Notch Signaling in Cancer

Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on differentiation, survival, and/or proliferation that are highly dependent on signal strength and cellular context. Because perturbations in the regulation of differentiation, survival, and/or proliferation underlie malignant transformation, pathophysiologic Notch signals potentially contribute to cancer development in several different ways. Notch signaling was first linked to tumorigenesis through identification of a recurrent t(7;9)(q34;q34.3) chromosomal translocation involving the human Notch 1 gene that is found in a small subset of human pre-T-cell acute lymphoblastic leukemias (T-ALL).1 Since this discovery, aberrant Notch signaling has been suggested to be involved in a wide variety of human neoplasms. In this review, we will focus on recent studies linking aberrant Notch signaling with cancer. First, we discuss various mechanisms through which Notch signaling may influence cellular transformation. Then, we critically review literature pertaining to the role of Notch signaling in several cancers, and discuss possible therapeutic targets in the Notch pathway

Functional Analysis of the TAN-1 Gene, a Human Homolog of Drosophila Notch

The TAN-1 gene was originally discovered at the breakpoint of a recurrent (7;9)(q34;q34.3) chromosomal translocation found in a subset of human T-lymphoblastic leukemias (Reynolds et al. 1987; Smith et al. 1988; Ellisen et al. 1991). This translocation joins roughly the 3′ half of TAN-1 head-to-head with the 3′ portion of the β T-cell-receptor gene (TCRB) beginning at the 5′ boundary of one or the other J segment. Intact TAN-1 is normally transcribed into an 8.2-kb transcript that is present in many tissues, most abundantly in developing thymus and spleen (Ellisen et al. 1991). This tissue distribution and the apparent involvement of an altered version of the gene in T-cell cancers have suggested that TAN-1 normally has some special function in lymphocytes or their precursors

Holography in 4D (Super) Higher Spin Theories and a Test via Cubic Scalar Couplings

The correspondences proposed previously between higher spin gauge theories and free singleton field theories were recently extended into a more complete picture by Klebanov and Polyakov in the case of the minimal bosonic theory in D=4 to include the strongly coupled fixed point of the 3d O(N) vector model. Here we propose an N=1 supersymmetric version of this picture. We also elaborate on the role of parity in constraining the bulk interactions, and in distinguishing two minimal bosonic models obtained as two different consistent truncations of the minimal N=1 model that retain the scalar or the pseudo-scalar field. We refer to these models as the Type A and Type B models, respectively, and conjecture that the latter is holographically dual to the 3d Gross-Neveu model. In the case of the Type A model, we show the vanishing of the three-scalar amplitude with regular boundary conditions. This agrees with the O(N) vector model computation of Petkou, thereby providing a non-trivial test of the Klebanov-Polyakov conjecture.Comment: 30p

Impaired Notch Signaling Promotes \u3cem\u3eDe novo\u3c/em\u3e Squamous Cell Carcinoma Formation

Signaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor–mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like 1 (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/LAG-1 (CSL)–dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear ß-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs, which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies

Learning Mazes with Aliasing States: An LCS Algorithm with Associative Perception

Learning classifier systems (LCSs) belong to a class of algorithms based on the principle of self-organization and have frequently been applied to the task of solving mazes, an important type of reinforcement learning (RL) problem. Maze problems represent a simplified virtual model of real environments that can be used for developing core algorithms of many real-world applications related to the problem of navigation. However, the best achievements of LCSs in maze problems are still mostly bounded to non-aliasing environments, while LCS complexity seems to obstruct a proper analysis of the reasons of failure. We construct a new LCS agent that has a simpler and more transparent performance mechanism, but that can still solve mazes better than existing algorithms. We use the structure of a predictive LCS model, strip out the evolutionary mechanism, simplify the reinforcement learning procedure and equip the agent with the ability of associative perception, adopted from psychology. To improve our understanding of the nature and structure of maze environments, we analyze mazes used in research for the last two decades, introduce a set of maze complexity characteristics, and develop a set of new maze environments. We then run our new LCS with associative perception through the old and new aliasing mazes, which represent partially observable Markov decision problems (POMDP) and demonstrate that it performs at least as well as, and in some cases better than, other published systems

Lyophilisation of influenza, rabies and Marburg lentiviral pseudotype viruses for the development and distribution of a neutralisation-assay based diagnostic kit

