How to share a quantum secret

We investigate the concept of quantum secret sharing. In a ((k,n)) threshold scheme, a secret quantum state is divided into n shares such that any k of those shares can be used to reconstruct the secret, but any set of k-1 or fewer shares contains absolutely no information about the secret. We show that the only constraint on the existence of threshold schemes comes from the quantum "no-cloning theorem", which requires that n < 2k, and, in all such cases, we give an efficient construction of a ((k,n)) threshold scheme. We also explore similarities and differences between quantum secret sharing schemes and quantum error-correcting codes. One remarkable difference is that, while most existing quantum codes encode pure states as pure states, quantum secret sharing schemes must use mixed states in some cases. For example, if k <= n < 2k-1 then any ((k,n)) threshold scheme must distribute information that is globally in a mixed state.Comment: 5 pages, REVTeX, submitted to PR

Some Directions beyond Traditional Quantum Secret Sharing

We investigate two directions beyond the traditional quantum secret sharing (QSS). First, a restriction on QSS that comes from the no-cloning theorem is that any pair of authorized sets in an access structure should overlap. From the viewpoint of application, this places an unnatural constraint on secret sharing. We present a generalization, called assisted QSS (AQSS), where access structures without pairwise overlap of authorized sets is permissible, provided some shares are withheld by the share dealer. We show that no more than $\lambda-1$ withheld shares are required, where $\lambda$ is the minimum number of {\em partially linked classes} among the authorized sets for the QSS. Our result means that such applications of QSS need not be thwarted by the no-cloning theorem. Secondly, we point out a way of combining the features of QSS and quantum key distribution (QKD) for applications where a classical information is shared by quantum means. We observe that in such case, it is often possible to reduce the security proof of QSS to that of QKD.Comment: To appear in Physica Scripta, 7 pages, 1 figure, subsumes arXiv:quant-ph/040720

Mathematical Constraint on Functions with Continuous Second Partial Derivatives

A new integral identity for functions with continuous second partial derivatives is derived. It is shown that the value of any function f(r,t) at position r and time t is completely determined by its previous values at all other locations r' and retarded times t'<t, provided that the function vanishes at infinity and has continuous second partial derivatives. Functions of this kind occur in many areas of physics and it seems somewhat surprising that they are constrained in this way.Comment: 10 pages, 6 figure

1191O MRTX-500: Phase II trial of sitravatinib (sitra) + nivolumab (nivo) in patients (pts) with non-squamous (NSQ) non-small cell lung cancer (NSCLC) progressing on or after prior checkpoint inhibitor (CPI) therapy

Background: Therapy with CPI has improved OS across many tumor types, including in a subset of pts with NSCLC. Mechanisms of CPI resistance, however, have been described, including an immunosuppressive TME, which may include recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-polarized macrophages within the TME. Sitra, a spectrum-selective TKI targeting TAM (Tyro3/Axl/MerTK) receptors and VEGFR2, reduces the number of MDSCs and Tregs while increasing the ratio of M1/M2-polarized macrophages, and thus is hypothesized to overcome an immunosuppressive TME and augment antitumor immune responses. Methods: MRTX-500 (NCT02954991) is a phase II study evaluating sitra (120 mg QD) + nivo (Q2W or Q4W) in pts with NSQ NSCLC who have progressed on or after treatment, with a CPI-based regimen (anti-PD1/PD-L1) and/or platinum doublet chemotherapy. The primary endpoint is ORR per RECIST 1.1. Secondary endpoints include OS, PFS, and safety. We report updated efficacy data for pts with NSCLC with PCB (prior clinical benefit; CR, PR, or SD ≥12 weeks) from a CPI who were treated with sitra + nivo as either 2L or 3L therapy. Results: As of 17 October 2020, 68 pts with PCB (57% female; median age, 66 years; ECOG PS 0/1/2, 27%/66%/7%) were treated. Median follow-up was 28 months, median OS was 15 months (95% CI 9.3, 21.1),1- and 2-year OS rates were 56% and 32%, respectively. Median PFS was 6 months, and ORR was 16% (11/68), including 2 CRs. Median duration of response was 13 months. In all CPI-experienced pts evaluable for safety (n=124), treatment related adverse events (TRAEs) occurred in 91% of pts, with Gr 3/4 TRAEs occurring in 60% of pts. The most common (≥10%) Gr 3/4 TRAEs were hypertension and diarrhea. There were no Gr 5 TRAEs. Discontinuation rates for sitra and nivo due to any AE were 30% and 27%, respectively. Conclusions: Sitra + nivo demonstrated antitumor activity and encouraging OS compared to historical controls and no new safety signals were observed in pts with NSQ NSCLC who progressed on prior CPI. This combination is being evaluated in the phase III SAPPHIRE study

Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.

