Citations

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Abstract Description Cellular immune responses are critical for protection from environmental and genetic insults, including pathogens and cancer. However, immunity can also drive pathogenic responses that damage organs and drive pathogenesis. Immune response quality is influenced by several factors including genetics, age, sex and the environment. Environmental influences including everyday activities and lifestyle have been shown to modulate the immune system but are often difficult to monitor. We have developed a system of serial monitoring of peripheral blood mononuclear cells that coincided with wearable device activity monitoring to further understand how biometric data correlates with the composition of blood derived immune cells. Using a 31-marker CyTOF phenotyping panel we monitored blood derived immune cell composition over a 14-week period in an individual volunteer while biometric data was collected via wearable technology. To determine whether interventions can be introduced that change peripheral blood immune cell phenotypes our volunteer introduced lifestyle changes at specific intervals in this period of monitoring. These included intermittent fasting and the introduction of regular exercise. In addition, the individual was immunized against COVID-19 during this time to provide an immune challenge that would perturb immune homeostasis. In this study, we find that lifestyle changes can promote alterations in immune cell phenotypes identified using high parameter mass cytometry. Topic Categories Translational and Interventional Immunology (TI)

Abstract Description This study dissects mechanisms of spontaneous tumor rejection leading to better understanding of successful immune responses to cancer. Cancers persist despite expression of tumor-specific neoantigens promoting ongoing anti-tumor immune responses. While some occult tumor cells likely are cleared by effective anti-tumor immune responses, the targeted antigens are not easily identifiable as those cells spontaneously disappear. Congenic mouse breast carcinoma models expressing a defined protein mimicking neoantigens were used to dissect the protective spontaneous immune response. BALB/c (MHC H-2d) mice challenged with BALB/c breast tumors expressing the rat-erbB2 oncoprotein succumb to their tumors despite demonstrated tumor immunogenicity, mimicking known patient responses to cancer. Meanwhile, H-2b positive BALB.B and H-2d/H-2b F1 hybrid mice spontaneously eliminate genetically matched tumors in an MHC-II dependent manner. CD4+ T-cells and B-cells or the rat-erbB2-specific antibodies they produce are crucial mediators of this protective response. Differences in the tumor microenvironments in rat-erbB2+ tumor-bearing BALB.B and BALB/c mice at the time of fate decision in the models reflect the differences between effective and ineffective anti-tumor immunity. Identifying the nature of the optimal MHC-II antigens, how they activate protective CD4+ T-cells, and the interactions that promote protective antibodies will better inform future cancer therapies. Funding Sources Bernie Fineman Research Fund Mayo Clinic Center for Biomedical Discovery Mayo Clinic Department of Immunology Mayo Clinic Graduate School of Biomedical Sciences NIH Traning Grant 5 R25 GM 55252 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Purpose: The purpose of this study was to compare the height of velopharyngeal (VP) closure in relation to the palatal plane between individuals with velopharyngeal insufficiency (VPI) with or without cleft palate and individuals without cleft palate and with normal speech, considering the effects of age and sex. Method: Magnetic resonance imaging was used to analyze the height of VP closure in the midsagittal view during phonation of /i/ and /s/ sounds among 105 individuals with VPI and 45 individuals without cleft palate and normal speech. Results: Independent-samples t tests demonstrated that individuals with VPI display a significantly lower mean height of VP closure (3.7 mm) compared to individuals without cleft palate and normal speech during phonation of /i/ and /s/ sounds ( p < .001). Analysis of variance was used to evaluate the impact of age and sex on the height of VP closure. Significant differences were observed between the height of VP closure in individuals with VPI and those without cleft palate and normal speech across the age span during the production of /i/ and /s/ sounds. However, nonsignificant differences were found between the height of VP closure in males and females of the VPI group and those without cleft palate and normal speech during the production of these sounds. Conclusions: The results revealed the variations of the height of VP closure in relation to the palatal plane. These findings provide insights into the presurgical planning for individuals with VPI undergoing palatal surgeries, especially the location of pharyngeal flap insertion.