Pseudotype viruses (PVs) are chimeric, replication-deficient virions that mimic wild-type virus entry mechanisms and can be safely employed in neutralisation assays, bypassing the need for high biosafety requirements and performing comparably to established serological assays. However, PV supernatant necessitates -80°C long-term storage and cold-chain maintenance during transport, which limits the scope of dissemination and application throughout resource-limited laboratories. We therefore investigated the effects of lyophilisation on influenza, rabies and Marburg PV stability, with a view to developing a pseudotype virus neutralisation assay (PVNA) based kit suitable for affordable global distribution. Infectivity of each PV was calculated after lyophilisation and immediate reconstitution, as well as subsequent to incubation of freeze-dried pellets at varying temperatures, humidities and timepoints. Integrity of glycoprotein structure following treatment was also assessed by employing lyophilised PVs in downstream PVNAs. In the presence of 0.5M sucrose-PBS cryoprotectant, each freeze-dried pseudotype was stably stored for 4 weeks at up to 37°C and could be neutralised to the same potency as unlyophilised PVs when employed in PVNAs. These results confirm the viability of a freeze-dried PVNA-based kit, which could significantly facilitate low-cost serology for a wide portfolio of emerging infectious viruses

Firearm Violence Following the Implementation of California's Gun Violence Restraining Order Law.

Importance: California's gun violence restraining order (GVRO) law, implemented beginning in 2016, allows for people at high risk of harming themselves or others with a firearm to be temporarily disarmed and prevented from purchasing firearms for 3 weeks to 1 year; many states have recently enacted similar laws. The research to date is on older and more limited risk-warrant laws. Objective: To determine whether implementation of the California GVRO law was associated with decreased rates of firearm assault or firearm self-harm in a large metropolitan county between 2016 and 2019. Design, Setting, and Participants: This serial cross-sectional study including data from 28 counties used the synthetic control method to evaluate differences in firearm violence between San Diego County and its synthetic control following implementation of the California law from 2016 to 2019. San Diego County was used as the treated unit because it issued substantially more GVROs than any other county in California during the study period. A total of 27 California counties that issued no or very few gun violence restraining orders from 2016 to 2019 and that had stable rates of firearm violence between 2005 and 2015 were included in the control pool. Data were analyzed from February 2021 to July 2021. Exposures: Implementation of the statewide GVRO law in 2016 in San Diego County. Main Outcomes and Measures: Annual rates of fatal and nonfatal firearm assault injuries and firearm self-harm injuries per 100 000 people. Results: In the study period, there were 355 GVROs in San Diego county, and a median (IQR) total of 8 (3-20) GVROs per donor county. The mean difference between the observed rate in San Diego County and the estimated rate in the synthetic San Diego County, 2016-2019, was -0.74 firearm assaults per 100 000 (-13% difference) and 0.13 firearm self-harm injuries per 100 000 (3% difference). Results from in-space placebo tests suggested that these differences cannot be distinguished from variation due to chance (pseudo-P values from a 1-sided test: P for assault = .35, P for self-harm = .67). Conclusions and Relevance: To our knowledge, this study was the first to analyze the association between GVRO implementation and firearm violence in California and the first to evaluate the association between risk-based firearm removal laws and firearm assault in any state. GVROs were not associated with reduced population-level rates of firearm violence in San Diego County, but this may change as the number of orders increases over time; the association between GVROs and firearm violence at the individual level cannot be inferred from our findings and should be the subject of future studies

The role of firearm and alcohol availability in firearm suicide: A population-based weighted case-control study

Firearm availability has been linked to firearm self-harm, but the joint relationship with alcohol availability, while supported by theory, has not been examined. This study sought to quantify the separate and joint relations of community firearm and alcohol availability with individual-level risk of (fatal and nonfatal) firearm self-harm. We conducted a case-control study of California residents, 2005-2015, using statewide mortality, hospital, firearm transfer, and alcohol license data. We estimated monthly marginal risk differences per 100,000 in the overall population and in white men aged 50+ under various hypothetical changes to firearm and alcohol availability and assessed additive interactions using case-control-weighted g-computation. In the overall population, non-pawn shop firearm dealer density was associated with firearm self-harm (RD: 0.02, 95% CI: 0.003, 0.04) but pawn shop firearm dealer and alcohol outlet densities were not. Secondary analyses revealed a relationship between firearm sales density and firearm self-harm (RD: 0.07, 95% CI: 0.04, 0.10). There were no additive interactions between measures of firearm and alcohol availability. Among older white men, generally the same exposures were related to self-harm as in the overall population, but point estimates were substantially larger. Findings suggest community-level approaches to reducing firearm sales may help mitigate suicide risk