The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Förster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials

43P MRTX-500: Phase II trial of sitravatinib (sitra) + nivolumab (nivo) in patients (pts) with non-squamous (NSQ) non-small cell lung cancer (NSCLC) progressing on or after prior checkpoint inhibitor (CPI) therapy

Background: Therapy with CPI has improved OS in a subset of pts with NSCLC. Mechanisms of CPI resistance, however, have been described, including an immunosuppressive tumor microenvironment (TME), which may recruit immunosuppressive myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-polarized macrophages in the TME. Sitra, a spectrum-selective TKI targeting TAM (Tyro3/Axl/MerTK) receptors and VEGFR2, reduces the number of MDSCs and Tregs and increases the M1/M2-polarized macrophage ratio. It is hypothesized to overcome an immunosuppressive TME and augment antitumor immune responses. Methods: MRTX-500 (NCT02954991) is a phase II study evaluating sitra (120 mg QD) + nivo (Q2W or Q4W) in pts with NSQ NSCLC who have progressed on or after treatment, with a CPI-based regimen (anti-PD1/PD-L1) and/or platinum doublet chemotherapy. The primary endpoint is ORR per RECIST 1.1. Secondary endpoints include OS, PFS, and safety. We report updated efficacy data for pts with NSCLC with PCB (prior clinical benefit; CR, PR, or SD ≥12 weeks) from a CPI who were treated with sitra + nivo as either 2L or 3L therapy. Results: As of 17 October 2020, 68 pts with PCB (57% female; median age, 66 years; ECOG PS 0/1/2, 27%/66%/7%) were treated. Median follow-up was 28 months, median OS was 15 months (95% CI 9.3, 21.1),1- and 2-year OS rates were 56% and 32%, respectively. Median PFS was 6 months, and ORR was 16% (11/68), including 2 CRs. Median duration of response was 13 months. In all CPI-experienced pts evaluable for safety (n=124), treatment related adverse events (TRAEs) occurred in 91% of pts, with Gr 3/4 TRAEs occurring in 60% of pts. The most common (≥10%) Gr 3/4 TRAEs were hypertension and diarrhea. There were no Gr 5 TRAEs. Discontinuation rates for sitra and nivo due to any AE were 30% and 27%, respectively. Conclusions: Sitra + nivo demonstrated antitumor activity and encouraging OS compared to historical controls and no new safety signals were observed in pts with NSQ NSCLC who progressed on prior CPI. This combination is being evaluated in the phase III SAPPHIRE study. Previously presented at ESMO 2021, FPN (Final Publication Number): 1191O, Ticiana Leal et al. - Reused with permission. Clinical trial identification: NCT02954991

cGMP-dependent protein kinase Iα associates with the antidepressant-sensitive serotonin transporter and dictates rapid modulation of serotonin uptake

<p>Abstract</p> <p>Background</p> <p>The Na⁺/Cl^--dependent serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is a critical element in neuronal 5-HT signaling, being responsible for the efficient elimination of 5-HT after release. SERTs are not only targets for exogenous addictive and therapeutic agents but also can be modulated by endogenous, receptor-linked signaling pathways. We have shown that neuronal A3 adenosine receptor activation leads to enhanced presynaptic 5-HT transport <it>in vitro </it>and an increased rate of SERT-mediated 5-HT clearance <it>in vivo</it>. SERT stimulation by A3 adenosine receptors derives from an elevation of cGMP and subsequent activation of both cGMP-dependent protein kinase (PKG) and p38 mitogen-activated protein kinase. PKG activators such as 8-Br-cGMP are known to lead to transporter phosphorylation, though how this modification supports SERT regulation is unclear.</p> <p>Results</p> <p>In this report, we explore the kinase isoform specificity underlying the rapid stimulation of SERT activity by PKG activators. Using immortalized, rat serotonergic raphe neurons (RN46A) previously shown to support 8-Br-cGMP stimulation of SERT surface trafficking, we document expression of PKGI, and to a lower extent, PKGII. Quantitative analysis of staining profiles using permeabilized or nonpermeabilized conditions reveals that SERT colocalizes with PKGI in both intracellular and cell surface domains of RN46A cell bodies, and exhibits a more restricted, intracellular pattern of colocalization in neuritic processes. In the same cells, SERT demonstrates a lack of colocalization with PKGII in either intracellular or surface membranes. In keeping with the ability of the membrane permeant kinase inhibitor DT-2 to block 8-Br-cGMP stimulation of SERT, we found that DT-2 treatment eliminated cGMP-dependent kinase activity in PKGI-immunoreactive extracts resolved by liquid chromatography. Similarly, treatment of SERT-transfected HeLa cells with small interfering RNAs targeting endogenous PKGI eliminated 8-Br-cGMP-induced regulation of SERT activity. Co-immunoprecipitation studies show that, in transporter/kinase co-transfected cells, PKGIα specifically associates with hSERT.</p> <p>Conclusion</p> <p>Our findings provide evidence of a physical and compartmentalized association between SERT and PKGIα that supports rapid, 8-Br-cGMP-induced regulation of SERT. We discuss a model wherein SERT-associated PKGIα supports sequentially the mobilization of intracellular transporter-containing vesicles, leading to enhanced surface expression, and the production of catalytic-modulatory SERT phosphorylation, leading to a maximal enhancement of 5-HT clearance capacity.</p

