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Improving Selection Criteria for Early Cystectomy in High-Grade T1 Bladder Cancer: A Meta-Analysis of 15,215 Patients

Mon, 02/09/2015 - 3:52pm

PURPOSE: High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer, with highly variable prognosis, poorly understood risk factors, and considerable debate about the role of early cystectomy. We aimed to address these questions through a meta-analysis of outcomes and prognostic factors.

METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology abstracts were searched for cohort studies in HGT1. We pooled data on recurrence, progression, and cancer-specific survival from 73 studies.

RESULTS: Five-year rates of recurrence, progression, and cancer-specific survival were 42% (95% CI, 39% to 45%), 21% (95% CI, 18% to 23%), and 87% (95% CI, 85% to 89%), respectively (56 studies, n = 15,215). In the prognostic factor meta-analysis (33 studies, n = 8,880), the highest impact risk factor was depth of invasion (T1b/c) into lamina propria (progression: hazard ratio [HR], 3.34; P < .001; cancer-specific survival: HR, 2.02; P = .001). Several other previously proposed factors also predicted progression and cancer-specific survival (lymphovascular invasion, associated carcinoma in situ, nonuse of bacillus Calmette-Guérin, tumor size > 3 cm, and older age; HRs for progression between 1.32 and 2.88, P ≤ .002; HRs for cancer-specific survival between 1.28 and 2.08, P ≤ .02).

CONCLUSION: In this large analysis of outcomes and prognostic factors in HGT1 bladder cancer, deep lamina propria invasion had the largest negative impact, and other previously proposed prognostic factors were also confirmed. These factors should be used for prognostication and patient stratification in future clinical trials, and depth of invasion should be considered for inclusion in TNM staging criteria. This meta-analysis can also help define selection criteria for early cystectomy in HGT1 bladder cancer, particularly for patients with deep lamina propria invasion combined with other risk factors.

Vector sequences are not detected in tumor tissue from research subjects with ornithine transcarbamylase deficiency who previously received adenovirus gene transfer

Mon, 02/09/2015 - 3:02pm

A 66-year-old woman heterozygous for a mutation in the ornithine transcarbamylase gene (Otc) participated in a phase I gene therapy trial for OTC deficiency. She received an adenovirus (Ad) vector expressing the functional OTC gene by intraportal perfusion. Fourteen years later she developed and subsequently died of hepatocellular carcinoma. A second subject, a 45-year-old woman, enrolled in the same trial presented with colon cancer 15 years later. We sought to investigate a possible association between the development of a tumor and prior adenoviral gene transfer in these two subjects. We developed and validated a sensitive nested polymerase chain reaction assay for recovering recombinant Ad sequences from host tissues. Using this method, we could not detect any Ad vector DNA in either tumor or normal tissue from the two patients. Our results are informative in ruling out the possibility that the adenoviral vector might have contributed to the development of cancer in those two subjects.

Detection of immune suppressive neutrophils in peripheral blood samples of cancer patients

Tue, 02/03/2015 - 4:53pm

Neutrophils provide first-line defense against infections and are potent effectors in innate and adaptive immunity. Recently neutrophils have been shown to play important roles in multiple antitumor reactions. A subset of mature neutrophils in human systemic inflammation has been identified as a unique circulating population of myeloid cells, which is capable of inhibiting T cell responses. These neutrophils show unique immunophenotype (CD11c bright/CD62L dim/CD11b bright/CD16 bright). This study reports detection of mature neutrophils with similar immunophenotype in the peripheral blood samples of cancer patients using flow cytometry analysis. This population of neutrophils is not detected in peripheral blood samples of normal controls. Thus this finding suggests the involvement of mature neutrophils in antitumor immunity.

Management of non-melanoma skin cancer

Tue, 02/03/2015 - 4:53pm

OBJECTIVES: To review types of, and treatment for, non-melanoma skin cancer (NMSC): basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and less common NMSC.

DATA SOURCES: Standards of care, dermatology texts, peer-reviewed journals.

