Leiomyosarcomas are malignant mesenchymal tumours that derive from the smooth muscle lineage. They are studied and frequently treated as if they are the same as other soft tissue sarcomas. Recent developments suggest that a different approach may be more appropriate. Their underlying genetic mechanisms remain unclear, and complex. Unbalanced karyotypic defects are the only shared features observed across different leiomyosarcoma subtypes. Unlike other soft tissue sarcomas, leiomyosarcomas are particularly sensitive to the combination of gemcitabine and docetaxel. Furthermore, treatment with trabectedin has shown a good efficacy in leiomyosarcomas, mainly in the form of chronic disease stabilisation.
The molecular and genetic mechanisms in most patients with inherited platelet dysfunction are unknown. There is increasing evidence that mutations in hematopoietic transcription factors are major players in the pathogenesis of defective megakaryopoiesis and platelet dysfunction in patients with inherited platelet disorders. These hematopoietic transcription factors include RUNX1, FLI1, GATA-1, and GFI1B. Mutations involving these transcription factors affect diverse aspects of platelet production and function at the genetic and molecular levels, culminating in clinical manifestations of thrombocytopenia and platelet dysfunction. This review focuses on these hematopoietic transcription factors in the pathobiology of inherited platelet dysfunction.
Significant progress in our understanding of Crohn's disease (CD), an archetypal common, complex disease, has now been achieved. Our ability to interrogate the deep complexities of the biological processes involved in maintaining gut mucosal homeostasis is a major over-riding factor underpinning this rapid progress. Key studies now offer many novel and expansive insights into the interacting roles of genetic susceptibility, immune function, and the gut microbiota in CD. Here, we provide overviews of these recent advances and new mechanistic themes, and address the challenges and prospects for translation from concept to clinic.
Pre-eclampsia complicates around 5% of pregnancies and hypertensive disorders of pregnancy are responsible for over 60,000 maternal deaths worldwide annually. Pre-eclampsia is characterized by hypertension and features of multiple organ disease. Diagnosis remains a challenge as clinical presentation is highly variable and even with severe disease a woman can be asymptomatic. Pre-eclampsia is characterized by abnormal placentation with subsequent maternal inflammatory and vascular response. Improved understanding of the underlying pathophysiology relating to the role of angiogenic factors, has emerged and placed intense interest on their role in prognostic modelling or diagnosis of pre-eclampsia. This article summarizes new developments in diagnosis with a focus on angiogenic biomarkers for prediction of disease onset, and recent advances in management strategies for patients with pre-eclampsia.
As mitochondria are the powerhouses of the cell, their damage during the cell suicide process of apoptosis is essentially responsible for cellular demise in most cells. A key family of proteins, the B-cell lymphoma-2 (BCL-2) family, determines the integrity of mitochondria in the face of apoptotic insult. A comprehensive understanding of the molecular details of how apoptosis is initiated and how it culminates is essential if apoptosis is to fulfil its undoubted potential as a therapeutic target to treat diseases ranging from cancer to neurodegenerative conditions. Recent advances have provided significant insight into the control of this fundamental process while prompting a re-evaluation of what was considered dogma in the field. Emerging evidence also points to a potential overarching control network that governs not only apoptosis but other fundamental mitochondrial processes, including mitochondrial fission/fusion and quality control.
The phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling network is a master regulator of processes that contribute to tumorigenesis and tumor maintenance. The PI3K pathway also plays a critical role in driving resistance to diverse anti-cancer therapies. This review article focuses on mechanisms by which the PI3K pathway contributes to therapy resistance in cancer, and highlights potential combination therapy strategies to circumvent resistance driven by PI3K signaling. In addition, resistance mechanisms that limit the clinical efficacy of small molecule inhibitors of the PI3K pathway are discussed.
Embryonic cell migration patterns are amazingly complex in the timing and spatial distribution of cells throughout the vertebrate landscape. However, advances in in vivo visualization, cell interrogation, and computational modeling are extracting critical features that underlie the mechanistic nature of these patterns. The focus of this review highlights recent advances in the study of the highly invasive neural crest cells and their migratory patterns during embryonic development. We discuss these advances within three major themes and include a description of computational models that have emerged to more rapidly integrate and test hypothetical mechanisms of neural crest migration. We conclude with technological advances that promise to reveal new insights and help translate results to human neural crest-related birth defects and metastatic cancer.
