Cortical abnormalities of synaptic vesicle protein 2A in focal cortical dysplasia type II identified in vivo with 18F-SynVesT-1 positron emission tomography imaging

Purpose The loss of synaptic vesicle glycoprotein 2A (SV2A) is well established as the major correlate of epileptogenesis in focal cortical dysplasia type II (FCD II), but this has not been directly tested in vivo. In this positron emission tomography (PET) study with the new tracer 18F-SynVesT-1, we evaluated SV2A abnormalities in patients with FCD II and compared the pattern to 18F-fluorodeoxyglucose (18F-FDG). Methods Sixteen patients with proven FCD II and 16 healthy controls were recruited. All FCD II patients underwent magnetic resonance imaging (MRI) and static PET imaging with both 18F-SynVesT-1 and 18F-FDG, while the controls underwent MRI and PET with only 18F-SynVesT-1. Visual assessment of PET images was undertaken. The standardized uptake values (SUVs) of 18F-SynVesT-1 were computed for regions of interest (ROIs), along with SUV ratio (SUVr) between ROI and centrum semiovale (white matter). Asymmetry indices (AIs) were analyzed between the lesion and the contralateral hemisphere for intersubject comparisons. Results Lesions in the brains of FCD II patients had significantly reduced 18F-SynVesT-1 uptake compared with contralateral regions, and brains of the controls. 18F-SynVesT-1 PET indicated low lesion uptake in 14 patients (87.5%), corresponding to hypometabolism detected by 18F-FDG PET, with higher accuracy for lesion localization than MRI (43.8%) (P < 0.05). AI analyses demonstrated that in the lesions, SUVr for each of the radiotracers were not significantly different (P > 0.05), and 18F-SynVesT-1 SUVr correlated with that of 18F-FDG across subjects (R2 = 0.41, P = 0.008). Subsequent visual ratings indicated that 18F-SynVesT-1 uptake had a more restricted pattern of reduction than 18F-FDG uptake in FCD II lesions (P < 0.05). Conclusion SV2A PET with 18F-SynVesT-1 shows a higher accuracy for the localization of FCD II lesions than MRI and a more restricted pattern of abnormality than 18F-FDG PET.

Evaluation of the Pulmonary Function Test (PFT) in Patients Affected by Severe COVID-19 Pneumonia: 6 to 12 Weeks After Discharge

The most lethal adverse effect of COVID-19 is acute respiratory distress syndrome, which can lead to rapid death. This symptom even causes concern for patients who have recovered and have been discharged. Therefore, it is obligatory to test and monitor variations in their lungs’ function after recovery. In this study, we evaluated the pulmonary function of 64 patients with severe COVID-19, six weeks to 3 months after discharge. Pulmonary function parameters were measured by spirometry and body box according to the criteria of the American Thoracic Society and under the supervision of an adult pulmonologist. According to the forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio and total lung capacity (TLC) values, it was found that 3.1% of people had an obstructive pattern, 40.63% of patients had the restrictive pattern, and 6.25% of improved individuals showed a mixed pattern. Furthermore, the study of diffusion capacity of carbon monoxide (DLCO) index revealed that 13.3%, 25%, and 53% of cases had mild, moderate, and severe disorders of gas exchange, respectively. In addition, determining the maximum amount of inspiratory muscles (PI max) and expiratory muscles (PE max) disclosed that the rate of these two indicators in 62.5% and 71.88% of the subjects were less than 50%, respectively. In general, the results of the present study suggest that pulmonary function test and follow-up of patients' condition are not only recommended but seems to be essential after recovery due to the large percentage of patients with the restricted pattern a few weeks after recovery.

The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies

Epstein-Barr virus (EBV) is closely linked to the development of a number of human cancers. EBV-associated malignancies are characterized by a restricted pattern of viral latent protein expression which is sufficient for the virus to both initiate and sustain cell growth and to protect virus-infected cells from immune attack. Expression of these EBV proteins in malignant cells provides an attractive target for therapeutic intervention. Among the viral proteins expressed in the EBV-associated epithelial malignancies, the protein encoded by the BamHI-A rightward frame 1 (BARF1) is of particular interest. BARF1 is a viral oncoprotein selectively expressed in latently infected epithelial cancers, nasopharyngeal carcinoma (NPC) and EBV-positive gastric cancer (EBV-GC). Here, we review the roles of BARF1 in oncogenesis and immunomodulation. We also discuss potential strategies for targeting the BARF1 protein as a novel therapy for EBV-driven epithelial cancers.

The Na+ and K+ transport system of sperm (ATP1A4) is essential for male fertility and an attractive target for male contraception†

One of the mechanisms that cells have developed to fulfil their specialized tasks is to express different molecular variants of a particular protein that has unique functional properties. Na,K-ATPase (NKA), the ion transport mechanism that maintains the transmembrane Na+ and K+ concentrations across the plasma membrane of cells, is one of such protein systems that shows high molecular and functional heterogeneity. Four different isoforms of the NKA catalytic subunit are expressed in mammalian cells (NKAα1, NKAα2, NKAα3, and NKAα4). NKAα4 (ATP1A4) is the isoform with the most restricted pattern of expression, being solely produced in male germ cells of the testis. NKAα4 is abundant in spermatozoa, where it is required for sperm motility and hyperactivation. This review discusses the expression, functional properties, mechanism of action of NKAα4 in sperm physiology, and its role in male fertility. In addition, we describe the use of NKAα4 as a target for male contraception and a potential approach to pharmacologically block its ion transport function to interfere with male fertility.

