Immune Exclusion-Wnt/CTNNB1 Class Predicts Resistance to Immunotherapies in HCC

Next-generation sequencing has provided information on actionable targets and biomarkers of response in oncology. In hepatocellular carcinoma (HCC), Wnt/CTNNB1 mutations characterize the immune-excluded class (cold tumors) and might represent the biomarkers predicting resistance to immune checkpoint inhibitors. Large-scale validation of these data is needed to customize immunotherapy in advanced HCC.See related article by Harding et al.©2019 American Association for Cancer Research

Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis

Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to transdifferentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features and assigned them to categories such as proliferation-progenitor, proliferation-transforming growth factor β, and Wnt-catenin β1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 15% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making

Molecular therapies and precision medicine for hepatocellular carcinoma

The global burden of hepatocellular carcinoma (HCC) is increasing and might soon surpass an annual incidence of 1 million cases. Genomic studies have established the landscape of molecular alterations in HCC; however, the most common mutations are not actionable, and only ~25% of tumours harbour potentially targetable drivers. Despite the fact that surveillance programmes lead to early diagnosis in 40–50% of patients, at a point when potentially curative treatments are applicable, almost half of all patients with HCC ultimately receive systemic therapies. Sorafenib was the first systemic therapy approved for patients with advanced-stage HCC, after a landmark study revealed an improvement in median overall survival from 8 to 11 months. New drugs — lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line — have also been demonstrated to improve clinical outcomes, although the median overall survival remains ~1 year; thus, therapeutic breakthroughs are still needed. Immune-checkpoint inhibitors are now being incorporated into the HCC treatment armamentarium and combinations of molecularly targeted therapies with immunotherapies are emerging as tools to boost the immune response. Research on biomarkers of a response or primary resistance to immunotherapies is also advancing. Herein, we summarize the molecular targets and therapies for the management of HCC and discuss the advancements expected in the near future, including biomarker-driven treatments and immunotherapies

Engineering Geology of Diversion Tunnel Area at the Meninting Dam Construction, West Lombok, Province of West Nusa Tenggara, Indonesia

The construction of Meninting Dam is undertaken to resolve the water needs in Meninting Watershed, West Lombok, Province of West Nusa Tenggara, Indonesia. Therefore, creating a diversion tunnel is imperative to avert the river flow as the dam project commences. Also, engineering geology work on the soil and rocks, including the classification of physical and mechanical properties were conducted in the intended tunnel site. These considerations were necessary because of the unavailability of rock identification data using the GSI (Geological Strength Index) method which used to design the portal slopes as a significant factor in tunnel safety. The results show the proposed area for diversion tunnel construction to be in the lithology of the polymict breccia and the lapilli tuff units, and the soil conditions were included in the SM category (silty sand). The level of surface rock weathering was divided into 3 units, including: highly weathered residual soil lapilli tuff, and highly, as well as moderately weathered polymict breccias. Meanwhile, 4 units were identified on the rock cores (subsurface) comprising highly weathered residual soil of lapilli tuff, and highly, moderately, and slightly weathered polymict breccias. Based on GSI (Geological Strength Index) of rock and surface data from the area of study, the rock quality was grouped as poor (GSI values: 21-40) to very poor (GSI values: 0-20). However, drilling data classified the mass quality subsurface rocks in fair (GSI values 41-55), poor (GSI values: 21-40), particularly in tunnels, and very poor (GSI values 0-20). Therefore, the rock mass quality is possibly used to design the slope of the tunnel portal as 45⁰-55⁰, in order to ensure safety

A High Diffusive Model for Nanomaterials

Considerable attention is today devoted to the engineering of films widely used in photocatalytic, solar energy converters, photochemical and photoelectrochemical cells, dye-sensitized solar cells (DSSCs), to optimize electronic time response following photogeneration. However, the precise nature of transport processes in these systems has remained unresolved. To investigate such aspects of carrier dynamics, we have suggested a model for the calculation of correlation functions, expressed as the Fourier transform of the frequency-dependent complex conductivity σ(ω). Results are presented for the velocity correlation functions, the mean square deviation of position and the diffusion coefficient in systems, like TiO2 and doped Si, of large interest in present devices. Fast diffusion occurs in short time intervals of the order of few collision times. Consequences for efficiency of this fast response are discussed in relation to nanostructured devices