Menstrual disorders are a major reason for gynaecological consultations worldwide and, unfortunately there are many different definitions and classifications of this condition. Clear definitions and terminology are necessary for scientific literature, particularly for clinicians, and for clinical trials comparing two treatments. The International Federation of Gynaecology and Obstetrics (FIGO) Menstrual Disorders Working Group has proposed abandoning the use of one common term, dysfunctional uterine bleeding (DUB), while continuing to use the terms abnormal uterine bleeding (AUB) and heavy menstrual bleeding (HMB). Furthermore, the group issued the PALM-COEIN classification system for menstrual disorders, which has quickly been adopted around the world. The PALM-COEIN system allows clinicians and researchers to identify and classify women with both AUB and HMB in a systematic manner, provides reliable information for research purposes and for epidemiological and prevalence studies in different settings, and supports accurate diagnoses and treatment. Additionally, this classification system is useful for selecting treatments appropriate for different stages of women's reproductive years and for different patterns of menstrual bleeding. Among the proposed treatments are the use of combined oral contraceptives, the levonorgestrel-releasing intrauterine system, tranexamic acid, mefenamic acid, and other nonsteroidal anti-inflammatory drugs (NSAIDs).
Over the last few decades, our understanding of directed cell growth in different organisms has substantially improved. Tip-growing cells in plants elongate rapidly via targeted deposition of cell wall and membrane material at the cell apex, and use turgor pressure as a driving force for expansion. This type of polar growth requires a high degree of coordination between a plethora of cellular and extracellular components and compounds, including calcium dynamics, apoplastic reactive oxygen species and pH, the cytoskeleton, and vesicular trafficking. In this review, we attempt to outline and summarize the factors that control root hair growth and how they work together as a team.
Overlooked for decades, antibodies have taken center stage in renal transplantation and are now widely recognized as the first cause of allograft failure. Diagnosis of antibody-mediated rejection has considerably improved with identification of antibody-mediated lesions in graft biopsies and advances made in the detection of circulating donor-specific antibodies. Unfortunately, this progress has not yet translated into better outcomes for patients. Indeed, in the absence of a drug able to suppress antibody generation by plasma cells, available therapies can only slow down graft destruction. This review provides an overview of the current knowledge of antibody-mediated rejection and discusses future interesting research directions.
Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNΔ7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value.
Food allergy is a common problem in childhood. The term is used to include both immunoglobulin E (IgE)-mediated and non-IgE-mediated food allergies, which have a significant effect on the quality of life of patients and their families. In this report, we aim to discuss recent advances in the diagnosis, management, and treatment modalities of food allergy in children.
Memory CD8 T cells generated after acute viral infections or live vaccines can persist for extended periods, in some instances for life, and play an important role in protective immunity. This long-lived immunity is achieved in part through cytokine-mediated homeostatic proliferation of memory T cells while maintaining the acquired capacity for rapid recall of effector cytokines and cytolytic molecules. The ability of memory CD8 T cells to retain their acquired properties, including their ability to remain poised to recall effector functions, is a truly impressive feat given that these acquired properties can be maintained for decades without exposure to cognate antigen. Here, we discuss general mechanisms for acquisition and maintenance of transcriptional programs in memory CD8 T cells and the potential role of epigenetic programming in maintaining the phenotypic and functional heterogeneity of cellular subsets among the pool of memory cells.
Our current understanding of glucose homeostasis is centered on glucose-induced secretion of insulin from pancreatic islets and insulin action on glucose metabolism in peripheral tissues. In addition, however, recent evidence suggests that neurocircuits located within a brain-centered glucoregulatory system work cooperatively with pancreatic islets to promote glucose homeostasis. Among key observations is evidence that, in addition to insulin-dependent mechanisms, the brain has the capacity to potently lower blood glucose levels via mechanisms that are insulin-independent, some of which are activated by signals emanating from the gastrointestinal tract. This review highlights evidence supporting a key role for a "gut-brain-liver axis" in control of glucose homeostasis by the brain-centered glucoregulatory system and the implications of this regulatory system for diabetes pathogenesis and treatment.
In development and disease, vascular endothelial growth factor (VEGF) regulates the expansion of the vascular tree. In response to hypoxia, VEGF promotes new capillary formation through the process of angiogenesis by inducing endothelial cell sprouting, proliferation, and migration. Wound healing, tissue regeneration, and tumor growth depend on angiogenesis for adequate nutrient and oxygen delivery. Under different conditions, VEGF promotes arterial growth, modulates lumen expansion, and induces collateral vessel formation, events collectively referred to as arteriogenesis. Induction of arteriogenesis after cardiac or cerebral arterial occlusion can reduce ischemia and improve disease outcome. Endothelial VEGF receptor 2 (VEGFR2) signaling governs both processes. However, modulation of downstream VEGF signaling effectors, such as extracellular-signal-regulated kinase (ERK) activation, differs in order to achieve angiogenic versus arteriogenic outcomes. Recent reports show that neuropilin 1 (NRP1), a VEGF receptor, can instill VEGF signaling outcomes that specifically regulate either angiogenesis or arteriogenesis. Here, we discuss how NRP1 functions as a VEGFR2 co-receptor in angiogenesis and a modulator of VEGFR2 trafficking in arteriogenesis. The unique role played by neuropilin in different endothelial processes makes it an exciting therapeutic target to specifically enhance angiogenesis or arteriogenesis in disease settings.
