Peripheral T cells are maintained in the absence of vigorous stimuli, and respond to antigenic stimulation by initiating cell cycle progression and functional differentiation. Here we show that ...depletion of the Ets family transcription factor GA-binding protein (GABP) in T cells impairs T-cell homeostasis. In addition, GABP is critically required for antigen-stimulated T-cell responses in vitro and in vivo. Transcriptome and genome-wide GABP-binding site analyses identify GABP direct targets encoding proteins involved in cellular redox balance and DNA replication, including the Mcm replicative helicases. These findings show that GABP has a nonredundant role in the control of T-cell homeostasis and immunity.
The coordinative chain transfer co- and ter-polymerizations of myrcene, isoprene and styrene have been achieved using Cp*La(BH4)2(THF)2 (Cp* = pentamethylcyclopentadienyl) combined with magnesium ...dialkyl and aluminum dialkyl. New highly stereoregular poly(myrcene-co-styrene), poly(myrcene-co-isoprene), and poly(myrcene-co-isoprene-co-styrene) copolymers have been obtained with good yields and a wide range of compositions. The concept of coordinative chain transfer polymerization (CCTP) induced control of the microstructure of statistical copolymers could be successfully extended to 1,4-conjugated dienes statistical copolymerization and terpolymerization and to a renewable monomer. In addition to significant transmetalation in the course of the polymerization, a modification of the apparent comonomers reactivity ratio was observed in the presence of a chain transfer agent. This could be combined, depending on the nature of the chain transfer agent, with either a stereospecific polymerization of both conjugated dienes or the introduction of 3,4 enchainments in the microstructure. The former 1,4-trans stereoselective homo-, co-, and terpolymerizations enable the growth of several stereoregular chains per catalyst atom, providing significant catalyst economy, at the expense of the activity however. The latter affords an easy and straightforward modification of the microstructure of conjugated dienes co- and terpolymers in terms of both composition and regioregularity. This is particularly interesting regarding long and tedious catalysts synthesis required to reach the same array of polymeric materials via a classical living approach.
In a high-speed single-molecule experiment with a force probe, a protein is tethered between two substrates that are manipulated to exert force on the system. To avoid nonspecific interactions ...between the protein and nearby substrates, the protein is usually attached to the substrates through long, flexible linkers. This approach precludes measurements of mechanical properties with high spatial and temporal resolution, for rapidly exerted forces are dissipated into the linkers. Because mammalian hearing operates at frequencies reaching tens to hundreds of kilohertz, the mechanical processes that occur during transduction are of very short duration. Single-molecule experiments on the relevant proteins therefore cannot involve long tethers. We previously characterized the mechanical properties of protocadherin 15 (PCDH15), a protein essential for human hearing, by tethering an individual monomer through very short linkers between a probe bead held in an optical trap and a pedestal bead immobilized on a glass coverslip. Because the two confining surfaces were separated by only the length of the tethered protein, hydrodynamic coupling between those surfaces complicated the interpretation of the data. To facilitate our experiments, we characterize here the anisotropic and position-dependent diffusion coefficient of a probe in the presence of an effectively infinite wall, the coverslip, and of the immobile pedestal.
Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune ...responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.
Objectives
(1) Assess the frequency and severity of long‐term swallowing and voice complaints, follow‐up care, risk factors for the development of long‐term swallowing and voice complications in ...patients who underwent anterior transcervical approach (ACA). (2) Determine incidence of long‐term swallowing and voice complications requiring follow‐up otolaryngologic care and assess the frequency of otolaryngologic follow‐up for postoperative swallowing and voice complaints.
Methods
Retrospective cohort study of patients between January 2017 and March 2020 who underwent ACA. Demographic information, data from preoperative evaluation, operative records, and data from postoperative visits were collected. Patients were contacted to complete the Eating Assessment Tool and the “Impairment” subset of the Voice Symptoms Scale.
