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。

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

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.

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

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.

Standards of Medical Care in Diabetes

Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

EASL-EORTC clinical practice guidelines : management of hepatocellular carcinoma

Breast cancer is inherently stressful. Every person diagnosed with the disease immediately experiences understandable fear of dying of cancer, despite the fact that half of all breast cancer patients will live to die of something else. They also fear disfigurement, despite the increasing prevalence of breast-sparing treatments such as lumpectomy and radiation. These concerns tend to isolate them from social support, since such fundamental concerns arouse anxiety in others as well, and may lead to avoidance on both sides. Cancer treatments can induce nausea, fatigue, burns, lymphedema, disfigurement, and pain. The illness and its treatment cause acute disruption of educational, vocational, and social roles. Thus, it is natural that breast cancer patients experience stress, distress, anxiety, and depression. Few people are well prepared by life for the multiple existential problems that come with a diagnosis of breast cancer. Recognizing that these issues are always part of returning a patient to a well-state allows the clinician to better support patients and enables the astute clinician to recognize the potential need for consultation from a psychologist or psychiatrist.

Psychiatric and Psychological Issues

Glucosepane is a structurally complex protein post-translational modification (PTM) believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging; yet comprehensive biological investigations of this 'metabolite have been 'greatly hindered by a scarcity of chemically homogeneous material available for study. Glucosepane possesses a unique chemical structure that incorporates a surprising, never-before-prepared non-aromatic tautomer of imidazole (hereafter termed an "iso-imidazole"), rendering it a challenging target for chemical synthesis. In this application, the inventors report the first total synthesis of glucosepane, enabled by the development of a novel one-pot method for preparation of the iso-imidazole core. The synthesis of the present invention is concise (8-steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. These results should prove useful to the art and practice of heterocyclic chemistry, and critical for the study of glucosepane and its role in human health and disease, especially the treatment of diabetic disorders or its impact on aging processes. Methods of synthesis, compounds obtained therefrom, pharmaceutical compositions and methods of treatment provide embodiments of the present invention.

The total synthesis of glucosepane and compounds obtained therefrom

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d-1) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses. ClinicalTrials.gov registration: NCT04497116 . 

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Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results

Samir Gautam,†,‡ Lokesh Sharma,† Charles S. Dela Cruz,† and David Adam Spiegel*,‡ †Internal Medicine, Section of Pulmonary and Critical Care, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, United States ‡Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06520, United States A Viewpoint for Biochemistry on the article in Cell, “Immunomimetic Designer Cells Protect Mice from MRSA Infection” In his 2002 essay entitled “Can a biologist fix a radio?Or, what I learned while studying apoptosis”, Yuri Lazebnik chides the biology community for its over-reliance on reductionistic experimental techniques such as genetic deletion to describe complex systems. He humorously illustrates his argument by describing how a biologist might attempt to fix a radio, including the obligatory annihilation of each electrical component “at close range with metal particles” to determine its function, an approach analogous to the murine knockout experiments upon which biologists so depend. In contrast, he submits that an engineer would solve the problem handily based on a facility with standardized technical language (electrical diagramming) that fully and unambiguously describes the mechanical device. The rub, of course, is that radios are built by engineers in the first place; cells, much less animals, are not. Indeed, a principle advantage engineers hold over biologists in terms of “handiness” derives from a hundred years of research into the fundamental principles of electromagnetism and another hundred in refining the practice of electrical engineering, which allows them to create electrical devices according to a standardized methodology. A similar position of privilege is enjoyed by modern organic chemists, who have likewise spent centuries designing and synthesizing a huge array of small molecules and natural products, including the chemical therapeutics that serve as the backbone of modern medicine, to establish a robust fundamental and technical appreciation for how molecules behave. Accordingly, it might be stated that the true understanding of a system, as achieved in areas of physics and chemistry, is indicated by the ability to construct one. In recent years, biologists have made strides toward this lofty goal as they have endeavored to create cells, either from scratch in the case of synthetic biology or by modifying existing cells for therapeutic ends. A particularly successful example of the latter comes from immuno-oncologists, who have genetically engineered T-cells to express specific sensors for cancer antigens called chimeric antigen receptors (CARs). Ligation of these receptors elicits robust effector responses (cytokine release by CD4+ cells and direct cytotoxicity by CD8+ cells), leading to the elimination of targeted tumor cells (Figure 1). The clinical success of CAR T-cells in the treatment of advanced hematologic malignancies is unprecedented; for instance, anti-CD19 CAR-T therapy induces complete remission in ∼90% of patients with chemo-resistant B cell leukemias, in whom life expectancy would otherwise be months. Now, Liu et al. apply this engineering principle to develop a novel therapeutic for infectious disease. They target methicillin-resistant Staphylococcus aureus (MRSA), a Grampositive bacterium that is responsible for more deaths in the United States than any other bacterial pathogen, and can infect virtually any tissue, including blood, lung, and skin. A particularly feared form of MRSA infection is establishment of biofilms on implanted hardware, such as prosthetic joints or heart valves, which almost invariably necessitates surgical removal of the foreign material due to resistance of the associated biofilms to antibiotics. To tackle this problem, Liu et al. construct an elegant genetic network consisting of three principal components (Figure 1): (i) a sensing mechanism for constituents of the S. aureus cell wall, namely, lipoproteins and wall teichoic acids, which are detected via the cell-surface pathogen recognition receptors TLR1, TLR2, and TLR6, along with the co-receptor CD14; (ii) a highly optimized signal transduction module based on the immune transcription factors NFκB and AP-1 and the promoter for interferon-β; and (iii) a response element leading to expression of proteins that function as either diagnostics (secreted alkaline phosphatase) or therapeutics

https://pubs.acs.org/doi/pdf/10.1021/acs.biochem.8b00916

David Spiegel

Papers

Psychiatric and Psychological Issues

The total synthesis of glucosepane and compounds obtained therefrom

Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results

A Slick Solution to a Sticky Problem.

Rest-activity rhythm as a clinical biomarker in cancer.