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41.
Triantafyllos Stylianopoulos John D. Martin Vikash P. Chauhan Saloni R. Jain Benjamin Diop-Frimpong Nabeel Bardeesy Barbara L. Smith Cristina R. Ferrone Francis J. Hornicek Yves Boucher Lance L. Munn Rakesh K. Jain 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(38):15101-15108
The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs. 相似文献
42.
Ravishankar B Liu H Shinde R Chandler P Baban B Tanaka M Munn DH Mellor AL Karlsson MC McGaha TL 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(10):3909-3914
Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169(+) cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL(lpr/lpr) mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease. 相似文献
43.
Human papillomavirus (HPV) infections have received considerable attention in recent years. Of the 120 or so known types of the virus, some cause a variety of benign wart‐like lesions of the skin and genital and oral mucosae, whilst others are aetiologically associated with cervical and anogenital cancers. Recent epidemiologic evidence suggests that HPV may also be an independent risk factor for oropharyngeal cancer. In this context it has been suggested that HPV virus may modulate the process of carcinogenesis in some tobacco and alcohol induced oropharyngeal cancers and act as the primary oncogenic agent for inducing carcinogenesis among non‐smokers. Dental practitioners have a major role in detecting all lesions of the oral mucosa caused, or possibly caused, by HPV. This paper briefly reviews the current state of knowledge of molecular and clinical aspects of HPV infections of the oral mucosa. 相似文献
44.
Paras Kumar Mohanlal Nemandra Sandiford John A Skinner SR Samsani 《Indian Journal of Orthopaedics》2013,47(1):63-66
Background:
Bleeding during total knee arthroplasty (TKA) can cause significant morbidity and mortality. One proposed benefit of computer assisted TKA is decreased bleeding as the femoral canal is not invaded. This study assessed blood loss between computer assisted surgery (CAS) and conventional TKA.Materials and Methods:
73 consecutive patients (37 males, 36 females) underwent primary TKA between 2006 and 2009. Thirty eight patients underwent navigated TKA and 35 underwent conventional TKA for symptomatic osteoarthritis of the knee. These patients were matched for age, gender, and body mass index (BMI). Average age was 70.3 years (range 47-91 years). Mean BMI was 30 (range 17-49). Average preoperative hemoglobin was 13.26 g/dL (range 8.7-18.4 g/dL) in the navigated group and 13.47 g/dL (range 9.6-15.8 g/dL) in the conventional group (P = 0.9). Average tourniquet time was 110 min (range 90-150 min) in the navigated group and 96.7 min (range 60-145 min) in the conventional group (P = 0.77).Results:
Average postoperative hemoglobin in the navigated group was 10.34 g/dL (range 7.5-14.8 g/dL) and in the conventional group was 10.03 g/dL (range 7.5-12.2 g/dL) (P = 0.17). Six patients in both groups required blood transfusions. The mean drain collection was 599 mL (range 150-1370 mL) in the navigated group and 562 mL (range 750-1000 mL) in the conventional group (P = 0.1724). These results suggest that there is no significant reduction in blood loss in CAS TKA.Conclusion:
These results suggest that there is no significant difference in blood loss in CAS TKA and conventional TKA. This study also highlights the heterogeneity of methods used in studies related to CAS TKA. We believe that there is a need for a large multicenter prospective randomized controlled trial to be performed before a consensus can be reached on the influence of CAS techniques on blood loss during primary TKA. 相似文献45.
46.
47.
Manlapat AK Kahler DJ Chandler PR Munn DH Mellor AL 《European journal of immunology》2007,37(4):1064-1071
Following CD80/86 (B7) and TLR9 ligation, small subsets of splenic dendritic cells expressing CD19 (CD19(+) DC) acquire potent T cell regulatory functions due to induced expression of the intracellular enzyme indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan. In CD19(+) DC, IFN type I (IFN-alpha) is the obligate inducer of IDO. We now report that IFN-alpha production needed to stimulate high-level expression of IDO following B7 ligation is itself dependent on basal levels of IDO activity. Genetic and pharmacologic ablation of IDO completely abrogated IFN-alpha production by CD19(+) DC after B7 ligation. In contrast, IDO ablation did not block IFN-alpha production by CD19(+) DC after TLR9 ligation. IDO-mediated control of IFN-alpha production depended on tryptophan depletion as adding excess tryptophan also blocked IFN-alpha expression after B7 ligation. Consistent with this, DC from mice deficient in general control of non-derepressible-2 (GCN2)-kinase, a component of the cellular stress response to amino acid withdrawal, did not produce IFN-alpha following B7 ligation, but produced IFN-alpha after TLR9 ligation. Thus, B7 and TLR9 ligands stimulate IFN-alpha expression in CD19(+) DC via distinct signaling pathways. In the case of B7 ligation, IDO activates cell-autonomous signals essential for IFN-alpha production, most likely by activating the GCN2-kinase-dependent stress response. 相似文献
48.
49.
Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice 下载免费PDF全文
Nicole L. Baganz Rebecca E. Horton Alfredo S. Calderon W. Anthony Owens Jaclyn L. Munn Lora T. Watts Nina Koldzic-Zivanovic Nathaniel A. Jeske Wouter Koek Glenn M. Toney Lynette C. Daws 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(48):18976-18981
Mood disorders cause much suffering and are the single greatest cause of lost productivity worldwide. Although multiple medications, along with behavioral therapies, have proven effective for some individuals, millions of people lack an effective therapeutic option. A common serotonin (5-HT) transporter (5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression in vivo and elevates risk for multiple mood disorders including anxiety, alcoholism, and major depression. Importantly, this variant is also associated with reduced responsiveness to selective 5-HT reuptake inhibitor antidepressants. We hypothesized that a reduced antidepressant response in individuals with a constitutive reduction in 5-HTT expression could arise because of the compensatory expression of other genes that inactivate 5-HT in the brain. A functionally upregulated alternate transporter for 5-HT may prevent extracellular 5-HT from rising to levels sufficiently high enough to trigger the adaptive neurochemical events necessary for therapeutic benefit. Here we demonstrate that expression of the organic cation transporter type 3 (OCT3, SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22 diminishes 5-HT clearance and exerts antidepressant-like effects in these mice but not in WT animals. OCT3 may be an important transporter mediating serotonergic signaling when 5-HTT expression or function is compromised. 相似文献
50.
The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable. 相似文献