Notch: architect, landscaper, and guardian of the intestine

In the past decade, enormous progress has been made in understanding the role of stem cells in physiologic tissue renewal and in pathologic processes such as cancer. These findings have shed light on the identity and biological properties of such cells and the intrinsic and extrinsic signals that balance stem cell self-renewal with differentiation. With its astonishing self-renewal capacity, the intestinal epithelium has provided a unique model to study stem cell biology, lineage specification, and cancer. Here we review the role of Notch signaling in physiologic cell renewal and differentiation in the intestine as well as during its malignant transformation.     

Liver cancer stem cells: implications for a new therapeutic target

Hepatocellular carcinoma (HCC) is an aggressive tumour with a poor prognosis. Current therapeutic strategies against this disease target mostly rapidly growing differentiated tumour cells. However, the result is often dismal due to the chemoresistant nature of this tumour type. Recent research efforts on stem cells and cancer biology have shed light on new directions for the eradication of cancer stem cells (CSCs) in HCC. The liver is a distinctive organ with the ability of tissue renewal in response to injury. Based on the hypothesis that cancer development is derived from the hierarchy of the stem cell system, we will briefly discuss the origin of liver stem cells and its relation to HCC development. We will also summarize the current CSC markers in HCC and discuss their relevance to the treatment of this deadly disease.     

New biomarkers and targets in pancreatic cancer and their application to treatment

Late diagnosis of pancreatic ductal adenocarcinoma (pancreatic cancer) and the limited response to current treatments results in an exceptionally poor prognosis. Advances in our understanding of the molecular events underpinning pancreatic cancer development and metastasis offer the hope of tangible benefits for patients. In-depth mutational analyses have shed light on the genetic abnormalities in pancreatic cancer, providing potential treatment targets. New biological studies in patients and in mouse models have advanced our knowledge of the timing of metastasis of pancreatic cancer, highlighting new directions for the way in which patients are treated. Furthermore, our increasing understanding of the molecular events in tumorigenesis is leading to the identification of biomarkers that enable us to predict response to treatment. A major drawback, however, is the general lack of an adequate systematic approach to advancing the use of biomarkers in cancer drug development, highlighted in a Cancer Biomarkers Collaborative consensus report. In this Review, we summarize the latest insights into the biology of pancreatic cancer, and their repercussions for treatment. We provide an overview of current treatments and, finally, we discuss novel therapeutic approaches, including the role of biomarkers in therapy for pancreatic cancer.     

Helicobacter pylori and gastric cancer: the causal relationship

Gastric cancer has been recognized as an important cause of morbidity and mortality all over the world. Helicobacter pylori has been shown to have a causal relationship to gastric cancer. The knowledge into the mechanisms related to this has advanced considerably over the last few years thereby unarguably defining the role of this host-pathogen interaction. Epidemiological studies, research in animal models, molecular pathways involving host and bacterial factors, environmental factors and recent work on stem cells have contributed to understanding the origin and progress of this neoplasia. These form part of the myriad of interplaying factors resulting in the causal relationship. Nevertheless, current evidence is insufficient to accurately identify a definitive population where prevention or treatment strategies have to be targeted. Future trials will have to define the people at risk and shed more light in these areas.     

Role of microRNAs in Arbovirus/Vector Interactions

The role of microRNAs (miRNAs) as small non-coding RNAs in regulation of gene expression has been recognized. They appear to be involved in regulation of a wide range of cellular pathways that affect several biological processes such as development, the immune system, survival, metabolism and host-pathogen interactions. Arthropod-borne viruses impose great economic and health risks around the world. Recent advances in miRNA biology have shed some light on the role of these small RNAs in vector-virus interactions. In this review, I will reflect on our current knowledge on the role of miRNAs in arbovirus-vector interactions and the potential avenues for their utilization in limiting virus replication and/or transmission.     

Lung cancer: future directions

Increasingly, basic research is being translated into clinical benefits for patients. Recent studies have shed more light on the clinical use of targeted therapies such as tyrosine kinase and angiogenesis inhibitors, and predictive factors for their clinical benefit and their role in different clinical settings are now being elucidated. New insights into the basic biology of lung cancer hold translational promise in risk assessment, early detection, molecular staging, treatment response prediction and novel therapies. New targeted agents directed at apoptotic and developmental pathways have the potential to exploit newly discovered vulnerabilities in the basic machinery of cancer. In addition, exploration of the cancer stem cell phenomenon in lung cancer may generate new approaches to prevent recurrence in surgically respectable lung cancer, and for the long-term control of extensive disease. Molecular profiling may also allow for highly individualized prognostic, predictive and therapeutic treatment plans tailored for each patient based on the molecular diagnostic profile of their tumour. Advances in genetic susceptibility, early detection and individualized therapy based on each tumour's unique biological properties all hold promise for the future management of lung cancer.     

