Can We Do Breast-Conserving Surgery Without Intraoperative Frozen Section of Margin?

PURPOSE: This study was a retrospective and nonrandomized study to assess the safety and reliability of identifying the surgical margin in breast cancer breast-conserving surgery (BCS) by using intraoperative ultrasonic location and specimen mammography instead of traditional intraoperative frozen pathological section. METHODS: Among the patients who underwent BCS from May 2019 to October 2021, according to the different methods of evaluating the intraoperative margin, 104 breast cancer patients were included in the frozen edge group, 53 breast cancer patients were included in the freeze-free group, and the surgeon judged whether extended resection was needed based on the results of pathological section or evaluation of intraoperative ultrasound and mammography. The surgical margins of the two groups were judged by postoperative pathological results as the gold standard. RESULTS: The median waiting pathology results time in the frozen edge group was 64 minutes, while the waiting time in the freeze-free group was 30 minutes, and the difference was statistically significant (P < .0001). The postoperative pathological results showed that the positive rate of the surgical margin in the frozen edge group was 0.96%. The coincidence rate of intraoperative frozen and postoperative pathological results was 99.04%. The coincidence rate between intraoperative mammography and postoperative pathological results was 100%. CONCLUSIONS: In BCS, the method of using intraoperative staining markers combined with mammography to evaluate the resection margin is highly accurate, reliable, economical and convenient, and at the same time reduces the waiting time of the operator during the operation. However, this was not a randomized controlled study, and there was patient selection bias, and its safety needs to be confirmed by long-term follow-up. In the future, it is expected to become the mainstream means of evaluating.

Neoadjuvant Endocrine Therapy: A Potential Way to Make Cold Hormone Receptor-Rich Breast Cancer Hot.

BACKGROUND: Turning the "cold" tumor immune microenvironment into "hot" is a critical issue in cancer treatment today. Hormone receptor-rich breast cancer (HR+ BC) was previously considered immunologically quiescent. OBJECTIVE: This study aims to explore the immunomodulatory effects of endocrine therapy on HR+ BCs. METHODS: The infiltrations and alterations of the tumor immune microenvironment in HR+ BCs before, after 10-14 days, and after three months of neoadjuvant endocrine therapy were computationally analyzed according to MCP-counter, CIBERSORT, xCell algorithms, and gene-set enrichment analysis (GSEA). The primary microarray data were obtained from three HR+ BC gene expression datasets (GSE20181, GSE55374, and GSE59515). Single-sample GSEA of hallmark and immune response gene sets was performed to evaluate the correlation between suspected treatment response and activated immune pathways in tumors. RESULTS: Both immune and stromal cells were specifically recruited into the HR+ BCs who responded to the neoadjuvant endocrine therapy by letrozole. Besides the enhanced infiltrations of immunosurveillance-related cells such as CD8+ T cells, dendritic cells, and the activation of immune response-related signals, the immunosuppressive M2-like macrophages, as well as the expression of immune checkpoint genes like PDCD1, SIRPA, and some HLA genes, were also stimulated in responders. We identified four pretreatment indicators (the intrinsic luminal subtype, the estrogen response early/late pathway, and the epithelial-mesenchymal transition pathway) as potential predictors of both clinical response and the activation of the tumor immune microenvironment post letrozole. CONCLUSION: Neoadjuvant endocrine therapy showed a promising way to convert the immunologically "cold" HR+ BCs into "hot" tumors. This study provides new insights into the application of immunotherapy for HR+ BCs, especially those who respond to endocrine therapy.

Prominin 1 Significantly Correlated with Bone Metastasis of Breast Cancer and Influenced the Patient's Prognosis.

