X-ray/gamma radiation shielding properties of zinc ferrite nanoparticles synthesised via solution combustion method.

Zinc ferrite (ZnFe2O4) nanoparticles were synthesised via solution combustion method using urea as a fuel. The synthesised samples were characterised with various techniques. The cubic structure with Fd-3 m space group is confirmed by Powder X-ray Diffraction and Bragg's reflection. The crystallite size estimated from Scherrer's method was found to be 40 nm. The agglomerated irregular shape and sized surface morphology was confirmed by Scanning Electron Microscopy image. The direct energy band gap determined from Wood and Tauc's relation was found to be 5.25 eV. Using a NaI (Tl) detector and multi-channel analyser, the described sample was examined for X-ray and gamma ray shielding characteristics in the energy range of 0.081-1.332 MeV. The measured shielding values are in good agreement with the theory, however below 356 keV, there is a little variation of up to 10%. The current work offers up new possibilities for using this simple, affordable, effective and low temperature approach to create nanomaterials for X-ray and gamma ray shielding.

Synthesis and characterisation of lead-magnesium-boron nanocomposite for radiation shielding application.

There is a need for the replacement of toxic lead with nontoxic materials in radiation shielding applications. Instead of pure lead, lead mixed compounds/mixtures/alloys are considered to be less toxic and hence preferred for radiation shielding purposes. The compounds with magnesium are said to be having good magnetic and mechanical properties. Meanwhile, the boron element avoids secondary radiation and absorbs neutrons. The compound which is a mixture of lead, magnesium and boron is expected to be a good shielding material for radiation for X-rays/gamma rays. Hence in the present study, we have synthesised the lead-magnesium-boron (LMB) nanocomposites (NCs) using the green synthesis approach for the first time. LMB is synthesised by solution combustion method using Aloe vera as a reducing agent. The synthesised NCs are characterised using well-known characterisation techniques. Powder X-ray diffraction confirmed the formation of multi-phase LMB NCs, and average crystal size is found to be 13-15 nm. Surface morphology and chemical composition are affirmed by SEM and EDX. The optical energy gap is found to be 1.87 eV. FTIR confirmed the functional groups. X-rays/gamma rays, neutrons and bremsstrahlung radiation shielding efficiency are measured by experimental and theoretical, compared with conventional shielding materials. LMB NCs have proved to be efficient. Hence, LMB NCs proved to be potential in X-rays/gamma rays, neutrons and bremsstrahlung radiation shielding.

Stimulation-induced changes at the electrode-tissue interface and their influence on deep brain stimulation.

Objective. During deep brain stimulation (DBS) the electrode-tissue interface (ETI) forms a critical path between device and brain tissue. Although changes in the electrical double layer (EDL) and glial scar can impact stimulation efficacy, the effects of chronic DBS on the ETI have not yet been established.Approach. In this study, we characterised the ETI surrounding chronically implanted DBS electrodes in rats and compared the impedance and histological properties at the electrode interface in animals that received daily stimulation and in those where no stimulation was applied, up to 8 weeks post-surgery. A computational model was developed based on the experimental data, which allowed the dispersive electrical properties of the surrounding encapsulation tissue to be estimated. The model was then used to study the effect of stimulation-induced changes in the ETI on the electric field and neural activation during voltage- and current-controlled stimulation.Main results. Incorporating the observed changes in simulationsin silico, we estimated the frequency-dependent dielectric properties of the EDL and surrounding encapsulation tissue. Through simulations we show how stimulation-induced changes in the properties of the ETI influence the electric field and alter neural activation during voltage-controlled stimulation. A substantial increase in the number of stimulated collaterals, and their distance from the electrode, was observed during voltage-controlled stimulation with stimulated ETI properties.In vitroexamination of stimulated electrodes confirmed that high frequency stimulation leads to desorption of proteins at the electrode interface, with a concomitant reduction in impedance.Significance. The demonstration of stimulation-induced changes in the ETI has important implications for future DBS systems including closed-loop systems where the applied stimulation may change over time. Understanding these changes is particularly important for systems incorporating simultaneous stimulation and sensing, which interact dynamically with brain networks.

Prof. B. Ramamurthi - A Glimpse into his Contributions to Neuroscience.