Results
A total of 48 patients (10.6%) followed up with a head and neck surgeon for swallowing complaints and 31 patients (6.8%) for voice complaints. Otolaryngology follow‐up for swallowing complaints among patients with at least 3 and 12 months of follow‐up was 16.4% and 17.8%, respectively. Otolaryngology follow‐up for voice complaints among patients with at least 3 and 12 months of follow‐up was 11.7% and 11.9%, respectively. Swallowing function was abnormal in 40.7% at least 3 months after surgery and in 41.8% 12 months after. Voice function was abnormal in 55.7% of respondents at least 3 months after surgery and in 54.5% of respondents 12 months after.
Conclusions
ACA is associated with otolaryngologic complications that include dysphagia and dysphonia. This study demonstrates that long‐term swallowing and voice dysfunction appear to persist longer than what is noted by patient utilization of follow‐up otolaryngologic care.
Level of Evidence
4 Laryngoscope, 134:3201–3205, 2024
Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating ...cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αβ, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells.
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•Cell transformation expands tissue-resident ILC1ls and ILTC1s•ILC1ls and ILTC1s share a distinct gene expression program•ILC1ls and ILTC1s exhibit potent cytotoxicity against tumor cells•IL-15 deficiency depletes ILC1ls and ILTC1s, resulting in tumor outgrowth
Cell transformation triggers a cancer immunosurveillance mechanism that engages tissue-resident lymphocytes derived from innate, TCRαβ, and TCRγδ lineages.
Introduction
Doxorubicin carries a risk of heart failure (HF). Black race has been suggested as a risk factor for doxorubicin-related HF or asymptomatic LVEF decline, but studies were limited by ...small sample size, unknown racial composition of the comparison group, or lack of assessment of potential confounders. We aimed to assess whether HF occurs at higher rates in black patients (pts) compared to non-Hispanic white pts who receive doxorubicin for DLBCL, and to evaluate race as an independent risk factor for the development of HF after adjusting for known risk factors.
Methods
We used the Surveillance, Epidemiology, End Results - Medicare (SEER-Medicare) database to identify pts >65 years who were diagnosed with DLBCL (ICD-O: 9680, 9684) between 1997-2015 and who received doxorubicin (HCPCS/NDC codes) within 30 days of diagnosis. We excluded pts with HF (ICD-9: 428, ICD-10: I50) documented prior to diagnosis with DLBCL. We recorded age at diagnosis, Ann Arbor stage, and race. We assessed pts for hypertension (HTN) and coronary artery disease (CAD) documented in the year prior to lymphoma diagnosis. The primary outcome was documented HF at any point following DLBCL diagnosis.
Descriptive statistics were performed for demographic and clinical variables. The proportion of pts who developed HF was calculated in both racial groups and compared with the chi-square test. A multivariable logistic regression model was formulated using race, age at diagnosis, Ann Arbor stage and comorbidities, as covariates. Adjusted odds ratios and 95% confidence intervals for racial group status and demographic/clinical variables of interest were estimated from the multivariable model. The Kaplan-Meier method was used to generate time-to-event curves for the onset of HF in each racial group. A multivariable Cox proportional hazards model was used to estimate the hazard ratio for the diagnosis of HF in black vs. white pts after adjusting for age at diagnosis, stage, HTN and CAD. All p-values were two-sided with statistical significance evaluated at the 0.05 alpha level.