Apoptosis in normal and cancer stem cells

Cancer stem cells, previously identified in acute leukemias, have now been isolated from several human malignancies, such as breast, brain and gastrointestinal tumors. The origin of these cells is still questionable, but a growing body of evidence supports the idea that they are responsible for tumor growth and maintenance. For this reason, they have become a primary subject of investigation with a view to developing novel therapies that might lead to the eradication of neoplastic diseases. As previously demonstrated, cancer stem cells in haematological diseases have biological properties similar to those of normal adult stem cells. Therefore, better knowledge of the apoptotic machinery in stem cells might help in the development of targeted therapy for treating cancers. In this review, we discuss some concepts relating to stem cell biology, focusing on the apoptotic responses of haematopoietic and neural stem cells to conventional and novel cancer treatment strategies.     

先天性肾上腺增生症与性发育异常

先天性肾上腺增生症是引起性发育异常最常见的病因,包括46,XX和46,XY性发育障碍。随着遗传学和分子生物学进展,人们对其发病机制以及基因型和表型之间关系的认识不断深入。本文从性别决定和性发育过程阐述先天性肾上腺增生症的临床特征和发生机制。     

Mouse models of colorectal cancer: Past,present and future perspectives

Colorectal cancer(CRC) is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union. While the incidence and mortality rates in western, high developed countries are declining,reflecting the success of screening programs and improved treatment regimen, a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index. Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades, preclinical in vivo models are still indispensable for the development of new treatment approaches. Since the development of carcinogen-induced rodent models for CRC more than 80 years ago, a plethora of animal models has been established to study colon cancer biology. Despite tenuous invasiveness and metastatic behavior, these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis. Genetically engineered mouse models(GEMM) mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited. Although the vast majority of CRC GEMM lack invasiveness, metastasis and tumor heterogeneity,they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses; thus, supporting development of new therapeutic avenues. Induction of metastatic disease by orthotopic injection of CRC cell lines is possible, but the so generated models lack genetic diversity and the number of suited cell lines is very limited. Patient-derived xenografts, in contrast, maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development – even in comparison to GEMM or cell line-based analyses. However, subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses. The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models.     

HIV viral diversity and escape from cellular immunity

Immune control of HIV often fails due to viral escape from cellular and humoral host immune responses. Vaccine development is a daunting task because of the ability of HIV to adapt rapidly to different selection pressures and quickly restore viral fitness when transmitted to new hosts. In addition, the global viral diversity poses significant difficulties for accurate and standardized testing of immune responses in the infected host, slowing the generation of data that are crucial to defining relevant immune correlates of controlled HIV infection. Many recent studies have shed light on some of the potentially important factors of protective immune responses and have provided further insight into the viral kinetics determining immune control, viral adaptation, and immune escape. This knowledge will likely further guide the design of broadly applicable HIV vaccine candidates.     

Hantavirus Immunology of Rodent Reservoirs: Current Status and Future Directions

Hantaviruses are hosted by rodents, insectivores and bats. Several rodent-borne hantaviruses cause two diseases that share many features in humans, hemorrhagic fever with renal syndrome in Eurasia or hantavirus cardiopulmonary syndrome in the Americas. It is thought that the immune response plays a significant contributory role in these diseases. However, in reservoir hosts that have been closely examined, little or no pathology occurs and infection is persistent despite evidence of adaptive immune responses. Because most hantavirus reservoirs are not model organisms, it is difficult to conduct meaningful experiments that might shed light on how the viruses evade sterilizing immune responses and why immunopathology does not occur. Despite these limitations, recent advances in instrumentation and bioinformatics will have a dramatic impact on understanding reservoir host responses to hantaviruses by employing a systems biology approach to identify important pathways that mediate virus/reservoir relationships.     

心肌代谢障碍与过氧化物酶体增殖激活受体

过氧化物酶体增殖激活受体在细胞能量代谢中起重要作用。既往的研究表明在各种心肌病变中均有不同程度的心肌能量代谢障碍,心肌细胞脂肪酸和葡萄糖的代谢失衡可能是心脏功能恶化的病理生理基础。近年来随着基因敲除和基因过表达技术的发展为我们了解心脏过氧化物酶体增殖激活受体的功能提供了更为方便、独特的途经,现对这一方面的进展作一综述。     

Problem pulmonary pathogens: Pseudomonas aeruinosa

Pseudomonas aeruginosa is a common and highly lethal agent of nosocomial pneumonia, especially among patients receiving mechanical ventilation. It is widespread in the environment and commonly recovered from water in nature and in hospital settings. P. aeruginosa is endowed with a formidable array of virulence factors that facilitate attachment to host cells, tissue invasion, and systemic disease. It is intrinsically resistant to many commonly used antibiotics due to a complex variety of mechanisms that we will briefly review. Recent advances in the understanding of the molecular biology of this organism have shed considerable light on its ability to form biofilms, which facilitate adherence especially in cystic fibrosis patients, and confer resistance to clearance by host immune mechanisms and antimicrobial killing. Treatment studies have demonstrated a significant risk of emergence of resistance during therapy with a variety of agents. Several studies suggest that two drugs are better than one for therapy of serious infections, although dual therapy does not always prevent emergence of resistant strains.     

