Showing papers in "Nature Medicine in 2011"
TL;DR: Findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
Abstract: Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics) We investigated whether metabolite profiles could predict the development of diabetes Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS) Cases and controls were matched for age, body mass index and fasting glucose Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile) The results were replicated in an independent, prospective cohort These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment
2,487 citations
TL;DR: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea as discussed by the authors.
Abstract: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.
2,368 citations
TL;DR: It is established that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity, and that the NlrP3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.
Abstract: Obesity is generally considered an inflammatory state. Vishwa Dixit and his colleagues have now shown that excess dietary lipids leads to the activation of the Nlrp3 inflammasome, a sensor of the innate immune system, and that its genetic deficiency results in decreased inflammation and improved insulin sensitivity. These results suggest a possible new therapeutic avenue to treat the effects of obesity.
2,000 citations
TL;DR: Gaining a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.
Abstract: Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.
1,949 citations
TL;DR: This work aims to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.
Abstract: Coronary artery disease (CAD) arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human CAD. The growing understanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. Here we aim to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.
1,834 citations
TL;DR: This review attempts to summarize the underlying concepts of the notion that tumors are maintained by their own stem cells, to distinguish hard facts from beliefs and to define the future challenges of the field.
Abstract: Over the last decade, the notion that tumors are maintained by their own stem cells, the so-called cancer stem cells, has created great excitement in the research community. This review attempts to summarize the underlying concepts of this notion, to distinguish hard facts from beliefs and to define the future challenges of the field.
1,753 citations
TL;DR: It is shown that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities, and adipocytes provide fatty acids for rapid tumor growth.
Abstract: Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.
1,665 citations
TL;DR: A long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells is described.
Abstract: Immunological memory is thought to depend on a stem cell–like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells. These cells, specific to multiple viral and self-tumor antigens, were found within a CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+ and IL-7Rα+ T cell compartment characteristic of naive T cells. However, they expressed large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and showed numerous functional attributes distinctive of memory cells. Compared with known memory populations, these lymphocytes had increased proliferative capacity and more efficiently reconstituted immunodeficient hosts, and they mediated superior antitumor responses in a humanized mouse model. The identification of a human stem cell–like memory T cell population is of direct relevance to the design of vaccines and T cell therapies.
1,526 citations
TL;DR: A durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment.
Abstract: As angiogenesis is essential for tumor growth and metastasis, controlling tumor-associated angiogenesis is a promising tactic in limiting cancer progression. The tumor microenvironment comprises numerous signaling molecules and pathways that influence the angiogenic response. Understanding how these components functionally interact as angiogenic stimuli or as repressors and how mechanisms of resistance arise is required for the identification of new therapeutic strategies. Achieving a durable and efficient antiangiogenic response will require approaches to simultaneously or sequentially target multiple aspects of the tumor microenvironment.
1,512 citations
TL;DR: It is found that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells.
Abstract: Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.
1,478 citations
TL;DR: In patients with ovarian cancer, intraoperative tumor-specific fluorescence imaging with an FR-α–targeted fluorescent agent showcased the potential applications in patients with Ovarian cancer for improved intraoperative staging and more radical cytoreductive surgery.
Abstract: The prognosis for patients with advanced stage ovarian cancer is poor. Here, Gooitzen van Dam and colleagues demonstrate the first human application of a tumor-specific intraoperative fluorescence imaging methodology using a folate receptor-α (FR-α)-targeted fluorescent agent that exploits the overexpression of FR-α in the majority of epithelial ovarian cancers. It is hoped this approach may lead to improved intraoperative staging and more radical cytoreductive surgery.
TL;DR: It is shown that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice, and Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.
Abstract: Elevated triglyceride levels often occur in obesity and can contribute to cardiovascular disease. Brown adipose tissue (BAT) is known to burn fat, and now Joerg Heeren and his colleagues show that BAT actively takes up triglycerides in cold conditions, suggesting a possible therapy to lower triglyceride levels in states of obesity. Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold1,2 and has recently been shown to be present in humans3,4,5. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL)6. Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver6. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease7,8,9,10,11. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.
TL;DR: Three PDA subtypes are defined: classical, quasimesenchymal and exocrine-like, and evidence for clinical outcome and therapeutic response differences between them is presented, and gene signatures for these subtypes that may have utility in stratifying patients for treatment are defined.
Abstract: Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast and lung cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.
TL;DR: How normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state are reviewed.
Abstract: Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.
TL;DR: This study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR -34a as a novel therapeutic agent against prostate CSCs.
Abstract: Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.
TL;DR: The discovery of mutations in the epigenetic machinery and the approval of the first epigenetic drugs for the treatment of subtypes of leukemias and lymphomas has been an eye-opener for many biomedical scientists and clinicians.
