David Spiegel

Bio: David Spiegel is an academic researcher from Stanford University. The author has contributed to research in topics: Medicine & Breast cancer. The author has an hindex of 106, co-authored 733 publications receiving 46276 citations. Previous affiliations of David Spiegel include Tel Aviv University & University of Adelaide.

Bifunctional small molecules to target the selective degradation of circulating proteins

Abstract: The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.

Système circadien et symptômes associés au cancer

Abstract: Resume Le systeme circadien controle de nombreux aspects temporels de la physiologie et du comportement tant chez l’animal que chez l’Homme. Le dysfonctionnement du systeme circadien se traduit par la survenue d’alterations a differents niveaux d’organisation : coordination centrale, physiologie circadienne, horloges moleculaires, voies de signalisation, desynchronisation. En particulier, une perturbation circadienne induite par les vols transmeridiens ou le travail poste est associee a la survenue de symptomes generaux, tels que fatigue, troubles de l’humeur et du sommeil et perte d’appetit. Ces symptomes, en liaison avec une perturbation circadienne, sont aussi frequemment ressentis par les patients atteints de cancer comme consequence de leur maladie tumorale ou de son traitement. La litterature scientifique ici resumee indique que la perturbation du systeme circadien, avant ou pendant la chimiotherapie, favorise la survenue de symptomes generaux, deteriore la qualite de vie et amoindrit l’efficacite et la tolerance de la chronotherapie chez les patients atteints de cancer. Ainsi, une approche therapeutique innovante visant a proteger et/ou restaurer l’integrite du systeme circadien pourrait etre proposee. Cette nouvelle strategie ameliorerait l’index therapeutique de la chimiotherapie en augmentant son efficacite et en diminuant sa toxicite tout en minorant la survenue de symptomes, en preservant la qualite de vie et en augmentant la survie des patients atteints de cancer. La mise en œuvre d’une telle strategie s’appuie sur l’enregistrement non invasif de biomarqueurs du systeme circadien, la personnalisation de l’administration chronotherapeutique et la rehabilitation circadienne obtenue par des interventions pharmacologiques et comportementales.

A phase 2 study of VS-6766 (RAF/MEK clamp) RAMP 202, as a single agent and in combination with defactinib (FAK inhibitor) in recurrent KRAS mutant (mt) and BRAF mt non–small cell lung cancer (NSCLC).

