Activation of the zinc-sensing receptor GPR39 promotes T-cell reconstitution after hematopoietic cell transplant in mice.

Prolonged lymphopenia represents a major clinical problem after cytoreductive therapies such as chemotherapy and the conditioning required for hematopoietic stem cell transplant (HCT), contributing to the risk of infections and malignant relapse. Restoration of T-cell immunity depends on tissue regeneration in the thymus, the primary site of T-cell development, although the capacity of the thymus to repair itself diminishes over its lifespan. However, although boosting thymic function and T-cell reconstitution is of considerable clinical importance, there are currently no approved therapies for treating lymphopenia.

Targeting an alternate Wilms' tumor antigen 1 peptide bypasses immunoproteasome dependency.

Designing effective antileukemic immunotherapy will require understanding mechanisms underlying tumor control or resistance. Here, we report a mechanism of escape from immunologic targeting in an acute myeloid leukemia (AML) patient, who relapsed 1 year after immunotherapy with engineered T cells expressing a human leukocyte antigen A*02 (HLA-A2)-restricted T cell receptor (TCR) specific for a Wilms' tumor antigen 1 epitope, WT1 (T). Resistance occurred despite persistence of functional therapeutic T cells and continuous expression of WT1 and HLA-A2 by the patient's AML cells.

Attenuation of apoptotic cell detection triggers thymic regeneration after damage.

The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development.

Dynamics of thymus function and T cell receptor repertoire breadth in health and disease.

T cell recognition of unknown antigens relies on the tremendous diversity of the T cell receptor (TCR) repertoire; generation of which can only occur in the thymus. TCR repertoire breadth is thus critical for not only coordinating the adaptive response against pathogens but also for mounting a response against malignancies. However, thymic function is exquisitely sensitive to negative stimuli, which can come in the form of acute insult, such as that caused by stress, infection, or common cancer therapies; or chronic damage such as the progressive decline in thymic function with age.

Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant.

Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP.

When the Damage Is Done: Injury and Repair in Thymus Function.

Even though the thymus is exquisitely sensitive to acute insults like infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation-therapy, it also has a remarkable capacity for repair. This phenomenon of endogenous thymic regeneration has been known for longer even than its primary function to generate T cells, however, the underlying mechanisms controlling the process have been largely unstudied. Although there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies or the conditioning regimes as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse.

Increased A20-E3 ubiquitin ligase interactions in bid-deficient glia attenuate TLR3- and TLR4-induced inflammation.

Background: Chronic pro-inflammatory signaling propagates damage to neural tissue and affects the rate of disease progression. Increased activation of Toll-like receptors (TLRs), master regulators of the innate immune response, is implicated in the etiology of several neuropathologies including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Previously, we identified that the Bcl-2 family protein BH3-interacting domain death agonist (Bid) potentiates the TLR4-NF-κB pro-inflammatory response in glia, and specifically characterized an interaction between Bid and TNF receptor associated factor 6 (TRAF6) in microglia in response to TLR4 activation.

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration.

The thymus is not only extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood, and this capacity diminishes considerably with age. We show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration via their production of bone morphogenetic protein 4 (BMP4) ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signaling or production by either pharmacologic or genetic inhibition impaired thymic repair.

A constitutively-active IKK-complex at the axon initial segment.

Background: Previous studies provided evidence for an accumulation of IκB-kinase (IKK) α/β at the axon initial segment (AIS), a neuronal compartment defined by ankyrin-G expression. Here we explored whether the presence of the IKK-complex at the AIS was associated with the activation of IKK signaling at this site.

Methods And Results: Proximity-ligation assays (PLAs) using pan-IKKα/β, phospho-IKKα/β-specific as well as ankyrin-G specific antibodies validated their binding to proximal epitopes in the AIS, while antibodies to other phosphorylated signaling proteins showed no preference for the AIS.

NF-κB regulates neuronal ankyrin-G via a negative feedback loop.

The axon initial segment (AIS) is a neuronal compartment defined by ankyrin-G expression. We here demonstrate that the IKK-complex co-localizes and interacts with the cytoskeletal anchor protein ankyrin-G in immunoprecipitation and proximity-ligation experiments in cortical neurons. Overexpression of the 270 kDa variant of ankyrin-G suppressed, while gene-silencing of ankyrin-G expression increased nuclear factor-κB (NF-κB) activity in primary neurons, suggesting that ankyrin-G sequesters the transcription factor in the AIS.

In the Middle of a Chain Interaction.

In this issue of Molecular Cell, Fu et al. (2016) present a detailed structural analysis of death-inducing signaling complex (DISC) assembly and regulation through flexible caspase-8 interactions with cFLIP, cFLIP, and the viral inhibitor MC159, thereby identifying novel apoptosis control mechanisms.

Bid Promotes K63-Linked Polyubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) and Sensitizes to Mutant SOD1-Induced Proinflammatory Signaling in Microglia.

Mutations in the superoxide dismutase 1 (SOD1) gene contribute to motoneuron degeneration and are evident in 20% of familial amyotrophic lateral sclerosis cases. Mutant SOD1 induces microglial activation through a stimulation of Toll-like receptors 2 and 4 (TLR2 and TLR4). In the present study, we identified the proapoptotic Bcl-2 family protein Bid as a positive regulator of mutant SOD1-induced TLR-nuclear factor-κB (NF-κB) signaling in microglia.