Prof B Ramamurthi was a pioneer of Indian neurosurgery and a major force in the development of Indian neuroscience. Founding the Madras Institute of Neurology and later the A Lakshmipathi Neurosurgical Centre (ALNC), both at Madras (or Chennai as it is now called), he developed centres of excellence in his career that spanned over five decades. During this period of time he made Madras, a destination for neurosurgery and neuroscience. Along with his colleagues a large number of publications were produced which influenced the world. Notable among his contributions were those in Stereotaxy for movement disorders, epilepsy, pain and psychiatric illness. He also had notable contributions in brain tumours especially acoustic neurinomas and pituitary tumours. His papers on the low incidence of aneurysms is still quoted widely. Head injuries formed a major part of the neurosurgical work and major contributions were made in that field too. As a developing country with socio-economic issues, infections of the nervous system were seen commonly. His publications on tuberculomas of the brain are noteworthy. He was intrigued by the neurophysiological basis of consciousness. He writings on the subject reflect his attempt to bring together ancient eastern thoughts and concepts of consciousness and life and western science. In the later part of his career he spoke on ethics in and the changing milieu of neurosurgery. While contributions to spinal surgery were not seen in the first half of his career, he along with his colleagues from ALNC published original articles on spinal surgery especially tumours and OPLL. Prof B Ramamurthi, has not only influenced, taught and mentored, during his lifetime, a great many neuroscientists, but he also continues to do so through his publications which continue to be relevant in todays world. A glimpse into his contributions show us how without the technology of today a lot was achieved - and we need to see that, to inspire us to achieve more and to strive for greater heights.

Cerebello-pontine and Cerebello-medullary Fissure Choroid Plexus Papilloma in a Child - Case Report and Review of Literature.

Choroid plexus papillomas (CPP) are commonly seen in the supratentorial compartment in children and only very rarely in the posterior fossa. CPP in the cerebello-pontine angle and cerebello-medullary fissure (CPA) in the pediatric age group are extremely rare with only seven previous cases reported in literature. The authors present the case of a 7-year-old girl who presented with neck tilt, imbalance, and headache. The MRI showed a lesion with a frond-like appearance in the CPA with heterogeneous enhancement. The tumor was excised radically using a cerebello-medullary fissure approach. The authors review and analyze the literature on this rare pediatric tumor, with specific attention to radiology and the surgical aspects.

Surgical Management of Frontal Bone Fractures.

INTRODUCTION: Frontal bone fractures show a low frequency of occurrence of about 5% to 15% of all maxillofacial fractures occurring due to high-velocity injuries such as in the case of road traffic accidents, sporting events, assaults. Successful surgical management revolves around the concept of minimizing cosmetic deformity, maintaining normal sinus function, avoidance of short and long-term complications. In this article, the authors report a case series of 24 cases of frontal bone fracture treated with various treatment modalities. MATERIALS AND METHODS: A total of 24 cases of frontal bone fracture admitted to our facility were treated accordingly and the subsequent follow up data were collected and compiled to be included in this study. RESULTS: In our study, 83.33% cases showed isolated anterior table fractures, 8.3% cases with combined anterior and posterior table fractures. 40% cases managed conservatively, 41.6% with titanium mini plates, 12.5% cases with titanium mesh and 4% with cranialisation with fat obliteration. CONCLUSION: Our treatment decisions were based upon the extent and severity of the injuries which aided in tailoring the treatment modality. Thereby, curbing the long-term complications which could be foreseen and hence, a better functional outcome was achieved.

Mandible reconstruction using a vascularized fibula flap from a post-polio paralytic limb.

The case of 69-year-old man with a post-polio paralytic limb who was diagnosed with carcinoma of the lower alveolus is presented. A successful mandible reconstruction was performed using a vascularized fibula osteocutaneous flap harvested from the polio-affected limb. The skin perfusion and quality of the bone were good. The donor defect healed uneventfully. Harvesting the flap from the polio-affected limb also significantly reduced the donor site morbidity. This case is novel in presenting the successful use of a free fibula flap harvested from a leg affected by paralytic poliomyelitis.

Facile manufacturing of fused-deposition modeled composite scaffolds for tissue engineering-an embedding model with plasticity for incorporation of additives.

