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BackgroundHyperthermia treatment has been explored as a strategy to overcome biological barriers that hinder effective drug delivery in solid tumors. Most studies have used mild hyperthermia treatment (MHT) to target the delivery of thermo-sensitive liposomes carriers. Others have studied its application to permeabilize tumor vessels and improve tumor interstitial transport. However, the role of MHT in altering tumor vessel interfacial and adhesion properties and its relationship to improved delivery has not been established. In the present study, we evaluated effects of MHT treatment on tumor vessel flow dynamics and expression of adhesion molecules and assessed enhancement in particle localization using mesoporous silicon vectors (MSVs). We also determined the optimal time window at which maximal accumulation occur.ResultsIn this study, using intravital microscopy analyses, we showed that temporal mild hyperthermia (∼1 W/cm(2)) amplified delivery and accumulation of MSVs in orthotopic breast cancer tumors. The number of discoidal MSVs (1000×400 nm) adhering to tumor vasculature increased 6-fold for SUM159 tumors and 3-fold for MCF-7 breast cancer tumors. By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation. Furthermore, MHT treatment was shown to increase tumor perfusion in a time-dependent fashion.ConclusionsOur findings reveal that well-timed mild hyperthermia treatment can transiently elevate tumor transport and alter vascular adhesion properties and thereby provides a means to enhance tumor localization of non-thermally sensitive particles such as MSVs. Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy.

We report cell mechanical changes in response to alteration of expression of the human equilibrative nucleoside transporter-1 (hENT1), a most abundant and widely distributed plasma membrane nucleoside transporter in human cells and/or tissues. Modulation of hENT1 expression level altered the stiffness of pancreatic cancer Capan-1 and Panc 03.27 cells, which was analyzed by atomic force microscopy (AFM) and correlated to microfluidic platform. The hENT1 knockdown induced reduction of cellular stiffness in both of cells up to 70%. In addition, cellular phenotypic changes such as cell morphology, migration, and expression level of epithelial-mesenchymal transition (EMT) markers were observed after hENT1 knockdown. Cells with suppressed hENT1 became elongated, migrated faster, and had reduced E-cadherin and elevated N-cadherin compared to parental cells which are consistent with epithelial-mesenchymal transition (EMT). Those cellular phenotypic changes closely correlated with changes in cellular stiffness. This study suggests that hENT1 expression level affects cellular phenotype and cell elastic behavior can be a physical biomarker for quantify hENT1 expression and detect phenotypic shift. Furthermore, cell mechanics can be a critical tool in detecting disease progression and response to therapy.

BackgroundAdolescent girls and young women (AGYW) are at increased risk of sexually transmitted infections (STIs). We assessed sexual-risk behaviours and HIV and syphilis prevalence among AGYW in Uganda to inform the design of target-specific risk-reduction interventions.MethodsThis analysis utilizes data from 8,236 AGYW aged 10-24 years, collected in 20 districts, between July and August 2018. AGYW engaged in sexual-risk behaviour if they: a) reported a history of STIs; or b) had their sexual debut before age 15; or c) engaged in sex with 2+ partners in the past 12 months; or c) did not use or used condoms inconsistently with their most recent partners. We diagnosed HIV using DetermineTM HIV-1/2, Stat-PakTM HIV-1/2 and SD Bioline. We used SD Bioline Syphilis test kits to diagnose syphilis and Treponema Pallidum Hemagglutination Assay for confirmatory syphilis testing. Comparison of proportions was done using Chi-square (χ2) tests. Data were analysed using STATA (version 14.1).ResultsOf 4,488 AGYW (54.5%) that had ever had sex, 12.9% (n = 581) had their sexual debut before age 15; 19.1% (n = 858) reported a history of STIs. Of those that had ever had sex, 79.6% (n = 3,573) had sex in the 12 months preceding the survey; 75.6% (n = 2,707) with one (1) and 24.2% (n = 866) with 2+ partners. Condom use with the most recent sexual partner was low, with only 20.4% (n = 728) reporting consistent condom use while 79.6% (n = 2,842) reported inconsistent or no condom use. In-school AGYW were significantly less likely to have ever had sex (35.6% vs. 73.6%, PConclusionIn-school AGYW engaged in more protective sexual behaviors and had less HIV and syphilis than their out-of-school counterparts. These findings suggest a need for target-specific risk-reduction interventions stratified by schooling status.

