. Previous studies have demonstrated that HAE can inhibit human prostate cancer metastasis and murine breast cancer proliferation. However, the effect of HAE on human breast cancer cells has not been clarified. AIM OF THE STUDY: To investigate the effects and underlying mechanism of HAE on self-renewal of stem-like cells and spontaneous and transforming growth factor (TGF)-ß1-enhanced wound healing, invasion and epithelial-mesenchymal transition (EMT) in breast cancer cells. METHODS: HAE was prepared from sika deer by sequential enzymatic digestions and the active compounds were determined by HPLC. The effects of HAE on the viability, mammosphere formation, wound healing and invasion of MDA-MB-231 and SK-BR3 cells were determined. The impact of HAE treatment on spontaneous and TGF-ß1-promoted EMT and the nuclear factor (NF)-κB signaling in breast cancer cells was examined by quantitative RT-PCR and western blotting. RESULTS: Treatment with HAE at varying concentrations did not change the viability of breast cancer cells. However, HAE at 0.25 or 0.5 mg/mL significantly reduced the number and size of formed mammospheres, and inhibited spontaneous and TGF-ß1-enhanced wound healing, invasion and EMT in MDA-MB-231 and SK-BR3 cells in a dose-dependent manner. TGF-ß1 treatment significantly decreased IκBα expression and increased NF-kBp65 phosphorylation in breast cancer cells, indicating that TGF-ß1 enhanced NF-κB signaling. In contrast, HAE treatment attenuated the spontaneous and TGF-ß1-enhanced NF-κB signaling in breast cancer cells. CONCLUSION: Our data indicated that HAE inhibited the self-renewal of stem-like cells and spontaneous and TGF-ß1-enhanced wound healing, invasion and EMT in breast cancer cells by attenuating the NF-κB signaling in vitro.

EZH2-Mediated microRNA-375 Upregulation Promotes Progression of Breast Cancer via the Inhibition of FOXO1 and the p53 Signaling Pathway.

Breast cancer (BC) is the most common gynecologic tumor worldwide where aberrant expression of microRNAs (miRNAs) is frequently involved. Here, we evaluated the function of miR-375 on BC development and the molecules implicated. Differentially expressed genes between tumor and paired normal tissues from BC patients were screened out by microarray analyses. miR-375 was abundantly expressed in BC tissues and cells, and it was correlated with the poor prognosis of patients. Downregulation of miR-375 was introduced into BC cell lines MCF-7 and HCC1954, after which the viability, colony formation, migration, and invasion were suppressed, while the apoptosis of cells was increased, and the xenograft tumors in nude mice were reduced as well. EZH2 increased methylation and phosphorylation of signal transducer and activator of transcription 3 (STAT3) and increased transcription activity of miR-375, while miR-375 directly targeted FOXO1. Either overexpression of EZH2 or downregulation of FOXO1 blocked the functions of anti-miR-375 in cells and animals. FOXO1 was found as an activator of the p53 signaling pathway. This study showed that miR-375 is an important oncogene in BC. EZH2 is an upstream regulator of miR-375 through mediating the methylation of STAT3, while FOXO1 is a downstream target mRNA of miR-375 that activates the p53 signaling pathway to suppress BC development.

Performance Analysis of Indentation Punch on High Energy Lithium Pouch Cells and Simulated Model Improvement.

In this research, the aim relates to the material characterization of high-energy lithium-ion pouch cells. The development of appropriate model cell behavior is intended to simulate two scenarios: the first is mechanical deformation during a crash and the second is an internal short circuit in lithium-ion cells during the actual effect scenarios. The punch test has been used as a benchmark to analyze the effects of different state of charge conditions on high-energy lithium-ion battery cells. This article explores the impact of three separate factors on the outcomes of mechanical punch indentation experiments. The first parameter analyzed was the degree of prediction brought about by experiments on high-energy cells with two different states of charge (greater and lesser), with four different sizes of indentation punch, from the cell's reaction during the indentation effects on electrolyte. Second, the results of the loading position, middle versus side, are measured at quasi-static speeds. The third parameter was the effect on an electrolyte with a different state of charge. The repeatability of the experiments on punch loading was the last test function analyzed. The test results of a greater than 10% state of charge and less than 10% state of charge were compared to further refine and validate this modeling method. The different loading scenarios analyzed in this study also showed great predictability in the load-displacement reaction and the onset short circuit. A theoretical model of the cell was modified for use in comprehensive mechanical deformation. The overall conclusion found that the loading initiating the cell's electrical short circuit is not instantaneously instigated and it is subsequently used to process the development of a precise and practical computational model that will reduce the chances of the internal short course during the crash.

Unexpected massive bleeding caused by extensive maxillary osteonecrosis in a breast cancer patient: a case report.