Background: This study is aimed at identifying the important biomarkers associated with bone metastasis (BM) in breast cancer (BRCA). Methods: The GSE175692 dataset was used to detect significant differential expressed genes (DEGs) between BRCA samples with or without BM, and DEG-related pathways were then explored. Further, we constructed the protein-protein interaction (PPI) network on GEGs and filtered 5 vital nodes. We then performed the Cox regression, Kaplan-Meier analysis, nomogram, and ROC curve to filter the most significant prognosis genes. The GSE14020 and GSE124647 datasets were used to verify the expression and prognostic value of hub genes, respectively. Finally, the gene set enrichment analysis (GSEA) was performed to reveal the potential mechanism. Results: Totally, 74 DEGs were detected, which mainly correlated with infectious disease, signaling molecules, and interaction. The 5 important DEGs were then filtered, and the Cox regression further showed that 2 genes, including prominin 1 (PROM1) and C-C motif chemokine ligand 2 (CCL2), were related to the prognosis of BRCA metastasis patients. Especially, PROM1 presented a better prognostic performance on the survival probability of patients than CCL2. Verification analysis further confirmed the abnormal expression and significant prognostic influence of PROM1. Finally, GSEA revealed that PROM1 was negatively related to IGF1 and mTOR pathways in BRCA metastasis. Conclusion: PROM1 was an important biomarker associated with BRCA bone metastasis and affected the prognosis of metastatic BRCA patients. It may play a vital role in metastatic BRCA by negatively regulating IGF1 and mTOR pathways.

Prognostic Models for Nonmetastatic Triple-Negative Breast Cancer Based on the Pretreatment Serum Tumor Markers with Machine Learning.

PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive disease with poorer prognosis than other subtypes. We aimed to investigate the prognostic efficacy of multiple tumor markers and constructed a prognostic model for stage I-III TNBC patients. Patients and Methods. We included stage I-III TNBC patients whose serum tumor markers levels were measured prior to the treatment. The optimal cut-off value of each tumor marker was determined by X-tile. Then, we adopted two survival models (lasso Cox model and random survival forest model) to build the prognostic model and AUC values of the time-dependent receiver operating characteristic (ROC) were calculated. The Kaplan-Meier method was used to plot the survival curves and the log-rank test was used to test whether there was a significant difference between the predicted high-risk and low-risk groups. We used univariable and multivariable Cox analysis to identify independent prognostic factors and did subgroup analysis further for the lasso Cox model. RESULTS: We included 258 stage I-III TNBC patients. CEA, CA125, and CA211 showed independent prognostic value for DFS when using the optimal cut-off values; their HRs and 95% CI were as follows: 1.787 (1.056-3.226), 2.684 (1.200-3.931), and 2.513 (1.567-4.877). AUC values of lasso Cox model and random survival forest model were 0.740 and 0.663 for DFS at 60 months, respectively. Both the lasso Cox model and random survival forest model demonstrated excellent prognostic value. According to tumor marker risk scores (TMRS) computed by the lasso Cox model, the high TMRS group had worse DFS (HR = 3.138, 95% CI: 1.711-5.033, p < 0.0001) and OS (3.983, 1.637-7.214, p=0.0011) than low TMRS group. Furthermore, subgroup analysis of N0-N1 patients in the lasso Cox model indicated that TMRS still had a significant prognostic effect on DFS (2.278, 1.189-4.346) and OS (2.982, 1.110-7.519). CONCLUSIONS: Our study indicated that pretreatment levels of serum CEA, CA125, and CA211 had independent prognostic significance for TNBC patients. Both lasso Cox model and random survival forest model that we constructed based on tumor markers could strongly predict the survival risk. Higher TMRS was associated with worse DFS and OS both in stage I-III and N0-N1 TNBC patients.

The oncometabolite R-2-hydroxyglutarate dysregulates the differentiation of human mesenchymal stromal cells via inducing DNA hypermethylation.

BACKGROUND: Isocitrate dehydrogenase (IDH1/2) gene mutations are the most frequently observed mutations in cartilaginous tumors. The mutant IDH causes elevation in the levels of R-enantiomer of 2-hydroxylglutarate (R-2HG). Mesenchymal stromal cells (MSCs) are reasonable precursor cell candidates of cartilaginous tumors. This study aimed to investigate the effect of oncometabolite R-2HG on MSCs. METHODS: Human bone marrow MSCs treated with or without R-2HG at concentrations 0.1 to 1.5 mM were used for experiments. Cell Counting Kit-8 was used to detect the proliferation of MSCs. To determine the effects of R-2HG on MSC differentiation, cells were cultured in osteogenic, chondrogenic and adipogenic medium. Specific staining approaches were performed and differentiation-related genes were quantified. Furthermore, DNA methylation status was explored by Illumina array-based arrays. Real-time PCR was applied to examine the signaling component mRNAs involved in. RESULTS: R-2HG showed no influence on the proliferation of human MSCs. R-2HG blocked osteogenic differentiation, whereas promoted adipogenic differentiation of MSCs in a dose-dependent manner. R-2HG inhibited chondrogenic differentiation of MSCs, but increased the expression of genes related to chondrocyte hypertrophy in a lower concentration (1.0 mM). Moreover, R-2HG induced a pronounced DNA hypermethylation state of MSC. R-2HG also improved promotor methylation of lineage-specific genes during osteogenic and chondrogenic differentiation. In addition, R-2HG induced hypermethylation and decreased the mRNA levels of SHH, GLI1and GLI2, indicating Sonic Hedgehog (Shh) signaling inhibition. CONCLUSIONS: The oncometabolite R-2HG dysregulated the chondrogenic and osteogenic differentiation of MSCs possibly via induction of DNA hypermethylation, improving the role of R-2HG in cartilaginous tumor development.