Abstract Objectives Pivotal trials have established the effectiveness of the Responsive Neurostimulation System (RNS® System) in treating focal epilepsy. In clinical trials, depth leads were primarily used to treat mesial temporal seizure onsets while cortical strip leads were used to treat neocortical seizure onsets. Here, we systematically analyze the safety and efficacy of stereoelectroencephalography (sEEG)‐guided depth leads to provide responsive stimulation to neocortical gray matter. Methods Patients were stratified as strong responders (>median cohort seizure reduction %), weak responders (>0% and ≤median cohort seizure reduction %), and anti‐responders (≤0%) based on percent seizure reduction at 1 year post‐implant (1‐Y). Pre‐operative T1‐weighted magnetic resonance imaging and post‐operative computed tomography images were merged, and the Euclidean distance between the sEEG epileptic focus (sEEG‐EF) and the nearest RNS System depth lead contacts was calculated. Results A total of 87 depth leads were implanted in 55 patients across neocortical brain regions. The median reduction in clinical seizures improved from 66.7% at 1‐Y to 77.5% at long‐term follow‐up (LTFU: 2.35 ± 0.95 years), with 10 patients (18.2%) achieving complete seizure freedom. Seven patients (12.7%) experienced six serious adverse events. At 1‐Y, shorter Euclidean distance between the sEEG‐EF and RNS System depth leads predicted improved seizure outcome in strong responders ( β = −0.84, p = 0.008) but not in weak responders ( β = 0.21, p = 0.9) or anti‐responders ( β = −20.34, p = 0.11). At LTFU, there was no significant relationship between Euclidean distance and seizure reduction in strong responders ( β = 0.77, p = 0.18), weak responders ( β = 2.05, p = 0.54), or anti‐responders ( β = 0.24, p = 0.99). Exploratory analyses at 1‐Y showed nominal associations between older age ( ρ = 0.32), longer epilepsy duration ( ρ = 0.27), and non‐mesial temporal sEEG‐EFs and greater seizure reduction; however, none survived Bonferroni correction (adjusted α = 0.0027; all post‐correction p > 0.0027), and no associations were observed at LTFU. Significance In this series, neocortical depth leads for RNS therapy had favorable safety and efficacy and proximity to the sEEG‐EF drove initial outcomes for strong responders to RNS therapy. Plain Language Summary In this multi‐center study, patients with difficult‐to‐treat seizures received brain‐responsive stimulation using a device called responsive neurostimulation (RNS), which delivers small electrical pulses to reduce seizures. We focused on patients treated with electrodes placed in the brain's outer regions (the neocortex) and guided by a mapping procedure called sEEG. On average, patients had their seizures cut by two‐thirds after one year and by more than three‐quarters with longer follow‐up, with about one in five becoming seizure‐free. The treatment was safe, and closer electrode placement to the seizure source helped explain early—but not long‐term—improvements.

OBJECTIVE Patient-reported outcome measures (PROMs) are standardized questionnaires used to evaluate patients’ quality of life and health status before and after medical procedures. While worse preoperative health is often associated with worse postoperative outcomes, the role of baseline PROMs in predicting postoperative dysphagia following cervical surgery has been unexplored with Eating Assessment Tool–10 (EAT-10) scores. This study aimed to investigate the relationship between baseline PROMs and the incidence of postoperative dysphagia. METHODS A prospectively collected multi-institutional quality registry of patients undergoing anterior cervical spine surgery was retrospectively reviewed. Eight baseline PROMs were assessed: Neck Disability Index (NDI), modified Japanese Orthopaedic Association scale, EQ-5D questionnaire, EuroQol visual analog scale, visual analog scales for neck pain (NP-VAS) and arm pain, and 10-item Patient-Reported Outcomes Measurement Information System Global Physical Health and Global Mental Health. Including baseline dysphagia as a fixed effect, multivariable logistic regressions were performed to examine the impact of patient-reported baseline PROMs on the incidence of dysphagia. RESULTS Baseline PROMs were collected from 1706 patients. When assessing baseline PROMs independently in multivariable analyses, worse baseline NDI score (OR 1.04, p = 0.001) was a significant predictor of dysphagia at 12 months after surgery, while other PROMs were not. When assessing baseline PROMs together in multivariable analysis, worse baseline NDI score (OR 1.07, p < 0.001) and better NP-VAS score (OR 0.88, p = 0.006) were significant predictors of dysphagia at 12 months, while other PROMs were not. Patients in the severe or complete disability NDI categories (NDI score ≥ 25; 465/1466 patients without baseline dysphagia) experienced significantly more new dysphagia at 1 month (65% vs 50%, p < 0.001), 3 months (30% vs 21%, p < 0.001), and 12 months (32% vs 14%, p < 0.001) after anterior cervical spine surgery. These patients also had no significant difference in baseline EAT-10 scores (0.103 ± 0.386 vs 0.115 ± 0.405, p = 0.6), yet experienced significantly worse EAT-10 score changes between baseline and 12 months (3.369 ± 5.954 vs 1.208 ± 3.332, p < 0.001). CONCLUSIONS Baseline NDI score appears to be the strongest independent predictor of the 8 PROMs in determining whether patients have dysphagia at 12 months after anterior cervical surgery.