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The small signal stability analysis has got much importance for a single machine infinite bus system (SMIB). Conventional controllers are not smart to give the faster response. Hence advanced and intelligent controllers like Fractional order PID (FOPID) and State space analysis methods are used to obtain the better responses. In this article, corresponding SMIB system is analyzed using simulation studies and are carried out in MATLAB 2017a.

In this paper, Sliding Mode Controller-based Distribution Static Compensator (DSTATCOM) is proposed for enhancement of power quality in the distribution network. The DSTATCOM plays a vital role to enhance the quality of power in the distribution network with linear and nonlinear loads under non-stiff sources. During the load disturbance in the systems, there is a sudden variation of voltage in DC link capacitor voltage connected with compensating device. The performance of DSTATCOM purely depends on the capacitor voltage level during load variation. It should be maintained within the prescribed limits. In general, the conventional controller is used in the converter to control dc-link capacitor voltage. Through, the conventional controller like PI transient response is still slow. Due to this reason, the harmonic elimination, load balancing, and reactive power compensation process are not satisfactory during different load variations in the distribution systems. To overcome these problems sliding mode controller is proposed in the control circuit for the proper operation of the compensator. The sliding mode controller regulates the DC link capacitor voltage to generate required reference currents. The reference currents play a vital role for switching pulse generation and control of DSTATCOM during various load disturbances. Sliding mode controller is designed to limit variation of DC-link voltage within limits. The proposed technique is modelled and its performance is simulated in MATLAB/SIMULINK platform and results are shown to validate the design and control of DSTATCOM under various load disturbance.

PDF file - 2.9MB, In-vitro kinase assay, Histology, Cell proliferation, MANOVA analysis for genomic correlates of drug sensitivity

Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC50 = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC50: PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials. Mol Cancer Ther; 12(2); 151–61. ©2012 AACR.

PDF file - 663K, Ambit kinome tree, Cell proliferation data, Pharmacokinetics, Body weight changes in PC3 efficacy study, Active vessel stain in COLO-205 efficacy study, MV4-11 efficacy model, Drug sensitivity profiling and correlation to mutation status

XLS file - 167K, Table 1: Cell line drug sensitivity data for SB2343 and mutations in cancer genes. Table 2: Results from MANOVA analysis of cancer genes as modifiers of drug sensitivity

SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 μg of protein lysate. AcH3 levels of liver, spleen, PBMCs, bone marrow and tumor were measured in BALB/c mice, HCT-116 xenografted BALB/c nude mice, or in SCID mice orthotopically engrafted with AML (HL-60) after oral treatment with SB939. AcH3 could only be detected after treatment. In all tissues, the highest signal detected was at the 3-hour time point on day 1. On day 15, the signal decreased in normal tissues but increased in cancerous tissues and became detectable in the bone marrow of leukemic mice. In all tissues, acH3 correlated with SB939 dose levels (r2 = 0.76–0.94). When applied to PBMCs from 30 patients with advanced solid malignancies in a phase I clinical trial, a dose-dependent (10–80 mg) increase in relative acH3 was observed 3-hour postdose on day 1, correlating with Cmax and AUC of SB939 concentrations in plasma (r = 0.97, P = 0.014). Our data show that the favorable pharmacokinetic and pharmacodynamic properties of SB939 are translated from preclinical models to patients. Mol Cancer Ther; 10(7); 1207–17. ©2011 AACR.

Supplementary Methods, Figures 1-2, Tables 1-2 from Pharmacodynamic Evaluation of the Target Efficacy of SB939, an Oral HDAC Inhibitor with Selectivity for Tumor Tissue

This paper presents, the enhancement of Electronic Voting Machine (EVM) performance using fingerprint and face recognition. In democratic countries, the EVM plays a vital role in the election process. Even though it has more benefits; still the malpractices are continued due to manual verification of electoral documents for all elections in democratic countries. In this proposed method EVM with biometric fingerprint and face recognition devices are used to overcome this problem. To conquer the issues existing in the election process for voter identification the biometric fingerprint and web cameras are introduced in the EVMs. The people at the polling booth need to put the finger in the fingerprint equipment and face to be captured by the web camera provided to recognize them. The controller fetches the data from the input devices and compares it with the database to enable the polling device to cast their votes. In practice, due to some technical issue either in the input devices or from the voter side the election process will be continued by document verification. In the polling booths, the presiding officers are having the right to enable the polling device by pressing the enable button after document verification. The performance of the proposed method was validated with EVM successfully.

