Over the past decade, the treatment landscape for patients with metastatic renal cell carcinoma (RCC) has evolved dramatically. The therapeutic options available have expanded and now include ...immune-checkpoint inhibitors, novel targeted agents and combination strategies, and thus optimal patient selection and treatment sequencing are increasingly pertinent for optimizing clinical outcomes. A better understanding of the underlying biology of the tumour and its microenvironment continues to drive the inception of new diagnostic and therapeutic approaches. Furthermore, many biomarkers robustly associated with treatment and disease-specific outcomes have been identified, and their integration into clinical decision-making for patients with advanced-stage disease will soon become a reality. Herein, we review relevant aspects of the molecular biology of metastatic RCC, with an emphasis on predictive and prognostic biomarkers, and suggest tailored algorithms to individualize and guide treatment approaches for specific subgroups of patients.
Adopting the framework of brain dynamics as a cornerstone of human consciousness, we determined whether dynamic signal coordination provides specific and generalizable patterns pertaining to ...conscious and unconscious states after brain damage. A dynamic pattern of coordinated and anticoordinated functional magnetic resonance imaging signals characterized healthy individuals and minimally conscious patients. The brains of unresponsive patients showed primarily a pattern of low interareal phase coherence mainly mediated by structural connectivity, and had smaller chances to transition between patterns. The complex pattern was further corroborated in patients with covert cognition, who could perform neuroimaging mental imagery tasks, validating this pattern's implication in consciousness. Anesthesia increased the probability of the less complex pattern to equal levels, validating its implication in unconsciousness. Our results establish that consciousness rests on the brain's ability to sustain rich brain dynamics and pave the way for determining specific and generalizable fingerprints of conscious and unconscious states.
There is considerable interest in therapeutic transfer of regulatory T cells (Tregs) for controlling aberrant immune responses. Initial clinical trials have shown the safety of Tregs in hematopoietic ...stem cell transplant recipients and subjects with juvenile diabetes. Our hypothesis is that infusion(s) of Tregs may induce transplant tolerance thus avoiding long-term use of toxic immunosuppressive agents that cause increased morbidity/mortality. Towards testing our hypothesis, we conducted a phase I dose escalation safety trial infusing billions of ex vivo expanded recipient polyclonal Tregs into living donor kidney transplant recipients. Despite variability in recipient's renal disease, our expansion protocol produced Tregs which met all release criteria, expressing >98% CD4
CD25
with <1% CD8
and CD19
contamination. Our product displayed >80% FOXP3 expression with stable demethylation in the FOXP3 promoter. Functionally, expanded Tregs potently suppressed allogeneic responses and induced the generation of new Tregs in the recipient's allo-responders in vitro. Within recipients, expanded Tregs amplified circulating Treg levels in a sustained manner. Clinically, all doses of Treg therapy tested were safe with no adverse infusion related side effects, infections or rejection events up to two years post-transplant. This study provides the necessary safety data to advance Treg cell therapy to phase II efficacy trials.
Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as ...the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types.
We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8
T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number.
Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.
Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic ...alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the
gene (
= 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies (
= 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and
-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways.
loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
Reduced height (Rht) genes are used in wheat (Triticum aestivum L.) breeding throughout the world. Fusarium head blight (FHB) is one of the most destructive wheat diseases caused by Fusarium ...graminearum (Schwabe) and F. culmorum (W.G. Sm.) Sacc. Objectives of this study were to analyze the effects of (i) specific Rht dwarfing genes on FHB reaction using two sets of near-isogenic lines (NILs) and (ii) genetic background and environment on FHB reaction. We inoculated NILs carrying Rht-B1b, Rht-B1d, Rht-D1b, Rht8c, and Rht-D1b+Rht8c in the background of the British winter wheat cultivar Mercia possessing medium height and moderate resistance, and NILs carrying Rht-B1b, Rht-B1c, Rht-D1b and Rht-B1b+Rht-D1b in the background of the rather tall, generally more resistant British cultivar Maris Huntsman, as well as three German check cultivars ('Toras', 'Certo', 'Travix') carrying the Rht-D1b allele. Entries were tested in eight (Mercia) and four (Maris Huntsman) environments, respectively, by inoculation with F. culmorum. In the Mercia data set, Rht-B1d and Rht-D1b significantly increased mean FHB rating by 35 and 52%, respectively. Rht-B1b and Rht8c increased FHB rating only by 19%, being not significantly different to the wild-type line (rht). Rht8c affected heading date due to its linkage with the photoperiod insensitive Ppd1 allele. In the Maris Huntsman data set, FHB rating was increased by 22 to 83%, but only the very short Rht-B1c and Rht-B1b+Rht-D1b lines showed significance. Although the mutant Rht alleles increased FHB susceptibility, the checks show that these negative effects can be largely counteracted by a more resistant genetic background.
Lessons Learned
Our results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from preclinical models.
Because of toxicity and lack of ...efficacy, BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma.
Background.
Allosteric inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) are approved for advanced renal cell carcinoma (RCC). Preclinical models have suggested that dual inhibition of phosphatidylinositol 3‐kinase (PI3K) and mTOR kinase may establish superior anticancer effect. We aimed to establish safety for BEZ235, a potent inhibitor of both PI3K and mTOR, in advanced RCC.
Methods.
Patients with advanced RCC who had previously failed standard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity. Primary endpoints were to identify the maximally tolerated dose (MTD) and to determine the recommended dose for the phase II study.
Results.
The study was terminated early because of high incidence of dose‐limiting toxicities (DLTs) across all dose levels tested. Ten patients were treated with BEZ235—six with clear cell and four with non‐clear cell subtypes. Five of these patients suffered DLTs: 2 of 2 patients in the original 400 mg b.i.d. cohort, 1 of 6 in the 200 mg b.i.d. cohort, and 2 of 2 in the 300 mg b.i.d. cohort. DLTs included fatigue, rash, nausea and vomiting, diarrhea, mucositis, anorexia, and dysgeusia. Five patients were evaluable for response: Two had stable disease as best response, and three had progressive disease.
