The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by ...angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4⁺ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.
The role of histocompatibility and immune recognition in stem cell transplant therapy has been controversial, with many reports arguing that undifferentiated stem cells are protected from immune ...recognition due to the absence of major histocompatibility complex (MHC) markers. This argument is even more persuasive in transplantation into the central nervous system (CNS) where the graft rejection response is minimal.
In this study, we evaluate graft survival and neuron production in perfectly matched vs. strongly mismatched neural stem cells transplanted into the hippocampus in mice. Although allogeneic cells survive, we observe that MHC-mismatch decreases surviving cell numbers and strongly inhibits the differentiation and retention of graft-derived as well as endogenously produced new neurons. Immune suppression with cyclosporine-A did not improve outcome but non-steroidal anti-inflammatory drugs, indomethacin or rosiglitazone, were able to restore allogeneic neuron production, integration and retention to the level of syngeneic grafts.
These results suggest an important but unsuspected role for innate, rather than adaptive, immunity in the survival and function of MHC-mismatched cellular grafts in the CNS.
Cell replacement therapy holds promise for a number of untreatable neurological or psychiatric diseases but the immunogenicity of cellular grafts remains controversial. Emerging stem cell and ...reprogramming technologies can be used to generate autologous grafts that minimize immunological concerns but autologous grafts may carry an underlying genetic vulnerability that reduces graft efficacy or survival. Healthy allogeneic grafts are an attractive and commercially scalable alternative if immunological variables can be controlled. Stem cells and immature neural progenitor cells (NPC) do not express major histocompatibility complex (MHC) antigens and can evade adaptive immune surveillance. Nevertheless, in an experimental murine model, allogeneic NPCs do not survive and differentiate as well as syngeneic grafts, even when traditional immunosuppressive treatments are used. In this study, we show that natural killer (NK) cells recognize the lack of self‐MHC antigens on NPCs and pose a barrier to NPC transplantation. NK cells readily target both syngeneic and allogeneic NPC, and killing is modulated primarily by NK‐inhibiting “self” class I MHC and NK‐activating NKG2D‐ligand expression. The absence of NKG2D signaling in NK cells significantly improves NPC‐derived neuron survival and differentiation. These data illustrate the importance of innate immune mechanisms in graft outcome and the potential value of identifying and targeting NK cell‐activating ligands that may be expressed by stem cell derived grafts. STEM Cells 2013;31:2024‐2030
B cell lymphoma survival requires tonic or ligand-independent signals through activation of Syk by the B cell receptor. The Epstein-Barr virus (EBV) protein latent membrane 2a (LMP2a), a mimic of the ...B cell receptor, provides constitutive survival signals for latently infected cells through Syk activation; however, the precise downstream mechanisms coordinating this survival response in EBV+ B cell lymphomas remain to be elucidated. Herein, we assess the mechanism of Syk survival signaling in EBV+ B cell lymphomas from post-transplant lymphoproliferative disorder (PTLD) to discover virally controlled therapeutic targets involved in lymphomagenesis and tumor progression. Using small molecule inhibition and siRNA strategies, we show that Syk inhibition reduces proliferation and induces apoptosis of PTLD-derived EBV+ B cell lines. Syk inhibition also reduces autocrine IL-10 production. Although Syk inhibition attenuates signaling through both the PI3K/Akt and Erk pathways, only PI3K/Akt inhibition causes apoptosis of PTLD-derived cell lines. Loss of the endogenous caspase inhibitor XIAP is observed after Syk or PI3K/Akt inhibition. The loss of XIAP and apoptosis that results from Syk or PI3K/Akt inhibition is reversed by inhibition of the mitochondrial protease HtrA2. Thus, Syk drives EBV+ B cell lymphoma survival through PI3K/Akt activation, which prevents the HtrA2-dependent loss of XIAP. Syk, Akt, and XIAP antagonists may present potential new therapeutic strategies for PTLD through targeting of EBV-driven survival signals.
Background: Syk activation is required for B cell survival. EBV can induce B cell lymphomas.
Results: Syk, PI3K/Akt inhibition induces apoptosis of EBV+ B cell lymphomas. Syk PI3K/Akt inhibition results in HtrA2-dependent loss of XIAP protein.
Conclusion: Syk activates PI3K/Akt to promote survival by preventing HtrA2-dependent loss of XIAP.
Significance: Syk, PI3K/Akt, and XIAP are new therapeutic targets for EBV+ B cell lymphomas.
Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for ...trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.
