Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: A phase 2 umbrella trial

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617

Al-Qur’an dan Bahasa Fusha

Tujuan penelitian ini adalah untuk mengetahui pengertian Al-Qur’an dan bahasa Fusha serta mengetahui hubungan Al-qur’an dan Bahasa Fusha. Penelitian ini menggunakan metode kepustakaan (library research) dengan pendekatan kualitatif untuk mendeskripsikan dan menganalisis pengertian Al-Qur'an dan bahasa Arab Fusha, serta hubungannya. Data dikumpulkan melalui studi literatur dan dokumentasi, yang kemudian diolah untuk mendapatkan kesimpulan. Hasil penelitian mengungkapkan bahwa kata "Al-Qur'an" secara etimologis memiliki beberapa makna, di antaranya "bacaan" (قرأ), "petunjuk" (قرائن), dan "himpunan" (القرء). Secara terminologis, Al-Qur'an didefinisikan sebagai firman Allah yang merupakan mukjizat dan diturunkan kepada Nabi Muhammad SAW. Bahasa Arab Fusha, yang digunakan dalam Al-Qur'an, adalah bahasa ilmiah yang dipahami secara luas di dunia Arab dan digunakan dalam konteks resmi. Penelitian ini juga menyoroti keistimewaan bahasa Arab dalam Al-Qur'an, yang bukan hanya kaya dalam pemilihan kata dan struktur, tetapi juga memiliki makna yang mendalam, menjadikannya sebagai mukjizat yang tidak dapat ditandingi oleh karya sastra lain. Al-Qur'an menggunakan bahasa Arab dengan tingkat keindahan yang luar biasa, yang diakui bahkan oleh para penyair dan ahli bahasa Arab pada zamannya. Hal ini menegaskan bahwa Al-Qur'an sebagai firman Allah memiliki perbedaan mendasar dengan syair-syair Arab lainnya, baik dalam pemilihan kata maupun struktur bahasany

Social Awareness and Safety Assistance of COVID-19 based on DLN face mask detection and AR Distancing

The outbreak of coronavirus disease (COVID-19) has forced major countries to apply strict policy toward society. People must wear a facemask and always keep their distance from each other's to avoid virus contamination. Government employ officers to monitor citizen and warn them if not wearing a face mask. The warning message also spread through SMS and social media to ensure people about safety and awareness. This paper aims to provide face mask detection using the Deep Learning Network(DLN) and warning system through video stream input from CCTV or images then analyzed. If people not wearing a mask are detected, they will alert them through the speaker and remind them about a penalty. AR distancing very useful to give position toward violator location based on the detected person in a certain area. The system is designed to work intelligently and automatically without human intervention. With the accuracy of 99% recognition, it's expected that the system can help the government to increase people awareness toward the safety of themselves and people around them

On the compactness of the set of invariant Einstein metrics

Let $M = G/H$ be a connected simply connected homogeneous manifold of a compact, not necessarily connected Lie group $G$. We will assume that the isotropy $H$-module $\mathfrak {g/h}$ has a simple spectrum, i.e. irreducible submodules are mutually non-equivalent. There exists a convex Newton polytope $N=N(G,H)$, which was used for the estimation of the number of isolated complex solutions of the algebraic Einstein equation for invariant metrics on $G/H$ (up to scaling). Using the moment map, we identify the space $\mathcal{M}_1$ of invariant Riemannian metrics of volume 1 on $G/H$ with the interior of this polytope $N$. We associate with a point ${x \in \partial N}$ of the boundary a homogeneous Riemannian space (in general, only local) and we extend the Einstein equation to $\bar{\mathcal{M}_1}= N$. As an application of the Aleksevsky--Kimel'fel'd theorem, we prove that all solutions of the Einstein equation associated with points of the boundary are locally Euclidean. We describe explicitly the set $T\subset \partial N$ of solutions at the boundary together with its natural triangulation. Investigating the compactification $\bar{\mathcal{M}_1}$ of $\mathcal{M}_1$, we get an algebraic proof of the deep result by B\"ohm, Wang and Ziller about the compactness of the set $\mathcal{E}_1 \subset \mathcal{M}_1$ of Einstein metrics. The original proof by B\"ohm, Wang and Ziller was based on a different approach and did not use the simplicity of the spectrum. In Appendix we consider the non-symmetric K\"ahler homogeneous spaces $G/H$ with the second Betti number $b_2=1$. We write the normalized volumes $2,6,20,82,344$ of the corresponding Newton polytopes and discuss the number of complex solutions of the algebraic Einstein equation and the finiteness problem.Comment: 25 pages, 4 figures. Some proofs, 3 references, and Appendix adde

Covariant derivative of the curvature tensor of pseudo-K\"ahlerian manifolds

It is well known that the curvature tensor of a pseudo-Riemannian manifold can be decomposed with respect to the pseudo-orthogonal group into the sum of the Weyl conformal curvature tensor, the traceless part of the Ricci tensor and of the scalar curvature. A similar decomposition with respect to the pseudo-unitary group exists on a pseudo-K\"ahlerian manifold; instead of the Weyl tensor one obtains the Bochner tensor. In the present paper, the known decomposition with respect to the pseudo-orthogonal group of the covariant derivative of the curvature tensor of a pseudo-Riemannian manifold is refined. A decomposition with respect to the pseudo-unitary group of the covariant derivative of the curvature tensor for pseudo-K\"ahlerian manifolds is obtained. This defines natural classes of spaces generalizing locally symmetric spaces and Einstein spaces. It is shown that the values of the covariant derivative of the curvature tensor for a non-locally symmetric pseudo-Riemannian manifold with an irreducible connected holonomy group different from the pseudo-orthogonal and pseudo-unitary groups belong to an irreducible module of the holonomy group.Comment: the final version accepted to Annals of Global Analysis and Geometr