Association of malignancy with diseases causing interstitial pulmonary changes

A number of studies have shown a high incidence of lung cancer in patients with idiopathic pulmonary fibrosis (9.8 to 38%) compared to control subjects (2 to 6.4%). A similar trend occurs in other entities that affect the interstitial lung compartment, such as systemic sclerosis and sarcoidosis, as well as occupational diseases. The pathogenesis of lung cancer in patients with diffuse pulmonary fibrosis is still unclear. Recent progress in molecular and cellular biology has shed some light on the possible interactions of several types of inflammatory cells, following the deleterious effects of toxic factors leading to alveolitis, and destruction and disorganization of lung parenchyma, which results in fibrosis. Further research in the field would enhance our understanding of the pathogenic mechanisms of cancer development in these patients, and to explain the reason for the different incidence of lung cancer in patients with various interstitial lung diseases.     

Gut microbiota as a candidate for lifespan extension: an ecological/evolutionary perspective targeted on living organisms as metaorganisms

An emerging central concept in evolutionary biology suggests that symbiosis is a universal characteristic of living organisms that can help in understanding complex traits and phenotypes. During evolution, an integrative circuitry fundamental for survival has been established between commensal gut microbiota and host. On the basis of recent knowledge in worms, flies, and humans, an important role of the gut microbiota in aging and longevity is emerging. The complex bacterial community that populates the gut and that represents an evolutionary adapted ecosystem correlated with nutrition appears to limit the accumulation of pathobionts and infections in all taxa, being able of affecting the efficiency of the host immune system and exerting systemic metabolic effects. There is an urgent need to disentangle the underpinning molecular mechanisms, which could shed light on the basic mechanisms of aging in an ecological perspective. Thus, it appears possible to extend healthy aging and lifespan by targeting the host as a metaorganism by manipulating the complex symbiotic ecosystem of gut microbiota, as well as other possible ecosystems of the body.     

Use of mouse models to study the role of tissue factor in tumor biology

Tissue factor (TF) is the primary initiator of the coagulation cascade and plays an essential role in hemostasis. TF also contributes to many diseases, including cancer. The correlation between thrombosis and cancer has been recognized for more than a century. However, it is only in the past two decades that we have begun to understand the role of TF in tumor biology. TF expression is upregulated on both tumor and host cells in cancer patients as well as in the circulation. Clinical observations indicate a direct correlation between the levels of tumor cell TF expression and poor prognosis for cancer patients. The role of TF in tumor biology has been extensively studied using various mouse tumor models. It has been demonstrated that tumor cell TF contributes to tumor metastasis, growth, and angiogenesis. The role of host TF in tumor progression is less clear. Recently developed mouse models with altered levels of TF may be useful in further analysis of the role of host cell TF in cancer.     

SIRT-ain relief from age-inducing stress

Aging is one of the most fundamental biological processes. It results in a decline in physiological function and an increased risk for pernicious diseases such as cancer. Oxidative stress has been proposed as a major cause of aging, but experimental tests of this hypothesis have been discouraging. Calorie restriction (CR) prevents age-related decline, but there are still gaps in our knowledge of the exact mechanisms underlying this feat. Finally, a tenuous balance exists between aging and cancer, calling for a search for interventions that prevent both aging and cancer. Recent work on the mammalian sirtuin SIRT3 has shed light on these long-standing issues and suggested new approaches to ameliorate the ravages of aging.     

Top-Down and Bottom-Up Proteomics Methods to Study RNA Virus Biology

RNA viruses cause a wide range of human diseases that are associated with high mortality and morbidity. In the past decades, the rise of genetic-based screening methods and high-throughput sequencing approaches allowed the uncovering of unique and elusive aspects of RNA virus replication and pathogenesis at an unprecedented scale. However, viruses often hijack critical host functions or trigger pathological dysfunctions, perturbing cellular proteostasis, macromolecular complex organization or stoichiometry, and post-translational modifications. Such effects require the monitoring of proteins and proteoforms both on a global scale and at the structural level. Mass spectrometry (MS) has recently emerged as an important component of the RNA virus biology toolbox, with its potential to shed light on critical aspects of virus–host perturbations and streamline the identification of antiviral targets. Moreover, multiple novel MS tools are available to study the structure of large protein complexes, providing detailed information on the exact stoichiometry of cellular and viral protein complexes and critical mechanistic insights into their functions. Here, we review top-down and bottom-up mass spectrometry-based approaches in RNA virus biology with a special focus on the most recent developments in characterizing host responses, and their translational implications to identify novel tractable antiviral targets.     

Genetics of Mechanosensation in the Heart

Mechanosensation (the ultimate conversion of a mechanical stimulus into a biochemical signal) as well as mechanotransduction (transmission of mechanically induced signals) belong to the most fundamental processes in biology. These effects, because of their dynamic nature, are particularly important for the cardiovascular system. Therefore, it is not surprising that defects in cardiac mechanosensation, are associated with various types of cardiomyopathy and heart failure. However, our current knowledge regarding the genetic basis of impaired mechanosensation in the cardiovascular system is beginning to shed light on this subject and is at the centre of this brief review.