The fused-deposition modeling (FDM) process is carried out at an elevated temperature, preventing the addition of biological factors, drugs, bioactive compounds, etc, during fabrication. To overcome this disadvantage, a 3D interlinked porous polylactic acid (PLA) scaffold was fabricated by FDM, followed by the embedding of a polycaprolactone (PCL) scaffold into the pores of the PLA at room temperature, yielding a PLA-PCL scaffold. In addition, PLA-PCL scaffolds with nanohydroxyapatite (PLA-PCL-nHAP) and multiwalled carbon nanotubes (PLA-PCL-MWCNT) were also fabricated. Here, the FDM-fabricated PLA scaffold functions as the structural component, whereas the embedded PCL scaffold acts as the functional component, which provides a the ability to functionalize the scaffolds with the desired chemical or biological materials. The embedding process is straightforward, cost effective, and does not require sophistication. A mechanical characterization of the scaffolds suggests that the Young's modulus of the PLA-PCL scaffold (16.02 MPa) was higher than that of the FDM-fabricated PLA (9.98 MPa) scaffold, by virtue of embedded PCL matrix. In addition, finite element analysis showed that the von Mises stress on a mandible with scaffolds was 4.04 MPa, whereas for a mandible with a defect, it was 6.7 MPa, confirming the stress distribution efficiency and mechanical stability of these scaffolds. Furthermore, field emission-scanning electron microscope analysis implied the presence of interlinked porous structures with pore diameters of 50 µm to 300 µm. X-ray diffraction results revealed an increased crystallinity (%) in the embedded models (PLA-PCL, PLA-PCL-nHAP and PLA-PCL-MWCNT), compared to a PLA printed scaffold. Additionally, Raman analysis revealed that the embedding process did not cause chemical alterations in the polymeric chains. In vitro analysis with human osteoblasts demonstrated the osteoconductive nature of the scaffold, which supported mineralization. In brief, the advantage of our model is that it helps to overcome the difficulties of manufacturing a filament with the desired additives for FDM, and offers the ability to incorporate the desired concentrations of heat-labile bioactive molecules during the embedding process at ambient temperatures.

Fabrication of tri-layered electrospun polycaprolactone mats with improved sustained drug release profile.

Modulation of initial burst and long term release from electrospun fibrous mats can be achieved by sandwiching the drug loaded mats between hydrophobic layers of fibrous polycaprolactone (PCL). Ibuprofen (IBU) loaded PCL fibrous mats (12% PCL-IBU) were sandwiched between fibrous polycaprolactone layers during the process of electrospinning, by varying the polymer concentrations (10% (w/v), 12% (w/v)) and volume of coat (1 ml, 2 ml) in flanking layers. Consequently, 12% PCL-IBU (without sandwich layer) showed burst release of 66.43% on day 1 and cumulative release (%) of 86.08% at the end of 62 days. Whereas, sandwich groups, especially 12% PCLSW-1 & 2 (sandwich layers-1 ml and 2 ml of 12% PCL) showed controlled initial burst and cumulative (%) release compared to 12% PCL-IBU. Moreover, crystallinity (%) and hydrophobicity of the sandwich models imparted control on ibuprofen release from fibrous mats. Further, assay for cytotoxicity and scanning electron microscopic images of cell seeded mats after 5 days showed the mats were not cytotoxic. Nuclear Magnetic Resonance spectroscopic analysis revealed weak interaction between ibuprofen and PCL in nanofibers which favors the release of ibuprofen. These data imply that concentration and volume of coat in flanking layer imparts tighter control on initial burst and long term release of ibuprofen.

Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more. RESULTS: Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy. CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).

Forty years of clinical excellence at the Dr A Lakshmipathi Neurosurgical Centre and Post-Graduate Institute of Neurological Surgery, Voluntary Health Services (VHS) Hospital.

The Achanta Lakshmipathi Neurosurgical Center (ALNC) and Post Graduate Institute of Neurological Surgery is a private teaching neurosurgical institution located in the VHS (Voluntary Health Services) Hospital Chennai. It has been a leader and trendsetter among the private academic neurosurgical training institutions, and because of its unique legacy, has influenced the progress of Neurosurgery in India. The center was the second neurosurgical Institute to be created by Prof. B Ramamurthi and has trained neurosurgeons in the unique ALNC school of Neurosurgery. The Institute has grown to become a centre of excellence in microsurgery, and spinal surgery and has become a training centre for neurosurgery since 1985. The unique humanitarian aspects of the Voluntary Health Services Hospital helped in bringing the best of Neurosurgery to all strata of society. Forty years after its inception, the ALNC continues its delivery of excellence in clinical neurosurgery and academics.

Buccal Mucosal Epithelial Cells Downregulate CTGF Expression in Buccal Submucosal Fibrosis Fibroblasts.

