Introduction
Cancer biology dominates the behavior and prognosis of a tumor. Although Nottingham histological grade is a subjective pathological determination, it has been accepted as a surrogate ...model for cancer biology. As such, histologic grade was incorporated into the latest 8th edition of the American Joint Committee on Cancer breast cancer staging system. In this study, we hypothesized that grade 3 breast cancers demonstrate aggressive molecular biological profiles, reflecting worse biology and possible underlying immunogenicity.
Methods
Transcriptomic and clinical data were obtained from the Molecular Taxonomy of Breast Cancer International Consortium, and the findings were validated by The Cancer Genome Atlas breast cancer cohort and GSE25066.
Results
Overall, 2876 patients were analyzed in this study. Grade 3 tumors were more common in estrogen receptor (ER)-negative, advanced-stage patients, and were associated with human epidermal growth factor receptor 2 and basal subtypes by the PAM50 classifier, as well as with increased MKI67 expression (all
p
<0.001). Disease-free survival was significantly worse in grade 3 tumors (all cohorts). Gene set enrichment analysis demonstrated that grade 3 tumors were significantly enriched with not only cell proliferation and cell cycle-related gene sets but also immune activity-related gene sets. CIBERSORT confirmed that grade 3 tumors were infiltrated with macrophage M1, follicular helper T cells, and activated natural killer cells (all
p
<0.001). Furthermore, grade 3 tumors were associated with more diverse T cell receptors (
p
=0.001) and increased cytolytic activity (
p
<0.001). Lastly, major T-cell exhaustion markers were significantly elevated in grade 3 breast cancers (
p
<0.001).
Conclusion
Grade 3 breast cancers demonstrated aggressive transcriptomic features with enhanced immunogenicity and elevated T-cell exhaustion markers.
Angiogenesis is one of the hallmarks of cancer. We hypothesized that intra-tumoral angiogenesis correlates with inflammation and metastasis in breast cancer patients. To test this hypothesis, we ...generated an angiogenesis pathway score using gene set variation analysis and analyzed the tumor transcriptome of 3999 breast cancer patients from The Cancer Genome Atlas Breast Cancer (TCGA-BRCA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE20194, GSE25066, GSE32646, and GSE2034 cohorts. We found that the score correlated with expression of various angiogenesis-, vascular stability-, and sphingosine-1-phosphate (S1P)-related genes. Surprisingly, the angiogenesis score was not associated with breast cancer subtype, Nottingham pathological grade, clinical stage, response to neoadjuvant chemotherapy, or patient survival. However, a high score was associated with a low fraction of both favorable and unfavorable immune cell infiltrations except for dendritic cell and M2 macrophage, and with Leukocyte Fraction, Tumor Infiltrating Lymphocyte Regional Fraction and Lymphocyte Infiltration Signature scores. High-score tumors had significant enrichment for unfavorable inflammation-related gene sets (interleukin (IL)6, and tumor necrosis factor (TNF)α- and TGFβ-signaling), as well as metastasis-related gene sets (epithelial mesenchymal transition, and Hedgehog-, Notch-, and WNT-signaling). High score was significantly associated with metastatic recurrence particularly to brain and bone. In conclusion, using the angiogenesis pathway score, we found that intra-tumoral angiogenesis is associated with immune reaction, inflammation and metastasis-related pathways, and metastatic recurrence in breast cancer.
Adhesion of nanoparticles (NPs) to the bacterial cell wall by modifying their physicochemical properties can improve the antibacterial activity of antibiotic. In this study, we prepared positively ...charged clindamycin-loaded poly (lactic-co-glycolic acid)-polyethylenimine (PLGA-PEI) nanoparticles (Cly/PPNPs) and negatively charged clindamycin-loaded PLGA NPs (Cly/PNPs) and investigated the effect of NP adhesion to bacteria on the treatment of methicillin-resistant
(MRSA)-infected wounds. The Cly/PPNPs and Cly/PNPs were characterized according to particle size, polydispersity index, surface charge, and drug loading. Both Cly/PPNPs and Cly/PNPs exhibited sustained drug release over 2 days. The Cly/PPNPs bind to the MRSA surface, thereby enhancing bactericidal efficacy against MRSA compared with the Cly/PNPs. Furthermore, compared with other groups, Cly/PPNPs significantly accelerated the healing and re-epithelialization of wounds in a mouse model of a MRSA-infected wounds. We also found that both NPs are harmless to healthy fibroblast cells. Therefore, our results suggest that the Cly/PPNPs developed in this study improve the efficacy of clindamycin for the treatment of MRSA-infected wounds.