Conclusion.
BEZ235 twice daily resulted in significant toxicity without objective responses; further development of this compound will not be pursued in this disease.
作者总结
经验
• 本研究结果强调了PI3K/mTOR双重抑制在临床环境中的额外毒性, 而在临床前模型中并未预见到这种毒性。
• 鉴于当前配方BEZ235具有毒性又缺乏有效性, 不应在肾细胞癌患者中开展进一步研究。
摘要
背景. 哺乳动物雷帕霉素靶蛋白复合物1 (mTORC1) 变构抑制剂获批用于治疗晚期肾细胞癌 (RCC)。临床前模型提示对磷脂酰肌醇3激酶 (PI3K) 和mTOR激酶的双重抑制可能产生更好的抗癌作用。本研究旨在确定强效PI3K和mTOR抑制剂BEZ235在晚期RCC患者中的安全性。
方法. 本研究对象为标准治疗失败的晚期RCC患者, 每日两次给予剂量递增的BEZ235微囊制剂治疗, 直至发生疾病进展或不可接受的毒性事件。主要终点为确定最大耐受剂量 (MTD) 以及决定II期研究的建议剂量。
结果. 本研究因剂量限制毒性 (DLT) 发生率高而提早终止。10例患者接受了BEZ235治疗, 其中6例为透明细胞癌亚型, 4例为非透明细胞癌亚型。5例患者发生DLT, 包括起始400 mg BID组的2/2例患者、200 mg BID组的1/6例患者, 以及300 mg BID组的2/2例患者。DLT包括疲劳、皮疹、恶心与呕吐、腹泻、黏膜炎、纳差以及味觉异常。5例患者可评价治疗反应, 其中2例患者的最佳治疗反应为疾病稳定, 3例发生疾病进展。
结论. BEZ235每日两次给药方案导致了明显的毒性, 并且未观察到客观缓解, 不建议在晚期RCC患者中对该化合物开展进一步研究。The Oncologist 2016;21:787–788d
It is well known that every planar graph contains a vertex of degree at most 5. A theorem of Kotzig states that every 3-connected planar graph contains an edge whose endvertices have degree-sum at ...most 13. Fabrici and Jendrol’ proved that every 3-connected planar graph G that contains a k-vertex path contains also a k-vertex path P such that every vertex of P has degree at most 5k. A result by Enomoto and Ota says that every 3-connected planar graph G of order at least k contains a connected subgraph H of order k such that the degree sum of vertices of H in G is at most 8k−1. Motivated by these results, a concept of light graphs has been introduced. A graph H is said to be light in a family G of graphs if at least one member of G contains a copy of H and there is an integer w(H,G) such that each member G of G with a copy of H also has a copy K of H such that ∑v∈V(K)degG(v)≤w(H,G).
In this paper we present a survey of results on light graphs in different families of plane graphs and multigraphs. A similar survey dealing with the family of all graphs embedded in surfaces other than the sphere was prepared as well.
Metastasis remains the main reason for renal cell carcinoma (RCC)-associated mortality. Tyrosine kinase inhibitors (TKI) impart clinical benefit for most patients with RCC, but the determinants of ...response are poorly understood. We report an integrated genomic and transcriptomic analysis of patients with metastatic clear cell RCC (ccRCC) treated with TKI therapy and identify predictors of response. Patients in the COMPARZ phase III trial received first-line sunitinib or pazopanib with comparable efficacy. RNA-based analyses revealed four distinct molecular subgroups associated with response and survival. Characterization of these subgroups identified mutation profiles, angiogenesis, and macrophage infiltration programs to be powerful predictors of outcome with TKI therapy. Notably, predictors differed by the type of TKI received. Our study emphasizes the clinical significance of angiogenesis and immune tumor microenvironment and suggests that the critical effects its various aspects have on TKI efficacy vary by agent. This has broad implications for optimizing precision treatment of RCC. SIGNIFICANCE: The determinants of response to TKI therapy in metastatic ccRCC remain unknown. Our study demonstrates that key angiogenic and immune profiles of the tumor microenvironment may affect TKI response. These findings have the potential to inform treatment personalization in patients with RCC.
.
Inflammasomes are multiprotein complexes that include members of the NLR (nucleotide-binding domain leucine-rich repeat containing) family and caspase-1. Once bacterial molecules are sensed within ...the macrophage, the inflammasome is assembled, mediating the activation of caspase-1. Caspase-11 mediates caspase-1 activation in response to lipopolysaccharide and bacterial toxins, and yet its role during bacterial infection is unknown. Here, we demonstrated that caspase-11 was dispensable for caspase-1 activation in response to Legionella, Salmonella, Francisella, and Listeria. We also determined that active mouse caspase-11 was required for restriction of L. pneumophila infection. Similarly, human caspase-4 and caspase-5, homologs of mouse caspase-11, cooperated to restrict L. pneumophila infection in human macrophages. Caspase-11 promoted the fusion of the L. pneumophila vacuole with lysosomes by modulating actin polymerization through cofilin. However, caspase-11 was dispensable for the fusion of lysosomes with phagosomes containing nonpathogenic bacteria, uncovering a fundamental difference in the trafficking of phagosomes according to their cargo.
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► Caspase-11 is dispensable for caspase-1 activation during bacterial infection ► Caspase-11 restricts Legionella infection independently of caspase-1 ► Caspase-11 uncouples phagosome trafficking according to their cargo ► Human caspase-4 and caspase-5 restrict Legionella pneumophila infection
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