B-Raf-Mutated Melanoma

Until fairly recently, treatment options for advanced melanoma have been relatively limited. Fortunately, the last decade has seen dramatic improvements in response rates and duration of overall survival after the introduction of checkpoint inhibitors and targeted therapies against mutations in the B-isoform of Raf (B-Raf) in metastatic or inoperable melanoma. This book chapter will discuss the role of wild type B-Raf in the cell, the changes induced by mutations in this protein, and current FDA approvals for targeted therapies against B-Raf, both as a monotherapy and in combination with MEK inhibitors. We will also summarize mechanisms of resistance against these targeted therapies as well as novel therapeutic regimens proposed to bypass resistance

Repurposing metformin for cancer treatment: current clinical studies.

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment

Geospatial Technologies in the extraction of Groundwater Potential Zones

The utmost source which is contributing to the supply of water to the society is groundwater. Depletion of undergroundwater is enormously caused by eruptive growing rate of human population along with needs in the form of industrialand urbanized growth, indigent practices in irrigation methods and deforestation. As surface fresh water is very limit, waterdemand is drastically increasing for the needs. In this connection, there is immense predominant for the natural sourcecalled groundwater. It is mandatory for the communities not only to targeting the resource called groundwater but also toprovide remedial measures to replenishment the groundwater. Enormous investigations are in the process globally, to meetthe requirement to compensate resource for the needs in all aspects. Geospatial techniques are playing vital role in theextraction of groundwater resources by means of spatial and temporal data variations along with its integration analysis inthe form of separable layers to derive the solutions. In this connection, Nandyal mandal of Kurnool is selected to demarcatethe potential zones of groundwater by using this geospatial technology.The main motto of the research work is to identifythe effective potential groundwater zones by applying methodsand integration techniques of Geographic InformationSystem and remote sensing. This gives more information for the planning and management of the ground water.Byemploying geospatial technologies, the integrated composite output for potential zones is demarcated with help of keyparameters such as drainage, lineament, slope, geology, geomorphology, land use land cover and existing groundwaterlevels. All these thematic layers are extracted by using the satellite data and other available sources by using remote sensingand GIS. All these themes are demarcated using basic elements to identify the respective classes. Proper weightages areassignedtoeachclassofallthemesintheformofseparatecategorybasedonimportanceofweightagefromexcellenttopoor based on suitability to avail the groundwater sources. This process is applied for the considered themes and isreclassified based on results. It is then integrated with weighted overlay operation in ARCGIS environment. Appropriateweightage percentages which are equal to 100%, are given prior to overlay analysis of hydrology tools of ArcGIS. Variouszones like excellent, very good, good, moderate, poor are categorized for the integrated potential zones of groundwatersource. The use of suggested methodology is applied and demonstrated for a selected case study area in Nandyal Mandal ofKurnool District of Andhra Pradesh, India. Integrated output layout will be effectively useful in the demarcation of potentialresource zones. This demarcation area zone system is not only to identify the zones but also helpful in the replenishing theresources of the study area. The digital elevation model is also used to extract slope and drainage themes of the study area.The groundwater potential zones were obtained by overlaying all the thematic maps in terms of weighted overlay analysismethod using the spatial analysis tool in ArcGIS 10.1. This ground water potential information will be useful for effectiveidentificationofsuitablelocationsfor extractionofsuchgroundwater

Demarcation of Ground Water Potential Zones using Remote Sensing and GIS Applications

Now-a-days, due to the high demand of water for the human needs, groundwater sources are drastically extracted and causing to least the source. The entire Yearly furnish is contributing from the utmost resource called Groundwater. Globally, groundwater is extracting primarily for the purpose of agricultural fields, domestic and for industrial water supply. Majority of the surface water is in the form of saline water which is not useful for the needs of human beings for their daily needs. Very less amount of fresh surface water is existing on the ground surface. To compensate the needs, it is essential to identify, extract and manage the groundwater which is available at different levels at different areas of the globe. Proper planning is required for the extraction of groundwater using updated technologies for using and maintaining of natural resources like water resources. The prime strive of the selected project area is to map out potential groundwater regions in the Pendlimarri Mandal of Kadapa District by using Geospatial Technology. The main impartial target of the work is to select appropriate methods and assessment criteria of the technology to identify the potential underground demarcations in geographic information system environment with help of ArcGIS software. To demarcate zones of groundwater potential, various key parameters called geology, lineament density, LU / LC, geomorphology, groundwater depths, slope and drainage pattern were prepared by utilizing remote sensing data and secondary data which can collect from concern departments. The thematic layers are to be finally integrated by using weighted overlay analysis of spatial analyst tools of data management tools of ArcMap software to delineate underground water prospects regions output layout of the project. Disparate groundwater prospects levels were categorized, from the range excellent to poor including very good, good and moderate in between. At last, decided that that the applications of geoinformatics are essential and effectively applied for the demarcation of potential zones of groundwater

Real-world outcomes among US Merkel cell carcinoma patients initiating immune checkpoint inhibitors or chemotherapy.

