Nanoparticle (NP)-based drug delivery systems accumulate in the disrupted epithelium of inflamed colon tissue in ulcerative colitis. However, premature early drug release and uptake or degradation of ...NPs during their passage through the harsh gastric or intestinal environment compromise their therapeutic outcomes. This study aimed to develop an advanced colitis-targeted hybrid nanoparticles-in-microparticles (NPsinMPs) drug delivery system to overcome the aforementioned challenges. First, sustained drug releasing poly(lactic-co-glycolic acid) NPs were generated and further encapsulated in pH-sensitive Eudragit FS30D MPs to ensure complete drug protection in a gastric-like pH and for selective delivery of NPs to the colon. SEM and confocal microscopy for the NPsinMPs revealed successful NP encapsulation. NPsinMPs prevented drug release in an acidic gastric-like and intestinal-like pH and presented a sustained release thereafter at an ileal and colonic pH, indicating the degradation of the outer pH-sensitive MPs and release of NPs. Furthermore, in vivo imaging of gastrointestinal tract of a colitis mouse orally administered with fluorescent NPsinMPs revealed higher fluorescence intensities selectively in the colon, demonstrating the release of loaded NPs and their concomitant accumulation at the site of colon inflammation. NPsinMPs markedly mitigated experimental colitis in mice indicated by improved histopathological analysis, decreased myeloperoxidase activity, neutrophils and macrophage infiltration, and expression of proinflammatory cytokines in colonic tissues compared with NP-treated mice. The present results show the successful formulation of an NPsinMP-based drug delivery system and provide a platform to improve NP-based colon-targeted drug delivery through improved protection of encapsulated NPs and their payload in the early small intestine.
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In this study, we developed oral core–shell nanoparticles composed of curcumin nanocrystals in the core and chitosan/alginate multilayers in the shell for inflammation-targeted alleviation of ...ulcerative colitis (UC). The release rate of curcumin from the core–shell nanoparticles was low at a pH mimicking the stomach and small intestine, whereas it was higher at a pH mimicking the colon. Further, biodistribution studies in the gastrointestinal tract of mice showed that distribution of nanoparticles was significantly higher in the colon than that in the stomach and small intestine. Quantitative analysis of drugs in colonic tissues and confocal imaging of colons revealed preferential accumulation of nanoparticles in inflamed tissues than that in healthy tissues. In vivo anti-inflammatory studies revealed that nanoparticles exhibit enhanced efficacy in alleviating inflammation-related symptoms in a mouse colitis model. The results suggest that the core–shell nanoparticles presented here can be exploited as efficient colon-targeted drug delivery systems for UC therapy.
CD8 T cell is an essential component of tumor-infiltrating lymphocytes (TIL) and tumor immune microenvironment (TIME). Using the xCell CD8 T cell score of whole tumor gene expression data, we ...estimated these cells in total of 3837 breast cancer patients from TCGA, METABRIC and various GEO cohorts. The CD8 score correlated strongly with expression of
genes. The score was highest for triple-negative breast cancer (TNBC), and a high score was associated with high tumor immune cytolytic activity and better survival in TNBC but not other breast cancer subtypes. In TNBC, tumors with a high CD8 score had enriched expression of interferon (
)-α and
-γ response and allograft rejection gene sets, and greater infiltration of anti-cancerous immune cells. The score strongly correlated with CD4 memory T cells in TNBC, and tumors with both a high CD8 score and high CD4 memory T cell abundance had significantly better survival. Finally, a high CD8 score was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, a high CD8 T cell score is associated with better survival in TNBC, particularly when tumor CD4 memory T cells were elevated. Our findings also suggest a possible use of the score as a predictive biomarker for response to immune checkpoint therapy.
Background
In Nigeria, little is known about the profile and treatment outcomes of smear-positive pulmonary TB (SPPTB) patients with persistent smear positivity after 2 months of treatment.
Methods
A ...retrospective cohort study was carried out to determine the characteristics and treatment outcomes of patients with persistent smear positivity after 2 months of treatment among adults with SPPTB between 2011 and 2012 in two large health facilities in Nigeria. Findings were compared with SPPTB patients who had a negative smear conversion in the same period.
