Tracheolaryngeal Adenoid Cystic Carcinoma : The tumour that almost took her breath away

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Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Deoxyribonucleic acid hybridization : fundamental studies and applications in directed assembly

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005.Includes bibliographical references.Programmed self-assembly using non-covalent DNA-DNA interactions is a promising technique for the creation of next-generation functional devices for electronic, optical, and magnetic applications. This thesis develops the ability to tailor surfaces for the DNA-driven assembly of molecular, nano-, and micron-sized objects. Specifically, DNA hybridization was employed to direct the regiospecific assembly of DNA molecules onto substrates and in the targeted assembly of supraparticulate structures from nanoparticles and microparticles that express DNA molecules on their surfaces. These studies provide fundamental information needed for deploying a programmable process for the 'bottom-up' assembly of smaller species into large aggregates. DNA-based assembly spans areas of molecular biology and nanotechnology. In the former area, DNA microarrays have become a standard tool for gene expression analysis. In spite of the large number of studies that employ DNA microarrays, fundamental aspects of DNA hybridization on these platforms have been largely unexplored. In this thesis, the effects of immobilized probe density on DNA hybridization were examined by employing a mixed silane chemistry to systematically control the density of immobilized probe DNA strands (0.2 x 10¹³ probes/cm² to 5.2 x 10¹³ probes/cm²) on glass surfaces. The surface density of the immobilized species was found to significantly affect the hybridization yields; the equilibrium dsDNA amounts being highest on surfaces with ss-DNA probe densities corresponding to average inter- strand distances of 18 [Angstroms]. The strong effects of surface probe density on hybridization performance indicate that it can be a useful parameter for improving the signal-to-noise ratios for assays performed on microarrays.(cont.) A target in nanotechnology is the generation of larger functional units from smaller nanoscale objects. Using a mixed silane chemistry, the DNA-directed assembly of gold nanoparticles was investigated on surfaces with different probe densities. Gold nanoparticles could be assembled at a dense coverage of [approx.] 28% corresponding to a density of [approx.] 1070 particles/[mu]m². As with DNA-DNA hybridization, particle coverage was reduced at high probe densities due to strong steric and electrostatic hindrances. Non-specific adsorption-crucial for the creation of defect-free assembled devices-was three orders of magnitude lower than the specific adsorption of nanoparticles demonstrating the effectiveness of the surface chemistry in blocking extraneous particle-substrate interactions. The effect of probe density on the thermodynamics of nanoparticle adsorption was found to be fundamentally different than that on the thermodynamics of molecular DNA adsorption due to the multivalent nature of nanoparticle attachment. Asymmetric building blocks can substantially broaden the creation of novel self- assembled devices because of their morphological and/or chemical asymmetry. In this thesis, DNA-based recognition was employed to achieve orthogonal self-assembly on asymmetric microspheres. Dual-functional microspheres with two different DNA sequences were made by a shadow deposition of gold onto silica microspheres in conjunction with DNA immobilization procedures using thiol and silane chemistries. The prepared microspheres were used as templates for the selective orthogonal assembly of fluorophore-tagged target oligonucleotides and for the regiospecific assembly of nanoparticles of two different sizes.(cont.) The selective attachment of nanoparticles and DNA molecules onto different specified regions of the building block was achieved solely by the sequence complementarity of the various components. Extending the shadow deposition technique a step further, tri-functional particles were formed by the shadow deposition of gold and aluminum. After functionalizing the silica and gold surfaces with two different DNA sequences and passivating the aluminum surface with stearic acid, an orthogonal assembly of DNA molecules was successfully performed within specified regions on these tri- functional particles. The flexibility for specifying the regio-selective attachment of DNA molecules and nanoparticles onto these building block objects will be important for the modular creation of a variety of novel self-assembled devices. In order to expand the assembly to other asymmetric structures and to understand the effect of shape on DNA-mediated attachment, microrods were selectively assembled via DNA- DNA interactions on complementary surfaces. Because of the weak nature of the DNA-DNA interactions, a large contact area between the building block and substrate-as made possible by the microrod geometry-was essential in ensuring robust assembly. Further, dual-functional microrods were prepared by a shadow deposition of gold and could be assembled on flat surfaces in an orientation-specific manner highlighting another advantage of DNA-directed assembly beyond regiospecificity.(cont.) In essence, employing DNA as the linker molecule and a robust chemistry for DNA attachment, asymmetric multi-functional particles were assembled into novel configurations, which would be difficult to realize using symmetrical building blocks. This programmable self-assembly approach exploits the multiplicity and specificity of DNA-DNA interactions and provides a powerful strategy for the generation of novel l-D, 2-D, and 3-D functional devices.by Manish G. Bajaj.Ph.D

