Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Contactin‐associated protein‐like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2‐related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting‐up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage‐gated potassium channel (VGKC) complex that is composed of TAG‐1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up‐to‐date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation.     

Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional IP3 receptor subtype 3 defects

Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca²⁺) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP₃R), a homo- or heterotetramer of the IP₃R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca²⁺ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP₃R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP₃R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca²⁺ signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca²⁺ signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP₃R3 in IP₃R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype–phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca²⁺ channels and immunodeficiency and identify IP₃Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca²⁺-associated immunodeficiency from store-operated entry to impaired Ca²⁺ mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca²⁺ signaling.     

Impact of the new kidney allocation system A2/A2B → B policy on access to transplantation among minority candidates

Blood group B candidates, many of whom represent ethnic minorities, have historically had diminished access to deceased donor kidney transplantation (DDKT). The new national kidney allocation system (KAS) preferentially allocates blood group A2/A2B deceased donor kidneys to B recipients to address this ethnic and blood group disparity. No study has yet examined the impact of KAS on A2 incompatible (A2i) DDKT for blood group B recipients overall or among minorities. A case‐control study of adult blood group B DDKT recipients from 2013 to 2017 was performed, as reported to the Scientific Registry of Transplant Recipients. Cases were defined as recipients of A2/A2B kidneys, whereas controls were all remaining recipients of non‐A2/A2B kidneys. A2i DDKT trends were compared from the pre‐KAS (1/1/2013‐12/3/2014) to the post‐KAS period (12/4/2014‐2/28/2017) using multivariable logistic regression. Post‐KAS, there was a 4.9‐fold increase in the likelihood of A2i DDKT, compared to the pre‐KAS period (odds ratio [OR] 4.92, 95% confidence interval [CI] 3.67‐6.60). However, compared to whites, there was no difference in the likelihood of A2i DDKT among minorities post‐KAS. Although KAS resulted in increasing A2/A2B→B DDKT, the likelihood of A2i DDKT among minorities, relative to whites, was not improved. Further discussion regarding A2/A2B→B policy revisions aiming to improve DDKT access for minorities is warranted.     

Optimal timing of hepatitis C treatment among HIV/HCV coinfected ESRD patients: Pre‐ vs posttransplant

Patients with end‐stage renal disease (ESRD) who are coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have access to effective treatment options for HCV infection. However, they also have access to HCV‐infected kidneys, which historically afford shorter times to transplantation. Given the high waitlist mortality and rapid progression of liver fibrosis among coinfected kidney‐only transplant candidates, identification of the optimal treatment strategy is paramount. Two strategies, treatment pre‐ and posttransplant, were compared using Monte Carlo microsimulation of 1 000 000 candidates. The microsimulation was stratified by liver fibrosis stage at waitlist addition and wait‐time over a lifetime time horizon. Treatment posttransplant was consistently cost‐saving as compared to treatment pretransplant due to the high cost of dialysis. Among patients with low fibrosis disease (F0‐F1), treatment posttransplant also yielded higher life months (LM) and quality‐adjusted life months (QALM), except among F1 candidates with wait times ≥ 18 months. For candidates with advanced liver disease (F2‐F4), treatment pretransplant afforded more LM and QALM unless wait time was <18 months. Moreover, treatment pretransplant was cost‐effective for F2 candidates with wait times >71 months and F3 candidates with wait times >18 months. Thus, optimal timing of HCV treatment differs based on liver disease severity and wait time, favoring pretransplant treatment when cirrhosis development prior to transplant seems likely.     

Are lipid‐lowering drugs associated with a risk of cataract? A pharmacovigilance study

Some reports have raised concerns regarding a potential risk of cataracts associated with statins. However, clinical and observational studies evaluating the risk led to conflicting results. We assessed whether lipid‐lowering drugs (LLD) use is associated with an increased risk of cataract using the WHO's Individual Case Safety Reports database, VigiBase^®. We performed a disproportionality analysis with all reports between 1/1/1988 and 12/31/2018 to measure the reporting risk of ‘cataract’ in patients ≥45 years. Primary analysis compared LLD users to non‐users. To mitigate some potential confounding bias, we performed several sensitivity analyses excluding reports (i) with an association of at least two LLD, (ii) with antidiabetic and glucocorticoids and (iii) with lovastatin. We also analyzed the data according to the different classes of age limiting the period of study to years 2002–2012. We identified 14 664 reports of cataract (3 049 in LLD users, 66% women, 66 ± 20 years). Statins (84%, atorvastatin, simvastatin, rosuvastatin and lovastatin) were mostly reported, followed by fibrates (5.7%), nicotinic acid (3%), bile acid sequestrants (2%), herbal cholesterol and triglyceride reducers (2%) and others (ezetimibe, PCSK9 inhibitors, 15%). LLD users were associated with a greater risk of reports than non‐users (ROR 2.47, 95% CI 2.37–2.57). This association was also found for statins in general, fibrates, bile sequestrants, nicotinic acid, herbal drugs and others. Similar trends were observed in sensitivity analyses (except for fibrates and nicotinic acid after exclusion of reports with at least two LLD or in older patients ≥75 years). Using a large real‐life database (>18.5 million reports), we found a signal of cataract for LLD as a whole and statins, bile sequestrants and herbal drugs in particular. The signal disappeared for fibrates and nicotinic acid in older patients. No definite conclusions can be made for ezetimibe or PCSK9 inhibitors (evolocumab and alirocumab). This suggests that a decrease in cholesterol could be important in the pathophysiology of cataract in patients exposed to the main LLD.     