CONCLUSION: BCC grows slowly and rarely metastasizes; some BCC subtypes can be aggressive and destructive. Early treatment of SCC is usually successful; untreated SCC will penetrate underlying tissue, invade lymph nodes, and metastasize. Treatment options for NMSC are based on patient and tumor characteristics, which determine whether a lesion is low or high risk for cancer recurrence after treatment.

IMPLICATIONS FOR NURSING PRACTICE: Nurses are integral for educating patients about measures to prevent new skin cancers and for monitoring for recurrence of NMSC.

Obesity Notches up fatty liver

Tue, 02/03/2015 - 4:53pm

Pathologic fatty liver paradoxically accompanies obesity and type 2 diabetes despite the crippling of insulin signaling, which is normally required for fat synthesis. The developmental signaling protein Notch is a hidden regulator of lipogenesis that amplifies signal transmissions to fat production in these metabolic diseases.

Investigation of statistical iterative reconstruction for dedicated breast CT

Tue, 02/03/2015 - 4:53pm

PURPOSE: Dedicated breast CT has great potential for improving the detection and diagnosis of breast cancer. Statistical iterative reconstruction (SIR) in dedicated breast CT is a promising alternative to traditional filtered backprojection (FBP). One of the difficulties in using SIR is the presence of free parameters in the algorithm that control the appearance of the resulting image. These parameters require tuning in order to achieve high quality reconstructions. In this study, the authors investigated the penalized maximum likelihood (PML) method with two commonly used types of roughness penalty functions: hyperbolic potential and anisotropic total variation (TV) norm. Reconstructed images were compared with images obtained using standard FBP. Optimal parameters for PML with the hyperbolic prior are reported for the task of detecting microcalcifications embedded in breast tissue.

METHODS: Computer simulations were used to acquire projections in a half-cone beam geometry. The modeled setup describes a realistic breast CT benchtop system, with an x-ray spectra produced by a point source and an a-Si, CsI:Tl flat-panel detector. A voxelized anthropomorphic breast phantom with 280 mum microcalcification spheres embedded in it was used to model attenuation properties of the uncompressed woman's breast in a pendant position. The reconstruction of 3D images was performed using the separable paraboloidal surrogates algorithm with ordered subsets. Task performance was assessed with the ideal observer detectability index to determine optimal PML parameters.

RESULTS: The authors' findings suggest that there is a preferred range of values of the roughness penalty weight and the edge preservation threshold in the penalized objective function with the hyperbolic potential, which resulted in low noise images with high contrast microcalcifications preserved. In terms of numerical observer detectability index, the PML method with optimal parameters yielded substantially improved performance (by a factor of greater than 10) compared to FBP. The hyperbolic prior was also observed to be superior to the TV norm. A few of the best-performing parameter pairs for the PML method also demonstrated superior performance for various radiation doses. In fact, using PML with certain parameter values results in better images, acquired using 2 mGy dose, than FBP-reconstructed images acquired using 6 mGy dose.

CONCLUSIONS: A range of optimal free parameters for the PML algorithm with hyperbolic and TV norm-based potentials is presented for the microcalcification detection task, in dedicated breast CT. The reported values can be used as starting values of the free parameters, when SIR techniques are used for image reconstruction. Significant improvement in image quality can be achieved by using PML with optimal combination of parameters, as compared to FBP. Importantly, these results suggest improved detection of microcalcifications can be obtained by using PML with lower radiation dose to the patient, than using FBP with higher dose.

Investigation of energy weighting using an energy discriminating photon counting detector for breast CT

Tue, 02/03/2015 - 4:53pm

PURPOSE: Breast CT is an emerging imaging technique that can portray the breast in 3D and improve visualization of important diagnostic features. Early clinical studies have suggested that breast CT has sufficient spatial and contrast resolution for accurate detection of masses and microcalcifications in the breast, reducing structural overlap that is often a limiting factor in reading mammographic images. For a number of reasons, image quality in breast CT may be improved by use of an energy resolving photon counting detector. In this study, the authors investigate the improvements in image quality obtained when using energy weighting with an energy resolving photon counting detector as compared to that with a conventional energy integrating detector.