A Study of Clinical and Biochemical Profile of Adrenal Insufficiency in AIDS Patients

ABSTRACT Most common and clinically relevant endocrine organ dysfunction in AIDS patients is that of adrenal cortex. But, adrenal insufficiency (AI) is seldom diagnosed in clinical practice because symptoms do not appear until more than 90% of the gland has been destroyed and symptoms suggestive of adrenal insufficiency are not uncommon in patients of AIDS without AI. There is lack of studies to look for characteristic features in such group, which can raise a suspicion and lead us to do biochemical evaluation, to detect early HPA axis involvement, to prolong as well as improve quality of life. Fifty HIV seropositive patients were selected, detailed history, clinical examination and biochemical parameters were recorded. Their basal cortisol and 30-min, 60-min, post synacthen test were performed, based on which the patients were grouped as AIDS with AI (AIDS-Ab) and AIDS without AI (AIDS-N) .The clinical feature and laboratory findings of these two groups were compared and interpreted using Chi square test as a test of significance and for comparison of laboratory data the Mann Whitney was used. In our study, in comparison to AIDS-N, AIDS-Ab patients had more frequency of weakness, weight loss, fever, gastrointestinal disturbances like nausea, vomiting. They also had lower range of CD4 count, hypoglycemia, high ESR, eosinophilia, hyponatremia, hyperkalemia, low Na/K ratio. In AIDS patients, symptoms like significant weight loss, low CD4 count, not on ART, hypoglycemia, increased ESR, hyponatremia, hyperkalemia, low Na/K ratio, low basal plasma cortisol levels as seen in the present study, should direct us in suspecting the risk of patient going for AI. In such patients stimulation tests could be done to confirm AI. The importance of early detection becomes clear from the fact that AI adds to the mortality of AIDS patient, and also early intervention in such patients prolongs as well as adds quality to life

A Subtle Change in Substituent Enabled Multi-Ways Fluoride Signals Including Paper-Strip Colorimetric Detection Using Urea Receptor Functionalized 1,1,4,4-Tetracyanobuta-1,3-Diene-Based Push-Pull Chromophore

A simple color change detection by the naked-eye using untreated paper for a biologically relevant fluoride (F–) anion in water is a challenge. New non-planar push-pull chromophore involving intramolecular charge-transfer (ICT) from urea donor in 2,3-disubstituted-1,1,4,4-tetracyanobuta-1,3-diene (TCBD) turns out to be an efficient system for detecting F– ion giving various output signals. But, replacing phenyl (Ph) at C3-position with 4-(dimethylamino)phenyl (DMA) led to the absence of colorimetric and fluorometric detections due to the masking and quenching, nature of strong ICT by the DMA. NMR and electrochemical studies revealed that the sensing mechanism is governed by H-bonding as well as the deprotonation of N–H attached with TCBD moiety which reduces the HOMO–LUMO gap and causes the dramatic color change. Coupled with excellent sensitivity (3 ppm) and specificity towards F–, a successful demonstration of cheap tissue paper-based visual strip-detection in aqueous is presented

Refolding and simultaneous purification by three-phase partitioning of recombinant proteins from inclusion bodies

Many recombinant eukaryotic proteins tend to form insoluble aggregates called inclusion bodies, especially when expressed in Escherichia coli. We report the first application of the technique of three-phase partitioning (TPP) to obtain correctly refolded active proteins from solubilized inclusion bodies. TPP was used for refolding 12 different proteins overexpressed in E. coli. In each case, the protein refolded by TPP gave either higher refolding yield than the earlier reported method or succeeded where earlier efforts have failed. TPP-refolded proteins were characterized and compared to conventionally purified proteins in terms of their spectral characteristics and/or biological activity. The methodology is scaleable and parallelizable and does not require subsequent concentration steps. This approach may serve as a useful complement to existing refolding strategies of diverse proteins from inclusion bodies