Ferroptosis in Cancer Treatment: Another Way to Rome.

Ferroptosis is a newly described type of programmed cell death and intensively related to both maintaining homeostasis and the development of diseases, especially cancers. Inducing ferroptosis leads to mitochondrial dysfunction and toxic lipid peroxidation in cells, which plays a pivotal role in suppressing cancer growth and progression. Here, we reviewed the existing studies about the molecular mechanisms of ferroptosis involved in different antitumor treatments, such as chemotherapy, targeted therapy, radiotherapy, and immunotherapy. We focused in particular on the distinct combinatorial therapeutic effects such as the synergistic sensitization effect and the drug-resistance reversal achieved when using ferroptosis inducers with conventional cancer therapy. Finally, we discussed the challenges and opportunities in clinical applications of ferroptosis. The application of nanotechnolgy and other novel technologies may provide a new direction in ferroptosis-driven cancer therapies.

Elevated long noncoding RNA MALAT-1 expression is predictive of poor prognosis in patients with breast cancer: a meta-analysis.

Accumulating evidence indicates that aberrant regulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), a long noncoding RNA (lncRNA), plays a vital role in tumorigenesis. However, its association with breast cancer has not been systematically evaluated. In the current study, a meta-analysis was conducted to clarify the association between MALAT-1 and the prognosis and clinicopathological features of breast cancer. Relevant literature published in several databases was searched. Hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated to evaluate the effect of MALAT-1 expression on the survival outcomes and clinicopathological features of breast cancer. A total of 12 studies involving 4106 patients were identified. Pooled HR demonstrated that elevated MALAT-1 expression significantly predicted unfavorable overall survival (HR = 2.06, 95% CI: 1.66-2.56, P<0.0001) in patients with breast cancer. Subgroup analysis stratified by cancer type, sample size, and method of variance analysis also showed statistically significant associations. Additionally, the HR of patients with up-regulated MALAT-1 expression concerning disease-free survival (DFS), recurrence-free survival (RFS), and disease-specific survival (DSS) was 1.91 (95% CI: 1.53-2.39, P<0.0001). Further, elevated MALAT-1 expression was positively correlated with the progesterone receptor (PR) status (OR = 1.47, 95% CI: 1.18-1.82). Thus, MALAT-1 is a promising biomarker for predicting survival outcomes in patients with breast cancer.

Global patterns and trends in the breast cancer incidence and mortality according to sociodemographic indices: an observational study based on the global burden of diseases.

OBJECTIVES: Disparities in the global burden of breast cancer have been identified. We aimed to investigate recent patterns and trends in the breast cancer incidence and associated mortality. We also assessed breast cancer-related health inequalities according to socioeconomic development factors. DESIGN: An observational study based on the Global Burden of Diseases. METHODS: Estimates of breast cancer incidence and mortality during 1990-2016 were obtained from the Global Health Data Exchange database. Subsequently, data obtained in 2016 were described using the age-standardised and age-specific incidence, mortality and mortality-to-incidence (MI) ratios according to sociodemographic index (SDI) levels. Trends were assessed by measuring the annual percent change using the joinpoint regression. The Gini coefficients and concentration indices were used to identify between-country inequalities. RESULTS: Countries with higher SDI levels had worse disease incidence burdens in 2016, whereas inequalities in the breast cancer incidence had decreased since 1990. Opposite trends were observed in the mortality rates of high and low SDI countries. Moreover, the decreasing concentration indices, some of which became negative, among women aged 15-49 and 50-69 years suggested an increase in the mortality burdens in undeveloped regions. Conversely, inequality related to the MI ratio increased. In 2016, the MI ratios exhibited distinct gradients from high to low SDI regions across all age groups. CONCLUSIONS: The patterns and trends in breast cancer incidence and mortality closely correlated with the SDI levels. Our findings highlighted the primary prevention of breast cancer in high SDI countries with a high disease incidence and the development of cost-effective diagnostic and treatment interventions for low SDI countries with poor MI ratios as the two pressing needs in the next decades.