INTRODUCTION: Oral submucosal fibrosis (OSMF) is a chronic debilitating fibrotic disease of the oral cavity and is a serious health hazard in south Asia and, increasingly, the rest of the world. The molecular basis behind various treatment modalities to treat OSMF still remains unclear. In this study, we have investigated the in vitro ability of the buccal mucosal cells to reduce the proliferation of the fibroblasts of the fibrotic area in co-culture of cells and also at the molecular levels to reduce the level of connective tissue growth factor (CTGF) in the OSMF fibroblasts (SMF-F). MATERIALS AND METHODS: The study compares isolation, morphological and proliferation kinetics of SMF-F and BMF cells with and without co-culturing with BMEs. In addition, we have compared the mRNA expression levels of CTGF in SMF-F co-cultured BME and non-co-cultured SMF-F cells using validated real-time quantitative PCR (RT-qPCR) method. RESULTS: The basic morphological characteristics of SMF-F were similar to BMF, but the former cells had higher proliferation rate in early passages compared to late passage state. We also observed that the CTGF expression levels in SMF-F under co-culture conditions of BME were consistently and significantly downregulated in all four different SMF-F-derived cells from four different patients. CONCLUSION: Rapid proliferation and collagen synthesis in SMF-F as against BMF cells are the factors that confirm the innate nature of fibrosis fibroblasts (SMF-F). Further, the CTGF expression level in SMF-F was significantly suppressed by BME in co-culture conditions against controls (BMF). Considered together, this suggests that the cell therapeutic candidate of BME could be used in treating OSMF.

Comparative study of isolation, expansion and characterization of epithelial cells.

BACKGROUND AIMS: The human epithelial cells (EPCs) have been identified as the essential element for the regeneration of skin construct for burns, wounds and various tissue engineer-based products. METHODS: In this study, the isolation, expansion and characterization of EPCs from various sources such as juvenile foreskin (JSK), buccal mucosa (BM), penile skin (PS) and urothelium (UR) in serum-free and xeno-free EpiLife media were evaluated. RESULTS: The growth kinetics study revealed that EPCs from JSK and BM had notably higher growth rates compared with the others. Overall, the EPCs from all sources retained basic morphological characteristics and the functional characteristics such as Pan Cytokeratin (AE1/AE3). In addition, the cryopreservation stability of EPCs was accessed for post-thaw viability and found to be greater than 80% at 1 year of storage, but demonstrated reduced cell recovery (51%) at the second year in fetal bovine serum-free cryopreservation media. CONCLUSIONS: Our result suggests that the EPCs from four cell sources can be grown in feeder-free, serum-free and xeno-free systems using commercially available EpiLife medium without losing epithelial cell characteristics even after passage 4. However, its suitability for clinical application must be accessed by preclinical and clinical studies.

Evaluation of optimum roughage to concentrate ratio in maize stover based complete rations for efficient microbial biomass production using in vitro gas production technique.

AIM: A study was undertaken to evaluate the optimum roughage to concentrate ratio in maize stover (MS) based complete diets for efficient microbial biomass production (EMBP) using in vitro gas production technique. MATERIALS AND METHODS: MS based complete diets with roughage to concentrate ratio of 100:0, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, and 30:70 were formulated, and 200 mg of oven-dried sample was incubated in water bath at 39°C along with media (rumen liquor [RL] - buffer) in in vitro gas syringes to evaluate the gas production. The gas produced was recorded at 8 and 24 h of incubation. In vitro organic matter digestibility (IVOMD), metabolizable energy (ME), truly digestible organic matter (TDOM), partitioning factor (PF), and EMBP were calculated using appropriate formulae. Ammonia nitrogen and total volatile fatty acids (TVFAs) production were analyzed in RL fluid-media mixture after 24 h of incubation. RESULTS: In vitro gas production (ml) at 24 h incubation, IVOMD, ME, TDOM, TVFA concentration, and ammonia nitrogen production were increased (p<0.01) in proportion to the increase in the level of concentrate in the diet. Significantly (p<0.01) higher PF and EMBP was noticed in total mixed ration with roughage to concentrate ratio of 60:40 and 50:50 followed by 70:30 and 40:60. CONCLUSION: Based on the results, it was concluded that the MS can be included in complete rations for ruminants at the level of 50-60% for better microbial biomass synthesis which in turn influences the performance of growing sheep.

Correlation between EGFR Gene Mutations and Lung Cancer: a Hospital-Based Study.