Abstract
Advanced gastric cancer (GC) is one of the most lethal cancer types, thus a better understanding of its biology in patients is urgently needed. MicroRNA (miR)-29a is a known tumor ...suppressive miR that is related to metastasis, but its clinical relevance in GC remains ambiguous. Here, using a large GC patient cohort we hypothesized that low expression of miR-29a in GC is associated with aggressive cancer biology and worse survival. We demonstrated that low miR-29a GC enriched cell proliferation, apoptosis, metastasis, and angiogenesis related gene sets, as well as the higher expression of related genes. Low miR-29a GC was associated with less anti-cancer immune cell infiltration as well as immune related scoring. Low miR-29a GC demonstrated a worse overall survival (OS) as well as disease specific survival (DSS) compared with high expressing miR-29a GC. Notably, low miR-29a expression was the only factor, other than residual tumor status, to be an independent prognostic biomarker of worse OS and DSS. In conclusion, low miR-29a GC was associated with aggressive cancer biology and worse OS as well as DSS. Additionally, low expression of miR-29a was an independent prognostic biomarker of OS and DSS in gastric cancer patients.
Globally, twice as many men as women are being diagnosed with tuberculosis (TB) annually. Little is known about gender differentials in TB in Africa. A retrospective cohort analysis of routine data ...was conducted on adult TB patients treated between 2011 and 2012 in two large healthcare facilities in Nigeria. Gender differences in their demographic characteristics and treatment outcomes were analysed accordingly. Of 1668 TB patients enrolled, the male:female ratio was 1·4:1. The mean ages of males and females were 40·2 ± 14·7 and 36·1 ± 14·6 years, respectively (t test 6·62, P < 0·001). Male gender was associated with a higher failure to smear convert after 2 months (21·8% vs. 17·5%, P = 0·06) and 5 months (4·3% vs. 1·5%, P = 0·02) of treatment for smear-positive TB patients. Moreover, men were more likely than women to fail treatment (2·2% vs. 0·7%, P = 0·01). No significant differences exist in the treatment success rates between women and men (78·2% vs. 74·5%, P = 0·08). Adjusted analyses showed significant association between being an urban male and a HIV-infected female with unsuccessful outcome adjusted by socio-demographic and clinical factors. We found that gender disparities exist in TB profile and treatment outcomes in Nigeria and gender-specific strategies are needed to optimize TB management.
The objective of this study was to assess whether students' sense of belonging at school was associated with cannabis use among secondary school students in Barbados. This was a cross-sectional study ...involving a nationally representative weighted sample of 8,538 students drawn from 2
nd
to 6
th
forms across public and private secondary schools in Barbados in 2013. Descriptive and inferential statistics was performed using SPSS. Students who had a sense of belonging at school, were attending public schools and were in the 2nd form, had higher odds of reporting past-year and past-month cannabis use. We conclude that there was a significant positive association between students' sense of belonging at school and cannabis use.
Plasma gelsolin (pGSN) correlates with clinical improvement in septic patients. We aimed to investigate pGSN levels as a diagnostic and prognostic marker of neonatal late-onset-sepsis (LOS). A ...case-control study was done on 184 neonates (92 with LOS and 92 controls). All participants were subjected to detailed history taking, full clinical evaluation, sepsis workup, and pGSN enzyme-linked immunosorbent-assay measurement. We detected significantly lower pGSN level among cases compared to controls (90.63 ± 20.64 vs 451.83 ± 209.59). It was significantly related to the severity of sepsis and mortality, with significantly lower values among cases with septic shock and multiorgan failure and non-survivors. Follow-up pGSN significantly increased after sepsis improvement in survivors compared to admission values. pGSN might be a reliable diagnostic and prognostic marker for LOS.
Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support ...estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives (
< 0.001,
< 0.001, respectively) and it correlated with ER expression (
= 0.630,
= 0.509, respectively). In ER-positive tumors, AR high tumors enriched UV response down (NES = 2.01,
< 0.001), and AR low tumors enriched DNA repair (NES = -2.02,
< 0.001). AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (
< 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC.
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