The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells
. It consists of an innate immune receptor/sensor, ...pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells
. Here we show that the DNA-binding inflammasome receptor AIM2
has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (T
) cells. AIM2 is highly expressed by both human and mouse T
cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with T
cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in T
cells. Mechanistically, AIM2 interacts with the RACK1-PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of T
cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT-mTOR signalling and altering immune metabolism to enhance the stability of T
cells.
Abstract
BACKGROUND
Despite progress in the treatment of brain metastasis (BrM) for HER2+ breast cancer (BC), outcomes for patients with HER2-negative BC BrM remain poor. Current standard of care ...consists of local therapies, including surgery and radiotherapy, followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective with radiation therapy as a DNA damage response inhibitor. Triple negative BC (TNBC) has higher rates of homologous recombination deficiency compared to other BC subtypes, and together with HER2-negative, BRCA-mutated BC would be particularly sensitive to PARP inhibition. PARP inhibition also shows promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with BrM. We hypothesize that this biologically-rational combination will enhance local control of SRS-treated BrM through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites via potentiation of the immune response.
METHOD
We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) BC BrM NCT04711824. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II) of this treatment combination. Secondary objectives include determining clinical activity via intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study will evaluate olaparib concentration/distribution in resected BrM.
Plasmablastic lymphoma (PBL) is a rare and aggressive form of B-cell non-Hodgkin lymphoma. This subtype of lymphoma has a post-germinal center cell-of-origin called the plasmablast, and the ...immunophenotype is more consistent with that of a plasma cell than a lymphocyte. Because of these unique features, PBL is notoriously difficult to treat. Case reports and small reviews have evaluated the addition of agents directed against plasma cell disorders in combination with traditional lymphoma-directed regimens. We describe the largest case series to date, with the longest follow-up, evaluating bortezomib in combination with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (V-EPOCH) for the treatment of PBL. Our results show that this is a safe and effective regimen with an overall and complete response rate of 100% and 2-year overall survival of 50%.
Background
Breast cancer mortality is higher for Black and younger women. This study evaluated 2 possible contributors to disparities—time to treatment and treatment duration—by race and age.
Methods
...Among 2841 participants with stage I‐III disease in the Carolina Breast Cancer Study, we identified groups of women with similar patterns of socioeconomic status (SES), access to care, and tumor characteristics using latent class analysis. We then evaluated latent classes in association with treatment delay (initiation >60 days after diagnosis) and treatment duration (in quartiles by treatment modality).
Results
Thirty‐two percent of younger Black women were in the highest quartile of treatment duration (versus 22% of younger White women). Black women experienced a higher frequency of delayed treatment (adjusted relative frequency difference RFD, 5.5% 95% CI, 3.2%‐7.8%) and prolonged treatment duration (RFD, 8.8% 95% CI, 5.7%‐12.0%). Low SES was significantly associated with treatment delay among White women (RFD, 3.5% 95% CI, 1.1%‐5.9%), but treatment delay was high at all levels of SES in Black women (eg, 11.7% in high SES Black women compared with 10.6% and 6.7% among low and high SES White women, respectively). Neither SES nor access to care classes were significantly associated with delayed initiation among Black women, but both low SES and more barriers were associated with treatment duration across both groups.
Conclusions
Factors that influence treatment timeliness persist throughout the care continuum, with prolonged treatment duration being a sensitive indicator of differences by race, SES, and care barriers.
Economic and other barriers to care appear to compound across the continuum, with treatment duration representing a sensitive indicator of barriers to care. By developing an integrated view of multiple patient factors that contribute to duration, appropriate multidimensional interventions can be conceptualized to reduce racial mortality disparities.
Purpose
This study aimed to examine psychometric properties of a caregiver version of the well-established Functional Assessment of Cancer Therapy-General Scale (FACT-G) after conducting focus groups ...and obtaining expert input.
Methods
We made minor wording modifications to the Patient FACT-G to enable caregivers to report how the illness affected their overall quality of life (QOL) and well-being on four subscales (physical, social, emotional, functional). We tested the acceptability, precision, factor structure, reliability and validity of the Caregiver FACT-G among partners of prostate cancer patients (
N
= 263) and caregivers (spouses, siblings, adult children) of patients with advanced cancer (breast, lung, colorectal, prostate) (
N
= 484) using data from two Randomized Clinical Trials (RCTs).