Epidermal growth factor receptor (EGFR) is one of the targeted molecular markers in many cancers including lung malignancies. Gefitinib and erlotinib are two available therapeutics that act as specific inhibitors of tyrosine kinase (TK) domains. We performed a case-control study with formalin-fixed paraffin-embedded tissue blocks (FFPE) from tissue biopsies of 167 non-small cell lung carcinoma (NSCLC) patients and 167 healthy controls. The tissue biopsies were studied for mutations in exons 18-21 of the EGFR gene. This study was performed using PCR followed by DNA sequencing. We identified 63 mutations in 33 men and 30 women. Mutations were detected in exon 19 (delE746-A750, delE746-T751, delL747-E749, delL747-P753, delL747-T751) in 32 patients, exon 20 (S786I, T790M) in 16, and exon 21 (L858R) in 15. No mutations were observed in exon 18. The 63 patients with EFGR mutations were considered for upfront therapy with oral tyrosine kinase inhibitor (TKI) drugs and have responded well to therapy over the last 15 months. The control patients had no mutations in any of the exons studied. The advent of EGFR TKI therapy has provided a powerful new treatment modality for patients diagnosed with NSCLC. The study emphasizes the frequency of EGFR mutations in NSCLC patients and its role as an important predictive marker for response to oral TKI in the south Indian population.

Nevoid Basal cell carcinoma syndrome: a case report and review.

Nevoid basal cell carcinoma syndrome, a rare autosomal dominant disorder, comprises of a number of abnormalities such as multiple nevoid basal cell carcinomas, skeletal abnormalities and multiple keratocystic odontogenic tumors. Diagnosis may be difficult because of the variability of expressivity and different ages of onset for different traits of this disorder. The dental clinician may be the first to encounter and identify this syndrome, when the multiple cysts like radiolucencies are discovered on panoramic view. This article reports a case of Nevoid basal cell carcinoma syndrome and provides an overview on diagnosis and management.

Replacement of inorganic zinc with lower levels of organic zinc (zinc nicotinate) on performance, hematological and serum biochemical constituents, antioxidants status, and immune responses in rats.

AIM: A study was undertaken to investigate the effect of organic zinc (zinc nicotinate, Zn-nic) supplementation (6, 9, and 12 ppm) compared to inorganic zinc (12 ppm) on growth performance, hematology, serum biochemical constituents oxidative stress, and immunity in weaned female Sprague-Dawley rats. MATERIAL AND METHODS: A 48 weaned rats (285.20±1.95 g) were randomly distributed to 4 dietary treatments with 6 replicates in each and reared in polypropylene cages for 10 weeks. Basal diet (BD) was formulated with purified ingredients without zinc (Zn). Four dietary treatments were prepared by adding 12 ppm Zn from ZnCO3 (control) and 6, 9, and 12 ppm Zn from Zn-nic to the BD. On 42(nd) day, blood was collected by retro-orbital puncture for analyzing hematological constituents, glucose, cholesterol, alkaline phosphatase, total protein, albumin, and globulin and antioxidant enzyme activities. At 43(rd) day, rats were antigenically challenged with sheep red blood cell (RBC) to assess humoral immune response and on 70(th) day cell-mediated immune response. RESULTS: Weekly body weight gains, daily feed intake, blood hematological constituents (white blood cell, RBC, hemoglobin concentration, packed cell volume, mean corpuscular volume, lymphocyte, monocyte, and granulocyte concentration) and serum glucose, total protein levels were comparable among the rats feed Zn from ZnCO3 and Zn-nic (6, 9, and 12 ppm). Serum cholesterol reduced with organic Zn supplementation at either concentration (6-12 ppm). Serum globulin concentration reduced (p<0.05) with 6 ppm Zn-nic supplementation compared to other dietary treatments. Lipid peroxidation lowered (p<0.05) reduced with 12 ppm organic Zn; thiobarbituric acid reacting substances and protein carbonyls concentrations in liver reduced (p<0.05) with 9 and 12 ppm levels of organic Zn supplementation compared to 12 ppm Zn supplementation from inorganic source. RBC catalase and glutathione peroxidase enzymes activities were highest (p<0.05) in rats supplemented with 12 ppm Zn-nic, followed by 9 ppm. Comparable immune response (humoral and cell-mediated) was observed between 12 ppm inorganic Zn and 9 ppm organic Zn and higher (p<0.05) immune response was noticed at 12 ppm Zn-nic supplementation. CONCLUSION: Based on the results, it is concluded that dietary Zn concentration can be reduced by 50% (6 ppm) as Zn nicotinate without affecting growth performance, hemato-biochemical constituents, antioxidant status, and immunity. In addition, replacement of 12 ppm inorganic Zn with 12 ppm organic Zn significantly improved antioxidant status and immune response.

Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.