Aim: Retrospectively assessed treatment patterns and clinical and economic outcomes in Merkel cell carcinoma (MCC) patients receiving recommended first-line regimens. Materials & methods: MCC patients newly treated with either immune checkpoint inhibitors (ICIs) or chemotherapies (CTs) were selected from the Veterans Health Administration database (2013–2018); 74 patients (ICIs: 20 and CTs: 54) were selected. Results: Median duration of therapy was 300 days for ICIs and 91 days for CTs. Time to next treatment was 245 and 184 days, respectively. Mean total (per patient per month) costs were $15,306 (ICIs) and$10,957 (CTs), of which 51% and 86%, respectively, were non-MCC therapy-related costs. Conclusion: Despite higher costs, utilization of ICIs in first-line MCC shows clinical advantages over CTs in the real world

A phase II study of glembatumumab vedotin for metastatic uveal melanoma

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease \u3e100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5-5.6), and the median overall survival was 11.9 months (95% CI 9.0-16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release

Saturation of electrical resistivity

Resistivity saturation is observed in many metallic systems with a large resistivity, i.e., when the resistivity has reached a critical value, its further increase with temperature is substantially reduced. This typically happens when the apparent mean free path is comparable to the interatomic separations - the Ioffe-Regel condition. Recently, several exceptions to this rule have been found. Here, we review experimental results and early theories of resistivity saturation. We then describe more recent theoretical work, addressing cases both where the Ioffe-Regel condition is satisfied and where it is violated. In particular we show how the (semiclassical) Ioffe-Regel condition can be derived quantum-mechanically under certain assumptions about the system and why these assumptions are violated for high-Tc cuprates and alkali-doped fullerides.Comment: 16 pages, RevTeX, 15 eps figures, additional material available at http://www.mpi-stuttgart.mpg.de/andersen/saturation

Structural, thermal, in vitro degradation and cytocompatibility properties of P2O5-B2O3-CaO-MgO-Na2O-Fe2O3 glasses

Borophosphate glasses with compositions of (48 − x)P2O5-(12 + x)B2O3-14CaO-20MgO-1Na2O-5Fe2O3 (where x = 0, 3, 8 mol%) were prepared via a melt-quenching process. The effects of replacing P2O5 with B2O3 on the structural, thermal, degradation properties and cytocompatibility were investigated. Fourier transform infrared (FTIR) spectroscopy analysis confirmed the existence of BO3 triangular units and BO4 tetrahedral units within all the glasses with an increase of B/P ratio from 0.25 to 0.5. The BO4 units within the glass structure were observed to cause an increase in density (ρ) as well as glass transition (Tg) temperature and to decrease the crystallisation temperature (Tc). A decrease in thermal stability which indicated by process window was also observed in the case of substitution of P2O5 with B2O3. Degradation analysis of the glasses indicated that the dissolution rate increased with the addition of B2O3. The decrease in the thermal stability and chemical durability were attributed to the increase of BO3 units, which could increase crystallisation tendency and be easily hydrolysed by solution. The effect of boron addition on the cytocompatibility of the glasses was analysed using Alamar Blue and alkaline phosphatase (ALP) assays and DNA quantification. MG63 osteosarcoma cells cultured in direct contact with the glass samples surface for 14 days showed better cytocompatibility, compared to the tissue culture plastic (TCP) control group. In summary, the glass formulation with 12 mol% B2O3 presented the best cytocompatibility and thermal stability, thus could be considered for continuous fibre fabrication in future research and downstream activities

Contemporary issues in glass science

7-11Glasses-including non-oxide glasses-continue to be investigated for basic understanding and potential applications. The inter-related issues: glass formation as a self-organization process, glass transition, fast-ion relaxation in glasses, nanocrystallization and mixed alkali effect have been presented. Last two issues in the light of relevant experimental work including our own work on tellurite glasses have been focussed