Abstract: Epigenetics is one of the most promising and expanding fields in the current biomedical research landscape. Since the inception of epigenetics in the 1940s, the discoveries regarding its implications in normal and disease biology have not stopped, compiling a vast amount of knowledge in the past decade. The field has moved from just one recognized marker, DNA methylation, to a variety of others, including a wide spectrum of histone modifications. From the methodological standpoint, the successful initial single gene candidate approaches have been complemented by the current comprehensive epigenomic approaches that allow the interrogation of genomes to search for translational applications in an unbiased manner. Most important, the discovery of mutations in the epigenetic machinery and the approval of the first epigenetic drugs for the treatment of subtypes of leukemias and lymphomas has been an eye-opener for many biomedical scientists and clinicians. Herein, we will summarize the progress in the field of cancer epigenetics research that has reached mainstream oncology in the development of new biomarkers of the disease and new pharmacological strategies.
TL;DR: It is demonstrated that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively.
Abstract: To date, the dogma in the field has been that RANKL, an essential cytokine in osteoclast maturation, is released by osteoblasts as a way to coordinate bone growth and bone loss during adult bone remodeling. Now, Hiroshi Takayanagi and colleagues, as well as Charles O'Brien and colleagues, have independently found that osteocytes are the predominant source of RANKL in the adult mouse. As RANKL signaling is a key target in treating osteoporosis, these results have potentially important implications for disease management.
TL;DR: It is shown that miR-1 is overexpression in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis and is a potential antiarrhythmic target.
Abstract: MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K(+) channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.
TL;DR: A population of Foxp3+Blimp-1+CD4+ T cells constituting 10–25% of the CXCR5highPD-1highCD4- T cells found in the germinal center after immunization with protein antigens are described.
Abstract: Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.
TL;DR: Joseph Goldstein has written in this journal that creation (through invention) and revelation (through discovery) are two different routes to advancement in the biomedical sciences.
Abstract: Joseph Goldstein has written in this journal that creation (through invention) and revelation (through discovery) are two different routes to advancement in the biomedical sciences1. In my work as a phytochemist, particularly during the period from the late 1960s to the 1980s, I have been fortunate enough to travel both routes. I graduated from the Beijing Medical University School of Pharmacy in 1955. Since then, I have been involved in research on Chinese herbal medicine in the China Academy of Chinese Medical Sciences (previously known as the Academy of Traditional Chinese Medicine). From 1959 to 1962, I was released from work to participate in a training course in Chinese medicine that was especially designed for professionals with backgrounds in Western medicine. The 2.5-year training guided me to the wonderful treasure to be found in Chinese medicine and toward understanding the beauty in the philosophical thinking that underlies a holistic view of human beings and the universe.
TL;DR: Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat neurological conditions such as aneurismal subarachnoid hemorrhage or traumatic brain injury.
Abstract: Brain injury, subarachnoid hemorrhage and the subsequent delayed ischemic stroke show spreading depolarization of neurons in the tissue at risk, where it leads to spreading ischemia, vasoconstriction and brain electrical silencing, exacerbating damage and thwarting recovery. Jens Dreier reviews the underlying molecular mechanisms and the potential use for clinical diagnosis and therapies aimed at blocking spreading depolarization and boosting vasodilation to treat neurological disease.
TL;DR: A Bcl-6-CXCR5 axis in Treg cells that drives the development of follicular regulatory T (TFR) cells that function to inhibit the germinal center reactions is unveiled.
Abstract: Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T(reg) cells depends on Bcl-6. These CXCR5(+)Bcl-6(+) T(reg) cells are absent in the thymus but can be generated de novo from CXCR5(-)Foxp3(+) natural T(reg) precursors. A lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T(reg) cells that drives the development of follicular regulatory T (T(FR)) cells that function to inhibit the germinal center reactions.
TL;DR: It is shown that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.
Abstract: Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.
TL;DR: The results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.
Abstract: Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.
TL;DR: It is reported that tumor engraftment is a prognostic indicator of disease outcome for women with newly diagnosed breast cancer and orthotopic breast tumor grafting is a step toward individualized models for tumor growth, metastasis and prognosis.
Abstract: By implementing the conditions for orthotopic implantation of different types of human breast tumors, the authors have created a publicly available bank of new mouse models that more faithfully recreate individual tumor properties and provide individualized information about tumor behavior and prognosis.
TL;DR: A new type of molecular-targeted cancer therapy, photoimmunotherapy (PIT), that uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (mAbs) targeting epidermal growth factor receptors is developed.
Abstract: Makoto Mitsunaga et al. have developed a new form of molecular-targeted cancer therapy that provides an alternative to current photodynamic approaches where damage to surrounding healthy cells and tissues can be a problem. They use a target-specific photosensitizer based on a near-infrared phthalocyanine dye, which is conjugated to monoclonal antibodies targeting human epidermal growth factor receptors (HER1 and HER2). Selective treatment using this approach was shown in vivo in subcutaneous cancer xenografts in mice.
TL;DR: This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.
Abstract: Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.
TL;DR: Observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.
Abstract: The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)--independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.
TL;DR: Findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix protein of stem cell niches of the metastatic niche.
Abstract: Tenascin C is an extracellular matrix protein previously linked to breast cancer metastasis. Here the authors uncover how tenascin C promotes the fitness of metastasis-initiating cells by sustaining the stem and survival signaling pathways NOTCH and Wnt through specific regulation of Msi1 and Lgr5, respectively.
TL;DR: It is reported that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases, and that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation.
Abstract: Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β(3) integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-β(3) integrin interaction through antibodies and small molecules targeting either uPAR or β(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.