The demographic transition and increasing life expectancy in Africa has lead to a rising elderly population. In Nigeria, little is known about the profile of and treatment outcomes of tuberculosis ...(TB) in the elderly.
Retrospective cohort study of adult TB patients treated between January 2011 and December 2012 in two large health facilities in Nigeria. The demographic, clinical and treatment outcomes of patients aged 60 and older were compared with those aged 15 to 59 years.
Elderly (≥ 60 years) TB patients accounted for 12.7% of all (1668) adult TB enrolled. Elderly patients had a higher proportion of men compared to non-elderly (64.2% vs 56.8%; p = 0.043); but a lower proportion of smear-positive TB at baseline (40.7% vs 65.8%; p<0.001). A higher proportion of elderly patients failed to smear convert after the intensive phase of treatment (23.7% vs 19.8%; p = 0.06), and overall elderly patients had lower treatment success rates (68.9% vs 77.1%; p = 0.009). Unsuccessful outcomes were mainly due to higher default and deaths in the elderly. The risk factors for unsuccessful outcomes in the elderly were: extrapulmonary TB case (adjusted odds ratio (aOR) 10.9; 95% confidence interval (CI) 1.1-108), and HIV co-infection (aOR 3.6; CI 1.1-11.7).
Treatment outcomes of elderly TB patients were inferior to non-elderly adults with higher death and default rates being implicated. With the rising elderly population, specific strategies are needed to quickly address TB management in the elderly in resource-limited settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: The vast majority of the mortality of breast cancer results from distant metastasis and pre-clinical models are in critical need for effective drug development. Patient-derived ...xenograft (PDX) maintains the features of the donor tumors such as intra-tumor heterogeneity; however, PDX model of breast cancer brain metastasis that delivers stable consistent results is not popularized. We demonstrate our novel methods (coined “Oshi”method) used to develop an orthotopic brain metastasis patient-derived xenograft model (PDMOX) for breast cancer brain metastasis via tumor tissue implantation. Methods: Brain metastasis PDX were created using metastatic brain tumors from breast cancer patients and implanting them in the brain of NSG female mice. Tumors of ~1 mm3 were implanted mechanically minced tissue with medium. We implant the tissue through a frontal bone burr hole into the right caudate putamen. Tumor growth was monitored by magnetic resonance imaging (MRI). Results: “Oshi” method utilizes a pipette tip in order to inoculate tumor at the same depth. A minced tumor was instilled using a 23G needle as the “non-oshi” method. One hour post-surgical survival after implantation of minced tumor by “non-oshi” method was only 37.5% (3/8), whereas 100% (40/40) by the “Oshi” method. All tumors were well engrafted in surviving mice after both methods. There was larger variation in tumor growth after “non-oshi” (Median 20±25.0 day, range: 12-24 day. Tumor volume: median 5.6±21.0 mm3, range 2.8-48.7 mm3). One mouse developed ptosis, and 2 out of 3 mice that underwent the “non-oshi” method had sudden death. On the other hand, all mice that underwent the “Oshi” method lived until the tumor grew to 125-200 mm3 without neurological symptoms. The engraftment rate of Mincing tumor were 100% at 1.5 months after implantation, while the engraftment rate of Enzymatic digestion tumors was only 50% at 2 months. Mincing tumor had faster growth speed than the tumor of enzymatic digestion. The engraftment time of enzymatic digestion tumor was slower than other tumor tissue forms. All 3rd generation tumors could be detected at the point of 1month after implantation, on the other hand, it took 2 month to detect 1st generation tumors. The growth of 3rd generation tumors was significantly faster and bigger than others. Conclusion: Various surgical techniques used to generate PDMOX breast cancer models showed major differences in the tumors and outcomes. These novel models are expected to become powerful tools for preclinical studies in metastatic breast cancer.
Citation Format: Masanori Oshi. Development of orthotopic breast cancer brain metastasis patient-derived xenograft(PDX) model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4620.
National tuberculosis (TB) programmes globally rely heavily on passive case finding for detecting TB in the community as advocated by the World Health Organization (WHO). TB case detection is low in ...Nigeria despite improvement in TB services and coverage.
A retrospective evaluation of an active case-finding intervention utilizing community-based approaches and targeted systematic TB screening in Ebonyi State, Nigeria was done. The analysis was performed using Epi Info.
