Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 ...has been implicated in a variety of diseases, including Alzheimer’s disease, type 2 diabetes, cancer, and mood disorders. GSK-3β has been linked to the formation of the neurofibrillary tangles associated with Alzheimer’s disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo1,2-bpyridazine derivatives that were evaluated as GSK-3β inhibitors are described herein. Structure–activity relationship studies led to the identification of potent GSK-3β inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer’s disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3β inhibitor that significantly lowered levels of phosphorylated tau.
Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. ...GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.
Display omitted
In our continuing efforts to explore structure–activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we ...extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer’s disease model. In general, these 2‑pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer’s disease as well as ...various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3β in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer’s disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer’s disease model.
Passive antibodies, maternal or transfusion-acquired, make serologic determination of pretransplant cytomegalovirus (CMV) status unreliable. We evaluated 3 assays unaffected by passive antibodies, in ...assignment of CMV infection status in children awaiting solid organ transplant and in controls: (1) CMV nucleic acid amplification testing (NAAT), (2) quantification of CMV-specific CD4+ T cells, and (3) quantification of CD27-CD28-CD4+ T cells. Our results highlight that CMV NAAT, from urine and oropharynx, is useful in confirming positive CMV status. Detection of CMV-specific CD4+ T cells was sensitive and specific in children >18 months but was less sensitive in children <12 months. CD27-CD28-CD4+ T cells are not likely useful in CMV risk stratification in children.
GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, ...proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer’s disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.
A classification scheme and general set of criteria for diagnosing mild cognitive impairment (MCI) were recently proposed by a multidisciplinary group of experts who met at an international symposium ...on MCI. One of the proposed criteria included preserved basic activities of daily living and minimal impairment in complex instrumental activities of daily living (IADLs).
To investigate whether older adults with MCI classified according to the subtypes identified by the Working Group (i.e. amnestic, single non-memory domain, and multiple domain with or without a memory component) differed from cognitively intact older adults on a variety of measures indexing IADLs and to examine how well measures of IADL predict concurrent MCI status.
Two hundred and fifty community-dwelling older adults, ranging in age from 66 to 92, completed self-report measures of IADLs (Lawton and Brody IADL Scale, Scales of Independent Behaviour-Revised--SIB-R) and a measure of everyday problem solving indexing IADLs (Everyday Problems Test--EPT). Ratings of participants' IADL functioning were also obtained from informants (e.g. spouse, adult child and friend).
Older adults with multiple-domain MCI demonstrated poorer IADL functioning than older adults with no cognitive impairment on the EPT and the SIB-R (both self- and informant-report versions). The multiple-domain MCI participants also demonstrated poorer IADLs than MCI participants with impairments in a single cognitive domain on the self-reported SIB-R and EPT. The single-domain MCI groups demonstrated poorer IADLs than older adults without cognitive impairment on the informant-reported SIB-R and EPT. No significant group differences were found on the Lawton and Brody IADL Scale. Using the EPT and SIB-R as predictors in a multinomial regression analysis, MCI group status was reliably predicted, but the classification rate was poor.
Individuals with MCI demonstrated poorer IADL functioning compared to cognitively intact older adults. However, the changes in IADL functioning observed in MCI may be too subtle to be detected by certain measures, such as the Lawton and Brody IADL Scale.
•Cell-mediated immunity assays help resolve CMV status when passive antibodies exist.•Flow cytometry detected CMV-specific CD4+Tcells useful to assign CMV status pre-SOT.•CD27-CD28-CD4 + T cell ...analysis lacks specificity in assignment of CMV status pre-SOT.•CMV DNA is rarely detected in blood/urine of CMV-seropositive adults awaiting SOT.
Background/objectives: Determination of Cytomegalovirus (CMV) status in solid organ transplant (SOT) candidates is essential to stratify risk of post-transplant CMV disease. Passive transfusion-acquired antibodies can make serologic determination of CMV status unreliable. We evaluated 3 assays, not affected by passive antibodies (PA), in assignment of CMV status: quantification of CMV-specific CD4 + T-cells (CMV-TC) and exhausted CD27-CD28- CD4 + T-cells, and detection of CMV DNA with Nucleic Acid Amplification Testing (NAAT).
Study design: We enrolled 50 adults awaiting SOT and 50 immunocompetent age-matched controls, and collected a throat swab, urine, saliva and blood sample on each. Using flow cytometry CD4 + T-cells were phenotypically analyzed for expression of CD27 and CD28 and CMV-specific CD4 + T-cells were identified by CD69 expression and intracellular IFN-γ quantification after stimulation with CMV-antigen lysate. CMV NAAT was performed on all specimens using real-time PCR. CMV serology (CMV IgG) was determined by enzyme immunoassay. Subjects were considered to have potential PA if they received blood products within 2 months of collection.
Results: The CMV-TC assay discriminated between CMV-seropositive and seronegative SOT candidates without PA well (sensitivity 79%, specificity 93%) while the CD27-CD28-CD4 + T-cell assay had good sensitivity (86%) but specificity of 74%. Detection of CMV DNA was uncommon in CMV-seropositive SOT candidates (2/21).
Conclusions: Given its high specificity, the CMV-TC assay is valuable in confirming true-positive CMV status in seropositive SOT candidates with PA, while use of CD27-CD28-CD4 + T-cell analysis is limited by moderate specificity. Detection of CMV DNA is of limited value in assignment of CMV status in adults.
Growing evidence suggests receipt of live‐attenuated viral vaccines after solid organ transplant (SOT) has occurred and is safe and needed due to lapses in herd immunity. A 2‐day consortium of ...experts in infectious diseases, transplantation, vaccinology, and immunology was held with the objective to review evidence and create expert recommendations for clinicians when considering live viral vaccines post‐SOT. For consideration of VV and MMR post‐transplant, evidence exists only for kidney and liver transplant recipients. For MMR vaccine post‐SOT, consider vaccination during outbreak or travel to endemic risk areas. Patients who have received antiproliferative agents (eg. mycophenolate mofetil), T cell–depleting agents, or rituximab; or have persistently elevated EBV viral loads, or are in a state of functional tolerance, should be vaccinated with caution and have a more in‐depth evaluation to define benefit of vaccination and net state of immune suppression prior to considering vaccination. MMR and/or VV (not combined MMRV) is considered to be safe in patients who are clinically well, are greater than 1 year after liver or kidney transplant and 2 months after acute rejection episode, can be closely monitored, and meet specific criteria of “low‐level” immune suppression as defined in the document.
Immunocompromised children are at increased risk of severe illness from vaccine-preventable infections. However, inadequate vaccine coverage remains a concern. This scoping review sought to determine ...the current state of knowledge regarding vaccine coverage of immunocompromised children. Bibliographic databases were searched for primary research from any year. Data were analyzed quantitatively and narratively. Ninety-seven studies met inclusion criteria. The most commonly studied vaccines were pneumococcal (n = 46), influenza (n = 44), diphtheria/tetanus/pertussis/poliomyelitis/Haemophilus influenzae type B/hepatitis B-containing (n = 36), and measles- and/or mumps- and/or rubella-containing (n = 29). Immunocompromising conditions studied included cancer/stem cell transplants (n = 24), solid organ transplants (n = 23), sickle cell disease (n = 21), immunosuppressive therapy (n = 14), human immunodeficiency virus (n = 12), splenectomy (n = 4), and primary immunodeficiency (n = 2). As more children are treated with immunosuppressive therapies, it is critical to identify whether they are being appropriately vaccinated for age and condition. We identified gaps in the current state of knowledge for specific vaccine types in specific immunocompromised populations.
PDF
