The Three Dimensions of Functional T-Cell Tolerance: From Research to Practice

In this issue, Paek et al. describe two phenomena. First, they show that intermediate concentrations of a “transgenic” autoantigen may cause a lichen planus–like autoimmune disease. Second, and more importantly, they show that high doses of peptide antigen suppress the expression of the T-cell receptor and coreceptors, particularly CD8, and that this suppression improves this T-cell-mediated, destructive inflammatory skin disease that is similar to erosive lichen planus

Predictive biomarkers in gastric cancer

Predictive biomarkers are the mainstay of precision medicine. This review summarizes the advancements in tissue-based diagnostic biomarkers for gastric cancer, which is considered the leading cause of cancer-related deaths worldwide. A disease seen in the elderly, it is often diagnosed at an advanced stage, thereby limiting therapeutic options. In Western countries, neoadjuvant/perioperative (radio-)chemotherapy is administered, and adjuvant chemotherapy is administered in the East. The morpho-molecular classification of gastric cancer has opened novel avenues identifying Epstein-Barr-Virus (EBV)-positive, microsatellite instable, genomically stable and chromosomal instable gastric cancers. In chromosomal instable tumors, receptor tyrosine kinases (RKTs) (e.g., EGFR, FGFR2, HER2, and MET) are frequently overexpressed. Gastric cancers such as microsatellite instable and EBV-positive types often express immune checkpoint molecules, such as PD-L1 and VISTA. Genomically stable tumors show alterations in claudin 18.2. Next-generation sequencing is increasingly being used to search for druggable targets in advanced palliative settings. However, most tissue-based biomarkers of gastric cancer carry the risk of a sampling error due to intratumoral heterogeneity, and adequate tissue sampling is of paramount importance

Accurate machine learning force fields via experimental and simulation data fusion

Machine Learning (ML)-based force fields are attracting ever-increasing interest due to their capacity to span spatiotemporal scales of classical interatomic potentials at quantum-level accuracy. They can be trained based on high-fidelity simulations or experiments, the former being the common case. However, both approaches are impaired by scarce and erroneous data resulting in models that either do not agree with well-known experimental observations or are under-constrained and only reproduce some properties. Here we leverage both Density Functional Theory (DFT) calculations and experimentally measured mechanical properties and lattice parameters to train an ML potential of titanium. We demonstrate that the fused data learning strategy can concurrently satisfy all target objectives, thus resulting in a molecular model of higher accuracy compared to the models trained with a single data source. The inaccuracies of DFT functionals at target experimental properties were corrected, while the investigated off-target properties remained largely unperturbed. Our approach is applicable to any material and can serve as a general strategy to obtain highly accurate ML potentials

Magnetic resonance imaging-based diagnosis of aortitis preceding development of a thoracic aneurysm in a patient with giant cell arteritis: a case report

Background Inflammatory manifestation in the aortic arch can be a complication of giant cell arteritis (GCA), potentially requiring surgical therapy in the case of aneurysmatic dilatation. Case summary We report the case of a 73-year-old female patient with GCA in whom a typical appearance of arteritis was visualized on magnetic resonance imaging of the superficial temporal arteries. Additionally, ectasia (4.7 cm) of the ascending aorta with a mural rim of increased contrast media uptake was detected at the time of the initial diagnosis, which is an indicator of aortitis. While the diameter had only minimally increased in a computed tomography angiography (CTA) examination after 8 months, a subsequent CTA revealed an increased diameter of 5.8 cm and maximum at the level of the ascending aorta another 22 months later, indicating urgent surgery to replace the ascending aorta. Discussion Magnetic resonance imaging can detect silent, generalized manifestations of GCA such as severe aortitis, which may possibly lead to aneurysmatic dilatation, urging closer follow-up imaging. Detection of the ongoing process and subsequent follow-up imaging protects patients by avoiding rupture

Probable cerebral amyloid angiopathy diagnosed on plain CT

Cerebral amyloid angiopathy (CAA) is the most common cause for lobar haemorrhages. The prevalence of CAA is believed to be app. 30% in non-demented elderly patients and increases with age [1]. CAA is diagnosed using the modified Boston criteria [2] which relies heavily on neuroimaging. Recently, the imaging signs “finger like projections” (FLP) and subarachnoid haemorrhage (SAH) adjacent to the main haemorrhage have been suggested as additional markers of CAA [3]. While MRI is desirable to advance the diagnosis of CAA non-invasively, in some patients, MRI is not feasible due to contraindications or logistics constraints. Moreover, plain CT remains the first-line imaging modality in the acute stage. We present a retrospectively compiled case series of patients with lobar haemorrhages in whom an MRI was not performed but many imaging features hinted towards the diagnosis of cerebral amyloid angiopathy on plain CT

Gastric carcinomas with stromal b7-h3 expression have lower intratumoural cd8+ t cell density

Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.CD8+ T cells are the main effector cells of anti-cancer immune response that can be regulated by various costimulatory and coinhibitory molecules, including members of the B7 family. B7 homolog 3 (B7-H3) appears as a promising marker for immunotherapy; however, its significance in gastric cancer (GC) is unclear yet. We evaluated the spatial distribution of CD8+ T cells in relation to the expression of B7-H3 by double immunohistochemical staining. The level of B7-H3 intensity was scored manually (0-3) and dichotomized into B7-H3-low and B7-H3-high groups. The distribution and density of CD8+ T cells was analysed using whole slide digital imaging. B7-H3 was expressed mainly in the stromal compartment of GC (n = 73, 76% of all cases). Tumours with high expression of B7-H3 showed larger spatial differences of CD8+ T cells (86.4/mm2 in tumour centre vs. 414.9/mm2 in invasive front) when compared to B7-H3-low group (157.7/mm2 vs. 218.7/mm2, respectively) (p < 0.001). This study provides insight into the expression pattern of B7-H3 in GC of Western origin. In GCs with higher level of B7-H3 expression, CD8+ T cells were spatially suppressed in the tumour centre suggesting that B7-H3 might be involved in tumour escape mechanisms from the immune response.publishersversionPeer reviewe

A woman with a rare p.Glu74Gly transthyretin mutation presenting exclusively with a rapidly progressive neuropathy: a case report

Introduction: Familial amyloid polyneuropathy is a rare autosomal dominant disorder caused by mutations in the transthyretin gene, TTR. Diagnosis can be challenging, especially if other family members are not affected or an obvious systemic involvement is lacking. The patients are often misdiagnosed, leading to a delay in the initiation of therapy. Case presentation: A 35-year-old woman of Turkish origin presented to our outpatient clinic with severe polyneuropathy associated with distally pronounced tetraparesis and hypesthesia of 2 to 3 years’ duration. In addition, small nerve fiber involvement with impaired detection of cold temperatures and tingling pain in the lower legs was reported. She did not complain of autonomic dysfunction or visual disturbance. Her family history was empty regarding neuromuscular disorders. The routine diagnostic work-up was unremarkable. A sural nerve biopsy disclosed amyloid deposits, which led to the identification of a rare heterozygous transthyretin mutation (p.Glu74Gly; old classification: p.Glu54Gly). Conclusions: Few cases with this very heterozygous mutation can be found in the literature. In contrast to the case of our patient, all of the previously described patients in the literature presented with additional severe autonomic symptoms, involvement of the eyes and a positive family history. In this case report, we emphasize that, in patients with progressive neuropathy with small fiber involvement, an amyloid neuropathy should be considered in the differential diagnosis, even if the family history is empty and other organs are not affected