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Characterizing kernels of operators related to thin-plate magnetizations via generalizations of Hodge decompositions

Recently developed scanning magnetic microscopes measure the magnetic field in a plane above a thin-plate magnetization distribution. These instruments have broad applications in geoscience and materials science, but are limited by the requirement that the sample magnetization must be retrieved from measured field data, which is a generically nonunique inverse problem. This problem leads to an analysis of the kernel of the related magnetization operators, which also has relevance to the 'equivalent source problem' in the case of measurements taken from just one side of the magnetization. We characterize the kernel of the operator relating planar magnetization distributions to planar magnetic field maps in various function and distribution spaces (e.g., sums of derivatives of Lp (Lebesgue spaces) or bounded mean oscillation (BMO) functions). For this purpose, we present a generalization of the Hodge decomposition in terms of Riesz transforms and utilize it to characterize sources that do not produce a magnetic field either above or below the sample, or that are magnetically silent (i.e. no magnetic field anywhere outside the sample). For example, we show that a thin-plate magnetization is silent (i.e. in the kernel) when its normal component is zero and its tangential component is divergence free. In addition, we show that compactly supported magnetizations (i.e. magnetizations that are zero outside of a bounded set in the source plane) that do not produce magnetic fields either above or below the sample are necessarily silent. In particular, neither a nontrivial planar magnetization with fixed direction (unidimensional) compact support nor a bidimensional planar magnetization (i.e. a sum of two unidimensional magnetizations) that is nontangential can be silent. We prove that any planar magnetization distribution is equivalent to a unidimensional one. We also discuss the advantages of mapping the field on both sides of a magnetization, whenever experimentally feasible. Examples of source recovery are given along with a brief discussion of the Fourier-based inversion techniques that are utilized

Compound heterozygous RMND1 gene variants associated with chronic kidney disease, dilated cardiomyopathy and neurological involvement: a case report

Background Nuclear gene mutations are being increasingly recognised as causes of mitochondrial disease. The nuclear gene RMND1 has recently been implicated in mitochondrial disease, but the spectrum of pathogenic variants and associated phenotype for this gene, has not been fully elucidated. Case presentation An 11-month-old boy presented with renal impairment associated with a truncal ataxia, bilateral sensorineural hearing loss, hypotonia, delayed visual maturation and global developmental delay. Over a 9-year period, he progressed to chronic kidney disease stage V and developed a dilated cardiomyopathy. Abnormalities in renal and muscle biopsy as well as cytochrome c oxidase activity prompted genetic testing. After exclusion of mitochondrial DNA defects, nuclear genetic studies identified compound heterozygous RMND1 (c.713A>G, p. Asn238Ser and c.565C>T, p.Gln189*) variants. Conclusion We report RMND1 gene variants associated with end stage renal failure, dilated cardiomyopathy, deafness and neurological involvement due to mitochondrial disease. This case expands current knowledge of mitochondrial disease secondary to mutation of the RMND1 gene by further delineating renal manifestations including histopathology. To our knowledge dilated cardiomyopathy has not been reported with renal failure in mitochondrial disease due to mutations of RMND1. The presence of this complication was important in this case as it precluded renal transplantation