METHODS: Using computer simulation, realistic CT images of multiple breast phantoms were generated. The simulation modeled a prototype breast CT system using an amorphous silicon (a-Si), CsI based energy integrating detector with different x-ray spectra, and a hypothetical, ideal CZT based photon counting detector with capability of energy discrimination. Three biological signals of interest were modeled as spherical lesions and inserted into breast phantoms; hydroxyapatite (HA) to represent microcalcification, infiltrating ductal carcinoma (IDC), and iodine enhanced infiltrating ductal carcinoma (IIDC). Signal-to-noise ratio (SNR) of these three lesions was measured from the CT reconstructions. In addition, a psychophysical study was conducted to evaluate observer performance in detecting microcalcifications embedded into a realistic anthropomorphic breast phantom. RESULTS: In the energy range tested, improvements in SNR with a photon counting detector using energy weighting was higher (than the energy integrating detector method) by 30%-63% and 4%-34%, for HA and IDC lesions and 12%-30% (with Al filtration) and 32%-38% (with Ce filtration) for the IIDC lesion, respectively. The average area under the receiver operating characteristic curve (AUC) for detection of microcalcifications was higher by greater than 19% (for the different energy weighting methods tested) as compared to the AUC obtained with an energy integrating detector.

CONCLUSIONS: This study showed that breast CT with a CZT photon counting detector using energy weighting can provide improvements in pixel SNR, and detectability of microcalcifications as compared to that with a conventional energy integrating detector. Since a number of degrading physical factors were not modeled into the photon counting detector, this improvement should be considered as an upper bound on achievable performance.

Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy

Tue, 02/03/2015 - 4:53pm

IMPORTANCE: The role of interval appendectomy after conservative management of perforated appendicitis remains controversial. Determining the etiology of perforated appendicitis is one reason to perform interval appendectomies.

OBJECTIVE: To determine whether adult patients undergoing interval appendectomy experience an increased rate of neoplasms.

DESIGN: Retrospective study.

SETTING: A single tertiary care institution.

PARTICIPANTS: All patients 18 years or older who underwent appendectomy for presumed appendicitis from January 1, 2006, through December 31, 2010.

EXPOSURES Appendectomy for presumed appendicitis.

MAIN OUTCOMES AND MEASURES: Underlying neoplasm as the cause of presentation for presumed appendicitis. Demographic data, clinicopathologic characteristics, interval resection rate, and complication data were collected and analyzed.

RESULTS: During the study period, 376 patients underwent appendectomies. Interval appendectomy was performed in 17 patients (4.5%). Neoplasms were identified in 14 patients (3.7%); 5 of those tumors occurred in patients who had undergone interval appendectomy (29.4%). Nine neoplasms were mucinous tumors (64.3%), including all neoplasms associated with interval appendectomies. The mean age of all patients with appendiceal tumors was 49 years (range, 35-74 years).

CONCLUSIONS AND RELEVANCE: Mucinous neoplasms of the appendix were found in 5 of 17 patients (29.4%) undergoing interval appendectomy. Interval appendectomies should be considered in all adult patients, especially those 40 years or older, to determine the underlying cause of appendicitis. A multi-institutional study to determine the generalizability of these findings is warranted.

En bloc tibial thrombectomy

Tue, 02/03/2015 - 4:53pm

A 58-year-old man with hypertension and 40-pack year smoking history presented to the emergency department complaining of approximately 20 hours of right lower extremity pain.

Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells

Tue, 02/03/2015 - 4:53pm

The serine/threonine kinase Akt/PKB promotes cancer cell growth and invasion through several downstream targets. Identification of novel substrates may provide new avenues for therapeutic intervention. Our study shows that Akt phosphorylates the cancer-related transcription factor Runx2 resulting in stimulated DNA binding of the purified recombinant protein in vitro. Pharmacological inhibition of the PI3K/Akt pathway in breast cancer cells reduces DNA-binding activity of Runx2 with concomitant reduction in the expression of metastasis-related Runx2 target genes. Akt phosphorylates Runx2 at three critical residues within the runt DNA-binding domain to enhance its in vivo genomic interactions with a target gene promoter, MMP13. Mutation of these three phosphorylation sites reduces Runx2 DNA-binding activity. However, Akt signaling does not appear to interefere with CBFbeta-Runx2 interactions. Consequently, expression of multiple metastasis-related genes is decreased and Runx2-mediated cell invasion is supressed. Thus, our work identifies Runx2 as a novel and important downstream mediator of the PI3K/Akt pathway that is linked to metastatic properties of breast cancer cells.