Using community-based and health-facility-based systematic screening strategies, 218,751 persons were screened, with 19.7% of them being presumptive TB cases. Among these, 23,729 (55.1%) submitted sputum samples for microscopy, and 764 (3.2%) had smear-positive TB. In addition, 683 individuals were diagnosed with other forms of TB using X-ray and clinical evaluation giving a total of 1447 all forms of TB cases. The overall number needed to screen (NNS) to find one person with all forms of TB through the project was 151. The NNS was 53 for general outpatients, 88 through contact tracing, and 110 among HIV-infected persons.
Active case-finding strategies achieved good yields though early loss to follow-up was high. Active case finding is recommended for integration into national TB control policy and practice.
Colon-targeted oral nanoparticles (NPs) have emerged as an ideal, safe, and effective therapy for ulcerative colitis (UC) owing to their ability to selectively accumulate in inflamed colonic mucosa. ...Cyclosporine A (CSA), an immunosuppressive agent, has long been used as rescue therapy in severe steroid-refractory UC. In this study, we developed CSA-loaded dual-functional polymeric NPs composed of Eudragit
FS30D as a pH-sensitive polymer for targeted delivery to the inflamed colon, and poly(lactic-co-glycolic acid) (PLGA) as a sustained-release polymer.
CSA-loaded Eudragit FS30D nanoparticles (ENPs), PLGA nanoparticles (PNPs), and Eudragit FS30D/PLGA nanoparticles (E/PNPs) were prepared using the oil-in-water emulsion method. Scanning electron microscope images and zeta size data showed successful preparation of CSA-loaded NPs.
PNPs exhibited a burst drug release of >60% at pH 1.2 (stomach pH) in 0.5 h, which can lead to unwanted systemic absorption and side effects. ENPs effectively inhibited the burst drug release at pH 1.2 and 6.8 (proximal small intestine pH); however, nearly 100% of the CSA in ENPs was released rapidly at pH 7.4 (ileum-colon pH) owing to complete NP dissolution. In contrast to single-functional PNPs and ENPs, the dual-functional E/PNPs minimized burst drug release (only 18%) at pH 1.2 and 6.8, and generated a sustained release at pH 7.4 thereafter. Importantly, in distribution studies in the gastrointestinal tracts of mice, E/PNPs significantly improved CSA distribution to the colon compared with PNPs or ENPs. In a mouse model of colitis, E/PNP treatment improved weight loss and colon length, and decreased rectal bleeding, spleen weight, histological scoring, myeloperoxidase activity, macrophage infiltration, and expression of proinflammatory cytokines compared with PNPs or ENPs.
Overall, this work confirms the benefits of CSA-loaded E/PNPs for efficiently delivering CSA to the colon, suggesting their potential for UC therapy.
is one of the most studied oncogenes that is known to promote cell proliferation. We utilized MYC targets v1 and MYC targets v2 scores of gene set variation analysis and hypothesized that these ...scores correlate with tumor aggressiveness and survival outcomes. We examined a total of 3109 breast cancer patients from TCGA, METABRIC, and GSE124647 cohorts. In each cohort, the patients were divided into high- and low-score groups using the upper third value as the cut off. As expected, higher scores were related to increased cell proliferation and worse clinical and pathologic features. High MYC targets scores were associated with worse survival, specifically in primary ER-positive breast cancer, consistently in both TCGA and METABRIC cohorts. In ER-positive breast cancer, high MYC targets v1, but not v2 score, was associated with high mutation load, and high MYC targets v1 and v2 scores were both associated with increased infiltration of pro- and anti-cancerous immune cells. We found that high MYC scores were associated with worse survival in metastatic breast cancer. Our findings show that the MYC targets v1 and v2 scores are associated with tumor aggressiveness and poor prognosis in ER-positive primary tumors, as well as in metastatic breast cancer.
Coronavirus 229E (HCoV-229E), one of the causes of the common cold, exacerbates chronic obstructive pulmonary disease (COPD) and bronchial asthma. Long-acting muscarinic antagonists and β2-agonists ...and inhaled corticosteroids inhibit the exacerbation of COPD and bronchial asthma caused by infection with viruses, including HCoV-229E. However, the effects of these drugs on HCoV-229E replication and infection-induced inflammation in the human airway are unknown.
Primary human nasal (HNE) and tracheal (HTE) epithelial cell cultures were infected with HCoV-229E.
