Background: Increasing attention has been given to the transparency of potential conflicts of interest in clinical medicine and biomedical sciences, particularly in journal publishing and science advisory panels. The authors examined the degree and type of financial ties to the pharmaceutical industry of panel members responsible for revisions of the Diagnostic and Statistical Manual of Mental Disorders(DSM). Methods: By using multimodal screening techniques the authors investigated the financial ties to the pharmaceutical industry of 170 panel members who contributed to the diagnostic criteria produced for the DSM-IV and the DSM-IV-TR. Results: Of the 170 DSM panel members 95 (56%) had one or more financial associations with companies in the pharmaceutical industry. One hundred percent of the members of the panels on ‘Mood Disorders’ and ‘Schizophrenia and Other Psychotic Disorders’ had financial ties to drug companies. The leading categories of financial interest held by panel members were research funding (42%), consultancies (22%) and speakers bureau (16%). Conclusions: Our inquiry into the relationships between DSM panel members and the pharmaceutical industry demonstrates that there are strong financial ties between the industry and those who are responsible for developing and modifying the diagnostic criteria for mental illness. The connections are especially strong in those diagnostic areas where drugs are the first line of treatment for mental disorders. Full disclosure by DSM panel members of their financial relationships with for-profit entities that manufacture drugs used in the treatment of mental illness is recommended.

Objective The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) vaccination in patients with various neuroimmunologic disorders on anti‐CD20 therapy. This included an analysis of the T cell vaccine response to the SARS‐CoV‐2 Delta variant. Methods We investigated prospectively humoral and cellular responses to SARS‐CoV‐2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti‐CD20 therapy and 82 age‐ and sex‐matched healthy controls. For quantification of antibodies, the Elecsys anti‐SARS‐CoV‐2 viral spike (S) immunoassay against the receptor‐binding domain (RBD) was used. IFN‐gamma enzyme‐linked immunosorbent spot assays were performed to assess T cell responses against the SARS‐CoV‐2 Wuhan strain and the Delta variant. Results SARS‐CoV‐2‐specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti‐CD20 treated patients. In contrast to the antibody response, the T‐cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B‐cell depleted compared to nondepleted patients. Interpretation Antibody responses to SARS‐CoV‐2 mRNA vaccinnation can be attained in patients on anti‐CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID‐19) in this high‐risk population. ANN NEUROL 2022;91:342–352

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Background: The interleukin-1-receptor antagonist IL1RA (encoded by the IL1RN gene) is a potent competitive antagonist to interleukin-1 (IL1) and thereby is mainly involved in the regulation of inflammation. Previous data indicated a role of IL1RA in muscle-invasive urothelial carcinoma of the bladder (UCB) as well as an IL1-dependent decrease in tissue barrier function, potentially contributing to cancer cell invasion. Objective: Based on these observations, here we investigated the potential roles of IL1RA, IL1A, and IL1B in bladder cancer cell invasion in vitro. Methods: Cell culture, real-time impedance sensing, invasion assays (Boyden chamber, pig bladder model), qPCR, Western blot, ELISA, gene overexpression. Results: We observed a loss of IL1RA expression in invasive, high-grade bladder cancer cell lines T24, UMUC-3, and HT1197 while IL1RA expression was readily detectable in the immortalized UROtsa cells, the non-invasive bladder cancer cell line RT4, and in benign patient urothelium. Thus, we modified the invasive human bladder cancer cell line T24 to ectopically express IL1RA, and measured changes in cell migration/invasion using the xCELLigence Real-Time-Cell-Analysis (RTCA) system and the Boyden chamber assay. The real-time observation data showed a significant decrease of cell migration and invasion in T24 cells overexpressing IL1RA (T24-IL1RA), compared to cells harboring an empty vector (T24-EV). Concurrently, tumor cytokines, e.g., IL1B, attenuated the vascular endothelial barrier, which resulted in a reduction of the Cell Index (CI), an impedance-based dimensionless unit. This reduction could be reverted by the simultaneous incubation with IL1RA. Moreover, we used an ex vivo porcine organ culture system to evaluate cell invasion capacity and showed that T24-IL1RA cells showed significantly less invasive capacity compared to parental T24 cells or T24-EV. Conclusions: Taken together, our results indicate an inverse correlation between IL1RA expression and tumor cell invasive capacity and migration, suggesting that IL1RA plays a role in bladder carcinogenesis, while the exact mechanisms by which IL1RA influences tumor cells migration/invasion remain to be clarified in future studies. Furthermore, we confirmed that real-time impedance sensing and the porcine ex vivo organ culture methods are powerful tools to discover differences in cancer cell migration and invasion.

IntroductionDNA‐based TLR9 agonists are potent activators of the immune system. ProMune® and dSLIM® belong to different families of TLR9 agonists and both have been established as cancer immunotherapeutics in clinical proof‐of‐concept studies. Unfortunately, ProMune® failed in pivotal oncological trials. dSLIM®, the active ingredient of Lefitolimod (MGN1703), successfully finished a double‐blinded, placebo‐controlled phase II study in patients with advanced colorectal cancer, exhibiting improved progression‐free survival and durable disease control.MethodsTo explain the different systemic efficacies of dSLIM® and ProMune®, both TLR9 agonists and chimeric molecules thereof are analyzed side‐by‐side in a panel of in vitro assays for immune activation.Results and conclusionsIndeed, dSLIM® exposure results in an IFN‐α dependent broad activation of immune cells whereas ProMune® strongly stimulates B cells. Moreover, all functional effects of dSLIM® strictly depend on the presence of CG‐motifs within its dumbbell‐shaped, covalently closed structural context. Conversely, several immunological effects of ProMune® like IL‐8 secretion are independent of CG‐motifs and could be ascribed to the phosphorothioate‐modifications of its DNA backbone, which may have caused the side effects of ProMune® in clinical trials. Finally, we showed that the implementation of ProMune® (ODN2006) base sequence into the characteristic dSLIM® dumbbell form resulted in dSLIM2006 with all beneficial effects for immunostimulation combined from both TLR9 classes without any CG‐independent effects.