The Role of lncRNAs in the Distant Metastasis of Breast Cancer.

Breast cancer (BC) remains the most frequently diagnosed cancer worldwide. Among breast cancer patients, distant metastasis and invasion is the leading cause of BC related death. Recently, long non-coding RNAs (lncRNAs), which used to be considered a genetic byproduct (owing to their unknown biological function), have been reported to be highly implicated in the development and progression of BC. In this review, we produce a summary of the functions and mechanisms of lncRNAs implicated in the different distant metastases of BC. The functions of lncRNAs have been divided into two types: oncogenic type and tumor suppressor. Furthermore, the majority of them exert their roles through the regulation of invasion, migration, epithelial-mesenchymal transition (EMT), and the metastasis process. In the final part, we briefly addressed future research prospects of lncRNAs, especially the testing methods through which to detect lncRNAs in the clinical work, and introduced several different tools with which to detect lncRNAs more conveniently. Although lncRNA research is still in the initial stages, it is a promising prognosticator and a novel therapeutic target for BC metastasis, which requires more research in the future.

Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China.

To gain more information on the prevalence of germline mutations in BRCA1/2 and PALB2 genes in the Chinese population, and to explore the effects of the mutation status of these genes on clinical outcomes in patients with breast cancer, we performed a screening for BRCA1/2 and PALB2 mutations in a consecutive series of unselected breast cancer patients in the Chinese population. A total of 2,769 cases were enrolled between June 1993 and September 2017. All of the exons and exon-intron boundaries of the BRCA1/2 and PALB2 genes were screened with next-generation sequencing. Of the 2,769 breast cancer patients, BRCA1, BRCA2 and PALB2 mutations accounted for 2.7% (n = 74), 2.7% (n = 76), and 0.9% (n = 24), respectively. The BRCA1 gene had the highest mutation frequency in patients with triple-negative breast cancer (TNBC), which was 9.6% (n = 42), while the BRCA2 gene had the highest mutation frequency in patients with Luminal, which was 3.2% (n = 58). The disease-free survival (DFS) of BRCA1 mutation carriers was significantly lower than that of noncarriers (adjusted HR = 2.20, 95% CI = 1.15-4.18, p = 0.017). The mutation status of the PALB2 gene was significantly associated with the decline in overall survival (OS) (adjusted HR = 8.38, 95% CI = 2.19-32.11, p = 0.002). No significant difference was found between BRCA2 pathogenic mutation carriers and noncarriers. These results demonstrate that BRCA1 mutation status may be associated with a worse disease progression in patients with breast cancer, and women who harbored a PALB2 mutation might be at a higher risk of death due to breast cancer compared to noncarriers.

CXCR4 Antagonist AMD3100 Promotes Mesenchymal Stem Cell Mobilization in Rats Preconditioned with the Hypoxia-Mimicking Agent Cobalt Chloride.

Mobilization of mesenchymal stem cells (MSCs) is an attractive strategy for cell therapy. Our previous study demonstrated that MSCs can be mobilized in circulating blood by short-term hypoxia, and hypoxia-inducible factor-1α is essential for MSC mobilization. In the present study, the effect of the hypoxia-mimicking agent CoCl2 was examined on MSC mobilization. The results indicated that the frequency of circulating MSCs increased slightly by administration of CoCl2. However, the mobilization efficiency was low. Considering the critical role of stromal cell-derived factor-1α (SDF-1)/CXCR4 axis in the regulation of MSC migration, the effects of granulocyte colony-stimulating factor (G-CSF) and the CXCR4 antagonist AMD3100 were investigated on MSC mobilization. The experiments were notably demonstrated in animals preconditioned with CoCl2. The frequency of colony-forming unit fibroblast and the proportion of CD45-CD90+ cells did not significantly increase in the peripheral blood of rats treated with G-CSF and/or AMD3100 alone. The concomitant administration of G-CSF with CoCl2 could not stimulate the release of MSCs. However, AMD3100 dramatically increased MSC mobilization efficiency in rats pretreated with CoCl2. Furthermore, we identified and compared the multilineage differentiation capacities of MSCs derived from bone marrow (BM-MSCs) and mobilized peripheral blood (PB-MSCs). The results indicated that PB-MSCs exhibited higher osteogenic potential and lower adipogenic differentiation as compared with BM-MSCs. The findings may inform studies investigating mechanisms of the regulation of MSC mobilization and can aid in the development of clinically useful therapeutic agents.

