Influence of noninvasive brain stimulation on connectivity and local activation: a combined tDCS and fMRI study.

The effect of transcranial direct current stimulation (tDCS) on neurobiological mechanisms underlying executive function in the human brain remains elusive. This study aims at examining the effect of anodal and cathodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) in comparison with sham stimulation on resting-state connectivity as well as functional activation and working memory performance. We hypothesized perturbed fronto-parietal resting-state connectivity during stimulation and altered working memory performance combined with modified functional working memory-related activation. We applied tDCS with 1 mA for 21 min over the DLPFC inside an fMRI scanner. During stimulation, resting-state fMRI was acquired and task-dependent fMRI during working memory task performance was acquired directly after stimulation. N = 36 healthy subjects were studied in a within-subject design with three different experimental conditions (anodal, cathodal and sham) in a double-blind design. Seed-based functional connectivity analyses and dynamic causal modeling were conducted for the resting-state fMRI data. We found a significant stimulation by region interaction in the seed-based ROI-to-ROI resting-state connectivity, but no effect on effective connectivity. We also did not find an effect of stimulation on task-dependent signal alterations in working memory activation in our regions of interest and no effect on working memory performance parameters. We found effects on measures of seed-based resting-state connectivity, while measures of effective connectivity and task-based connectivity did not show any stimulation effect. We could not replicate previous findings of tDCS stimulation effects on behavioral outcomes. We critically discuss possible methodological limitations and implications for future studies.

No association of malignant B-cell non-Hodgkin lymphomas with ipsilateral SARS-CoV-2 vaccination.

PURPOSE: SARS-CoV-2 vaccines cause acute ipsilateral lymph node swelling in an important proportion of vaccines. Thus far, no malignant lymphadenopathies have been reported in temporal context to vaccination in the ipsilateral draining lymph node areas. EXPERIMENTAL DESIGN: Prompted by two cases with unilateral axillary lymphomas that occurred ipsilaterally to prior SARS-CoV-2 vaccination, we systematically retrieved all B-cell non-Hodgkin lymphomas at two German University Medical Centers diagnosed before and after introduction of SARS-CoV-2 vaccines in Germany. Available lymphoma tissue (n=19) was subjected to next-generation immunosequencing of the IGH locus. Malignant clonotypes were mined in the CoVabDab database and published data sets from 342 uninfected individuals, 55 individuals 28 days after anti-SARS-CoV-2 vaccination and 139 individuals with acute COVID-19 together encompassing over 1 million CDR3 sequences in total. RESULTS: Of 313 newly diagnosed cases in the two centers and observation periods, 27 unilateral manifestations in the defined deltoid draining regions were identified. The majority thereof were diffuse large B-cell lymphomas (18 of 27 cases). Eleven unilateral cases were diagnosed in the era of SARS-CoV-2 vaccination and 16 in the control period before introduction of such vaccines. Of the 11 unilateral lymphomas that occurred during the vaccination period, ten had received a SARS-CoV-2 vaccine prior to lymphoma diagnosis. These cases were further evaluated. While left-sided were more frequent than right-sided lymphomas (19 vs 8 cases), no statistically significant association of vaccination site and laterality of the lymphoma manifestation was found. The unilateral lymphomas showed a normal range of B-cell receptors typically found in these lymphoma subtypes with no evidence for anti-SARS-CoV-2 sequences in the malignant clonotype. CONCLUSIONS: Together, we found no evidence that the current SARS-CoV-2 vaccines could serve as a trigger for lymphomagenesis in the draining lymph node areas of the deltoid region used for vaccination.

PD-L1 Amino Acid Position 88 Represents a Hotspot for PD-L1 Stability With Relevance for PD-L1 Inhibition.

The two most common antibody targeting principles in oncology are the induction of direct antitumor effects and the release of antitumor T cell immunity by immune checkpoint blockade. These two principles, however, may be overlapping if the targeted checkpoint molecule is not located on the immune cell but on the tumor cell itself. Secondary resistance by epitope escape may therefore remain a challenge in both settings. We previously reported epitope escape through L88S and truncating programmed cell death ligand 1 (PD-L1) gene mutations in colorectal cancer patients on selective pressure with avelumab, a PD-L1-directed checkpoint blocker that-in addition to T cell disinhibition-allows direct tumor cell killing via its unmodified Fc portion. Here, we confirmed this principle by liquid biopsy monitoring in a colorectal cancer patient from an independent clinical trial. In this patient, both PD-L1 L88E and L88fs mutations emerged under selective pressure with avelumab. By ectopically expressing PD-L1 L88E, we show that this mutation leads to a reduction of full-length glycosylated PD-L1 and greatly reduced avelumab surface binding. Further experiments indicated that PD-L1 L88E represents a phosphomimetic variant of PD-L1 L88S leading to loss of protein stability and increased proteasomal degradation. The association of this PD-L1 mutation with the high-affinity FCGR3A single nucleotide polymorphism rs396991 confirms prior evidence that patients harboring this polymorphism experience the strongest selective pressure by avelumab. Together, position 88 of PD-L1 is a hotspot residue critically regulating PD-L1 cell surface expression with clinical significance in the context of immune checkpoint blockade.