Mitral valve repair is the gold standard therapy for the treatment of degenerative mitral regurgitation (MR). Although outcomes following surgical mitral valve repair have been well described, few ...data are available on the longitudinal performance of mitral repair for patients according to the age at surgery. These data are particularly relevant in the era of percutaneous therapies, which are increasingly employed in younger patient groups. The purpose of this study was to report mortality and recurrent MR rates following mitral valve repair according to patient age at surgery.
We performed a retrospective cohort study with 1156 patients who underwent surgical mitral valve repair, in isolation or with concomitant procedures, for degenerative MR between 2003-2019. Clinical follow up was achieved through the University of Ottawa Heart Institute Mitral Valve Clinic. Echocardiographic follow up was performed at 1, 3, 6 and 12 months post-operatively and subsequently every 1-3 years or when clinically indicated. The mean patient age was 63.1±12.4 years and 320 (28%) were female. At the time of surgery, there were 51 patients < 40 years, 119 between 40-49, 245 between 50-59, 339 between 60-69, 304 between 70-79, and 98 >80 years. Clinical follow up averaged 4.7±4.0 years, with a total of 4776 postoperative transthoracic echocardiograms available for analysis in this cohort. Perioperative mortality for elective mitral valve repair was 1.3%. Ten-year freedom from recurrent MR that was at least moderate (≥2+) was 96±4%, 99±2%, 98±2%, 96±2%, 98±1%, and 92±5% for patients < 40 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, and >80 years. Ten-year survival was 98±2%, 95±2%, 93±2%, 91±2%, 71±3%, and 34±9% for these age groups, respectively. Older age groups were more likely to have mitral annular calcification at the time of surgery (P < 0.001), although the incidence of complex bileaflet prolapse was not different (P=0.4). Although the age of a patient at surgery was associated with survival (P < 0.001), it was not associated with the development of recurrent MR ≥2+ (P=0.1).
These novel surgical data provide insights into the prognosis and performance of surgical mitral valve repair in patients with degenerative disease according to their age at operation. These data might be helpful in shaping indications for future catheter-based approaches.
Introduction
Metastatic castration‐resistant prostate cancer (mCRPC) is a heterogeneous disease with prognoses varying from months to years at time of castration‐resistant diagnosis. Optimal ...first‐line therapy for those with different prognoses is unknown.
Methods
We conducted a retrospective cohort study of men in a national healthcare delivery system receiving first‐line therapy for mCRPC (abiraterone, enzalutamide, docetaxel, or ketoconazole) from 2010 to 2017, with follow‐up through 2019. Using commonly drawn prognostic labs at start of mCRPC therapy (hemoglobin, albumin, and alkaline phosphatase), we categorized men into favorable, intermediate, or poor prognostic groups depending on whether they had none, one to two, or all three laboratory values worse than designated laboratory cutoffs. We used Kaplan–Meier methods to examine prostate specific antigen (PSA) progression‐free and overall survival (OS) according to prognostic group and first‐line therapy, and multivariable cox regression to determine variables associated with survival outcomes.
Results
Among 4135 patients, median PSA progression‐free survival (PFS) was 6.9 months (95% confidence interval CI 6.6–7.3), and median OS 18.8 months (95% CI 18.0–19.6), ranging from 5.7 months (95% CI 4.8–7.0) in the poor prognosis group to 31.3 months (95% CI 29.7–32.9) in the favorable group. OS was similar regardless of initial treatment received for favorable and intermediate groups, but worse for those in the poor prognostic group who received ketoconazole (adjusted hazard ratio 2.07, 95% CI 1.2–3.6). PSA PFS was worse for those who received ketoconazole compared to abiraterone across all prognostic groups (favorable HR 1.76, 95% CI 1.34–2.31; intermediate HR 1.78, 95% CI 1.41–2.25; poor HR 8.01, 95% CI 2.93–21.9).
Conclusion
Commonly drawn labs at mCRPC treatment start may aid in predicting survival and response to therapies, potentially informing discussions with care teams. First‐line treatment selection impacts disease progression for all men with mCRPC regardless of prognostic group, but impacted OS only for men with poor prognosis at treatment start.
