Cellular immunotherapeutics targeting the human papillomavirus (HPV)-16 E6 and E7 proteins have achieved limited success in HPV-positive oropharyngeal cancer (OPC). Here we have conducted ...proteome-wide profiling of HPV-16-specific T cell responses in a cohort of 66 patients with HPV-associated OPC and 22 healthy individuals. Unexpectedly, HPV-specific T cell responses from OPC patients were not constrained to the E6 and E7 antigens; they also recognized E1, E2, E4, E5, and L1 proteins as dominant targets for virus-specific CD8+ and CD4+ T cells. Multivariate analysis incorporating tumor staging, treatment status, and smoking history revealed that treatment status had the most significant impact on HPV-specific CD8+ and CD4+ T cell immunity. Specifically, the breadth and overall strength of HPV-specific T cell responses were significantly higher before the commencement of curative therapy than after therapy. These data provide the first glimpse of the overall human T cell response to HPV in a clinical setting and offer groundbreaking insight into future development of cellular immunotherapies for HPV-associated OPC patients.
Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in ...alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 μmol/L) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for anticancer therapy.
Oxidative deamination of norepinephrine (NE) and dopamine (DA) by monoamine oxidase (MAO) generates the catecholaldehydes 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and ...3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively, and H
2
O
2
. Catecholaldehydes are highly reactive electrophiles that have been implicated as causal factors in the etiology of neurodegenerative diseases and cardiac injury from ischemia and diabetes. The reactivity of both catechol and aldehyde groups enables the catecholaldehdyes to cross-link proteins and other biological molecules. Carnosine is a β-alanyl-histidine dipeptide found in millimolar concentrations in brain and myocardium. It is well known to detoxify aldehydes formed from oxidized lipids and sugars, yet the reactivity of carnosine with catecholaldehydes has never been reported. Here, we investigated the ability of carnosine to form conjugates with DOPAL and DOPEGAL. Both catecholaldehydes were highly reactive towards
l
-cysteine (
l
-Cys), as well as carnosine; however, glutathione (GSH) showed essentially no reactivity towards DOPAL. In contrast, GSH readily reacted with the lipid peroxidation product 4-hydroxy-2-nonenal (4HNE), while carnosine showed low reactivity to 4HNE by comparison. To determine whether carnosine mitigates catecholaldehyde toxicity, samples of atrial myocardium were collected from patients undergoing elective cardiac surgery. Using permeabilized myofibers prepared from this tissue, mitochondrial respiration analysis revealed a concentration-dependent decrease in ADP-stimulated respiration with DOPAL. Pre-incubation with carnosine, but not GSH or
l
-Cys, significantly reduced this effect (
p
< 0.05). Carnosine was also able to block formation of catecholaldehyde protein adducts in isolated human cardiac mitochondria treated with NE. These findings demonstrate the unique reactivity of carnosine towards catecholaldehydes and, therefore, suggest a novel and distinct biological role for histidine dipeptides in this detoxification reaction. The therapeutic potential of carnosine in diseases associated with catecholamine-related toxicity is worthy of further examination.
Pulsed electromagnetic field (PEMF) therapy can non-invasively treat a variety of pathologies by delivering electric and magnetic fields to tissues via inductive coils. The electromagnetic fields ...generated by these devices have been found to affect a variety of biological processes and basic science understanding of the underlying mechanisms of action of PEMF treatment has accelerated in the last 10 years. Accumulating clinical evidence supports the use of PEMF therapy in both animals and humans for specific clinical indications including bone healing, wound healing, osteoarthritis and inflammation, and treatment of post-operative pain and edema. While there is some confusion about PEMF as a clinical treatment modality, it is increasingly being prescribed by veterinarians. In an effort to unravel the confusion surrounding PEMF devices, this article reviews important PEMF history, device taxonomy, mechanisms of action, basic science and clinical evidence, and relevant trends in veterinary medicine. The data reviewed underscore the usefulness of PEMF treatment as a safe, non-invasive treatment modality that has the potential to become an important stand-alone or adjunctive treatment modality in veterinary care.
•PEMF treatment is increasingly being used for both human and veterinary care.•PEMF devices deliver electromagnetic fields to tissue to promote healing.•Basic and clinical research on PEMF treatment has matured over the last decade.•Evidence supports PEMF treatment for fractures, pain, wounds, and other indications.•PEMF, as part of multimodal treatment, may improve veterinary clinical outcomes.
Immune checkpoint inhibitor combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The phase 3 clinical trials that ...led to the approval of chemoimmunotherapy in ES-SCLC excluded patients who had an Eastern Cooperative Group (ECOG) performance status (PS) of 2-3. Therefore, data on the efficacy of chemoimmunotherapy in patients with an ECOG PS of 2-3 are limited.
A retrospective analysis was performed on patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. The objective of this study was to compare the overall survival (OS), progression-free survival (PFS), and best clinical response to therapy in patients with an ECOG PS of 0-1 vs. patients with an ECOG PS of 2-3 who received chemoimmunotherapy for newly diagnosed ES-SCLC.
