648 research outputs found
Agree on much, except it is time for change
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149742/1/ajt15362_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149742/2/ajt15362.pd
Locally Advanced and Unresectable Cutaneous Squamous Cell Carcinoma: Outcomes of Concurrent Cetuximab and Radiotherapy
Background. Advanced age and immune dysfunction are risk factors for cutaneous squamous cell carcinoma (cSCC) and often render patients with locally-advanced disease medically inoperable or surgically unresectable, but potentially curable with radiotherapy. Concurrent chemotherapy and radiotherapy may not be well tolerated in this population, but another systemic therapy may improve disease control. Objective. Determine the tolerance and efficacy of concurrent cetuximab and radiotherapy (CRT) for patients with locally advanced and unresectable cSCC. Methods. Retrospective analysis of 12 patients treated with CRT for locally advanced and unresectable cSCC. Results. Patients were elderly and 75% had moderate-to-severe comorbidities, while 42% had immune dysfunction. Grades 3-4 adverse events were noted in 83% of patients; 67% required hospital admission for adverse events. Complete and partial response was noted in 36% and 27% (response rate, 64%). Stable and progressive disease was noted in 3 and 1 patients, respectively (disease control rate, 91%). Median progression-free and overall survival were 6.4 and 8.0 months, respectively. Limitations. Retrospective small-cohort, single-institution analysis. Conclusion. Patients selected for CRT were elderly, with comorbidities and immune dysfunction, but treatment responses were observed. Patients selected for this treatment approach have a poor prognosis with limited capacity for therapy; more effective treatment is needed
Changes in liver and spleen volumes after living liver donation: A report from the adultātoāadult living donor liver transplantation cohort study (A2ALL)
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110585/1/lt24062.pd
Biliary reconstructive techniques and associated anatomic variants in adult living donor liver transplantations: The adultātoāadult living donor liver transplantation cohort study experience
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140020/1/lt24872.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140020/2/lt24872_am.pd
Causes of Arterial Bleeding After Living Donor Liver Transplantation and the Results of Transcatheter Arterial Embolization
Genetic determinants of co-accessible chromatin regions in activated T cells across humans.
Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression
Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts
BackgroundāThe standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable.
MethodsāWe prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression.
ResultsāA three-gene signature of 18S ribosomal (rRNA)ānormalized measures of CD3Īµ mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operatingcharacteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the HosmerāLemeshow test indicated good fit (P = 0.77). In an externalvalidation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P = 0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received antiāinterleukin-2 receptor antibodies from those who received T-cellādepleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P = 0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001).
ConclusionsāA molecular signature of CD3Īµ mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts
A Gamma Interferon Independent Mechanism of CD4 T Cell Mediated Control of M. tuberculosis Infection in vivo
CD4 T cell deficiency or defective IFNĪ³ signaling render humans and mice
highly susceptible to Mycobacterium tuberculosis (Mtb)
infection. The prevailing model is that Th1 CD4 T cells produce IFNĪ³ to
activate bactericidal effector mechanisms of infected macrophages. Here we test
this model by directly interrogating the effector functions of Th1 CD4 T cells
required to control Mtb in vivo. While Th1 CD4 T cells specific for the Mtb
antigen ESAT-6 restrict in vivo Mtb growth, this inhibition is independent of
IFNĪ³ or TNF and does not require the perforin or FAS effector pathways.
Adoptive transfer of Th17 CD4 T cells specific for ESAT-6 partially inhibited
Mtb growth while Th2 CD4 T cells were largely ineffective. These results imply a
previously unrecognized IFNĪ³/TNF independent pathway that efficiently
controls Mtb and suggest that optimization of this alternative effector function
may provide new therapeutic avenues to combat Mtb through vaccination
T cell repertoire dynamics during pregnancy in multiple sclerosis
Identifying T cell clones associated with autoimmunity has remained challenging. Intriguingly, many human autoimmune diseases including multiple sclerosis (MS) show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease in individual patients. Here, we characterized immunomodulation at the single clone level by sequencing the T cell receptor (TCR) repertoire in healthy women and female MS patients longitudinally over the course of pregnancy. Clonality was significantly reduced from the first to the third trimester of pregnancy in MS patients, indicating that the TCR repertoire during MS pregnancy becomes less dominated by expanded clones. Only few T cell clones were substantially modulated during pregnancy. In a proof-of-concept approach, we demonstrate that relapse-associated T cell clones identified in an individual patient contracted during pregnancy and expanded during a postpartum relapse. Our data provide evidence that profiling the TCR repertoire during pregnancy could serve as a tool to discover and track āprivateā T cell clones that are associated with disease activity in individual patients
Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes
Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)ācoupled retinoic acidāinducible gene 1 (RIG-I)ālike receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFNādependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFNāmediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation
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