RIP3: a molecular switch for necrosis and inflammation

Tue, 02/03/2015 - 4:53pm

The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3 can promote inflammation independent of its pronecrotic activity. Here, we review our current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases.

Immune senescence: new insights into defects but continued mystery of root causes

Tue, 02/03/2015 - 4:53pm

Editorial overview of the August 2013 issue of Current Opinion in Immunology.

Molecular determinants of co- and post-translational N-glycosylation of type I transmembrane peptides

Tue, 02/03/2015 - 4:53pm

Type I transmembrane peptides acquire N-linked glycans during and after protein synthesis to facilitate anterograde trafficking through the secretory pathway. Mutations in N-glycosylation consensus sites (NXT and NXS, where X not equalP) that alter the kinetics of the initial N-glycan attachment have been associated with cardiac arrhythmias; however, the molecular determinants that define co- and post-translational consensus sites in proteins are not known. In the present study, we identified co- and post-translational consensus sites in the KCNE family of K+ channel regulatory subunits to uncover three determinants that favour co-translational N-glycosylation kinetics of type I transmembrane peptides which lack a cleavable signal sequence: threonine-containing consensus sites (NXT), multiple N-terminal consensus sites and long C-termini. The identification of these three molecular determinants now makes it possible to predict co- and post-translational consensus sites in type I transmembrane peptides.

Diffusion-tensor imaging of small nerve bundles: cranial nerves, peripheral nerves, distal spinal cord, and lumbar nerve roots--clinical applications

Tue, 02/03/2015 - 4:53pm

OBJECTIVE: The purpose of this article is to review recent advances in diffusion-tensor imaging (DTI) and tractography of the cranial and peripheral nerves.

CONCLUSION: Advances in MR data acquisition and postprocessing methods are permitting high-resolution DTI of the cranial and peripheral nerves in the clinical setting. DTI offers information beyond routine clinical MRI, and DTI findings have implications for the diagnosis and treatment of nerve disease.

Microbiota signalling through MyD88 is necessary for a systemic neutrophilic inflammatory response

Tue, 02/03/2015 - 4:53pm

In the present study, we have found that intestinal flora strongly influence peritoneal neutrophilic inflammatory responses to diverse stimuli, including pathogen-derived particles like zymosan and sterile irritant particles like crystals. When germ-free and flora-deficient (antibiotic-treated) mice are challenged with zymosan intraperitoneally, neutrophils are markedly impaired in their ability to extravasate from blood into the peritoneum. In contrast, in these animals, neutrophils can extravasate in response to an intraperitoneal injection of the chemokine, macrophage inflammatory protein 2. Neutrophil recruitment upon inflammatory challenge requires stimulation by microbiota through a myeloid differentiation primary response gene (88) (MyD88) -dependent pathway. MyD88 signalling is crucial during the development of the immune system but depending upon the ligand it may be dispensable at the time of the actual inflammatory challenge. Furthermore, pre-treatment of flora-deficient mice with a purified MyD88-pathway agonist is sufficient to restore neutrophil migration. In summary, this study provides insight into the role of gut microbiota in influencing acute inflammation at sites outside the gastrointestinal tract.