Mechanisms and Therapeutic Targets of Depression After Intracerebral Hemorrhage.

The relationship between depression and intracerebral hemorrhage (ICH) is complicated. One of the most common neuropsychiatric comorbidities of hemorrhagic stroke is Post-ICH depression. Depression, as a neuropsychiatric symptom, also negatively impacts the outcome of ICH by enhancing morbidity, disability, and mortality. However, the ICH outcome can be improved by antidepressants such as the frequently-used selective serotonin reuptake inhibitors. This review therefore presents the mechanisms of post-ICH depression, we grouped the mechanisms according to inflammation, oxidative stress (OS), apoptosis and autophagy, and explained them through their several associated signaling pathways. Inflammation is mainly related to Toll-like receptors (TLRs), the NF-kB mediated signal pathway, the PPAR-γ-dependent pathway, as well as other signaling pathways. OS is associated to nuclear factor erythroid-2 related factor 2 (Nrf2), the PI3K/Akt pathway and the MAPK/P38 pathway. Moreover, autophagy is associated with the mTOR signaling cascade and the NF-kB mediated signal pathway, while apoptosis is correlated with the death receptor-mediated apoptosis pathway, mitochondrial apoptosis pathway, caspase-independent pathways and others. Furthermore, we found that neuroinflammation, oxidative stress, autophagy, and apoptosis experience interactions with one another. Additionally, it may provide several potential therapeutic targets for patients that might suffer from depression after ICH.

The Outcome of Breast Cancer Is Associated with National Human Development Index and Health System Attainment.

Breast cancer is a worldwide threat to female health with patient outcomes varying widely. The exact correlation between global outcomes of breast cancer and the national socioeconomic status is still undetermined. Mortality-to-incidence ratio (MIR) of breast cancer was calculated with the contemporary age standardized incidence and mortality rates for countries with data available at GLOBOCAN 2012 database. The MIR matched national human development indexes (HDIs) and health system attainments were respectively obtained from Human Development Report and World Health Report. Correlation analysis, regression analysis, and Tukey-Kramer post hoc test were used to explore the effects of HDI and health system attainment on breast cancer MIR. Our results demonstrated that breast cancer MIR was inversely correlated with national HDI (r = -.950; P < .001) and health system attainment (r = -.898; P < .001). Countries with very high HDI had significantly lower MIRs than those with high, medium and low HDI (P < .001). Liner regression model by ordinary least squares also indicated negative effects of both HDI (adjusted R2 = .903, standardize ß = -.699, P < .001) and health system attainment (adjusted R2 =. 805, standardized ß = -.009; P < .001), with greater effects in developing countries identified by quantile regression analysis. It is noteworthy that significant health care disparities exist among countries in accordance with the discrepancy of HDI. Policies should be made in less developed countries, which are more likely to obtain worse outcomes in female breast cancer, that in order to improve their comprehensive economic strength and optimize their health system performance.

Electro-Acupuncture Promotes Endogenous Multipotential Mesenchymal Stem Cell Mobilization into the Peripheral Blood.

BACKGROUND/AIMS: Mobilization of endogenous stem cells is an appealing strategy for cell therapy However, there is little evidence for reproducible, effective methods of mesenchymal stem cell (MSC) mobilization. In the present study, we investigated the mobilizing effect of electro-acupuncture (EA) on endogenous MSCs. METHODS: Normal adult rats were randomly divided into six groups, namely, EA for 14 days (EA14d), sham EA14d, EA21d, sham EA21d and matched control groups. MSC mobilization efficiency was determined by colony-forming unit fibroblast (CFU-F) assays. Mobilized peripheral blood (PB)-derived MSCs were identified by immunophenotype and multi-lineage differentiation potential. RESULTS: CFU-F frequency was significantly increased in the PB of EA14d rats compared with the sham EA and control groups. Moreover, the number of CFU-Fs was increased further in the EA21d group. MSCs derived from EA-mobilized PB were positive for CD90 and CD44, but negative for CD45. Additionally, these cells could differentiate into adipocytes, osteoblasts, chondrocytes and neural-like cells in vitro. Finally, stromal cell-derived factor-1α (SDF-1α) was increased in the PB of rats subjected to EA, and the migration of MSCs was improved in response to SDF-1α. CONCLUSIONS: MSCs with multi-lineage differentiation potential can be mobilized by EA. Our data provide a promising strategy for MSC mobilization.