Abstract: TPS9147 Background: KRAS is mutated (mt) in 25% of NSCLC adenocarcinoma, with KRAS G12V and G12C mt occurring in ̃7% and ̃13% of patients (pts), respectively. Whereas G12C inhibitors have demonstrated promising activity in pts with KRAS G12C NSCLC, KRAS G12V NSCLC remains an unmet need. BRAF mt occurs in ̃4% of NSCLC with roughly equal split between BRAF V600E and non-V600E. VS-6766 is a small molecule RAF/MEK clamp that inhibits BRAF, CRAF and MEK, enabling VS-6766 to block MEK signaling without compensatory activation of MEK observed with MEK-only inhibitors. VS-6766 potently inhibits proliferation of KRAS and BRAF mt cell lines. Focal adhesion kinase (FAK) activation is a putative resistance mechanism to RAF and MEK inhibition, and defactinib, a small molecule FAKi, has shown synergistic anti-tumor activity with VS-6766 in KRAS mt NSCLC models. In a KRAS G12V mt NSCLC mouse model, which was shown to be especially dependent on CRAF, VS-6766 induced strong tumor regressions both as monotherapy and in combination with FAKi (Coma AACR 2021). Clinically, VS-6766 monotherapy has shown responses in KRAS mt NSCLC including pts with KRAS G12V and in pts with BRAF V600E solid tumors (Guo 2020; Martinez-Garcia 2012). The combination of VS-6766 + defactinib is currently being evaluated in the Investigator Sponsored FRAME study. In an updated analysis of response in 20 pts with KRAS mt NSCLC, there were 2 confirmed PRs, 1 unconfirmed PR and 10 SDs (ORR = 15%; DCR = 65%) with 7/20 pts remaining on treatment for ≥24 weeks. The 2 pts with KRAS G12V NSCLC both had confirmed PRs (ORR = 100%). This combination regimen exhibited a manageable safety profile with no NSCLC pts discontinuing for adverse events (Krebs AACR 2021). Methods: This is an international phase 2, adaptive, multicenter, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 vs. VS-6766 + defactinib in pts with recurrent KRAS or BRAF mt NSCLC (NCT04620330). Part A will determine the optimal regimen, either VS-6766 monotherapy or VS-6766 + defactinib based on pts with KRAS G12V. Part A will consist of 5 NSCLC arms: Arm 1 VS-6766 monotherapy in KRAS G12V, Arm 2 VS-6766 + defactinib in KRAS G12V, Arm 3 the combination in KRAS non-G12V, Arm 4 the combination in BRAF V600E and Arm 5 the combination in BRAF non-V600E. Part B will determine the efficacy of the optimal regimen identified in Part A. Pts must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1, known KRAS or BRAF mt and at least 1 prior systemic therapy (appropriate therapy for activating mutation and/or platinum-based therapy). Part A will enroll 102 pts Arms 1 and 2 (KRAS G12V), and Arms 4 and 5 (BRAF V600E and non-V600E) are currently open. Arm 3 (KRAS non-G12V) enrollment is completed. The total number of pts in Part B will be determined by results from Part A. Clinical trial information: NCT04620330.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The Benefits of Being Present: Mindfulness and Its Role in Psychological Well-Being

Abstract: Mindfulness is an attribute of consciousness long believed to promote well-being. This research provides a theoretical and empirical examination of the role of mindfulness in psychological well-being. The development and psychometric properties of the dispositional Mindful Attention Awareness Scale (MAAS) are described. Correlational, quasi-experimental, and laboratory studies then show that the MAAS measures a unique quality of consciousness that is related to a variety of well-being constructs, that differentiates mindfulness practitioners from others, and that is associated with enhanced selfawareness. An experience-sampling study shows that both dispositional and state mindfulness predict self-regulated behavior and positive emotional states. Finally, a clinical intervention study with cancer patients demonstrates that increases in mindfulness over time relate to declines in mood disturbance and stress. Many philosophical, spiritual, and psychological traditions emphasize the importance of the quality of consciousness for the maintenance and enhancement of well-being (Wilber, 2000). Despite this, it is easy to overlook the importance of consciousness in human well-being because almost everyone exercises its primary capacities, that is, attention and awareness. Indeed, the relation between qualities of consciousness and well-being has received little empirical attention. One attribute of consciousness that has been much-discussed in relation to well-being is mindfulness. The concept of mindfulness has roots in Buddhist and other contemplative traditions where conscious attention and awareness are actively cultivated. It is most commonly defined as the state of being attentive to and aware of what is taking place in the present. For example, Nyanaponika Thera (1972) called mindfulness “the clear and single-minded awareness of what actually happens to us and in us at the successive moments of perception” (p. 5). Hanh (1976) similarly defined mindfulness as “keeping one’s consciousness alive to the present reality” (p. 11). Recent research has shown that the enhancement of mindfulness through training facilitates a variety of well-being outcomes (e.g., Kabat-Zinn, 1990). To date, however, there has been little work examining this attribute as a naturally occurring characteristic. Recognizing that most everyone has the capacity to attend and to be aware, we nonetheless assume (a) that individuals differ in their propensity or willingness to be aware and to sustain attention to what is occurring in the present and (b) that this mindful capacity varies within persons, because it can be sharpened or dulled by a variety of factors. The intent of the present research is to reliably identify these inter- and intrapersonal variations in mindfulness, establish their relations to other relevant psychological constructs, and demonstrate their importance to a variety of forms of psychological well-being.

Standards of Medical Care in Diabetes

Abstract: XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.