The Legionella pneumophila GTPase activating protein LepB accelerates Rab1 deactivation by a non-canonical hydrolytic mechanism

Tue, 02/03/2015 - 4:53pm

GTPase activating proteins (GAPs) from pathogenic bacteria and eukaryotic host organisms deactivate Rab GTPases by supplying catalytic arginine and glutamine fingers in trans and utilizing the cis-glutamine in the DXXGQ motif of the GTPase for binding rather than catalysis. Here, we report the transition state mimetic structure of the Legionella pneumophila GAP LepB in complex with Rab1 and describe a comprehensive structure-based mutational analysis of potential catalytic and recognition determinants. The results demonstrate that LepB does not simply mimic other GAPs but instead deploys an expected arginine finger in conjunction with a novel glutamic acid finger, which forms a salt bridge with an indispensible switch II arginine that effectively locks the cis-glutamine in the DXXGQ motif of Rab1 in a catalytically competent though unprecedented transition state configuration. Surprisingly, a heretofore universal transition state interaction with the cis-glutamine is supplanted by an elaborate polar network involving critical P-loop and switch I serines. LepB further employs an unusual tandem domain architecture to clamp a switch I tyrosine in an open conformation that facilitates access of the arginine finger to the hydrolytic site. Intriguingly, the critical P-loop serine corresponds to an oncogenic substitution in Ras and replaces a conserved glycine essential for the canonical transition state stereochemistry. In addition to expanding GTP hydrolytic paradigms, these observations reveal the unconventional dual finger and non-canonical catalytic network mechanisms of Rab GAPs as necessary alternative solutions to a major impediment imposed by substitution of the conserved P-loop glycine.

Safety and efficacy of autologous hemopoietic progenitor cell collection in tandem with hemodialysis in multiple myeloma with myeloma cast nephropathy

Tue, 02/03/2015 - 4:53pm

Autologous hemopoietic progenitor cell (HPC) collection is the most frequent indication for an apheresis procedure in patients with multiple myeloma, up to 10% of whom may also require hemodialysis because of myeloma kidney. We investigated whether HPC collection could be performed in tandem with hemodialysis, to avoid extra outpatient visits for extracorporeal procedures, without compromising the efficacy of the hemodialysis, the HPC collection efficiency (CE) or patient safety. Four dialysis-dependent patients with multiple myeloma underwent 5 large volume leukapheresis HPC collections in tandem with hemodialysis. Under our protocol, all of the blood processed through the apheresis instrument was dialyzed against a standard calcium-rich bath prior to being returned to the patient, therefore no supplemental calcium was needed. No significant changes in pulse rate (P = 0.625) or mean arterial pressure (P = 0.188) were noted between the start and end of the procedures. The patients exhibited no signs or symptoms of hypocalcemia or other adverse effects. Calculated urea reduction ratios ranged between 62.5 and 73.9%, and HPC CE was between 53 and 84% for 4 of the 5 procedures, indicating that there was no compromise of either procedure when performed in tandem. Ionized calcium measured at the beginning, midpoint and end of every procedure did not change (P = 0.954). The two patients who proceeded to autologous HPC transplant engrafted on Days 11 and 10, respectively. We conclude that autologous HPC collection can safely be performed in tandem with hemodialysis without compromising the efficacy of dialysis, HPC CE, or patient safety.

alpha1,3Galactosyltransferase knockout pigs produce the natural anti-Gal antibody and simulate the evolutionary appearance of this antibody in primates

Tue, 02/03/2015 - 4:53pm

BACKGROUND: Anti-Gal is the most abundant natural antibody in humans and Old World primates (apes and Old World monkeys). Its ligand, the alpha-gal epitope (Galalpha1-3Galbeta1-4GlcNAc-R), is abundant in nonprimate mammals, prosimians and New World monkeys whereas it is absent in humans and Old World primates as a result of inactivation of the alpha1,3galactosyltransferase (alpha1,3GT) gene in ancestral Old World primates, as recent as 20-28 million years ago. Since anti-Gal has been a "forbidden" autoantibody for greater than 140 million years of evolution in mammals producing alpha-gal epitopes it was of interest to determine whether ancestral Old World primates could produce anti-Gal once alpha-gal epitopes were eliminated, i.e. did they carry anti-Gal encoding immunoglobulin genes, or did evolutionary selection eliminate these genes that may be detrimental in mammals synthesizing alpha-gal epitopes. This question was studied by evaluating anti-Gal prodution in alpha1,3GT knockout (GT-KO) pigs recently generated from wild-type pigs in which the alpha-gal epitope is a major self-antigen.

