Abstract
We have modeled the velocity-resolved reverberation response of the H
β
broad emission line in nine Seyfert 1 galaxies from the Lick Active Galactic Nucleus (AGN) Monitoring Project 2016 ...sample, drawing inferences on the geometry and structure of the low-ionization broad-line region (BLR) and the mass of the central supermassive black hole. Overall, we find that the H
β
BLR is generally a thick disk viewed at low to moderate inclination angles. We combine our sample with prior studies and investigate line-profile shape dependence, such as
log
10
(
FWHM
/
σ
)
, on BLR structure and kinematics and search for any BLR luminosity-dependent trends. We find marginal evidence for an anticorrelation between the profile shape of the broad H
β
emission line and the Eddington ratio, when using the rms spectrum. However, we do not find any luminosity-dependent trends, and conclude that AGNs have diverse BLR structure and kinematics, consistent with the hypothesis of transient AGN/BLR conditions rather than systematic trends.
Abstract only
167
Background: Low PSMA uptake on positron-emission tomography is seen in up to 30% of mCRPC pts and represents a clinically distinct subgroup with adverse outcomes. We assessed ...transcriptional and clinical features associated with low PSMA ( FOLH1) gene expression in mCRPC. Methods: A retrospective analysis of mCRPC biopsy samples with RNA-seq data was undertaken. Normalized FOLH1 expression was compared across histologic subtypes and sites of disease. We assessed the association between FOLH1 expression, selected androgen receptor (AR) target genes, master regulators of neuroendocrine differentiation, and previously validated AR activity and treatment-associated small cell neuroendocrine carcinoma (t-SCNC) transcriptional signature scores using Pearson correlations. Associations between FOLH1 and both PSA
50
response to subsequent AR-targeted therapy and overall survival (OS) were examined by logistic regression and Cox proportional hazard models, respectively. Results: Samples from 97 pts were identified, of which 18% harbored t-SCNC histology. 45% of pts had visceral metastases at the time of biopsy, and 41% received subsequent AR-targeted therapy. Median FOLH1 expression was lower in pts with visceral metastases vs no visceral metastases (14.7 vs 15.6, p = 0.02) but was not significantly different across t-SCNC vs adenocarcinoma biopsies (14.3 vs 15.4, p = 0.13). FOLH1 expression was positively correlated with AR transcriptional activity and AR target genes, and negatively correlated with master regulators of neuroendocrine differentiation and t-SCNC transcriptional signature scores (Table). Low FOLH1 expression did not predict PSA
50
response to subsequent AR-targeted therapy (OR 0.97, p = 0.8), but was associated with shorter OS on univariate analysis (HR 1.09, 95% CI 1.02-1.16, p=0.01). A post-hoc analysis revealed a trend towards decreased median OS in pts with FOLH1 expression <12 (7.5 vs 17.1 months, log-rank p = 0.06). Conclusions: In this retrospective analysis of mCRPC pts, low FOLH1 expression was associated with transcriptional features of t-SCNC, decreased AR activity, and shorter OS. These findings are hypothesis-generating and prospective validation is needed.Table: see text
Objectives
To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint ...inhibitors (ICIs).
Patients and Methods
We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression‐free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni‐ and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line).
Results
Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio aOR 0.73, 95% confidence interval CI 0.43–1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio aHR 0.93, 95% CI 0.73–1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81–1.27). Patients with mixed‐histology UTUC had a significantly lower ORR and shorter PFS vs mixed‐histology LTUC (aOR 0.20, 95% CI 0.05–0.91 and aHR 1.66, 95% CI 1.06–2.59), respectively).
Conclusion
Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed‐histology UTUC had a lower ORR and shorter PFS compared to mixed‐histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.
Follicular helper T cells (TFH cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high-affinity antibodies. We found that ...expression of microRNAs (miRNAs) by T cells was essential for TFH cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR-17∼92 was critical for robust differentiation and function of TFH cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17∼92 restrained the expression of genes 'inappropriate' to the TFH cell subset, including the direct miR-17∼92 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-17∼92-deficient TFH cells. Our results identify the miR-17∼92 cluster as a critical regulator of T cell-dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We previously have shown that Nicotiana sylvestris cytoplasmic male sterile (CMS) mutants I and II present large mtDNA deletions and that the NAD7 subunit of complex I (the main dehydrogenase of the ...mitochondrial respiratory chain) is absent in CMS I. Here, we show that, despite a large difference in size in the mtDNA deletion, CMS I and II display similar alterations. Both have an impaired development from germination to flowering, with partial male sterility that becomes complete under low light. Besides NAD7, two other complex I subunits are missing (NAD9 and the nucleus-encoded, 38-kDa subunit), identified on two-dimensional patterns of mitochondrial proteins. Mitochondria isolated from CMS leaves showed altered respiration. Although their succinate oxidation through complex II was close to that of the wild type, oxidation of glycine, a priority substrate of plant mitochondria, was significantly reduced. The remaining activity was much less sensitive to rotenone, indicating the breakdown of Complex I activity. Oxidation of exogenous NADH (coupled to proton gradient generation and partly sensitive to rotenone) was strongly increased. These results suggest respiratory compensation mechanisms involving additional NADH dehydrogenases to complex I. Finally, the capacity of the cyanide-resistant alternative oxidase pathway was enhanced in CMS, and higher amounts of enzyme were evidenced by immunodetection.
Follicular helper T cells (T sub(FH) cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high-affinity antibodies. We found that ...expression of microRNAs (miRNAs) by T cells was essential for T sub(FH) cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR-1792 was critical for robust differentiation and function of T sub(FH) cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-1792 restrained the expression of genes 'inappropriate' to the T sub(FH) cell subset, including the direct miR-1792 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-1792-deficient T sub(FH) cells. Our results identify the miR-1792 cluster as a critical regulator of T cell-dependent antibody responses, T sub(FH) cell differentiation and the fidelity of the T sub(FH) cell gene-expression program.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Follicular helper T cells (T.sub.FH cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high-affinity antibodies. We found that ...expression of microRNAs (miRNAs) by T cells was essential for T.sub.FH cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR- 17~92 was critical for robust differentiation and function of T.sub.FH cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17~92 restrained the expression of genes 'inappropriate' to the T.sub.FH cell subset, including the direct miR-17~92 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-17~92-deficient T.sub.FH cells. Our results identify the miR-17~92 cluster as a critical regulator of T cell- dependent antibody responses, T.sub.FH cell differentiation and the fidelity of the T.sub.FH cell gene-expression program.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
T follicular helper (T
FH
) cells are the prototypic helper T cell subset specialized to enable B cells to form germinal centers and produce high-affinity antibodies. We found that miRNA expression ...by T cells was essential for T
FH
cell differentiation. More specifically, we show that after protein immunization the microRNA cluster miR-17~92 was critical for robust T
FH
cell differentiation and function in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17~92 restrained the expression of T
FH
subset-inappropriate genes, including the direct target RAR-related orphan receptor alpha (
Rora
). Genetically removing one
Rora
allele partially rescued the inappropriate gene signature in miR-17~92-deficient T
FH
cells. Our results identify the miR-17~92 cluster as a critical regulator of T cell-dependent antibody responses, T
FH
cell differentiation and the fidelity of the T
FH
cell gene expression program.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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