Pretreatment of HNE and HTE cells with glycopyrronium or formoterol decreased viral RNA levels and/or titers, the expression of the HCoV-229E receptor CD13, the number and fluorescence intensity of acidic endosomes where HCoV-229E RNA enters the cytoplasm, and the infection-induced production of cytokines, including IL-6, IL-8, and IFN-β. Treatment of the cells with the CD13 inhibitor 2′2′-dipyridyl decreased viral titers. Pretreatment of the cells with a combination of three drugs (glycopyrronium, formoterol, and budesonide) exerted additive inhibitory effects on viral titers and cytokine production. Pretreatment of HNE cells with glycopyrronium or formoterol reduced the susceptibility to infection, and pretreatment with the three drugs inhibited activation of nuclear factor-kappa B p50 and p65 proteins. Pretreatment with formoterol increased cAMP levels and treatment with cAMP decreased viral titers, CD13 expression, and the fluorescence intensity of acidic endosomes.
These findings suggest that glycopyrronium, formoterol, and a combination of glycopyrronium, formoterol, and budesonide inhibit HCoV-229E replication partly by inhibiting receptor expression and/or endosomal function and that these drugs modulate infection-induced inflammation in the airway.
While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less ...common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRNA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs.
Objective:To evaluate the rates,timing and determinants of default and death among adult tuberculosis patients in Nigeria.Methods:Routine surveillance data were used.A retrospective cohort study of ...adult tuberculosis patients treated during 2011 and 2012 in two large health facilities in Ebonyi State.Nigeria was conducted.Multivariable logistic regression analyses were used to tdentify independent predictors for treatment default and death.Results:Of 1668 treated patients,the default rate was 157(9.4%),whilst 165(9.9%) died.Also,35.7%(56) of the treatment defaults and 151(91.5%) of deaths occurred during the intensive phase of treatment.Risk of default increased with increasing age(adjusted odds ratio(aOR) 1.2;95%confidence interval(CI)1.1-1.9).smear-negative TB case(aOR 2.3:CI 1.5-3.6).extrapulmonary TB case(aOR 2.7:CI 1.3-5.2).and patients who received the longer treatment regimen(aOR 1,6;1.1-2.2).Risk of death was highest in extrapulmonary TB(aOR 3.0:CI 1.4-6.1) and smear-negative TB cases(aOR 2.4:CI1.7-3.51.rural residents(aOR 1.7:CI 1.2-2.6),HIV co-infected(aOR 2.5:CI 1.7-3.6),not receiving antiretroviral therapy(aOR 1.6:CI 1.1-2.9),and not receiving cotrimoxazole prophylaxis(aOR 1.7:CI 1.2—2.6).Conclusions:Targeted interventions to improve treatment adherence for patients with the highest risk of default or death are urgently needed.This needs to he urgently addressed by the National Tuberculosis Programme.
Background
Mutations of
BRCA
genes are the most studied in breast cancer, but the clinical relevance of
BRCA2
gene expression has been less well studied. Given that
BRCA2
is a DNA repair gene, we ...hypothesized that high
BRCA2
expression is associated with highly proliferative and aggressive biology in breast cancer.
Materials and Methods
A total of 4342 breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA,
n
= 1069) as the testing cohort and Gene Expression Omnibus (GEO) dataset GSE96058 (
n
= 3273) as a validation cohort.
Results
There was no relationship between
BRCA2
mutation and
BRCA2
gene expression.
BRCA2
high expression breast cancer was associated with higher Nottingham grade (
p
< 0.001), with high proliferation (MKI-67,
p
< 0.001), and with higher intratumor heterogeneity, homologous recombination deficiency, mutation rate, fraction altered, and neoantigens (all
p
< 0.001).
BRCA2
high expression was associated with
E2F1
,
RB1
,
PALB2
, and
PARP
, as well as cell proliferation-related gene sets, E2F targets, G2M checkpoints, and mitotic spindle, and with less ESR1 and ER response early and late gene sets. They were associated with significantly reduced number of stroma cells and with high infiltration of both favorable and unfavorable immune cells.
BRCA2
high expression significantly correlated with response to olaparib, a PARP inhibitor, and inversely with cyclophosphamide in ER-positive/HER2-negative tumors, but not in TNBC.
Conclusions
BRCA2
high gene expression was associated with highly proliferative and aggressive breast cancer that was highly immunogenic with better response to PARP inhibitors in ER-positive patients.
BRCA2
gene expression may become a candidate marker for aggressive biology and to tailor specific treatment strategies in the future.
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