Diphosphonate application is routinely recommended to treat bone metastasis (BM) in cancer patients. However, the severe side effects of diphosphonate, especially after long-term use, are often overlooked by clinicians. In this article, we describe a case in which a heavily-treated breast cancer patient, suffered from massive bleeding as a result of maxillary osteonecrosis by zoledronic acid (ZA) and apatinib. In October 2018, a 48-year-old Chinese female with breast cancer presented at our department with brain metastases. The patient had experienced progression multiple times and had received several lines of systemic interventions. ZA was administered monthly for a rather long period of 37 months. She also took 250 mg of apatinib, a small molecular tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor 2, daily for 11 days. However, massive bleeding from the oral and nasal cavity occurred that could not be alleviated by conventional means. Computed tomography revealed severe destruction and loss of the right maxillary bone and maxillary sinus wall. A pathological examination of the exfoliated bone tissue further confirmed that the patient was suffering from necrosis rather than metastasis. An emergency interventional embolization was performed, and the bleeding was stopped. In this case, maxillary osteonecrosis developed from the antiresorptive agents. Antiangiogenesis drugs should be avoided whenever possible. In clinical practice, the high risk of osteonecrosis needs to be carefully considered. Further, care needs to be taken to ensure osteonecrosis is not misdiagnosed as BM, especially in stage IV patients. Pathology is a prerequisite for the timely and correct diagnosis and management. Life-threatening toxicity such as massive bleeding, should be avoided to ensure that patients receive adequate antitumor treatments.

Giant Fungated Locally Advanced Breast Carcinoma Responded to Hypofractionated Radiotherapy Combined with Apatinib: A Case Report and Literature Review.

Locally advanced breast cancer (LABC) is frequently encountered in clinical practice. Primary systemic therapy is regarded as the cornerstone of LABC management to downstage the disease and enable surgery. However, multiple lines of systemic agents may fail to control tumor growth in a considerable number of patients, and few options remain available for such patients. Here, we present a case of triple-negative, right breast cancer that progressed aggressively despite 3 lines of standard chemotherapy. The patient suffered from severe skin ulceration, bleeding, pain, infection, and fungation. The small-molecular tyrosine kinase inhibitor (TKI) apatinib was initiated, which targets vascular endothelial growth factor receptor 2 (VEGFR2). The patient then underwent hypofractionated irradiation applied to the whole right breast at 40 Gy/8 f. The tumor responded dramatically to this combination, and a near-complete remission (CR) response was achieved 2 months after irradiation. Our case is novel and instructional and demonstrated the efficacy and safety of hypofractionated irradiation combined with antiangiogenesis for the treatment of intractable LABC, shedding light on this difficult situation. In the near future, large-scale clinical trials will be initiated to further explore this issue.

Aldehyde dehydrogenase 1 (ALDH1) immunostaining in axillary lymph node metastases is an independent prognostic factor in ALDH1-positive breast cancer.

OBJECTIVE: To determine whether aldehyde dehydrogenase 1 (ALDH1) immunostaining in axillary lymph node metastases in patients with breast cancer is associated with poor clinical prognosis. METHODS: This retrospective study reviewed data from the medical records of patients with immunohistochemistry-confirmed invasive ductal carcinoma (IDC) and 1-3 metastatic lymph nodes in the ipsilateral axilla between December 2012 and July 2015. The association between ALDH1 immunostaining in axillary lymph node metastases and clinical parameters and prognosis was analysed using χ2-test, Kaplan-Meier survival analysis, univariate and multivariate Cox regression analyses. RESULTS: A total of 229 patients with IDC were enrolled in the study. The median follow-up was 61 months (range, 20-89 months). Patients with ALDH1-positive axillary lymph node metastases had significantly shorter relapse-free survival and overall survival compared with those with ALDH1-negative axillary lymph node metastases. ALDH1 immunostaining in axillary lymph node metastases was a significant predictor of poor prognosis in univariate and multivariate analyses. CONCLUSION: This large study with long-term follow-up suggests that ALDH1 immunostaining in axillary lymph node metastases is an independent predictor of poor prognosis in patients with breast cancer. The clinical relevance of this finding should be confirmed in further well-designed prospective studies.

Application of neoadjuvant chemotherapy combined with anlotinib in occult breast cancer: A case report and review of literature.