Separation of wind's influence on harmful cyanobacterial blooms.

Wind is an important physical factor involved in Harmful Cyanobacterial blooms (CyanoHABs). Its integrated influence was separated to three components: (a) Direct Disturbance Impact (DDI) on cyanbacterial proliferation, (b) Indirect Nutrient Impact (INI) by sediment release and (c) Direct Transportation Impact (DTI) by both gentle wind-induced surface drift and wave-generated Stokes drift. By the combination of field investigation, laboratory experiment and numerical simulation their individual contributions to the severe bloom event in May 2007 in Meiliang Bay, Lake Taihu, was explored. Wind synthetically made 10.5 percent promotion to the bloom on May 28, 2007, but the impact varied with locations. DTI was featured with the strongest contribution of wind's impacts on CyanoHABs, while INI stood at the lowest level and DDI played an intermediate role. From the point of whole Meiliang Bay, the influencing weights of DTI, DDI and INI were approximately 48.55%, 32.30% and 19.15% respectively. DTI exerted the higher promotion in the regions of middle-east (ME), southwest (SW) and southeast (SE), and its actual contribution rate on CyanoHABs ranged from 6.41% to 7.46%. Due to the background nutrient load, INI was characterized by a tiny effect with the contribution rate being 2.18% on average. From the south bay to the north, DDI was detected with a decreasing tendency, with the practical contribution rate generally falling from 4.13% to 2.7%.

Prognostic role of the neutrophil-lymphocyte ratio in renal cell carcinoma: a meta-analysis.

OBJECTIVE: Increasing evidence suggests that cancer-associated inflammation is associated with poor prognosis in patients with cancer. The role of the neutrophil-lymphocyte ratio (NLR) as a predictor in renal cell carcinoma (RCC) remains controversial. We conducted the meta-analysis to determine the association between NLR and clinical outcome of patients with RCC. METHODS AND MATERIALS: Studies were identified from PubMed and EMBASE databases in March 2014. Meta-analysis was performed to generate combined HRs with 95% CIs for overall survival (OS) and recurrence-free/progress-free survival (RFS/PFS). RESULTS: 15 cohorts containing 3357 patients were included. Our analysis results indicated that elevated NLR predicted poorer OS (HR=1.82, 95% CI 1.51 to 2.19) and RFS/PFS (HR=2.18, 95% CI 1.75 to 2.71) in patients with RCC. These findings were robust when stratified by study region, sample size, therapeutic intervention, types of RCC and study quality. However, it differed significantly by assessment of the cut-off value defining 'elevated NLR' in RFS/PFS (p=0.004). The heterogeneity in our meta-analysis was mild to moderate. CONCLUSIONS: Elevated NLR indicates a poorer prognosis for patients with RCC. NLR should be monitored in patients with RCC for rational risk stratification and treatment individualisation.

Phenotypical and functional characterization of bone marrow mesenchymal stem cells in patients with chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a critical complication after allogeneic hematopoietic stem cell transplantation. The conditioning therapy has been involved in the impairment of bone marrow (BM) mesenchymal stem/stromal cells (MSCs). However, the potential implication of MSCs in the pathophysiology of cGVHD has not been investigated. We analyzed expanded MSCs from patients with cGVHD and compared them with those from transplantation patients without cGVHD. The MSCs from both groups were of host origin and their reserves were comparable. They showed similar morphology, immunophenotype, population doubling times, self-renewal capacity, differentiation, and migration potential. The immunomodulatory potential of the 2 groups was also identical, they were both capable of inhibiting phytohemagglutinin-activated peripheral blood mononuclear cells (PBMCs) proliferation and inducing regulatory T cells after coculturing with CD4(+) T cells, and the immunosuppressive factors were secreted similarly in both MSCs whether in normal culture or coculture with PBMCs. No significant differences were observed in the cellular senescence and apoptosis between 2 groups. In addition, MSCs from patients with cGVHD displayed normal phenotype and function compared with their counterparts from healthy donors, although reduced frequency in BM mononuclear cell fraction was observed in these patients. Taken together, our results suggest that MSCs do not seem to contribute to the pathogenesis of cGVHD and indicate the feasibility of autologous cell therapy in patients who are not completely responding to standard immunosuppressive therapy for cGVHD.