Results
Of 929 eligible patients, 187 (20.1%) had persistent smear positivity after 2 months of treatment. Independent predictors for persistent smear positivity were older age (p<0.001) and care at a public facility (p<0.001). Patients with persistent smear positivity had a higher proportion of unsuccessful treatment outcomes compared with those with a negative smear conversion (21.9% vs 12.4%; p<0.001), mainly due to treatment failure (p<0.001). Across treatment category (new versus previously treated cases), age group and residence category (urban versus rural), rates of unsuccessful outcomes were significantly higher among patients with persistent smear positivity.
Conclusion
Treatment outcomes of SPPTB patients with persistent smear positivity were inferior to those who smear converted, with treatment failure being a major problem. This needs to be urgently addressed by the National Tuberculosis Control Programme.
Abstract
Cancer-associated adipocytes are known to cause inflammation; however, the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. We hypothesized that intra-tumoral ...adipogenesis reflects a different cancer biology than abundance of intra-tumoral adipocytes. The Molecular Signatures Database Hallmark adipogenesis gene set of gene set variant analysis was used to quantify adipogenesis. Total of 5,098 breast cancer patients in multiple cohorts (training; GSE96058 (
n
= 3273), validation; TCGA (
n
= 1069), treatment response; GSE25066 (
n
= 508) and GSE20194 (
n
= 248)) were analyzed. Adipogenesis did not correlate with abundance of adipocytes. Adipogenesis was significantly lower in triple negative breast cancer (TNBC). Elevated adipogenesis was significantly associated with worse survival in TNBC, but not in the other subtypes. High adipogenesis TNBC was significantly associated with low homologous recombination deficiency, but not with mutation load. High adipogenesis TNBC enriched metabolism-related gene sets, but neither of cell proliferation- nor inflammation-related gene sets, which were enriched to adipocytes. High adipogenesis TNBC was infiltrated with low CD8
+
T cells and high M2 macrophages. Although adipogenesis was not associated with neoadjuvant chemotherapy response, high adipogenesis TNBC was significantly associated with low expression of
PD-L1
and
PD-L2
genes, and immune checkpoint molecules index. In conclusion, adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes.
This is a qualitative, descriptive study to explore gender-related factors that influence health seeking for tuberculosis (TB) care by women in Ebonyi State, Nigeria. In-depth interviews based on ...interview guides were conducted with participants selected through purposive sampling in communities in the state. The results show that gender relations prohibit women from seeking care for symptoms of TB and other diseases outside their community without their husbands' approval. Gender norms on intra-household resource ownership and control divest women of the power to allocate money for health care seeking. Yet, the same norms place the burden of spending on health care for minor illnesses on women, and such repeated, out-of-pocket expenditures on health care at the village level make it difficult for women to save money for use for health care seeking for major illnesses such as TB, which, even if subsidized, still involves hidden costs such as transport fare. The opening hours of TB clinics do not favour their use by most women as they are open when women are usually engaged in income-generating activities. Attending the clinics may therefore entail opportunity costs for many women. People with chronic, infectious diseases such as TB and HIV are generally stigmatized and avoided. Women suffer more stigma and discrimination than men. Stigma and discrimination make women reluctant to seek care for TB until the disease is advanced. Policies and programmes aimed at increasing women's access to TB services should not only take these gender norms that disempower women into explicit consideration but also include interventions to address them. The programmes should integrate flexible opening hours for TB treatment units, including introduction of evening consultation for women. Interventions should also integrate anti-stigma strategies led by the community members themselves.
The vast majority of breast cancer death is a result of metastasis. Thus, accurate identification of patients who are likely to have metastasis is expected to improve survival. The G2M checkpoint ...plays a critical role in cell cycle. We hypothesized that breast cancer tumors with high activity of G2M pathway genes are more aggressive and likely to metastasize. To test this, we used the single-sample gene set variation analysis method to calculate the score for the Hallmark G2M checkpoint pathway using gene expression data of a total of 4626 samples from 12 human breast cancer cohorts. As expected, a high G2M pathway score correlated with enriched tumor expression of other cell proliferation-related gene sets. The score was significantly associated with clinical aggressive features of tumors and patient survival in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Interestingly, a high G2M score of metastasis tumors was also significantly associated with worse survival. In primary as well as metastasis tumors with high scores, the infiltration of both pro- and anti-cancerous immune cells increased. Tumor G2M score was also associated with treatment response to systemic chemotherapy in ER-positive/HER2-negative cancer, and was predictive of response to cyclin-dependent kinase inhibition therapy.