BACKGROUND: Occult breast cancer (OBC) is a special type of breast cancer presenting as axillary lymph node metastasis with undetectable primary lesions in the breast. Due to its low incidence and unique clinical manifestations, there is a lack of consensus on the diagnosis and treatment of OBC. We report a case of OBC treated with neoadjuvant chemotherapy combined with anlotinib. The treatment was well tolerated, and the patient achieved a pathologic complete response. CASE SUMMARY: A 53-year-old woman presented with a lump in her right axillary area with no primary lesions in the breast. Pathological biopsy confirmed right axillary metastatic carcinoma. Immunohistochemical staining results were positive for progesterone receptor, cytokeratin 7, specific breast markers GATA3 and gross cystic disease fluid protein-15. Tumor cells were negative for estrogen receptor, human epidermal growth factor receptor-2, cytokeratin 5/6, cytokeratin 20, and villin. The patient was diagnosed with OBC, and she underwent neoadjuvant chemotherapy combined with anlotinib. Mastectomy plus axillary lymph node dissection was performed. The patient achieved pathologic complete response with no residual invasive tumor cells in the breast or axillary lymph nodes. Postoperatively, she received adjuvant radiotherapy and endocrine therapy. CONCLUSION: Neoadjuvant chemotherapy and anlotinib had good efficacy and safety in the treatment of OBC and may be a new therapeutic option.

Higher efficacy and reduced adverse reactions in neoadjuvant chemotherapy for breast cancer by using pegylated liposomal doxorubicin compared with pirarubicin.

The present study aimed to investigate the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) in preoperative neoadjuvant chemotherapy for patients with breast cancer by comparing with conventional anthracycline. This study is a non-randomized controlled trial. Prospective analysis was conducted after matching as required. A total of 146 patients with confirmed diagnosis of breast cancer by histopathological examinations were enrolled into the observation group and control group in 1:1 ratio. Each of the cases in the observation group was required to correspond to another in the control group according to the requirements including age, molecular subtype, axillary node status, and regimen of the preoperative neoadjuvant chemotherapy. The chemotherapy was based on regimens consisting of anthracyclines, paclitaxel or docetaxel, and/or platinum. PLD was used at least twice in the observation group, with traditional anthracycline as a contrast in the control group. Clinical responses as well as cardiac side effects and other adverse reactions were evaluated by clinical and imaging examinations such as electrocardiogram (ECG) and color Doppler ultrasound during the chemotherapy. Pathologic examinations were performed following the surgeries after preoperative neoadjuvant chemotherapy. All the patients in both groups completed the preoperative neoadjuvant chemotherapy according to their original regimens. The postoperative pathological evaluation revealed a higher pathologic complete response (PCR) rate and significantly more patients of grade V of the Miller-Payne grading system in the observation group as compared to the control group (p = 0.047). In addition, the observation group recorded an evidently lower occurrence of the adverse cardiac events (p = 0.014), ECG changes (p = 0.048), and the relatively severe adverse reactions such as myelosuppression. Compared with conventional anthracycline drugs, PLD has a better pathologic response and safety performance, as well as a similar clinical effectiveness in preoperative neoadjuvant chemotherapy for breast cancer.

Mouse mesenchymal stem cells can support human hematopoiesis both in vitro and in vivo: the crucial role of neural cell adhesion molecule.

BACKGROUND: We previously established a mesenchymal stem cell line (FMS/PA6-P) from the bone marrow adherent cells of fetal mice. The cell line expresses a higher level of neural cell adhesion molecule and shows greater hematopoiesis-supporting capacity in mice than other murine stromal cell lines. DESIGN AND METHODS: Since there is 94% homology between human and murine neural cell adhesion molecule, we examined whether FMS/PA6-P cells support human hematopoiesis and whether neural cell adhesion molecules expressed on FMS/PA6-P cells contribute greatly to the human hematopoiesis-supporting ability of the cell line. RESULTS: When lineage-negative cord blood mononuclear cells were co-cultured on the FMS/PA6-P cells, a significantly greater hematopoietic stem cell-enriched population (CD34(+)CD38(-) cells) was obtained than in the culture without the FMS/PA6-P cells. Moreover, when lineage-negative cord blood mononuclear cells were cultured on FMS/PA6-P cells and transplanted into SCID mice, a significantly larger proportion of human CD45(+) cells and CD34(+)CD38(-) cells were detected in the bone marrow of SCID mice than in the bone marrow of SCID mice that had received lineage-negative cord blood mononuclear cells cultured without FMS/PA6-P cells. Furthermore, we found that direct cell-to-cell contact between the lineage-negative cord blood mononuclear cells and the FMS/PA6-P cells was essential for the maximum expansion of the mononuclear cells. The addition of anti-mouse neural cell adhesion molecule antibody to the culture significantly inhibited their contact and the proliferation of lineage-negative cord blood mononuclear cells. CONCLUSIONS: These findings suggest that neural cell adhesion molecules expressed on FMS/PA6-P cells play a crucial role in the human hematopoiesis-supporting ability of the cell line.