Molecular prediction of clinical response to anti-PD-1/anti-PD-L1 immune checkpoint inhibitors: New perspectives for precision medicine and mass spectrometry-based investigations

Monoclonal antibodies (mAbs) acting as immune checkpoint inhibitors (ICIs) are among the most frequently used immunotherapies in oncology. However, precision medicine approaches to adapt the treatment to the patient are still poorly exploited. Given the risk of severe adverse reactions, predicting patient eligibility for ICI therapy represents a great asset for precision medicine. Today, the extended panel of mass spectrometric approaches, accompanied by newly developed sample preparation methods is a strategy of choice for responder and non-responder stratification on a molecular basis, and early detection of resistance. In this perspective article, we review the biodisposition of mAbs, the interest in molecular stratification of patients treated with these mAbs, and the possible analytical strategies to achieve this goal, with a major emphasis on mass spectrometric approaches.     

Sex differences in serotonin enhancement of capsaicin-evoked calcitonin gene-related peptide release from human dental pulp

Serotonin (5HT) is a pronociceptive mediator in the periphery, and evidence implicates involvement in trigeminal pain processing. However, the mechanism(s) by which 5HT modulates trigeminal nociceptors remains unclear. Trigeminal pain can be evoked by the transient receptor potential V1 channel (TRPV1), which is expressed by nociceptive trigeminal neurons and induces release of proinflammatory calcitonin gene-related peptide (CGRP). In our preclinical models, 5HT evoked thermal hyperalgesia and enhanced calcium influx and CGRP release from the TRPV1 population of trigeminal nociceptors. Whether this occurs in humans is unknown. As dental pulp is densely innervated by trigeminal nociceptors, routine tooth extractions offer a unique opportunity to examine whether 5HT enhances CGRP release from human nociceptors. Pulpal tissue was collected from 140 extracted molar teeth from men and women, and basal release samples were collected before treatment with saline or 5HT 100μmol/L. CGRP release was then stimulated with the TRPV1 agonist capsaicin 1μmol/L and quantitated by enzyme immunoassay. Additional samples were collected for Western blots to examine 5HT receptor expression. We report that 5HT induced a significant increase in capsaicin-evoked CGRP release, and that this enhancement was observed only in female dental pulp, with no effect of 5HT on male dental pulp. The greatest amount of CGRP release occurred in dental pulp from women in the luteal phase of the menstrual cycle. These results indicate that 5HT enhances capsaicin-evoked CGRP release from human trigeminal nociceptors in a sexually dimorphic manner providing a mechanistic basis for prevalence of trigeminal pain disorders in women.     

Very early modulation of brain responses to neutral faces by a single prior association with an emotional context: evidence from MEG

Recent electrophysiological studies have demonstrated modulations of the very first stages of visual processing (<100 ms) due to prior experience. This indicates an influence of a memory trace on the earliest stages of stimulus processing. Here we investigated if emotional audio-verbal information associated with faces on first encounter can affect the very early responses to those faces on subsequent exposure. We recorded magneto-encephalographic (MEG) responses to neutral faces that had been previously associated with positive (happy), negative (angry) or neutral auditory verbal emotional contexts. Our results revealed a very early (30-60 ms) difference in the brain responses to the neutral faces according to the type of previously associated emotional context, with a clear dissociation between the faces previously associated to positive vs. negative or neutral contexts. Source localization showed that two main regions were involved in this very early association effect: the bilateral ventral occipito-temporal regions and the right anterior medial temporal region. These results provide evidence that the memory trace of a face integrates positive emotional cues present in the context of prior encounter and that this emotional memory can influence the very first stages of face processing. These experimental findings support the idea that face perception can be shaped by experience from its earliest stages and in particular through emotional association effects.