Hearing damage is one of the main toxic effects of platinum compounds, it derives from the irreversible degeneration of hair cells of the ear. Genetic association studies have suggested an ...association between GSTP1 c.313A>G variant and platinum-induced ototoxicity in childhood cancer survivors. We aimed to detect the frequency of ototoxicity and associated risk factors in survivors of childhood cancer receiving platinum-based chemotherapy and to detect the relation between GSTP1 c.313A>G (rs1695) polymorphisms and ototoxicity. We conducted a cross-sectional study on 64 cancer survivors who received platinum agents (cisplatin and/or carboplatin) at least 2 years after the end of chemotherapy. The patients underwent comprehensive audiological evaluations and genotyping to detect the presence of the GSTP1 c.313A>G polymorphisms. Hearing loss (HL) was identified in 16/64 patients (25%), including 62.5% treated with cisplatin and 37.5% treated with carboplatin. The greater incidence of ototoxicity was found in children treated for osteosarcoma (28.1%) followed by patients with germ cell tumors (25%) and neuroblastoma (21.9%). The AA, AG, and GG types of GSTP1 c.313A>G variant were detected in 84.4%, 9.4%, and 6.3%, respectively, of patients with HL with a significant association between mutant genotype of GSTP1 rs1695 and platinum-induced ototoxicity (P = .035). HL was not significantly associated with the total cumulative dose of cisplatin and carboplatin. GSTP1 c.313A>G variant may increase the risk of HL in pediatric oncology patients treated with cisplatin or carboplatin chemotherapy.
•Dexamethasone microcrystals with colon-targeted chitosan/alginate/Eudragit S multilayers were fabricated.•Unwanted burst release of dexamethasone was prevented in the upper gastrointestinal tract ...pH.•Dexamethasone was released in a sustained manner after reaching the colonic pH.•Excellent therapeutic activity was found in a mouse model of colitis.
Oral colon-targeted drug delivery has gained popularity as an effective strategy for treatment of inflammatory bowel disease (IBD). In this study, we prepared colon-targeted dexamethasone microcrystals (DXMCs) coated with multilayers of chitosan oligosaccharide (CH), alginate (AG), and finally Eudragit S 100 (ES) (ES1AG4CH5-DXMCs) using a layer-by-layer (LBL) coating technique. Particle size, surface charge, in vitro drug release, and in vivo anti-inflammatory activity of ES1AG4CH5-DXMCs were evaluated. ES1AG4CH5-DXMCs had an average particle size of 2.34 ± 0.19 μm and a negative surface charge of - 48 ± 9 mV. ES1AG4CH5-DXMCs demonstrated pH-dependent dexamethasone release, avoiding initial burst drug release in acidic pH conditions of the stomach and small intestine, and providing subsequent sustained drug release in the colonic pH. Importantly, ES1AG4CH5-DXMCs exhibited a significant therapeutic activity in a mouse model of colitis compared to other DXMCs. Overall, the LBL-coated DXMCs presented here could be a promising colon-targeted therapy for IBD.
Tumor associated macrophages (TAMs) play a critical role in biology of various cancers, including breast cancer. In the current study, we defined "M1" macrophage and "M1"/"M2" ratio by transcriptomic ...signatures using xCell. We investigated the association between high level of "M1" macrophage or "M1"/"M2" ratio and the tumor immune microenvironment by analyzing the transcriptome of publicly available cohorts, TCGA and METABRIC. We found that "M1" high tumors were not associated with prolonged survival compared with "M1" low tumors, or with the response to neoadjuvant chemotherapy. "M1" high tumors were associated with clinically aggressive features and "M1" high tumors enriched the cell proliferation and cell cycle related gene sets in GSEA. At the same time, "M1" high tumors were associated with high immune activity and favorable tumor immune microenvironment, as well as high expression of immune check point molecules. Strikingly, all these results were mirrored in "M1"/"M2" ratio high tumors. In conclusion, transcriptomically defined "M1" or "M1"/"M2" high tumors were associated with aggressive cancer biology and favorable tumor immune microenvironment but not with survival benefit, which resembled only part of their conventional clinical characteristics.
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