Posttransplant Lymphoproliferative Disorders in Irish Renal Transplant Recipients: Insights From a National Observational Study.

Background: Posttransplant lymphoproliferative disorders (PTLD) are a common malignancy after renal transplantation with a high incidence of PTLD described in the first posttransplant year. We sought to determine incidence and risk determinants of PTLD in Irish kidney transplant recipients.

Methods: Retrospective observational study of 1996 adult first kidney transplant recipients between 1991 and 2010 in the Republic of Ireland.

Do patient-reported measures of symptoms and health status predict mortality in hemodialysis? An assessment of POS-S Renal and EQ-5D.

Introduction Experience with the use of patient-reported outcome measures such as EQ-5D and the symptom module of the Palliative care Outcome Scale-Renal Version (POS-S Renal) as mortality prediction tools in hemodialysis is limited. Methods A prospective survival study of people receiving hemodialysis (N = 362). The EQ-5D and the POS-S Renal were used to assess symptom burden and self-rated health (with a self-rated component).

Comparison of single CT scan assessment of bone mineral density, vascular calcification and fat mass with standard clinical measurements in renal transplant subjects: the ABC HeART study.

Background: Despite limitations of routine methods, Clinical Practice Guidelines support the assessment of bone mineral density (BMD) and vascular calcification in renal transplant recipients. Changes in fat mass also occur post-transplantation, although they are traditionally difficult to measure accurately. We report the feasibility, convenience and accuracy of measuring the above 3 parameters using a novel CT protocol.

The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration.

Blood pressure measurement in peritoneal dialysis: which method is best?

Background: The optimal approach to monitoring blood pressure (BP) in the peritoneal dialysis (PD) population is unclear. Ambulatory BP monitoring reliably predicts prognosis, but can be inconvenient. The accuracy of home BP monitoring in this population is unproven.

Serum phosphate varies with degree of proteinuria in nephrotic syndrome and is associated with elevated pulse wave velocity.

Background: The occurrence of vascular stiffness in the setting of the nephrotic syndrome and the influence of serum phosphate on this association is unknown.

Methods: A retrospective study of 42 prevalent, adult nephrotic patients who underwent carotid-femoral pulse wave velocity (PWV) measurement, a median of 24 months after kidney biopsy. Elevated PWV was determined using published age-specific reference ranges.

Cumulative ionizing radiation exposure in patients with end stage kidney disease: a 6-year retrospective analysis.

Objective: To quantify cumulative exposure to ionizing radiation in patients with end stage kidney disease (ESKD). To investigate factors which may be independently associated with risk of high cumulative effective dose (CED).

Materials And Methods: The study had local institutional review board ethical approval.

In-office assessment of blood pressure in chronic kidney disease: usual measurement versus automated BpTRU measurement.

Objectives: The automated BpTRU device has been shown to improve the accuracy of in-office blood pressure assessment in hypertensive populations. We aimed to determine whether this was also true for patients with chronic kidney disease.

Materials And Methods: We recorded the blood pressure of 80 hypertensive outpatients with chronic kidney disease by usual automated measurement and BpTRU automated measurement.

Moderate chronic kidney disease in women is associated with fracture occurrence independently of osteoporosis.

Background: Chronic kidney disease (CKD) is associated with increased risk of fragility fracture but whether this is independent of osteoporosis is unclear.

Methods: We conducted a retrospective cross-sectional study of 1,702 female patients referred for dual-energy X-ray absorptiometry (DXA) scanning (Lunar IDXA) between September 2006 and April 2007. Estimated glomerular filtration rate (eGFR; ml/min/1.

Maintenance hemodialysis patients have high cumulative radiation exposure.

Hemodialysis is associated with an increased risk of neoplasms which may result, at least in part, from exposure to ionizing radiation associated with frequent radiographic procedures. In order to estimate the average radiation exposure of those on hemodialysis, we conducted a retrospective study of 100 patients in a university-based dialysis unit followed for a median of 3.4 years.

Hyponatremia independent of osteoporosis is associated with fracture occurrence.

Background And Objectives: Mild hyponatremia has traditionally been considered benign, but it may be associated with gait and attention deficits and an increased risk of falls that may result in fracture. A retrospective study was conducted to quantify the association of hyponatremia with fracture occurrence and to examine whether this relationship is independent of osteoporosis.

Design, Setting, Participants, & Measurements: This study analyzed 1408 consecutive female patients who underwent bone mineral density measurement (Lunar IDXA) between September 1, 2006 and April 11, 2007 and who had available laboratory data.

Lack of correlation between calcium intake and serum calcium levels in stable haemodialysis subjects.

Background: The relationship between calcium intake and serum calcium level in hemodialysis patients is poorly understood.

Methods: We quantify total oral calcium intake using detailed 7-day food diaries with 294 patient days of observation in 42 stable, non-diabetic hemodialysis subjects.

Results: Mean (SD) albumin-corrected serum calcium was 9.