Hemoglobin, albumin, and alkaline phosphatase, used to categorize patients with metastatic castration resistant prostate cancer at start of new treatment into prognostic groups, was strongly predictive of survival, but survival did not vary substantially based on which treatment patients received within prognostic groups.
Risk of malignancy with long-term immunosuppression in renal transplant recipients.
Improvements in immunosuppressive regimens have significantly enhanced patient and graft survival in renal ...transplant recipients. However, susceptibility to neoplastic disorders is increased as a consequence of prolonged immunosuppression. Available data pertaining to cancer risks in renal transplant recipients have been inconsistent, and much of it is derived from international studies, which may not be truly representative of the United States population.
We studied a total of 1979 transplants performed in 1739 patients from a single center in the United States with a mean follow-up of 6.1 years, and a total of 9852 person-years' follow-up.
The mean age at the time of diagnosis of cancer was 50 years, and the mean interval between transplant and diagnosis of cancer was 95 months. Older patients receiving a transplant had a significantly higher risk for developing cancer as opposed to younger patients (RR 6.2 for >60 years compared with <40 years). When compared with the general population using data from the Surveillance, Epidemiology and End Results (SEER) registry, the overall risk for nonskin malignancies was modestly increased in our transplant recipients, with a standardized incidence ratio (SIR) of 1.4 (P = 0.01). When stratified by age groups, younger age at transplant (<40 years) had the highest SIR, at 2.3 (P < 0.001). Similarly, duration post-transplant >10 years had an SIR of 2.4 (P < 0.001).
We believe that this study is representative of the United States' renal transplant population, and highlights the need for reduced immunosuppression in the long-term and increased vigilance for cancers in younger patients receiving renal transplantation.
18F-FBAU and
18F-FCAU have been synthesized and evaluated
in vivo as markers for HSV1-tk gene expression. At 2 hours, uptake of
18F-FBAU and
18F-FCAU in HSV1-tk–positive tumors was 7.9-fold and ...6.0-fold higher than the control tumors, respectively. Micro-PET images also showed very high uptake in HSV-tk tumors. Compared to
14C-FMAU, total uptake of
18F-FBAU and
18F-FCAU was similar in tk-positive cells, but the uptake ratio (tk+/wild) was higher.
18F-FBAU and
18F-FCAU appear to be potential PET imaging agents for gene expression.
T-cell activation requires co-stimulation through receptors such as CD28 (refs 1,2,3) and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine co-stimulatory ...receptor-ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS, is expressed on activated T cells and resting memory T cells. The ligand, which has homology to B7 molecules and is called B7-related protein-1 (B7RP-1), is expressed on B cells and macrophages. ICOS and B7RP-1 do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells in vitro independently of CD28. Transgenic mice expressing a B7RP-1-Fc fusion protein show lymphoid hyperplasia in the spleen, lymph nodes and Peyer's patches. Presensitized mice treated with B7RP-1-Fc during antigen challenge show enhanced hypersensitivity. Therefore, B7RP-1 exhibits co-stimulatory activities in vitro and in vivo. ICOS and B7RP-1 define a new and distinct receptor-ligand pair that is structurally related to CD28-B7 and is involved in the adaptive immune response.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The outcome of T-cell responses after T-cell encounter with specific antigens
is modulated by co-stimulatory signals, which are required for both lymphocyte
activation and development of adaptive ...immunity. ICOS, an inducible co-stimulator with homology to CD28, is expressed
on activated, but not resting T cells, and shows T-cell co-stimulatory
function in vitro. ICOS binds specifically to its counter-receptor
B7RP-1 (refs 5,6,7), but not to B7-1 or B7-2. Here we provide in vivo
genetic evidence that ICOS delivers a co-stimulatory signal that is essential
both for efficient interaction between T and B cells and for normal antibody
responses to T-cell-dependent antigens. To determine the physiological function
of ICOS, we generated and characterized gene-targeted ICOS-deficient mice.
In vivo, a lack of ICOS results in severely deficient T-cell-dependent
B-cell responses. Germinal centre formation is impaired and immunoglobulin
class switching, including production of allergy-mediating IgE, is defective.