African swine fever virus (ASFV) infection is fatal in domesticated pigs, with a mortality rate approaching 100%. This may result in economic losses and threats to food security. Currently, there are no approved vaccines or antiviral therapies for ASFV. Therefore, in this study, we evaluated congocidine congeners and a tris-benzimidazole as potential inhibitors of ASFV transcription using an in silico approach. We applied redocking of congocidine and docking of its congeners and a tris-benzimidazole to a receptor containing B-DNA with AT-motifs as a target to mimic conserved ASFV late gene promoters. Subsequently, the binding scores of DNA-ligand docked complexes were evaluated and their binding affinity was estimated. Molecular dynamics (MD) simulation was then used to assess ligand behavior within the minor groove. From our results, it is evident the less toxic congocidine congeners and tris-benzimidazole could dock to AT-rich regions significantly. Additionally, the predicted binding affinities had suitable values comparable to other experimentally determined minor groove binders, MD simulation of the docked DNA-ligand complexes and subsequent molecular trajectory visualization further showed that the ligands remained embedded in the minor groove during the time course of simulation, indicating that these ligands may have potential applications in abrogating ASFV transcription.

BackgroundWe aimed to determine the prevalence of pulmonary TB amongst the adult population (≥15 years) in 2016 in Kenya.MethodA nationwide cross-sectional survey where participants first underwent TB symptom screening and chest x-ray. Subsequently, participants who reported cough >2weeks and/or had a chest x-ray suggestive of TB, submitted sputum specimen for laboratory examination by smear microscopy, culture and Xpert MTB/RIF.ResultThe survey identified 305 prevalent TB cases translating to a prevalence of 558 [95%CI 455-662] per 100,000 adult population. The highest disease burden was reported among people aged 25-34 years (716 [95% CI 526-906]), males (809 [(95% CI 656-962]) and those who live in urban areas (760 [95% CI 539-981]). Compared to the reported TB notification rate for Kenya in 2016, the prevalence to notification ratio was 2.5:1. The gap between the survey prevalence and notification rates was highest among males, age groups 25-34, and the older age group of 65 years and above. Only 48% of the of the survey prevalent cases reported cough >2weeks. In addition, only 59% of the identified cases had the four cardinal symptoms for TB (cough ≥2 weeks, fever, night sweat and weight loss. However, 88.2% had an abnormal chest x-ray suggestive of TB. The use of Xpert MTB/RIF identified 77.7% of the cases compared to smear microscopy's 46%. Twenty-one percent of the survey participants with respiratory symptoms reported to have sought prior health care at private clinics and chemists. Among the survey prevalent cases who reported TB related symptoms, 64.9% had not sought any health care prior to the survey.ConclusionThis survey established that TB prevalence in Kenya is higher than had been estimated, and about half of the those who fall ill with the disease each year are missed.

Community-based conservation (CBC) aims to benefit local people as well as to achieve conservation goals, but has been criticised for taking a simplistic view of "community" and failing to recognise differences in the preferences and motivations of community members. We explore this heterogeneity in the context of Kenya's conservancies, focussing on the livelihood preferences of men and women living adjacent to the Maasai Mara National Reserve. Using a discrete choice experiment we quantify the preferences of local community members for key components of their livelihoods and conservancy design, differentiating between men and women and existing conservancy members and non-members. While Maasai preference for pastoralism remains strong, non-livestock-based livelihood activities are also highly valued and there was substantial differentiation in preferences between individuals. Involvement with conservancies was generally perceived to be positive, but only if households were able to retain some land for other purposes. Women placed greater value on conservancy membership, but substantially less value on wage income, while existing conservancy members valued both conservancy membership and livestock more highly than did non-members. Our findings suggest that conservancies can make a positive contribution to livelihoods, but care must be taken to ensure that they do not unintentionally disadvantage any groups. We argue that conservation should pay greater attention to individual-level differences in preferences when designing interventions in order to achieve fairer and more sustainable outcomes for members of local communities.