Prevalence and risk factors for diabetes mellitus among tuberculosis patients in Moshi Municipal Council, Kilimanjaro Tanzania

Background: Diabetes Mellitus (DM) is a worldwide public health problem and its prevalence has been rising rapidly in low and middle income countries (LMICs) including Tanzania. According to WHO report 2015, DM is ranked number six as a leading cause of death  worldwide. Strong evidence suggests that DM may be associated with Tuberculosis (TB) and could affect TB treatment outcomes. Tanzania is among the 22 countries that have a high burden of TB and currently facing increased epidemic of DM. The increasing diabetes  prevalence may be a threat to TB control and counteract strategies to end TB by 2030 as proposed by WHO.Objective: To determine proportion of TB patients who are co-infected with DM in Moshi municipal council, Kilimanjaro Tanzania.Methodology: This study was a hospital based cross-sectional study conducted in April to July 2018 at 4 health facilities; Mawenzi Regional Referral hospital, St. Joseph District Designated hospital, Pasua Health center and Majengo Health centre in Moshi municipal. The study included adults aged 18 years and above attending either of the 4 health facilities for TB care. The study included newly diagnosed and those who were on TB treatment. Interviews were conducted followed by blood glucose testing. Data was entered and analysed using SPSSResults: A total of 153 TB patients were enrolled, their mean age was 42.5 (±14.75) years and 46 (30.1%) were females. The prevalence of DM among TB patients in this study was 9.2%. Factors associated with TB-DM comorbidity were: age (OR 4.43, 95% CI: 1.18-16.55), HIV status (OR 3.88, 95% CI: 1.06-14.11), and family history of DM (OR 6.50, 95% CI 0.67-25.56).Conclusion: One in ten patients with TB had confirmed DM. There is a need for future studies to assess if DM influences TB treatment and outcomes in this setting

An Upgraded Transverse Electromagnetic Parallel Plates for Dielectric Measurement

A new version of transverse electromagnetic parallel plates with irregular plates’ width and plate separation has been developed for dielectric measurement. The separations between the plates are supported by four rectangular Teflon block and 1 mm of groove is proposed at the center of the upper plate to maintain the measurement repeatability. The groove enables the samples which are slightly higher than 2 cm to be fitted well between the plates without introducing extra force to the plates. Theperformance of both parallel plates has been compared in the frequency range from 100 MHz to 1.1 GHz. It is found that the upgraded parallel plate offers better return loss and insertion loss above 500 MHz compared to the previous parallel plate. It is reported from this work that the return loss of the parallel plate must be lower than -15 dB in order to achieve accurate dielectric constant. However, the insertion loss of the parallel plates does not influence the real permeability significantly. The upgraded TEM parallel plateproduces a consistent reading with a standard deviation of less than 0.05 above frequency 200 MHz. The dielectric measurement of Polypropylene (PP) has proven the capability of this upgraded TEM parallelplate

Duality properties of indicatrices of knots

The bridge index and superbridge index of a knot are important invariants in knot theory. We define the bridge map of a knot conformation, which is closely related to these two invariants, and interpret it in terms of the tangent indicatrix of the knot conformation. Using the concepts of dual and derivative curves of spherical curves as introduced by Arnold, we show that the graph of the bridge map is the union of the binormal indicatrix, its antipodal curve, and some number of great circles. Similarly, we define the inflection map of a knot conformation, interpret it in terms of the binormal indicatrix, and express its graph in terms of the tangent indicatrix. This duality relationship is also studied for another dual pair of curves, the normal and Darboux indicatrices of a knot conformation. The analogous concepts are defined and results are derived for stick knots.Comment: 22 pages, 9 figure

A Fluorine-18 Radiolabeling Method Enabled by Rhenium(I) Complexation Circumvents the Requirement of Anhydrous Conditions

Azeotropic distillation is typically required to achieve fluorine-18 radiolabeling during the production of positron emission tomography (PET) imaging agents. However, this time-consuming process also limits fluorine-18 incorporation, due to radioactive decay of the isotope and its adsorption to the drying vessel. In addressing these limitations, the fluorine-18 radiolabeling of one model rhenium(I) complex is reported here, which is significantly improved under conditions that do not require azeotropic drying. This work could open a route towards the investigation of a simplified metal-mediated late-stage radiofluorination method, which would expand upon the accessibility of new PET and PET-optical probes