The genetics,structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease

The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved. Here we discuss what is known about their structure and function and highlight some of the knowledge gaps that affect development of drugs targeting these enzymes.     

Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions

BackgroundDendritic cells (DCs) are usually immunogenic, but they are also capable of inducing tolerance under anti-inflammatory conditions. Immunotherapy based on autologous DCs loaded with an allogeneic melanoma cell lysate (TRIMEL/DCs) induces immunological responses and increases melanoma patient survival. Glucocorticoids can suppress DC maturation and function, leading to a DC-mediated inhibition of T cell responses.MethodsThe effect of dexamethasone, a glucocorticoid extensively used in cancer therapies, on TRIMEL/DCs phenotype and immunogenicity was examined.ResultsDexamethasone induced a semi-mature phenotype on TRIMEL/DC with low maturation surface marker expressions, decreased pro-inflammatory cytokine induction (IL-1β and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-β). Dexamethasone-treated TRIMEL/DCs inhibited allogeneic CD4⁺ T cell proliferation and cytokine release (IFNγ, TNF-α and IL-17). Co-culturing melanoma-specific memory tumor-infiltrating lymphocytes with dexamethasone-treated TRIMEL/DC inhibited proliferation and effector T cell activities, including cytokine secretion and anti-melanoma cytotoxicity.ConclusionsThese findings suggest that dexamethasone repressed melanoma cell lysate-mediated DC maturation, generating a potent tolerogenic-like DC phenotype that inhibited melanoma-specific effector T cell activities. These results suggest that dexamethasone-induced immunosuppression may interfere with the clinical efficacy of DC-based melanoma vaccines, and must be taken into account for optimal design of cellular therapy against cancer.     

Warranting the decision-maker,not the decision: How healthcare practitioners evaluate the legitimacy of patients’ unprompted requests for risk-reducing mastectomy

ObjectiveShared decision-making exists to reconcile healthcare practitioners’ responsibilities to respect patients’ autonomy whilst ensuring well-made decisions. Patients sometimes make unprompted requests for procedures that carry medical and other risks, such as risk-reducing mastectomy (RRM). Faced with pre-formed decisions into which they have had little input, it is unclear how practitioners can reconcile respecting autonomy with ensuring well-made decisions.MethodsQualitative study of linked patient-practitioner interviews in a breast unit in North-West England. We examined how 10 practitioners addressed 19 patients’ unprompted requests for RRM.ResultsPractitioners empathised with patients’ distress about cancer risk, regarded RRM as legitimate to help, but were wary of choices made ‘emotionally’. Practitioners did not seek to establish whether choices were well-made but, instead, ‘warranted’ patients by satisfying themselves that patients were ‘sensible’ and ‘informed’ decision-makers, and thus their decisions could be trusted. Practitioners provided information, and tested patients’ resolve by delaying decisions and presenting ‘what if’ scenarios depicting failure or harm from RRM.ConclusionPatients who present emotionally and with resolution can receive RRM without evidence of a well-made decision.Practice Implications: Argumentation theory proposes an ethically robust and clinically practicable approach, whereby practitioners elicit, examine and, where appropriate, challenge arguments underpinning patients’ decisions.     

Assessment of objective dynamic knee joint control in anterior cruciate ligament deficient and reconstructed individuals

BackgroundThere is a lack of objective dynamic knee joint control measures that can be related to the status of the anterior cruciate ligament (ACL). The purpose of this study was to introduce two novel measures and apply a third to determine how dynamic knee joint control changes in relation to ACL status during dynamic movements.MethodsTwenty patients (13 male) were tested pre- (ACLd) and 10-months post- (ACLr) ACL reconstructive surgery and matched to an uninjured participant (CON). Kinetic and kinematic data were synchronously recorded with a force platform and motion capture system. Three objective control measures including dynamic angular stiffness, knee joint center excursion (KJCE), and knee joint center boundary (KJCB) were assessed for each participant when completing the side cut and hop tasks.ResultsDuring the side cut, stiffness was found to be significantly lower in ACLd (0.06 ± 0.01 Nm/kg/°) and ACLr (0.07 ± 0.02 Nm/kg/°) compared to CON (0.08 ± 0.02 Nm/kg/°), while there were no differences in stiffness during the hop. No significant differences were observed in the KJCE during the side cut, while KJCE was significantly greater (p = 0.006) during the hop in CON compared to the ACLd. There were no differences in KJCB.ConclusionsThese high-functioning ACL injured in both ACLd and ACLr phases, aside from reduced stiffness, were able to complete both tasks with similar dynamic control as the CON. Although improvements in self-perceived control between ACLd and ACLr have been observed, this lack of improvement in objective control demonstrates a gap between a patient's self-efficacy and the level of control.     

Need for sustainable approaches in antileishmanial drug discovery

Leishmaniasis is a neglected parasitic disease for which the current antileishmania therapeutics are hampered by drug toxicity, high cost, need for parenteral administration, increasing treatment failure rates, and emergence of drug resistance. The R&D pipeline had run fairly dry for several years, but fortunately some new drug candidates are now under (pre)clinical development. Identification of novel drugs will nevertheless remain essential to adequately sustain and improve effective disease control in the future. In this review, a package of standard and accessible R&D approaches is discussed with expansion to some alternative strategies focusing on parasite–host and vector–host interactions.

     

ER stress abrogates the immunosuppressive effect of IL-10 on human macrophages through inhibition of STAT3 activation

Inflammation Research - To determine whether ER stress affects the inhibitory pathways of the human immune system, particularly the immunosuppressive effect of IL-10 on macrophages. In vitro...     

Fructose 1,6-bisphosphate inhibits osteoclastogenesis by attenuating RANKL-induced NF-κB/NFATc-1

Inflammation Research - Although some glycolytic intermediates have been shown to modulate several cell type formation and activation, the functional role of fructose 1,6-bisphosphate (FBP) on...     

Under inflammatory stimuli mesenteric mesothelial cells transdifferentiate into macrophages and produce pro-inflammatory cytokine IL-6

Inflammation Research - Inflammatory stimuli inducing epithelial-to-mesenchymal transition (EMT) can transdifferentiate mesenteric mesothelial cells into macrophages. Sprague Dawley rat mesenteric...     

The relationship of actual height loss with health-seeking behaviors and risk factors in perimenopausal and menopausal women

PURPOSE: To explore whether there is a difference in the perceived height and actual height in the perimenopausal or menopausal woman and discover the difference's effect on osteoporosis health-seeking preventive behaviors and risk factor awareness. DATA SOURCES: Sixty-three perimenopausal and menopausal women, aged 45-70 years, who presented at three Midwestern clinics for their annual physical exam. Data were collected with The Osteoporosis Questionnaire, which included the Osteoporosis Risk Questionnaire, Health-O-Meter height measuring stick, tape measure with inch-rule for arm span measurements, and balance scale for weight. CONCLUSIONS: There were a significant relationship between actual height loss and osteoporosis risk factors (r = 0.41595, p = 0.0007) and a trend for a relationship between adjusted height loss and osteoporosis risk factors (r = 0.2407, p = 0.0574). IMPLICATIONS FOR PRACTICE: Due to the great expense of current testing for bone mass density loss, the results of this study may help clinicians more readily identify markers for increased risk of osteoporosis through simple height measurements and osteoporosis risk factor assessments during annual visits.