ABSTRACT
Social isolation is associated with increased risk and mortality from many diseases, such as breast cancer. Socially isolated breast cancer survivors have a 43% higher risk of recurrence and a 64% higher risk of breast cancer-specific mortality than socially integrated survivors. Since Covid-19 has dramatically increased the incidence of social isolation, it is important to determine if social isolation affects the response to endocrine therapy and/or recurrence after the therapy is completed. Since previous studies indicate that social isolation increases circulating inflammatory cytokines, we investigated if an anti-inflammatory herbal mixture Jaeumkanghwa-tang (JGT) prevents the adverse effects of social isolation on breast cancer mortality. Estrogen receptor positive mammary tumors were initiated with 7,12-dimethylbenz[a]anthracene. When a rat developed a palpable mammary tumor, it was either socially isolated (SI) by housing it singly or a rat was allowed to remain group-housed (GH). Tamoxifen (340ppm via diet) or tamoxifen + JGT (500ppm via drinking water) started when the first mammary tumor reached a size of 11 mm in diameter. Tamoxifen administration ended when a complete response to this therapy had lasted for 9 weeks (corresponds to 5 years in women). During tamoxifen therapy, social isolation non-significantly reduced the rate of complete responses to 21%, from 31% in GH group (p>0.05). After the therapy was completed, SI significantly increased local mammary tumor recurrence (p<0.001;45% GH vs 75% SI). RNAseq analysis was performed in the mammary glands. Gene set enrichment analysis (GSEA) of transcriptome showed that the increased recurrence risk in socially isolated rats was associated with an enrichment of IL6/JAK/STAT3 signaling: this result was confirmed in the tumors. In addition, oxidative phosphorylation (OXPHOS) pathway was suppressed: the suppressed genes included those involved in mitochondrial pyruvate transport and conversion of pyruvate to acetyl CoA as well as genes in the TCA cycle and mediating electron transport in mitochondrial complexes I-IV. Social isolation also increased the expression of inflammatory receptor for advanced glycation end-products (RAGE) (p≤0.05). Consumption of an anti-inflammatory JGT inhibited IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling and prevented the increased risk of mammary cancer recurrence in socially isolated animals. The percentage of recurrences in the SI rats dropped from 75% without JGT to 22% with JGT (p<0.001). Breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following endocrine therapy using tools that inhibit IL6/JAK/STAT3 inflammatory cytokine signaling and correct disrupted OXPHOS and mitochondrial dysfunction.
ABSTRACT
Introduction: Sphingosine-1-phosphate receptor (S1P) modulators and B cell depleting agents significantly impair humoral responses to SARS-CoV-2 mRNA vaccines. Whether disease modifying therapies (DMTs) impact cell-mediated immune (CMI) response to vaccination is unknown. Objectives/ Aims: To evaluate humoral and CMI response to SARS CoV-2 vaccination in people with MS and the impact of specific DMTs on these responses. Methods: We recruited participants from the Johns Hopkins MS center who underwent phlebotomy either 4 or 8 weeks following the terminal vaccine dose. Blood was processed to isolate serum and peripheral blood mononuclear cells (PBMCs). We measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. Blinded experimenters measured CMI responses using FluoroSpot assay for interferon gamma (IFN-γ) (Mabtech,Sweden) using cryopreserved PBMCs rested overnight and then incubated in cRPMI with 1μg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools of 158 peptides each). Plates were read on an AID iSpot Spectrum. Results were expressed as spot forming cells (SFC)/106 PBMCs. We evaluated concordance between humoral and CMI responses and tested for differences across DMTs using linear models. Results: We included 102 participants (82% female;mean age 49.5y [SD: 10.4y];94% mRNA vaccine recipients) who were on average 6.8 weeks post-vaccine. 22/39 (56%) of participants exposed to B-cell depleting agents exhibited a humoral response to the vaccine, whereas all participants on no (n=13), injectable (n=16), or natalizumab (n=17) therapies and most (12/14;86%) on non-S1P modulating orals responded. In a subset (n=58) with CMI response data, a lack of humoral immunity was marginally associated with an 120.3% greater IFN-γ SFC counts (120.3% higher;95% CI: -25.2%, 542.4%;p=0.09). B-cell depleting agents were associated with greater IFN-γ SFC counts relative to those on no DMT or other DMTs (for B-cell vs. no DMT: 270.6% higher [95% CI: 0.0%, 1373.2%];p=0.05;for B-cell vs. other DMTs: 182.9% higher [95% CI: 15.0%, 609.9%];p=0.03). Updated CMI data with 48 additional patients will be presented. Conclusions: We noted a robust CMI response in MS patients on B-cell depleting agents despite the lack of a humoral response in about half of these patients. Follow up studies are needed to determine if this translates to protection against clinical COVID-19 infection.
ABSTRACT
Background: Positron Emission Tomography (PET) findings suggest that increased striatal dopamine neurotransmission may underlie Obsessive-Compulsive Disorder (OCD) in adults. This is untested in pediatric OCD since PET is overly invasive and untenable for pediatric research. Thus, we used neuromelanin-sensitive MRI (NM-MRI) to assess nigrostriatal dopamine transmission in children with OCD and predict response to cognitive behavioral therapy (CBT). Methods: NM-MRI data was collected from 35 children on a GE 3T scanner with a 64-channel head coil. Those with OCD received manualized CBT before being re-scanned after 16-10 weeks. Following stringent QC procedures, 10 scans were excluded, leaving baseline and follow-up data from 15 children with OCD (9.7±1.7 years) and 10 matched controls (10.0 ± 1.8 years). Data were preprocessed with in house procedures (Wengler et al, Neuroimage, 2020). Linear regression analyses assessed group differences in dopamine signal and associations with CBT response. Results: Group differences in NM-MRI signal were detected in the VTA with greater signal in the OCD compared to HC group (t(14.45)=-2.13, p=.05). NM-MRI signal did not correlate significantly with baseline OC symptoms, but predicted better CBT response in the OCD group (p=.04), as measured by change in symptoms pre-post CBT. Conclusions: These new findings suggest alterations in the mesocortical dopaminergic system in pediatric OCD, stemming from the VTA. Dopaminergic hyperactivity may contribute to the reward processing deficits noted in OCD and mark CBT response in pediatric patients. Data collection has resumed (post COVID-19) and we anticipate increasing the sample size before the SOBP meeting in April. Supported By: NIMH R01MH115024-01A1 Keywords: Pediatric Obsessive-Compulsive Disorder, Neuromelanin-Sensitive MRI, Precision Psychiatry, Dopamine, Cognitive Behavioral Therapy