BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment ...of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
BackgroundHematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and ...kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy.MethodsHuman primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo.ResultsCompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease.ConclusionCompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
The vestibular system contributes to regulating sympathetic nerve activity and blood pressure. Initial studies in decerebrate animals showed that neurons in the rostral ventrolateral medulla (RVLM) ...respond to small-amplitude (<10°) rotations of the body, as in other brain areas that process vestibular signals, although such movements do not affect blood distribution in the body. However, a subsequent experiment in conscious animals showed that few RVLM neurons respond to small-amplitude movements. This study tested the hypothesis that RVLM neurons in conscious animals respond to signals from the vestibular otolith organs elicited by large-amplitude static tilts. The activity of approximately one-third of RVLM neurons whose firing rate was related to the cardiac cycle, and thus likely received baroreceptor inputs, was modulated by vestibular inputs elicited by 40° head-up tilts in conscious cats, but not during 10° sinusoidal rotations in the pitch plane that affected the activity of neurons in brain regions providing inputs to the RVLM. These data suggest the existence of brain circuitry that suppresses vestibular influences on the activity of RVLM neurons and the sympathetic nervous system unless these inputs are physiologically warranted. We also determined that RVLM neurons failed to respond to a light cue signaling the movement, suggesting that feedforward cardiovascular responses do not occur before passive movements that require cardiovascular adjustments.
Objective
Psychosexual morbidity is common after prostate cancer treatment, however, long‐term prospective research is limited. We report 5‐year outcomes from a couples‐based intervention in dyads ...with men treated for localised prostate cancer with surgery.
Methods
A randomised controlled trial was conducted involving 189 heterosexual couples, where the man received a radical prostatectomy for prostate cancer. The trial groups were peer support vs. nurse counselling versus usual care. Primary outcomes were sexual adjustment, unmet sexual supportive care needs, masculine self‐esteem, marital satisfaction, and utilisation of erectile aids at 2‐, 3‐, 4‐ and 5‐year follow‐up.
Results
The effects of the interventions varied across the primary outcomes. Partners in the peer group had higher sexual adjustment than those in the usual care and nurses group at 2 and 3 years (P = 0.002‐0.035). Men in usual care had lower unmet sexual supportive care needs than men in the peer and nurse groups (P = 0.001; P = 0.01) at 3 years. Women in usual care had lower sexual supportive care needs than women in the peer group at 2 and 3 years (P = 0.038; P = 0.001). Men in the peer and nurse group utilised sexual aids more than men in usual care; at 5 years 54% of usual care men versus 87% of men in peer support and 80% of men in the nurse group.
Conclusion
Peer and nurse‐administered psychosexual interventions have potential for increasing men's adherence to treatments for erectile dysfunction. Optimal effects may be achieved through an integrated approach applying these modes of support.
While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent ...need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.
We continue the study of the first sample of shear-selected clusters from the initial 8.6 square degrees of the Deep Lens Survey (DLS); a sample with well-defined selection criteria corresponding to ...the highest ranked shear peaks in the survey area. We aim to characterize the weak lensing selection by examining the sample's X-ray properties. There are multiple X-ray clusters associated with nearly all the shear peaks: 14 X-ray clusters corresponding to seven DLS shear peaks. An additional three X-ray clusters cannot be definitively associated with shear peaks, mainly due to large positional offsets between the X-ray centroid and the shear peak. Here we report on the XMM-Newton properties of the 17 X-ray clusters. The X-ray clusters display a wide range of luminosities and temperatures; the LX−TX relation we determine for the shear-associated X-ray clusters is consistent with X-ray cluster samples selected without regard to dynamical state, while it is inconsistent with self-similarity. For a subset of the sample, we measure X-ray masses using temperature as a proxy, and compare to weak lensing masses determined by the DLS team. The resulting mass comparison is consistent with equality. The X-ray and weak lensing masses show considerable intrinsic scatter (∼48%), which is consistent with X-ray selected samples when their X-ray and weak lensing masses are independently determined.
We present DLSCL J0916.2+2951 (z = 0.53), a newly discovered major cluster merger in which the collisional cluster gas has become dissociated from the collisionless galaxies and dark matter (DM). We ...identified the cluster using optical and weak-lensing observations as part of the Deep Lens Survey. Our follow-up observations with Keck, Subaru, Hubble Space Telescope, and Chandra show that the cluster is a dissociative merger and constrain the DM self-interaction cross-section sigma sub(DM)(ProQuest: Formulae and/or non-USASCII text omitted) <, ~ 7 cm super(2) g super(?1). Hie system is observed at least 0.7 + or - 0.2 Gyr since first pass-through, thus providing a picture of cluster mergers 2-5 times further progressed than similar systems observed to date. This improved temporal leverage has implications for our understanding of merging clusters and their impact on galaxy evolution.
Autonomous and AI-enabled systems present a challenge for integration within the System of Sys-tems (SoS) paradigm. A full system of systems (SoS) testbed is necessary to verify the integrity of a ...given system and preserve the modularization and accountability of its constituent systems. This integrated system needs to support iterative, continuous testing and development. This need war-rants the development of a virtual environment that provides the ground truth in a simulated sce-nario, interfaces with real-world data, and uses various domain-specific and domain-agnostic simulation systems for development, testing, and evaluation. These required features present a non-trivial challenge wherein constructive models and systems at different levels of fidelity need to interoperate to advance the testing, evaluation, and integration of complex systems. Such a virtual and constructive SoS architecture should be independent of the underlying computational infra-structure but must be cloud-enabled for wider integration of AI-enabled software components. This paper will present a modular Simulation, Experimentation, Analytics, and Test (SEAT) Lay-ered Architecture Framework, a 10-step methodology. This paper will also demonstrate a case study of a hybrid cloud-enabled simulation SoS that allows extensibility, composability, and de-ployability in different target environments.
We continue the study of the first sample of shear-selected clusters from the initial 8.6 square degrees of the Deep Lens Survey (DLS); a sample with well-defined selection criteria corresponding to ...the highest ranked shear peaks in the survey area. We aim to characterize the weak lensing selection by examining the sample’s X-ray properties. There are multiple X-ray clusters associated with nearly all the shear peaks: 14 X-ray clusters corresponding to seven DLS shear peaks. An additional three X-ray clusters cannot be definitively associated with shear peaks, mainly due to large positional offsets between the X-ray centroid and the shear peak. Here we report on the XMM-Newton properties of the 17 X-ray clusters. The X-ray clusters display a wide range of luminosities and temperatures; the L X −T X relation we determine for the shear-associated X-ray clusters is consistent with X-ray cluster samples selected without regard to dynamical state, while it is inconsistent with self-similarity. For a subset of the sample, we measure X-ray masses using temperature as a proxy, and compare to weak lensing masses determined by the DLS team. The resulting mass comparison is consistent with equality. The X-ray and weak lensing masses show considerable intrinsic scatter (∼48%), which is consistent with X-ray selected samples when their X-ray and weak lensing masses are independently determined.
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