Results
We identified 71,072 pts with DLBCL (white 82.2%, black 5.7%). We excluded 13,651 (19%) pts with HF prior to lymphoma diagnosis (white 84.4%, black 5.7%). We identified 6630 pts (white 88.8%, black 3%) with DLBCL who had received doxorubicin within 30 days of diagnosis. We excluded 797 pts <65 years and 802 pts with unknown stage at diagnosis. Of the remaining 4555 pts (white 97.7%, black 2.3%), 3398 (74.6%) had a history of HTN (white 74.3%, black 88.7%) and 1841 (40.4%) had a history of CAD (white 40.5%, black 37.7%). A total of 1607 (35%) pts developed HF (white 35%, black 33%). By univariate analysis, factors associated with development of HF included history of HTN (OR 1.27; 95% CI 1.10-1.47; p=0.001), CAD (OR 1.39; 95% CI 1.23-1.57); p<0.001), age at diagnosis of DLCBL (median 72.5 vs. 74; p=<0.001) and stage (OR 0.87; 95% CI 0.77-0.98; p=0.02). Race was not associated with risk of HF (OR 1.11; 95% CI 0.74-1.68; p=0.70). Our multivariable logistic regression model showed that older age at diagnosis (OR 1.03; 95% CI 1.02-1.04) and CAD (OR, 1.28; 95% CI 1.12-1.46) were associated with HF. Stage III/IV (OR 0.86; 95% CI 0.76-0.97) was associated with a lower risk of HF compared to stage I/II. Race (OR 1.05; 95% CI 0.70-1.60) and prior history of HTN (OR 1.12; 95% CI 0.96-1.30) were not significantly associated with development of HF. The median overall CHF-free survival time was 10.28 years after diagnosis (95% CI 9.75-11.13; Figure 1). Log-rank testing showed no difference in probability of developing HF between black and white pts (p=0.80), and the Cox model showed that after accounting for age at diagnosis, stage, HTN, and CAD, there was no statistically significant association between race and HF (HR, 0.92; 95% CI 0.66-1.30; p=0.62).
Discussion
HF is a common condition in older individuals following use of anthracycline for DLBCL, and it is associated with worse survival. No association was observed between black race and the onset of heart failure following treatment with doxorubicin for DLBCL. However, there was a greater proportion of black pts excluded for pre-existing HF than in the final study population. This highlights the importance of rigorous screening for pre-existing HF or LV dysfunction as a means of mitigating the risk of worsening cardiac function in this population.
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Martin:I-MAB: Consultancy; Sandoz: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Janssen: Consultancy.
Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist ...largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.
Doxorubicin carries a risk of congestive heart failure (CHF). Black race has been suggested as a risk factor for doxorubicin-related cardiotoxicity, but data are limited. We assessed whether HF ...occurs at higher rates in Black patients compared to White patients who receive doxorubicin for DLBCL, and evaluated race as an independent risk factor for the development of HF after adjusting for known risk factors.
We used SEER-Medicare to identify patients 66 years and older with DLBCL. We excluded patients with CHF documented prior to diagnosis with DLBCL. We assessed for hypertension, type 2 diabetes, coronary artery disease, and arrhythmias prior to diagnosis with DLBCL. The primary outcome was documented CHF at any point following DLBCL diagnosis. Secondary outcomes included CHF in the first year following diagnosis and death. We performed analyses additionally stratified by cumulative dose of doxorubicin.
Our study population consisted of 8,604 patients (White 96.8%, Black 3.2%). In both Kaplan-Meier and competing risk analyses, we observed no significant difference in the incidence of CHF between Black and White patients, both before and after adjusting for covariates. Finally, we observed no significant differences in the incidence of CHF by race after stratification by cumulative doxorubicin dose.
CHF is common following doxorubicin chemotherapy for DLBCL in older patients. No association was observed between Black race and the onset of heart failure in this setting. Rigorous screening for known clinical risk factors is likely more relevant than race in treatment selection and optimization.
Doxorubicin is a widely-used chemotherapy agent in diffuse large B-cell lymphoma (DLBCL) and it carries a significant risk of cardiac toxicity. Previous research has suggested that Black patients are at increased risk for doxorubicin-related cardiac dysfunction, but data are limited. Using SEER-Medicare, we found that Black race was not significantly associated with heart failure following treatment with doxorubicin in DLBCL, both in unstratified analyses and in analyses stratified by cumulative dose of doxorubicin.
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