Safety of Novel Targeted Therapies in Oncology.

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PNIPAM Poly (N-isopropylacrylamide): A Thermoresponsive “Smart” Polymer in Novel Drug Delivery Systems

Over the past years, extensive research has been carried out in designing and optimizing various drug delivery systems in order to maximize therapeutic effect and minimize unwanted effects of drugs. Many drug carrier systems have been developed on the basis of nanotechnology including systems based on polymeric nanoparticles. Polymeric drug delivery research has been extended to targeting of the drug at the specific site by utilizing various stimuli responsive systems which depend upon physiological conditions of the body such as pH of biological fluids and temperature of the human body. Thermoresponsive polymers with Lower Critical Solution Temperature (LCST) have been investigated for various biomedical and pharmaceutical formulations. One such polymer of considerable focus is PNIPAM Poly (N-isopropylacrylamide). PNIPAM is a thermosensitive polymer which has been utilized in many drug delivery systems including for cancer therapeutics. The present article deals with the properties of PNIPAM and their applications in different drug delivery systems.Keywords: PNIPAM; LCST; Properties; Synthesis; ApplicationsInternet Journal of Medical Update 2012 July;7(2):59-6

Studies in the reactions of α-keto acids

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Ahmedabad tolerance induction protocol and chronic renal allograft dysfunction: pathologic observations and clinical implications

<p>Abstract</p> <p>Background</p> <p>Chronic Renal Allograft Dysfunction (CRAD) is responsible for a large number of graft failures. We have abrogated acute T-cell rejections using Ahmedabad Tolerance Induction Protocol (ATIP) with hematopoietic stem cell transplantation (HSCT) under non-myeloablative conditioning pre-transplant. However B-cell mediated rejections and CRAD continue to haunt us. We carried out retrospective analysis of renal allograft biopsies performed in the last 4 years to evaluate the effect of ATIP on CRAD.</p> <p>Materials and methods</p> <p>Biopsies diagnosed as per modified Banff criteria belonged to 2 groups: ATIP under low dose immunosuppression of cyclosporine/Azathioprine/Mycofenolate mofetil+ Prednisolone, subjected to donor leucocyte transfusion, anti-T/B cell antibodies, low dose target specific irradiation, cyclophosphamide, cyclosporin followed by HSCT pre-transplant; controls who opted out of ATIP were transplanted under standard triple drug immunosuppression. Demographics of both groups were comparable.</p> <p>Results</p> <p>Incidence of chronic changes was higher in controls (17.5%) vs. 10.98% in ATIP over a mean follow up of 151.9 months in the former and 130.9 months in the latter. Proteinuria and hypertension were higher in controls (48.4%) vs. ATIP (32.7%) with chronic transplant glomerulopathy, focal global sclerosis in 67.7% in controls vs. 46.7% in ATIP, acute on chronic T/B cell rejection in 51.6% controls vs. 28.1% ATIP, with peritubular capillary C4d deposits in 19.4% controls vs. 1.9% ATIP biopsies. Acute on chronic calcineurin inhibitor toxicity was higher in ATIP (71.9%) vs. 48.4% in controls.</p> <p>Conclusion</p> <p>Chronic immune injury was less with ATIP vs controls as compared to a higher incidence of chronic calcineurin inhibitor toxicity in the former.</p

Radiometric Calibration Techniques for Signal-of-Opportunity Reflectometers

Bi-static reflection measurements utilizing global navigation satellite service (GNSS) or other signals of opportunity (SoOp) can be used to sense ocean and terrestrial surface properties. End-to-end calibration of GNSS-R has been performed using well-characterized reflection surface (e.g., water), direct path antenna, and receiver gain characterization. We propose an augmented approach using on-board receiver electronics for radiometric calibration of SoOp reflectometers utilizing direct and reflected signal receiving antennas. The method calibrates receiver and correlator gains and offsets utilizing a reference switch and common noise source. On-board electronic calibration sources, such as reference switches, noise diodes and loop-back circuits, have shown great utility in stabilizing total power and correlation microwave radiometer and scatterometer receiver electronics in L-band spaceborne instruments. Application to SoOp instruments is likely to bring several benefits. For example, application to provide short and long time scale calibration stability of the direct path channel, especially in low signal-to-noise ratio configurations, is directly analogous to the microwave radiometer problem. The direct path channel is analogous to the loopback path in a scatterometer to provide a reference of the transmitted power, although the receiver is independent from the reflected path channel. Thus, a common noise source can be used to measure the gain ratio of the two paths. Using these techniques long-term (days to weeks) calibration stability of spaceborne L-band scatterometer and radiometer has been achieved better than 0.1. Similar long-term stability would likely be needed for a spaceborne reflectometer mission to measure terrestrial properties such as soil moisture

Lymphangioma Circumscriptum of the Vulva- A Case Series

Vulval dermatoses pose a diagnostic and therapeutic challenge for the dermatologists. Lymphangioma Circumscriptum (LC) is a form of lymphangioma affecting the skin and subcutaneous tissues that is characterised by benign dilation of lymphatic channels. This uncommon condition is known to occur over the chest, mouth, axilla, tongue, and rarely in the vulva. In this series, authors present three cases of LC of vulva in women between the age group of 45 to 60 years with late-onset fluid-filled lesions over the vulva. The first case had history of hysterectomy prior to onset of lesions, the second case had a spontaneous onset of lesions while the third was a suspected case of pelvic tuberculosis with secondary lymphangioma

Snooping Around: Observation Planning for the Signals of Opportunity P-Band Investigation (SNOOPI)

Launching October 2022, the SigNals Of Opportunity P-band Investigation (SNOOPI) is a 6U CubeSat dedicated to demonstrating spaceborne remote sensing of root zone soil moisture and snow water equivalent using signals of opportunity. P-band (240-500 MHz) frequencies are required to penetrate dense vegetation or snow and into the top 200 cm of soil, but this band is heavily subscribed. Rather than transmitting its own signal SNOOPI will observe reflected signals from the U.S. Navy’s Mobile User Objective System satellites. This makes planning observations challenging. The point of reflection is a function of both the transmitter and receiver satellite positions as well as terrain. The direct signal must be observed simultaneously on the same antenna pattern with sufficient gain. Ionospheric delay must also be accounted for. To satisfy these requirements and maintain a cadence of one observation per day, the SNOOPI science operations center at Purdue University has developed custom software for scheduling activities onboard the satellite. The software is highly automated, involving the user only in the definition of observation targets, priorities, and giving final approval to the proposed schedule. Orbit, attitude, power, communication, memory, and observation constraints are handled by a combination of linear programming and pattern search optimization methods. The purpose of this paper is to describe the challenges of scheduling observations for a signals of opportunity mission and illustrate how they were solved for SNOOPI

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome

Conservation, Variability and the Modeling of Active Protein Kinases

The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy