Pharmacokinetic Measurements in Dose Finding Model Guided by Escalation with Overdose Control

Oncology drug development starts with a dose escalation phase to find the maximal tolerable dose (MTD). Dose limiting toxicity (DLT) is the primary endpoint for dose escalation phase. Traditionally, model-based dose escalation trial designs recommend a dose for escalation based on an assumed dose-DLT relationship. Pharmacokinetic (PK) data are often available but are currently only used by clinical teams in a subjective manner to aid decision making. Formal incorporation of PK data in dose-escalation models can make the decision process more efficient and lead to an increase in precision. In this talk we present a Bayesian joint modeling framework for incorporating PK data in Oncology dose escalation trials. This framework explores the dose-PK and PK-DLT relationships jointly for better model informed dose escalation decisions. Utility of the proposed model is demonstrated through a real-life case study along with simulation

Terahertz sensing of reduced graphene oxide nanosheets using sub-wavelength dipole cavities

Because of extraordinary optoelectronic properties, two-dimensional (2D) materials are the subject of intense study in recent times. Hence, we investigate sub-wavelength dipole cavities (hole array) as a sensing platform for the detection of 2D reduced graphene oxide (r-GO) using terahertz time-domain spectroscopy (THz-TDS). The r-GO is obtained by reducing graphene oxide (GO) via Hummer's method. Its structural characteristics are verified using X-ray diffraction (XRD) and Raman spectroscopy. We also assessed the morphology and chemistry of r-GO nanosheets by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDAX), and Fourier Transformed Infrared (FTIR) spectroscopy. Further, we studied the surface plasmon resonance (SPR) characteristics of r-GO nanosheets hybridized dipole cavities using THz-TDS by varying the r-GO thickness on top of the dipole cavities, since these cavities are well known for sustaining strong SPRs. Based on these, we experimentally obtained a sensitivity of 12 GHz/mu m for the porous r-GO film. Thus, a modification in SPR characteristics can be employed towards the identification and quantification of r-GO by suitably embedding it on an array of dipole cavities. Moreover, we have adopted a generic approach that can be expanded to sense other 2D materials like Boron Nitride (BN), phosphorene, MoS2, etc., leading to the development of novel THz nanophotonic sensing devices

Leakage Certification Made Simple

Side channel evaluations benefit from sound characterisations of adversarial leakage models, which are the determining factor for attack success. Two questions are of interest: can we estimate a quantity that captures the ideal adversary (who knows the distributions that are involved in an attack), and can we judge how good one (or several) given leakage models are in relation to the ideal adversary? Existing work has led to a proliferation of custom quantities (the hypothetical information HI, perceived informatino PI, training information TI, and learnable information LI). These quantities all provide only (loose) bounds for the ideal adversary, they are slow to estimate, convergence guarantees are only for discrete distributions, and they have bias. Our work shows that none of these quantities is necessary: it is possible to characterise the ideal adversary precisely via the mutual information between the device inputs and the observed side channel traces. We achieve this result by a careful characterisation of the distributions in play. We also put forward a mutual information based approach to leakage certification, with a consistent estimator, and demonstrate via a range of case studies that our approach is simpler, faster, and correct

Indigenous technical knowledge on the medicinal uses of natural resins and gums in India

India has a rich heritage of species biodiversity. Many plant species and their products, especially resins and gums, have been used by people through Indigenous Technical Knowledge (ITK) to cure several ailments, including complex diseases, for ages. Due to the probable side effects of modern drugs, the trend for using traditional medicines is increasing. Natural resins and gums (NRGs), which are mostly exudated from plants to heal their injuries, comprise a balance of nutrients, energy, and various phytoactive compounds and hence possess high medicinal values. It is required to document know-how related to the use of herbal products so that they can be scientifically established for exploring their potential. This review discusses the medicinal benefits of important natural resins and gums to highlight their potential and popularity as a medicine.

Attitude of Muslim Parents Towards Girls Higher Education in India

This review paper discusses Muslim parents’ attitudes about their daughters’ desire to pursue higher education in India. The method used in this study is the use of secondary data gathered from publicly accessible platforms, including reliable articles retrieved using online platforms, including Science Direct, Research Gate, Google Scholar, and Scopus. Initially, 186 papers were screened, and 105 met the requirements to move on to the assessment step. For the 72 papers that made it through the final round of examination, the paper maintains strict standards of accuracy, external validity, citation conventions, and review methods. The results of this review article shed light on the many factors that contribute to the educational crises that Muslim girls in India experience and the crucial role that parental attitudes play in determining their daughters’ academic success. The study emphasizes how socioeconomic factors influence Muslim females’ access to higher education. The report finishes with suggestions on dealing with these problems and encouraging females in India’s Muslim population to pursue higher education

The Killing of African Trypanosomes by Ethidium Bromide

Introduced in the 1950s, ethidium bromide (EB) is still used as an anti-trypanosomal drug for African cattle although its mechanism of killing has been unclear and controversial. EB has long been known to cause loss of the mitochondrial genome, named kinetoplast DNA (kDNA), a giant network of interlocked minicircles and maxicircles. However, the existence of viable parasites lacking kDNA (dyskinetoplastic) led many to think that kDNA loss could not be the mechanism of killing. When recent studies indicated that kDNA is indeed essential in bloodstream trypanosomes and that dyskinetoplastic cells survive only if they have a compensating mutation in the nuclear genome, we investigated the effect of EB on kDNA and its replication. We here report some remarkable effects of EB. Using EM and other techniques, we found that binding of EB to network minicircles is low, probably because of their association with proteins that prevent helix unwinding. In contrast, covalently-closed minicircles that had been released from the network for replication bind EB extensively, causing them, after isolation, to become highly supertwisted and to develop regions of left-handed Z-DNA (without EB, these circles are fully relaxed). In vivo, EB causes helix distortion of free minicircles, preventing replication initiation and resulting in kDNA loss and cell death. Unexpectedly, EB also kills dyskinetoplastic trypanosomes, lacking kDNA, by inhibiting nuclear replication. Since the effect on kDNA occurs at a >10-fold lower EB concentration than that on nuclear DNA, we conclude that minicircle replication initiation is likely EB's most vulnerable target, but the effect on nuclear replication may also contribute to cell killing

Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death. Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006. A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression

Normalized difference vegetation index sensor-based nitrogen management in bread wheat (Triticum aestivum L.): Nutrient uptake, use efficiency, and partial nutrient balance

The present experiment was conducted to assess the impact of fixed and variable doses (using a normalized difference vegetation index-sensor) of nitrogen (N) on wheat yields, nutrient uptake, nitrogen use efficiency, and soil nitrogen balance through the optimization of nitrogen dose. There were 10 treatments based on fixed and variable doses with different splits, and each treatment was replicated three times under a randomized complete block design. The treatments comprised fixed doses of 120 and 150 kg N ha–1 with different splits; variable doses based on sensor readings after application of 60, 90, and 120 kg N ha–1; 225 kg N ha–1 as a nitrogen-rich control; and no application of nitrogen as the absolute control. It was revealed that the application of a basal dose of 60 kg N ha–1 and another 60 kg N ha–1 at the crown root initiation stage followed by a sensor-guided N application significantly improved wheat grain yields and grain nitrogen uptake. However, straw nitrogen uptake was highest in N-rich plots where 225 kg N ha–1was applied. It was found that any curtailment in these doses at basal and crown root initiation stages followed by nitrogen application using a normalized difference vegetation index sensor later could not bring about higher crop yields. On average, wheat crops responded to 152–155 kg N ha–1 in both years of the study. Partial factor productivity along with agronomic and economic nitrogen use efficiency showed a declining trend with an increased rate of N application. Apparent N recovery values were comparable between normalized difference vegetation index sensor-based N application treatments and treatments receiving lesser N doses. Soil N status decreased in all the treatments except the nitrogen-rich strip, where there was a marginal increase in soil N status after the wheat crop harvest in the rotation. Partial nitrogen balance was negative for all the treatments except the control. From these 2-year field trials, it can be concluded that applying a normalized difference vegetation index sensor could be an essential tool for the rational management of fertilizer nitrogen in wheat grown in eastern sub-Himalayan plains

Measurements of the pp → ZZ production cross section and the Z → 4ℓ branching fraction, and constraints on anomalous triple gauge couplings at √s = 13 TeV

Four-lepton production in proton-proton collisions, pp -> (Z/gamma*)(Z/gamma*) -> 4l, where l = e or mu, is studied at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The ZZ production cross section, sigma(pp -> ZZ) = 17.2 +/- 0.5 (stat) +/- 0.7 (syst) +/- 0.4 (theo) +/- 0.4 (lumi) pb, measured using events with two opposite-sign, same-flavor lepton pairs produced in the mass region 60 4l) = 4.83(-0.22)(+0.23) (stat)(-0.29)(+0.32) (syst) +/- 0.08 (theo) +/- 0.12(lumi) x 10(-6) for events with a four-lepton invariant mass in the range 80 4GeV for all opposite-sign, same-flavor lepton pairs. The results agree with standard model predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ. couplings at 95% confidence level: -0.0012 < f(4)(Z) < 0.0010, -0.0010 < f(5)(Z) < 0.0013, -0.0012 < f(4)(gamma) < 0.0013, -0.0012 < f(5)(gamma) < 0.0013