Drug-induced liver injury (DILI) is a potentially fatal adverse event with significant medical and economic impact. Many drugs, especially anti-infective, neurologic or pain-modifying substances, act as hepatotoxins. With cardiovascular toxicity, liver toxicity is one of the two leading causes for drug withdrawal from the market. The liver can be affected directly, in a predictable and dose-dependent manner, or idiosyncratically, independent of the dose and therefore unpredictable. Currently DILI is a diagnosis of exclusion that physicians have to bear in mind in patients with an unexplained increase of liver enzymes. The type of injury is categorized into hepatocellular, cholestatic, or mixed by the respective enzyme pattern of injury. Symptoms of affected patients can mimic any other liver disease. Therefore, new diagnostic and prognostic biomarkers for early liver injury are currently being evaluated in multi-centre clinical trials that are conducted by international consortia and other initiatives. Pharmacogenetic testing, next-generation sequencing, proteomics, metabolomics and mechanistic markers can help to preselect susceptible patient populations and tailor drug therapy to individual patients. Proposed DILI indicators that are under investigation include microRNAs, cytokeratin-18 (CK18), high mobility group box protein 1 (HMGB-1), and several other biomarkers. These developments can change clinical practice, and improve patients' safety and management. However, they have not been translated into clinical practice or approved for routine use yet. Management of DILI usually consists of initial withdrawal of the suspected drug and—if applicable—administration of specific antidotes, such as N-acetylcysteine. However, the overall management of DILI could change in the near future with the advent of novel diagnostic and prognostic DILI markers.
Alzheimer's disease (AD), the leading cause of dementia, has reached epidemic proportions, with major social, medical and economical burdens. With no currently available curative treatments, both the World Health Organization and the G8 Dementia Summit recently identified dementia and AD prevention as a major public health priority. Dementia and AD have a wide range of risk factors (genetic, vascular/metabolic and lifestyle-related), which often co-occur and thus interact with each other. Previous intervention efforts aimed at preventing dementia and AD focused on the management of single risk factors, with relatively modest findings. Also, the effect of risk factors depends on age at exposure, indicating that the timing of preventive interventions needs to be carefully considered. In view of the complex multifactorial nature of AD, as well as its long pre-clinical (asymptomatic) phase, interventions simultaneously targeting multiple risk factors and disease mechanisms at an early stage of the disease are most likely to be effective. Three large European multidomain prevention trials have been launched with the goal of preventing cognitive decline, dementia and AD in older adults with different risk profiles. Pharmacological trials are also shifting towards prevention of Alzheimer dementia, by targeting at-risk individuals prior to the onset of cognitive symptoms. The current review will summarize and discuss the evidence on risk and protective factors from observational studies, ongoing lifestyle-related and pharmacological randomized controlled trials (RCTs), as well as future directions for dementia and AD prevention.
Basal cell carcinoma (BCC), a malignant neoplasm derived from non-keratinizing cells that originate in the basal layer of the epidermis, is the most common cancer in humans. Several factors such as anatomic location, histologic features, primary or recurrent tumors, and patient characteristics influence the choice of treatment modality for BCC. Mohs micrographic surgery (MMS) facilitates optimal margin control and conservation of normal tissue for the management of BCC; however, other treatment modalities may also be implemented in the correct clinical scenario. Other treatment modalities that will be reviewed include simple excision, electrodesiccation and curettage, cryotherapy, topical immunotherapy and chemotherapy, photodynamic therapy, and radiation therapy. In addition, targeted molecular therapeutic options for the treatment of advanced or metastatic BCC will be discussed in this informal review based on recent literature obtained by using PubMed with relevant search terms.
Despite recent advances in delineating the pathogenic mechanisms of autoimmune disease, the puzzle that reveals the true picture of these diverse immunological disorders is yet to be solved. We know that the human leukocyte antigen (HLA) loci as well as many different genetic susceptibility loci with relatively small effect sizes predispose to various autoimmune diseases and that environmental factors are involved in triggering disease. Models for mechanisms of disease become increasingly complex as relationships between components of both the adaptive and innate immune systems are untangled at the molecular level. In this article, we pose some of the important questions about autoimmunity where the answers will advance our understanding of disease pathogenesis and improve the rational design of novel therapies. How is autoimmunity triggered, and what components of the immune response drive the clinical manifestations of disease? What determines whether a genetically predisposed individual will develop an autoimmune disease? Is restoring immune tolerance the secret to finding cures for autoimmune disease? Current research efforts seek answers to these big questions.
The potential of the systemic antifungal treatment of non-immunocompromised patients with sepsis, extra-digestive Candida colonization and multiple organ failure is unknown, although it represents three out of four antifungal treatments prescribed in intensive care units. It may allow an early treatment of invasive fungal infection at incubation phase, but exposes patients to unnecessary antifungal treatments with subsequent costs and antifungal selection pressure. As early diagnostic tests for invasive candidiasis are still considered insufficient, the potential of this strategy needs to be demonstrated by a randomized controlled trial. Such a trial is currently ongoing.