Now a day's energy is generated from both renewable and non-renewable resources. But the generation of electricity from a renewable resource is more authentic and less harmful than the non-renewable resource. Solar energy is the amplest source of renewable energy. Generation of electricity using sun energy that is possible by the solar panels. But the efficiency of solar panels is ostentatious by environmental effects like dust accumulation, temperature and humidity. Therefore, it is essential to have regular and proper cleaning of panel. In general cleaning is done by manually. This type of cleaning is not uniform and has the following drawbacks like damage of panels, injuries to people and movement difficulties. These disadvantages can be overcome by using an automated robot for cleaning the solar panel. This will also increase the efficiency. The vital role of the automatic robotic cleaner is cleaning the floating solar panels where manual cleaning is highly impossible. The robot is driven by the gear motors, motor driver and the robot consists of another motor such that a cleaning membrane is attached to that motor for cleaning them with water. The camera monitors the solar panels and uploads the data to the cloud storage for damage and cleaning references.

This paper presents the design of high frequency wireless power transfer system (HFWPT) to reduce power transmission complexity. This philosophy plays a vital role for next generation technology due to its impact in real time applications. In recent years most of the scientists are mainly concentrating on improving the efficiency of magnetic link section. This proposed method of the design of coils, driving converters and creating resonance are used for transfer the power without any conducting wire. Design of the HFWPT system is to be operated at resonance frequency of 50khz. It can be expected that the high frequency resonance coupling will improve the efficiency of transmission allowing one to transmit at lesser frequency which is nearly in a range of few kHz range. The performance of HFWPT is observed satisfactory to maintain the output voltage as required by changing the coupling coefficient.

This paper focus on the idea of automatic lightning system and peculiar way of implementation with embedded tool systems. The proposed method is used to measure and control the intensity of light in room which is essential and good for vision for a particular work. Also with user adjustable light intensity control without using LUX meter and light sensors required intensity is obtained. This technique is implemented with help of LDR’s, microprocessor and IRF520 MOSFET Driver Module to measure as well as to control the intensity of light as per the requirement of the user. In this project four LDR’ are placed at four different corners of the room precisely taken care of their blockage of light. The required intensity of light is obtained by taking the average of all four LDR’s and compared with the reference intensity of the light as specified by the user. Accordingly the whole intensity of the room is adjusted by using the MOSFET, it stepup the arduino voltage to a value able to drive some higher loads. This project reduces the power consumption as well as eye strain for the user to execute the smart work in real time application.

This paper mainly focuses on establishing a wireless communication to transmit and receive the temperature and humidity monitoring data in wireless mode by interfacing arduino and RF module nRF24L01. In recent advancements the wireless communication plays a vital role to make the system faster and easier. In real time application, analog data measurement with human effort may causes error and difficult to store the precious values of parameters. To overcome this problem there is a demand for smart system with automation to monitor all the environment factors. Besides, the smart system should be accurate, reliability and cost effective. In this proposed monitoring system the temperature and humidity data are transferred through wireless data communication using RF module nRF24L01, DHT11 sensor and arduino Uno. Finally the actual temperature and humidity is going to be displayed on the 16*2 LCD with the arduino Uno, nRF24L01 module are interfaced. By this method the wireless communication can be implemented with less price and low consumption of the power. This paper provides the details of implementation and experimentation results of an environmental monitoring system.

An implementation of smart attendance management system using Radio Frequency Identification (RFID) is presented to reduce time consuming, avoid malpractices and human errors during attendance taking process. In real time applications to reduce the human efforts there are many existing technologies in the world. Amongst the RFID is the most efficient and cost reducing technology, it uses wireless communication between the reader and the tag. It is needed for accurate attendance recording for all the sectors. The proposed technique is used to development of attendance simulation in any field using RFID that connected directly to the excel sheet. The performance of the smart attendance management system is found satisfactory with the proposed technique which is commonly used in all sectors.

The paper focuses on the idea of providing surveillance using a robot with the techniques of IOT. Surveillance is a major issue in public restricted areas. The robot is hired here to monitor throughout the day. This robotic vehicle has ability to substitute the human in hazardous area to provide surveillance. The robot is operated manually by connecting it to Wi-Fi and consists of sensors for identifying any obstacles and identifying humans and give live streaming to respective admin. This is operated over Wi-fi using blynk app software. Arduino IDE is used in programming the robot. ICs like L293D (motor driver) and sensors like PIR, ultrasonic helps in movement of the mechanical body and detection of obstacles respectively. A camera is equipped for capturing the image of the person identified. A face recognition algorithm can help in spotting the intruder. The gas sensor provided can sense the presence of toxic chemicals in its surroundings. Thus the robot continuously provides data in remote location in addition to the advantages of reduced human loss and detection of threats.

Background: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI). Objective: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients. Methods: Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, and other clinical signs were assessed twenty-four hours post-treatment. Results: CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC=1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2=0.979), kidney (r2=0.951) and rectal temperature (r2=0.67). A plasma AUC/MIC ratio of 412 was associated with maximum PD effect of Imax=3.7 Log10CFU/bladder and Imax=1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC ratio showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80) followed by Cmax/MIC ratio in bladder (r2=0.68). Conclusion: Plasma AUC/MIC showed the highest correlation with the efficacy of Ciprofloxacin on E. coli in diabetic mice with cUTI.

This paper focuses on implementation of differential equation of the single-phase source-load system based control algorithm for three-phase distribution static compensator (DSTATCOM) in a ...

Background Thymidine kinase 1 (TK1) is a cytosolic enzyme involved in DNA precursor synthesis and it is up-regulated in proliferating cells. Serum TK1 is an established biomarker for prognosis and therapy monitoring of malignancies. However, commercial TK1 enzyme activity assays have limitations for their use in xenograft models as they cross-react with TK1 activity from the host. The AroCell TK 210 ELISA is specific for human TK1 and offers the opportunity to measure the release of TK1 from human xenografts free from the background of TK1 release from the host (mouse). Here we studied the changes in serum TK1 protein levels using the AroCell TK 210 ELISA in a xenograft model during 5-fluorouracil (5FU) treatment of Acute Myeloid Leukemia (AML). Experimental Procedures Human MV-4-11 leukemic cells from ATCC were cultured with 95% O2 and 5% CO2 at 37°C and in IMD medium (Sigma) supplemented with 10% FBS (HI media) containing 4mmol/L L-glutamine, 5 ng/mL GM-CSF and 1% penicillin and streptomycin. The cells were harvested during exponential growth and injected subcutaneously into the left flank of athymic BALB/c nude mice 8-10 weeks old. The mice were divided into controls that received no therapy (n=8) and an active group receiving 5FU (n=8). The treatment was initiated when the average tumor volume reached 50-100 mm3. Tumor bearing mice were treated with PBS (control) or 5-FU (active group 10 mg/kg, once daily) for three weeks. Serum samples (70-80 µL) were collected before treatment initiation, during treatment (once weekly for 3 weeks) and a final termination. Serum samples were stored at -80°C and TK1 protein levels were determined with the AroCell TK 210 ELISA. All the animal experiments were performed at TheraIndx life sciences Pvt Ltd, India. Results The tumor volumes were measured post-implantation of cells every 3 days throughout the study. There was a significant difference (p Conclusions This study is the first evaluation of TK 210 ELISA as a biomarker for monitoring therapy with anticancer drugs in an AML xenograft model. The changes in TK1 protein levels were significant enough to monitor the response of the xenograft to 5FU therapy in this animal model. Furthermore, the use of the AroCell TK 210 ELISA in xenograft models may enable more accurate measurement of the anti-cancer drug effects on cell proliferation and these results encourage further applications of TK 210 ELISA in drug development projects. Citation Format: Kiran Kumar Jagarlamudi, Ramesh Jayaraman, Sundaresh Babu, Martin Shaw, Staffan Eriksson. Evaluation of TK1 protein changes using the AroCell TK 210 ELISA in an acute myeloid leukemia (AML) xenograft model during 5-fluoruracil treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3130.

Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-β-cyclodextrin (HPβCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPβCD is limited by the need for high doses, ototoxicity and intrathecal administration. These limitations can be attributed to its poor pharmacokinetic profile. In the attempt to overcome these limitations, we have designed a β-cyclodextrin (βCD) based polymer prodrugs (ORX-301) for an enhanced pharmacokinetic and biodistribution profile, which in turn can potentially provide an improved efficacy at lower doses. We demonstrated that subcutaneously injected ORX-301 extended the mean lifespan of NPC mice at a dosage 5-fold lower (800 mg/kg, body weight) the HPβCD dose proven efficacious (4000 mg/kg). We also show that ORX-301 penetrates the blood brain barrier and counteracts neurological impairment. These properties represent a substantial improvement and appear to overcome major limitations of presently available βCD-based therapy, demonstrating that this novel prodrug is a valuable alternative/complement for existing therapies.

The mechanism of efflux is a tour-de-force in the bacterial armoury that has thwarted the development of novel antibiotics. We report the discovery of a novel chemical series with potent antibacterial properties that was engineered to overcome efflux liability. Compounds liable to efflux specifically via the Resistance Nodulation and cell Division (RND) pump, AcrAB-TolC were chosen for a hit to lead progression. Using structure-based design, the compounds were optimised to lose their binding to the efflux pump, thereby making them potent on wild-type bacteria. We discovered these compounds to be pro-drugs that require activation in E. coli by specific bacterial nitroreductases NfsA and NfsB. Hit to lead chemistry led to the generation of compounds that were potent on wild-type and multi-drug resistant clinical isolates of E. coli, Shigella spp., and Salmonella spp. These compounds are bactericidal and efficacious in a mouse thigh infection model.

The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and in vivo in preclinical species and humans. Pacritinib showed ~ 5 fold higher affinity to human plasma proteins relative to mouse in vitro. It was metabolized by human CYP3A4 in vitro, and did not significantly induce CYP3A and 1A2 in human hepatocytes. In vitro metabolism studies with mouse and human liver microsomes showed the presence of four major metabolites of Pacritinib -M1 (oxidation), M2 (dealkylation), M3 (oxidation), M4 (reduction). The in vitro and in vivo metabolic patterns observed in mice and humans were in good agreement. Qualitatively and quantitatively, none of the metabolites formed in vivo was > 10% of Pacritinib in mouse, dog and humans. Pacritinib showed systemic clearance of 8.0, 1.6, 1.6 l/h/kg, volume of distribution of 14.2, 7.9, 8.5 l/kg, t 1/2 of 5.6, 6.0, 4.6 h, and oral bioavailability of 39, 10, and 24% in mouse, rat and dog, respectively. In radiolabeled mass balance and QWBA studies in mice, ~ 91% of the dose was recovered in feces, suggesting biliary clearance, and maximum radioactivity was seen in the gastrointestinal tract followed by the kidney, heart and low activity in the brain. The relatively high exposures of Pacritinib in humans might be attributed to its very high plasma protein binding, low metabolic and/or biliary clearance.

We present the first display panels exploiting the nVerPix CN-VOLET technology that reduces the pixel circuit of the conventional AMOLED display to two discrete components: the switching transistor and the CN-VOLET. This permits high aperture ratio bottom emission displays—as high as 70% here— and greatly simplifies the manufacturing. Mono-color QVGA AMOLED displays (6.4 cm diagonal) playing video will be shown.

Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. Patients and Methods Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. Results Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration–time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥ 300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%. Conclusion SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 mu M) but inhibited 2C19 (IC50 = 5.8 mu M). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between similar to 84 and 94%. The blood-to-plasma ratio was similar to 1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l . h(-1) . kg(-1) and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and similar to 3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.

TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo, TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias.

The large current densities attained by carbon nanotube enabled vertical field effect transistors using crystalline organic channel materials are somewhat unexpected given the known large anisotropy in the mobility of crystalline organics and their conventional ordering on dielectric surfaces which tends to orient their high mobility axes parallel to the surface. This seeming contradiction is resolved by the finding that the nanotubes induce a molecular ordering that reorients the high mobility axes to favor current flow in a direction perpendicular to the substrate surface.

Background: Dengue is a life-threatening viral infection which has become an epidemic in India in the postmonsoon period (August–November). It mostly associated with nonspecific fever and rashes, arthralgia, myalgia, and thrombocytopenia in severe cases. Objective: This study aimed to study the oral manifestations of dengue fever and to observe the various features of oral presentation then to validate the significance and importance of oral manifestation in the diagnosis of dengue fever. Materials and Methods: Patients meeting the inclusion criteria were subjected to detailed history, oral examination, and relevant investigations. Results: Intraoral manifestations were present in 24 (48%) patients, anf these included petechiae (29.2%), bleeding gums (16.6%), ulcer (4.2%), dryness of mouth (4.2%), and combined features (45.8%). Extraoral manifestations were present in 4% of the cases. Conclusion: This study highlights the thrombocytopenia related oral haemosrrhagic manifestations of dengue fever.

Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC50 = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC50: PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials. Mol Cancer Ther; 12(2); 151–61. ©2012 AACR.

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

The processes of absorption (A), distribution (D), metabolism (M) and excretion (E) (collectively referred as ADME) determine the pharmacokinetics (PK) of a compound. Lack of optimum PK is one of the major reasons for compounds to fail in the clinic resulting in high attrition rates. In the beginning of 1990, 39% of the drugs failed in the clinic due to poor PK emphasizing its importance in drug development (Waterbeemd and Gifford, 2003). In 1988, a study of the pharmaceutical companies in UK showed that non-optimal PK was one of the major reasons (~40%) for termination of drugs in development (Prentis et al., 1988). In the last two decades this number dropped to ~ 10% (Yengi et al., 2007). The main reasons for this significant drop in the number of compounds failing for PK reasons can be attributed to the following: a) application of concepts of drug metabolism and PK to design compounds in medicinal chemistry programs (Smith et al., 1996); b) development of in vitro ADME assays that are predictive of in vivo behavior (PK) of drugs (Obach et al., 1997; Venkatakrishnan et al.,2003; Pelkonen and Raunio, 2005; Thompson,2000; Fagerholm, 2007); c) use of the Lipinski rule of 5 to design oral drugs (Lipinski, 2000); d) development of computer programs to predict the human PK parameters and profiles based on in vitro ADME properties of drugs (Jamei et al., 2009); e) PK/PD correlation studies in preclinical setting and f) high throughput screening of ADME properties in in vitro and in vivo assays for hundreds of compounds in the lead identification to lead optimization stages of drug discovery. The consequence of all the above mentioned developments in ADME have resulted in the frontloading of non-drug like compounds early in drug discovery and ultimately reducing the attrition rates of compounds in the clinic. Histone acetylases (HATs) and Histone deacetylases (HDACs) are enzymes that carry out acetylation and deacetylation, respectively, of histone proteins (Minucci and Pelicci, 2006). Histone proteins form a complex with DNA called as nucleosomes, which are the structural units of chromatin. The interplay of HATs and HDACs activities regulate the structure of chromatin and control gene expression. The aberrant expression of HDACs has been linked to the pathogenesis of cancer (Minucci and Pelicci, 2006). Histone deacetylase inhibitors

SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed >99% binding to plasma from mice, dog and humans. It was metabolically stable in human and dog liver microsomes relative to mouse and rat. SB1317 was mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 did not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). SB1317 did not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro. The metabolic profiles in liver microsomes from preclinical species were qualitatively similar to humans. In pharmacokinetic studies SB1317 showed moderate to high systemic clearance (relative to liver blood flow), high volume of distribution (>0.6 L/kg), oral bioavailability of 24%, ~ 4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice. The favorable ADME of SB1317 supported its preclinical development as an oral drug candidate. © 2012 Bentham Science Publishers.

SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.

SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 μg of protein lysate. AcH3 levels of liver, spleen, PBMCs, bone marrow and tumor were measured in BALB/c mice, HCT-116 xenografted BALB/c nude mice, or in SCID mice orthotopically engrafted with AML (HL-60) after oral treatment with SB939. AcH3 could only be detected after treatment. In all tissues, the highest signal detected was at the 3-hour time point on day 1. On day 15, the signal decreased in normal tissues but increased in cancerous tissues and became detectable in the bone marrow of leukemic mice. In all tissues, acH3 correlated with SB939 dose levels (r2 = 0.76–0.94). When applied to PBMCs from 30 patients with advanced solid malignancies in a phase I clinical trial, a dose-dependent (10–80 mg) increase in relative acH3 was observed 3-hour postdose on day 1, correlating with Cmax and AUC of SB939 concentrations in plasma (r = 0.97, P = 0.014). Our data show that the favorable pharmacokinetic and pharmacodynamic properties of SB939 are translated from preclinical models to patients. Mol Cancer Ther; 10(7); 1207–17. ©2011 AACR.