METHODS: Anti-Gal antibody activity in pig sera was assessed by ELISA, flow cytometry and complement mediated cytolysis and compared to that in human sera.

RESULTS: The study demonstrates abundant production of the natural anti-Gal antibody in GT-KO pigs at titers even higher than in humans. The fine specificity of GT-KO pig anti-Gal is identical to that of human anti-Gal.

CONCLUSIONS: Pigs and probably other mammals producing alpha-gal epitopes carry immunoglobulin genes encoding anti-Gal as an autoantibody. Once the alpha-gal epitope is eliminated in GT-KO pigs, they produce anti-Gal. These findings strongly suggest that similar to GT-KO pigs, inactivation of the alpha1,3GT gene in ancestral Old World primates enabled the immediate production of anti-Gal, possibly as a protective antibody against detrimental microbial agents carrying alpha-gal epitopes.

Surgeon-industry conflict of interest: survey of North Americans' opinions regarding surgeons consulting with industry

Tue, 02/03/2015 - 4:53pm

BACKGROUND CONTEXT: Surgeon-industry conflict of interest (COI) has become a source of considerable interest. Professional medical societies, industry, and policy makers have attempted to regulate potential COI without consideration for public opinion. PURPOSE: The objective of this study was to report on the opinions of individuals representing the general public regarding surgeon-industry consulting relationships.

STUDY DESIGN/SETTING: Web-based survey.

METHODS: Survey was administered using a "spine Web site," and opinions are collected on surgeon-industry consulting and regulation. Associations among responses to similar questions were assessed to ensure validity and subgroup analysis performed for respondent age, sex, education, insurance, employment, and patient status.

RESULTS: Six hundred ten of 642 surveys had complete data. The sample population comprised more females and was older and more educated than the American population. About 80% of respondents felt it was ethical and either beneficial or of no influence to the quality of health care if surgeons were consultants for surgical device companies. Most felt disclosure of an industry relationship was important and paying surgeons royalties for devices, other than those they directly implant, would not affect quality of care. Respondents support multidisciplinary surgeon-industry COI regulation and trust doctors and their professional societies to head this effort.

CONCLUSIONS: Despite the known potential negative impact of surgeon-industry COI on patient care, this study revealed that this does not seem to be reflected in the opinion of the general public. The respondents felt that disclosure is deemed one of the most important means of self-regulation and COI management, which is in agreement with current trends of most spine societies and journals that are increasing the stringency of disclosure policies.

Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus

Tue, 02/03/2015 - 4:53pm

Loss-of-function mutations in the Fas death receptor or its ligand result in a lymphoproliferative syndrome and exacerbate clinical disease in most lupus-prone strains of mice. One exception is mice injected with 2,6,10,14-tetramethylpentadecane (TMPD), a hydrocarbon oil commonly known as pristane, which induces systemic lupus erythematosus-like disease. Although Fas/Fas ligand (FasL) interactions have been strongly implicated in the activation-induced cell death of both lymphocytes and other APCs, FasL can also trigger the production of proinflammatory cytokines. FasL is a transmembrane protein with a matrix metalloproteinase cleavage site in the ectodomain. Matrix metalloproteinase cleavage inactivates membrane-bound FasL and releases a soluble form reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage on both the proapoptotic and proinflammatory activity of FasL, its cleavage site was deleted through targeted mutation to produce the deleted cleavage site (DeltaCS) mouse line. DeltaCS mice express higher levels of membrane-bound FasL than do wild-type mice and fail to release soluble FasL. To determine to what extent FasL promotes inflammation in lupus mice, TMPD-injected FasL-deficient and DeltaCS BALB/c mice were compared with control TMPD-injected BALB/c mice. We found that FasL deficiency significantly reduced the early inflammatory exudate induced by TMPD injection. In contrast, DeltaCS mice developed a markedly exacerbated disease profile associated with a higher frequency of splenic neutrophils and macrophages, a profound change in anti-nuclear Ab specificity, and markedly increased proteinuria and kidney pathology compared with controls. These results demonstrate that FasL promotes inflammation in TMPD-induced autoimmunity, and its cleavage limits FasL proinflammatory activity.