Entropies, volumes, and Einstein metrics

We survey the definitions and some important properties of several asymptotic invariants of smooth manifolds, and discuss some open questions related to them. We prove that the (non-)vanishing of the minimal volume is a differentiable property, which is not invariant under homeomorphisms. We also formulate an obstruction to the existence of Einstein metrics on four-manifolds involving the volume entropy. This generalizes both the Gromov--Hitchin--Thorpe inequality and Sambusetti's obstruction.Comment: This is a substantial revision and expansion of the 2004 preprint, which I prepared in spring of 2010 and which has since been published. The version here is essentially the published one, minus the problems introduced by Springer productio

Prioritisation of pharmaceuticals based on risks to aquatic environments in Kazakhstan

Over the last 20 years, there has been increasing interest in the occurrence, fate, effects and risk of pharmaceuticals in the natural environment. However, we still have only limited or no data on ecotoxicological risks of many of the active pharmaceutical ingredients (APIs) currently in use. This is partly due to the fact that the environmental assessment of an API is an expensive, time-consuming and complicated process. Prioritisation methodologies, that aim to identify APIs of most concern in a particular situation, could therefore be invaluable in focusing experimental work on APIs that really matter. The majority of approaches for prioritising APIs require annual pharmaceutical usage data. These methods cannot therefore be applied to countries, such as Kazakhstan, which have very limited data on API usage. This paper therefore presents an approach for prioritising APIs in surface waters in information-poor regions such as Kazakhstan. Initially data were collected on the number of products and active ingredients for different therapeutic classes in use in Kazakhstan and on the typical doses. These data were then used alongside simple exposure modelling approaches to estimate exposure indices for active ingredients (about 240 APIs) in surface waters in the country. Ecotoxicological effects data were obtained from the literature or predicted. Risk quotients were then calculated for each pharmaceutical based on the exposure and the substances ranked in order of risk quotient. Highest exposure indices were obtained for benzylpenicillin, metronidazole, sulbactam, ceftriaxone and sulfamethoxazole. The highest risk was estimated for amoxicillin, clarithromycin, azithromycin, ketoconazole and benzylpenicillin. In the future, the approach could be employed in other regions where usage information are limited. This article is protected by copyright. All rights reserved

Dynamical Cobordisms in General Relativity and String Theory

We describe a class of time-dependent solutions in string- or M-theory that are exact with respect to alpha-prime and curvature corrections and interpolate in physical space between regions in which the low energy physics is well-approximated by different string theories and string compactifications. The regions are connected by expanding "domain walls" but are not separated by causal horizons, and physical excitations can propagate between them. As specific examples we construct solutions that interpolate between oriented and unoriented string theories, and also between type II and heterotic theories. Our solutions can be weakly curved and under perturbative control everywhere and can asymptote to supersymmetric at late times.Comment: 35 pages, 5 figures, LaTeX v2: reference adde

An Efficient Representation of Euclidean Gravity I

We explore how the topology of spacetime fabric is encoded into the local structure of Riemannian metrics using the gauge theory formulation of Euclidean gravity. In part I, we provide a rigorous mathematical foundation to prove that a general Einstein manifold arises as the sum of SU(2)_L Yang-Mills instantons and SU(2)_R anti-instantons where SU(2)_L and SU(2)_R are normal subgroups of the four-dimensional Lorentz group Spin(4) = SU(2)_L x SU(2)_R. Our proof relies only on the general properties in four dimensions: The Lorentz group Spin(4) is isomorphic to SU(2)_L x SU(2)_R and the six-dimensional vector space of two-forms splits canonically into the sum of three-dimensional vector spaces of self-dual and anti-self-dual two-forms. Consolidating these two, it turns out that the splitting of Spin(4) is deeply correlated with the decomposition of two-forms on four-manifold which occupies a central position in the theory of four-manifolds.Comment: 31 pages, 1 figur

Oxidised cosmic acceleration

We give detailed proofs of several new no-go theorems for constructing flat four-dimensional accelerating universes from warped dimensional reduction. These new theorems improve upon previous ones by weakening the energy conditions, by including time-dependent compactifications, and by treating accelerated expansion that is not precisely de Sitter. We show that de Sitter expansion violates the higher-dimensional null energy condition (NEC) if the compactification manifold M is one-dimensional, if its intrinsic Ricci scalar R vanishes everywhere, or if R and the warp function satisfy a simple limit condition. If expansion is not de Sitter, we establish threshold equation-of-state parameters w below which accelerated expansion must be transient. Below the threshold w there are bounds on the number of e-foldings of expansion. If M is one-dimensional or R everywhere vanishing, exceeding the bound implies the NEC is violated. If R does not vanish everywhere on M, exceeding the bound implies the strong energy condition (SEC) is violated. Observationally, the w thresholds indicate that experiments with finite resolution in w can cleanly discriminate between different models which satisfy or violate the relevant energy conditions.Comment: v2: corrections, references adde