ICOS-deficient T cells primed in in vivo and restimulated in vitro
with specific antigen produce only low levels of interleukin-4, but remain
fully competent to produce interferon-γ.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
TRAF2 is an intracellular signal-transducing protein recruited to the TNFR1 and TNFR2 receptors following TNF stimulation. To investigate the physiological role of TRAF2, we generated TRAF2-deficient ...mice.
traf2
−/−
mice appeared normal at birth but became progressively runted and died prematurely. Atrophy of the thymus and spleen and depletion of B cell precursors also were observed. Thymocytes and other hematopoietic progenitors were highly sensitive to TNF-induced cell death and serum TNF levels were elevated in these TRAF2-deficient animals. Examination of
traf2
−/−
cells revealed a severe reduction in TNF-mediated JNK/SAPK activation but a mild effect on NF-κB activation. These results suggest that TRAF2-independent pathways of NF-κB activation exist and that TRAF2 is required for an NF-κB–independent signal that protects against TNF-induced apoptosis.
Induction of NF‐κB‐dependent transcription requires phosphorylation and subsequent degradation of I‐κB, an inhibitor of NF‐κB, followed by nuclear translocation and DNA binding of NF‐κB. Tumor ...necrosis factor receptor‐associated factor 2 (TRAF2) plays a role in NF‐κB activation in response to cytokines such as tumor necrosis factor α (TNFα). In this study, we purified and characterized a novel kinase (T2K, also known as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activity towards I‐κBα in vitro. The physiological function of T2K was investigated using T2K‐deficient mice. Heterozygotes appear normal, but t2k−/− animals die at ∼E14.5 of massive liver degeneration and apoptosis. Never theless, hematopoietic progenitors from T2K‐deficient fetal liver support normal lymphocyte development. Furthermore, t2k−/− embryonic fibroblasts and thymocytes do not display increased sensitivity to TNFα‐induced apoptosis. In response to either TNFα or IL‐1 induction, t2k−/− embryonic fibroblasts exhibit normal degradation of I‐κB and κB‐binding activity. However, NF‐κB‐directed transcription is dramatically reduced. These results demonstrate that, like I‐κB kinase β and the RelA subunit of NF‐κB, T2K is critical in protecting embryonic liver from apoptosis. However, T2K has a unique role in the activation of NF‐κB‐directed transcription, apparently independent of I‐κB degradation and NF‐κB DNA binding.
Little is known about how mammalian cells maintain cell size homeostasis. We conducted a novel genetic screen to identify cell-size-controlling genes and isolated Largen, the product of a gene ...(PRR16) that increased cell size upon overexpression in human cells. In vitro evidence indicated that Largen preferentially stimulates the translation of specific subsets of mRNAs, including those encoding proteins affecting mitochondrial functions. The involvement of Largen in mitochondrial respiration was consistent with the increased mitochondrial mass and greater ATP production in Largen-overexpressing cells. Furthermore, Largen overexpression led to increased cell size in vivo, as revealed by analyses of conditional Largen transgenic mice. Our results establish Largen as an important link between mRNA translation, mitochondrial functions, and the control of mammalian cell size.
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•PRR16/Largen is identified in a screen for genes controlling mammalian cell size•Largen enhances mRNA translation•Largen increases mitochondrial mass and activity•Largen controls cell size in vivo
Using a genetic screen, Yamamoto et al. identify PRR16 as a controller of mammalian cell size. Overexpression of the PRR16 gene product “Largen” increased cell size by modulating mitochondrial activity and mRNA translation in an mTOR-independent manner, both in vitro and in vivo.
Costimulation through the inducible costimulator (ICOS) and its ligand (ICOSL) is essential for T cell-dependent B cell responses, but the cellular and temporal dynamics underlying its in vivo ...effects are poorly defined. Here we have shown that Icosl(-/-) and Icos(-/-) mice had similar phenotypes and that ICOS-ICOSL costimulation modulated the early but not late phases of IgG1 affinity maturation. Exploiting the adoptive transfer of T or B cells from primed Icosl(-/-) mice, we provided genetic evidence that costimulation through ICOSL was essential for primary but not secondary helper T cell responses and for the control of both T and B cell activities, resulting in T cell-dependent IgG1 production.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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