Galectin-3 mediates bone marrow microenvironment-induced drug resistance in acute leukemia cells via Wnt/ß-catenin signaling pathway.

BACKGROUND: Acute leukemia is currently the major cause of death in hematological malignancies. Despite the rapid development of new therapies, minimal residual disease (MRD) continues to occur and leads to poor outcomes. The leukemia niche in the bone marrow microenvironment (BMM) is thought to be responsible for such MRD development, which can lead to leukemia drug resistance and disease relapse. Consequently further investigation into the way in which the leukemia niche interacts with acute leukemia cells (ALCs) and development of strategies to block the underlying process are expected to improve disease prognosis. Recent studies indicated that galectin-3 (gal-3) might play a pivotal role in this process. Thus we aimed to elucidate the exact role played by gal-3 in this process and clarify its mechanism of action. METHODS: We used human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) to mimic the leukemia BMM in vitro, and investigated their effects on drug resistance of ALCs and the possible mechanisms involved, with particular emphasis on the role of gal-3. RESULTS: In our study, we demonstrated that hBM-MSCs induced gal-3 up-regulation, promoting ß-catenin stabilization and thus activating the Wnt/ß-catenin signaling pathway in ALCs, which is critical in cytotoxic drug resistance of leukemia. This effect could be reversed by addition of gal-3 short hairpin RNA (shRNA). We also found that up-regulation of gal-3 promoted Akt and glycogen synthase kinase (GSK)-3ß phosphorylation, thought to constitute a cross-bridge between gal-3 and Wnt signaling. CONCLUSIONS: Our results suggest that gal-3, a key factor mediating BMM-induced drug resistance, could be a novel therapeutic target in acute leukemia.

The relationship between hepatic lipase gene variant and advanced age-related macular degeneration: a meta-analysis.

IMPORTANCE: To date, no consistency exists across studies that have evaluated the relationship between hepatic lipase gene (LIPC) rs10468017 variant and advanced age-related macular degeneration (AMD). OBJECTIVE: To summarize all relevant evidence for a relationship between LIPC variant and advanced AMD. DATA SOURCES: The PubMed and Embase databases were searched for studies potentially eligible in any language published up to September 15, 2013. STUDY SELECTION: Case-control studies of 2 or more comparison groups that included patients with advanced AMD (choroidal neovascularization or geographic atrophy). DATA EXTRACTION AND SYNTHESIS: Allele frequencies and genotype distributions of rs10468017 variant. MAIN OUTCOMES AND MEASURES: Summary odds ratios (ORs) and 95% CIs were estimated under different genetic models using meta-analytic methods. A stratified analysis by advanced AMD subtypes and race/ethnicity was performed, as well as a sensitivity analysis. RESULTS: Data from 10 case-control studies were included in the meta-analysis. The rs10468017 variant (C→T) showed significant summary ORs of 0.81 (95% CI, 0.75-0.88), 0.83 (95% CI, 0.70-0.98), and 0.60 (95% CI, 0.44-0.81) under the allelic (T vs C), heterozygous (TC vs CC), and homozygous (TT vs CC) models, respectively. Carrying at least 1 copy of the T allele decreased the risk of choroidal neovascularization and geographic atrophy by 20% (OR, 0.80; 95% CI, 0.74-0.87) and 29% (OR, 0.71; 95% CI, 0.59-0.86), respectively. The pooled OR for white race/ethnicity under an allelic model was 0.80 (95% CI, 0.74-0.87). The sensitivity analysis indicated the robustness of our findings, and no evidence of publication bias was observed in our meta-analysis. CONCLUSIONS AND RELEVANCE: Our meta-analysis indicates that LIPC rs10468017 variant is associated with a reduced risk of advanced AMD. This finding may lead to insights regarding the pathogenesis, prevention, and treatment of AMD.