In total, 82 patients were included in the study. The mean ± standard deviation age was 68.1 ± 8.3 years. Of these, 56 patients were identified with an ECOG PS of 0-1, and 26 patients were identified with an ECOG PS of 2-3. The median PFS was similar regardless of ECOG PS (5.8 months 95% CI, 4.3-6.0 months in the ECOG PS 0-1 group vs. 4.1 months 95% CI, 3.8-6.9 months in the ECOG PS 2-3; p = .2994). The median OS was also similar regardless of ECOG PS (10.6 months 95% CI, 8.4-13.4 months in the ECOG PS 0-1 group vs. 9.3 months 95% CI, 4.9-12.8 months; p = .2718) in the ECOG PS 2-3 group.
The study results demonstrated no significant difference in PFS or OS among the ECOG PS 2-3 and ECOG PS 0-1 groups. Therefore, chemoimmunotherapy should be considered for patients who have ES-SCLC with an ECOG PS of 2-3.
Since the late 1980s, with the first identification of individuals who were exposed to human immunodeficiency virus type 1 (HIV-1) yet remained uninfected, or “HIV-1—resistant” individuals, a large ...number of cohorts that include HIV-exposed seronegative (HESN) subjects have been identified globally for the purpose of investigating the genetic, immunologic, and environmental factors that may help alter susceptibility to HIV-1. In this article, in light of the recent International Symposium on Natural Immunity to HIV, we review the characteristics of different groups with respect to their relative risks and briefly summarize the known cohorts that include exposed uninfected subjects worldwide.
Studies of human immunodeficiency virus (HIV)-exposed seronegative individuals are crucial to inform vaccine design. In the present study we demonstrated that HIV-exposed seronegative commercial sex ...workers produce lower levels of proinflammatory cytokines at baseline than HIV-negative control subjects. We also showed that CD4+ T cells of HIV-exposed seronegative commercial sex workers have a characteristically lower level of gene expression that can be seen in differentially expressed genes and systems crucial for HIV replication, such as the T cell receptor pathway and previously identified HIV dependency factors. This apparent lowered activation results in a phenomenon we term “immune quiescence,” which may contribute to host resistance to HIV.
Objective
The purpose of this study was to examine whether the relative frequency of leading causes and total associated costs of readmission after acute ischemic stroke changed with Medicaid ...expansion, and how these changes differed by racial/ethnic group.
Methods
We used a difference-in-differences approach to compare changes in the relative frequency of leading causes of unplanned 30-day readmission and to examine changes in the costs associated with unplanned readmission between expansion states (AR, MD, NM, and WA) and non-expansion states (FL and GA). To estimate the differential effect of Medicaid expansion by race/ethnicity on the causes and cost of readmission, we added a time*treatment*race interaction. Multinomial logistic regression was performed to analyze the changes in readmission cause. Gamma log-link modeling was used to study changes in readmission costs for expansion compared to non-expansion states.
Results
The final multinomial model showed an association between expanded Medicaid and the relative frequency of sepsis readmission for White patients. According to predictive margins, White patients in expansion states had an estimated increase of 3.3 percentage points in the share of readmissions for sepsis but not for White patients in non-expansion states. In contrast, non-White patients in expansion states had a decrease of 1.8 percentage points in the share of readmissions for sepsis. Overall, Medicaid expansion was associated with a net increase of 6.7 percentage points in the share of readmissions for sepsis among non-Hispanic Whites relative to all other groups. In the final gamma model, Medicaid expansion was associated with a decrease in readmission costs overall. According to predictive margins, the net cost reduction in expansion versus non-expansion states was an average of $2509.
Conclusions
Medicaid expansion is associated with an overall decrease in unplanned readmission costs and an increase among readmitted White patients in the likelihood of readmission for sepsis.
•The convergence of self-report happiness scores and changes in insular activity.•Significant relationship between self-reported anxiety measures and left insular activity.•Unique responses of the ...left insula, right inferior parietal lobule, and left uncus to fearful, joyful, and neutral stimuli.
Musical stimuli can induce a variety of emotions in individuals. We sought to determine whether different valenced music would induce EEG profile changes and self-reported emotional states in individuals following the viewing of a complex video with a concrete narrative and emotional ambivalence. We used a five-minute video titled “El Empleo”, coupled with either joyful, fearful, or no music. EEG recordings were taken throughout the duration of the experiment and a self-reported questionnaire on emotional state was administered after viewing of the video. We found self-reported measures of happiness increased following viewing of the video paired with joyful music, while EEG data demonstrated that the following brain regions displayed significant changes in activity following both fearful and joyful music: the right inferior parietal lobule, left uncus, and left insula. Additionally, we found that anxiety self-report scores correlated negatively with average gamma activity within the insula within each group. The convergence of self-reported data and quantitative EEG data was consistent across 27 participants. These data indicate that different valenced music can alter EEG activity in emotion specific regions, reflected in participants perceived emotional state.
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