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Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system. [ABSTRACT FROM AUTHOR]

Background:Objectively measured circulating biomarkers of prognosis complementing existing clinicopathological models are needed in renal cell carcinoma (RCC).Methods:Blood samples collected from 216 RCC patients in Leeds before nephrectomy (median follow-up 7 years) were analysed for C-reactive protein (CRP), osteopontin (OPN) and carbonic anhydrase IX (CA9) and prognostic significance determined.Results:CA9, OPN and CRP were univariately prognostic for overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) with CRP and CA9 being independently prognostic for OS/CSS and OS, respectively. Including CA9, OPN and CRP with other conventional prognostic factors gave a superior predictive capacity when compared with a previously published pre-operative clinical nomogram (Karakiewicz et al, 2009). Osteopontin outperformed this nomogram and the post-operative SSIGN score for OS but not for CSS, being significantly predictive for non-cancer deaths. Osteopontin, CRP and CA9 outperformed stage (c-index 76% compared with 70% for stage) and OPN or CA9 identified several subsets of poor prognosis patients including in T1 patients, who may benefit from adjuvant therapy and increased surveillance.Conclusion:Circulating CA9, OPN and CRP add value to existing clinicopathological prognostic factors/models and support further studies to investigate their potential use in improving the clinical management of RCC. [ABSTRACT FROM AUTHOR]

Introduction Temporal discrimination threshold (TDT) and temporal motor discrimination threshold (TMDT) are measures of somatosensory processing indicating the shortest time interval at which two stimuli applied to skin or muscle, respectively, are detected to be asynchronous. TDT and/or TDMT have been shown to be increased in patients with movement disorders, like essential tremor, dystonia, or Parkinson”s disease. However, the meaning of these findings is still quite unclear. Here, we assessed the association of TDT and TDMT with age, proprioception, and polyneuropathy (PNP). Materials and methods 54 healthy subjects (age 29–75 years) and 15 patients with neurophysiologically confirmed PNP were included. TDT was tested with surface electrodes placed over thenar or dorsal foot region, respectively. TDMT was measured via an insulated tungsten needle microelectrode inserted at the motor point of flexor carpi radialis (FCR) or tibialis anterior (TA) muscle. Pairs of subsequent electric stimuli with varying interstimulus intervals (ISI) were provided, and discrimination thresholds were defined as the shortest ISI at which subjects were able to identify two separate stimuli. Proprioception of upper and lower limbs was assessed by custom-built devices, basically consisting of a goniometer without direct visual feedback of the respective extremity and its movements (flexion/extension). Subjects were instructed (i) to point to LED markers attached to the outside of the device, (ii) to move in proportion to arrows of different length shown on a computer screen, and (iii) to estimate their limb position after passive hand movements. Part of the assessment was conducted under dual task condition (tone-counting task). Pointing (or estimation) error (in degree) was taken as a measure of proprioceptive performance. Results In healthy subjects higher age was associated with higher TDT in every tested condition (right hand [ r = 0.358, p < 0.01], left hand [ r = 0.359, p < 0.01] and right foot [ r = 0.591, p < 0.0001]), and higher TDMT of lower limb (right foot [ r = 0.505, p < 0.001]). Additionally there was a moderate, though significant correlation between performance in the arrow proprioception task and TDMT of upper (but not lower) extremities (right hand [ r = 0.317, p = 0.05]). In PNP patients, TDMT and TDT were significantly higher at all sites as compared to controls ( p < 0.001; e.g. mean TDMT at the right hand: 137.8 ms vs. 81.2 ms). Moreover, PNP patients performed worse in all active pointing tasks. Discussion Our results point to an association between higher age and poorer capacity of discriminating somatosensory stimuli. The correlation of performance in a particular pointing task of the hand with lower TDMT suggests this measure as a potential surrogate marker of proprioceptive function. Both TDT and TDMT were markedly increased in PNP patients, indicating their clinical meaning in diseases with affection of the proprioceptive system. This might also be the pathophysiological link to previous findings of elevated thresholds in movement disorders. [ABSTRACT FROM AUTHOR]