Background Oxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the ...potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis. Study Design Placebo-controlled, 3-arm, double-blind, randomized, clinical trial. Setting & Participants 65 patients undergoing thrice-weekly maintenance hemodialysis. Intervention Patients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10 ; 600 or 1,200 mg) or matching placebo for 4 months. Outcomes The primary outcome was plasma oxidative stress, defined as plasma concentration of F2 -isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability. Measurements F2 -isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro−brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months. Results Of 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200 mg, but not 600 mg, of CoQ10 significantly reduced plasma F2 -isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of −10.7 95% CI, −7.1 to −14.3 pg/mL P < 0.001 and −8.3 95% CI, −5.5 to −11.0 pg/mL P = 0.1, respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures. Limitations Study not powered to detect small treatment effects; difference in baseline characteristics among randomized groups. Conclusions In patients undergoing maintenance hemodialysis, daily supplementation with 1,200 mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2 -isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.
While family caregivers provide 70-90% of care for people living in the community and assist with 10-30% of the care in congregate living, most healthcare providers do not meaningfully involve family ...caregivers as partners in care. Recent research recommends that the healthcare workforce receive competency-based education to identify, assess, support, and partner with family caregivers across the care trajectory.
This paper reports a mixed-methods evaluation of a person-centered competency-based education program on Caregiver-Centered Care for the healthcare workforce.
This foundational education was designed for all healthcare providers and trainees who work with family caregivers and is offered free online (caregivercare.ca). Healthcare providers from five healthcare settings (primary, acute, home, supportive living, long-term care) and trainees in medicine, nursing, and allied health were recruited via email and social media. We used the Kirkpatrick-Barr health workforce training evaluation framework to evaluate the education program, measuring various healthcare providers' learner satisfaction with the content (Level 1), pre-post changes in knowledge and confidence when working with family caregivers (Level 2), and changes in behaviors in practice (Level 3).
Participants were primarily healthcare employees (68.9%) and trainees (21.7%) and represented 5 healthcare settings. Evaluation of the first 161 learners completing the program indicated that on a 5-point Likert scale, the majority were satisfied with the overall quality of the education (Mean(M) = 4.69; SD = .60). Paired T-tests indicated that out of a score of 50, post-education changes in knowledge and confidence to work with family caregivers was significantly higher than pre-education scores (pre M = 38.90, SD = 6.90; post M = 46.60, SD = 4.10; t(150) = - 16.75, p < .0001). Qualitative results derived from open responses echoed the quantitative findings in satisfaction with the education delivery as well as improvements in learners' knowledge and confidence.
Health workforce education to provide person-centered care to all family caregivers is an innovative approach to addressing the current inconsistent system of supports for family caregivers. The education program evaluated here was effective at increasing self-reported knowledge and confidence to work with family caregivers.
Boreal regions are warming at more than double the global average, creating opportunities for the northward expansion of agriculture. Expanding agricultural production in these regions will involve ...the conversion of boreal forests to agricultural fields, with cumulative impacts on soil microbial communities and associated biogeochemical cycling processes. Understanding the magnitude or rate of change that will occur with these biological processes will provide information that will enable these regions to be developed in a more sustainable manner, including managing carbon and nitrogen losses. This study, based in the southern boreal region of Canada where agricultural expansion has been occurring for decades, used a paired forest-adjacent agricultural field approach to quantify how soil microbial communities and functions were altered at three different stages post-conversion (< 10, > 10 and < 50, and > 50 years). Soil microbial functional capacity was assessed by quantitative PCR of genes associated with carbon (C), nitrogen, and phosphorous (P) cycling; microbial taxonomic diversity and community structure was assessed by amplicon sequencing.
Fungal alpha diversity did not change, but communities shifted from Basidiomycota to Ascomycota dominant within the first decade. Bacterial alpha diversity increased, with Gemmatimonadota groups generally increasing and Actinomycetota groups generally decreasing in agricultural soils. These altered communities led to altered functional capacity. Functional genes associated with nitrification and low molecular weight C cycling potential increased after conversion, while those associated with organic P mineralization potential decreased. Stable increases in most N cycling functions occurred within the first decade, but C cycling functions were still changing 50 years post conversion.
Microbial communities underwent a rapid shift in the first decade, followed by several decades of slower transition until stabilizing 50 years post conversion. Understanding how the microbial communities respond at different stages post-conversion improves our ability to predict C and N losses from emerging boreal agricultural systems, and provides insight into how best to manage these soils in a way that is sustainable at the local level and within a global context.
Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may ...identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.
Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or
mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.
Specificity for ultrasound referral was 92% versus 90% (
= 0.0001), and PPV was 4.6% versus 10% (
> 0.10). Eighteen of 19 malignant ovarian neoplasms prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9 were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical
controls;
= 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).
For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation.
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