High-Grade Endometrioid Carcinoma of the Endometrium With a GATA-3-Positive/PAX8-Negative Immunophenotype Metastatic to the Breast: A Potential Diagnostic Pitfall

This report describes clinicopathologic findings from the case of a patient with a breast mass that was ultimately diagnosed as a metastatic high-grade endometrioid carcinoma of endometrial origin. The breast lesion as well as the solid areas of the endometrial lesion displayed a similar immunoprofile: GATA3-positive; synaptophysin positive; negative for mammaglobin, gross cystic disease fluid protein-15, chromogranin, estrogen receptor, progesterone receptor, and HER2/neu; and intact expression of the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. The breast lesion was negative for PAX-8, whereas the solid areas of the endometrial lesion showed focal weak positivity. A review of the literature on GATA-3 expression in endometrial carcinomas found a reported frequency of expression that ranged from 0% to 13% of cases, typically in a patchy, focal, and generally restricted pattern. However, GATA-3 may be diffusely expressed in high-grade endometrial carcinomas. Since the potential for PAX-8 expression to be lost in high-grade endometrioid carcinomas is well known, a GATA-3-positive/PAX8-negative immunoprofile may be encountered in high-grade endometrioid carcinomas of the endometrium, and this composite immunoprofile is a potential diagnostic pitfall when such a lesion is being evaluated in a breast metastasis.

Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2—whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

Mechanoadaptive Responses in the Periodontium Are Coordinated by Wnt

Despite an extensive literature documenting the adaptive changes of bones and ligaments to mechanical forces, our understanding of how tissues actually mount a coordinated response to physical loading is astonishingly inadequate. Here, using finite element (FE) modeling and an in vivo murine model, we demonstrate the stress distributions within the periodontal ligament (PDL) caused by occlusal hyperloading. In direct response, a spatially restricted pattern of apoptosis is triggered in the stressed PDL, the temporal peak of which is coordinated with a spatially restricted burst in PDL cell proliferation. This culminates in increased collagen deposition and a thicker, stiffer PDL that is adapted to its new hyperloading status. Meanwhile, in the adjacent alveolar bone, hyperloading activates bone resorption, the peak of which is followed by a bone formation phase, leading ultimately to an accelerated rate of mineral apposition and an increase in alveolar bone density. All of these adaptive responses are orchestrated by a population of Wnt-responsive stem/progenitor cells residing in the PDL and bone, whose death and revival are ultimately responsible for directly giving rise to new PDL fibers and new bone.

Exploration of Anti-Yo and Anti-Hu paraneoplastic neurological disorders by PhIP-Seq reveals a highly restricted pattern of antibody epitopes

Paraneoplastic neurological disorders (PNDs) are immune-mediated diseases of the nervous system understood to manifest as part of a misdirected anti-tumor immune response. Identifying PND-associated autoantibodies and their cognate antigens can assist with proper diagnosis and treatment while also enhancing our understanding of tumor-associated immune processes, triggers for autoimmune disease, and the functional significance of onconeuronal proteins. Here, we employed an enhanced version of phage display immunoprecipitation and sequencing (PhIP-Seq) leveraging a library of over 731,000 unique phage clones tiling across the entire human proteome to detect autoantibodies and create high-resolution epitope profiles in serum and CSF samples from patients suffering from two common PNDs, the anti-Yo (n = 36 patients) and anti-Hu syndromes (n = 44 patients). All patient samples positive for anti-Yo antibody by a validated clinical assay yielded polyspecific enrichment of phage presenting peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients (17/44) had a serum and/or CSF sample that significantly enriched peptides deriving from the ELAVL family of proteins, the anti-Hu autoantigenic target. The anti-Hu antibodies showed a remarkably convergent antigenic signature across 15/17 patients corresponding to residues surrounding and including the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, PhIP-Seq identified several known and novel autoantigens in these same patient samples, representing potential biomarkers that could aid in the diagnosis and prognosis of PND and cancer.

The link between an Nav1.7 mutation and erythromelalgia

The landmark paper discussed in this chapter is ‘Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons’, published by Dib-Hajj et al. in 2005. The voltage-dependent sodium channels Nav1.7, Nav1.8, and Nav1.9 have a restricted pattern of expression in sensory neurons in the periphery and are concentrated in small nociceptive neurons of the dorsal root ganglion, the trigeminal ganglion, and the nodose ganglion. In this paper, Dib-Hajj and colleagues studied a family with erythromelalgia (Weir Mitchell disease), an autosomal-dominant, inherited pain disorder in which burning pain in the extremities can be triggered by warming of the skin or moderate exertion. By identifying a novel mutation in SCN9A, which encodes Nav1.7, they established the critical role of this specific ion channel in this patient population. These findings represent an important first step towards developing isoform-specific channel blockers for the treatment of an inherited chronic pain condition.