Results
With a factor structure similar to the Patient FACT-G, Caregiver FACT-G was acceptable and precise in measuring caregiver QOL, with high inter-factor correlations and internal consistency reliability (Cronbach’s alphas 0.81–0.91). The Caregiver FACT-G had strong convergent validity demonstrated by significant positive correlations with caregiver self-efficacy (0.25–0.63), dyadic communication (0.18–0.51), and social support (0.18–0.54) in both samples. It also had strong discriminant validity evidenced by significant inverse correlations with negative appraisal of caregiving (− 0.37 to − 0.69), uncertainty (− 0.28 to − 0.53), hopelessness (− 0.25 to − 0.60), and avoidant coping (− 0.26 to − 0.58) in both samples. Caregivers’ baseline FACT-G scores were significantly associated with their physical (0.23) and mental well-being (0.54; 4-month follow-up) and their depression (− 0.69; 3-month follow-up), indicating strong predictive validity.
Conclusion
This is the first study evaluating the psychometric properties of the Caregiver FACT-G. More psychometric testing is warranted, especially among caregivers of diverse sociocultural backgrounds.
Postmarket drug safety database like vaccine adverse event reporting system (VAERS) collect thousands of spontaneous reports annually, with each report recording occurrences of any adverse events ...(AEs) and use of vaccines. We hope to identify signal vaccine‐AE pairs, for which certain vaccines are statistically associated with certain adverse events (AE), using such data. Thus, the outcomes of interest are multiple AEs, which are binary outcomes and could be correlated because they might share certain latent factors; and the primary covariates are vaccines. Appropriately accounting for the complex correlation among AEs could improve the sensitivity and specificity of identifying signal vaccine‐AE pairs. We propose a two‐step approach in which we first estimate the shared latent factors among AEs using a working multivariate logistic regression model, and then use univariate logistic regression model to examine the vaccine‐AE associations after controlling for the latent factors. Our simulation studies show that this approach outperforms current approaches in terms of sensitivity and specificity. We apply our approach in analyzing VAERS data and report our findings.
Leaf hydraulic conductance (Kleaf) is a critical determinant of photosynthesis. Prior research has assessed the influence of light intensity on Kleaf by affecting leaf veins. However, whether the ...mesophyll structure is associated with leaf hydraulic acclimation to different light intensities remains unclear. We investigated the responses of leaf gas exchange and Kleaf to different growth light intensities and checked for the correlation of Kleaf with leaf structural traits in soybean. Low light significantly reduced Kleaf, but Kleaf and stomatal conductance remain coordinated. Low light decreased the stomatal density to match the balance between in water supply and carbon gain capacity. The decline in Kleaf under low growth light condition was partly due to for the reduction of the water movement through leaf veins because of reduced leaf vein thickness and density and xylem conduit size. In addition, low light reduces the mesophyll cell‐to‐cell connectivity and increased the volume fraction of intercellular air space. As a result, the area available for liquid‐phase flow decreases, and subsequently decreased Kleaf. The present study highlights the coordination role between leaf venation architecture and mesophyll structure influencing Kleaf in response to light intensity.
•Low light significantly reduces the leaf hydraulic conductance of soybean.•Leaf hydraulic conductance and stomatal conductance remain coordinated to adapt to low light, and this correlation is mediated by stomatal density.•The coordination role between leaf venation architecture and mesophyll structure influencing leaf hydraulic conductance in response to light intensity is highlighted.
Abstract Resistance to platinum‐based chemotherapies remains a significant challenge in advanced‐stage high‐grade serous ovarian carcinoma, and patients with malignant ascites face the poorest ...outcomes. It is, therefore, important to understand the effects of ascites, including the associated fluid shear stress (FSS), on phenotypic changes and therapy response, specifically FSS‐induced chemotherapy resistance and the underlying mechanisms in ovarian cancer. This study investigated the effects of FSS on response to cisplatin, a platinum‐based chemotherapy, and doxorubicin, an anthracycline, both of which are commonly used to manage advanced‐stage ovarian cancer. Consistent with prior research, OVCAR‐3 and Caov‐3 cells cultivated under FSS demonstrated significant resistance to cisplatin. Examination of the role of mitochondria revealed an increase in mitochondrial DNA copy number and intracellular ATP content in cultures grown under FSS, suggesting that changes in mitochondria number and metabolic activity may contribute to platinum resistance. Interestingly, no resistance to doxorubicin was observed under FSS, the first such observation of a lack of resistance under these conditions. Finally, this study demonstrated the potential of photodynamic priming using benzoporphyrin derivative, a clinically approved photosensitizer that localizes in part to mitochondria and endoplasmic reticula, to enhance the efficacy of cisplatin, but not doxorubicin, thereby overcoming FSS‐induced platinum resistance.
PDF
