Παρασκευή 10 Φεβρουαρίου 2023

SARS‐CoV‐2 NSP7 inhibits type I and III IFN production by targeting the RIG‐I/MDA5, TRIF, and STING signaling pathways

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Abstract

SARS-CoV-2 is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS-CoV-2 NSP7 inhibited the production of type I and III IFNs by targeting the RIG-I/MDA5, TLR3-TRIF, and cGAS-STING signaling pathways. SARS-CoV-2 NSP7 suppressed the expression of IFNs and IFN-stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS-CoV-2 virus-like particles. NSP7 impaired type I and III IFN production activated by components of the cytosolic dsRNA-sensing pathway, including RIG-I, MDA5, and MAVS, but not TBK1, IKKε, and IRF3-5D, an active form of IRF3. In addition, NSP7 also suppressed TRIF- and STING-induced IFN responses. Mechanistically, NSP7 associated with RIG-I and MDA5 prevented the formation of the RIG-I/MDA5−MAVS signalosome and interacted with TRIF and STING to inhibit TRIF-TBK1 and STING-TBK1 complex formation, thus reducing the subsequent IRF3 phosphorylation and nu clear translocation that are essential for IFN induction. In addition, ectopic expression of NSP7 impeded innate immune activation and facilitated virus replication. Taken together, SARS-CoV-2 NSP7 dampens type I and III IFN responses via disruption of the signal transduction of the RIG-I/MDA5−MAVS, TLR3-TRIF, and cGAS-STING signaling pathways, thus providing novel insights into the interactions between SARS-CoV-2 and innate antiviral immunity.

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The Long Outer-Hair-Cell RC Time Constant: A Feature, Not a Bug, of the Mammalian Cochlea

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AbstractThe cochlea of the mammalian inner ear includes an active, hydromechanical amplifier thought to arise via the piezoelectric action of the outer hair cells (OHCs). A classic problem of cochlear biophysics is that theRC (resistance-capacitance) time constant of the hair-cell membrane appears inconveniently long, producing an effective cut-off frequency much lower than that of most audible sounds. The longRC time constant implies that the OHC receptor potential —and hence its electromotile response—decreases by roughly two orders of magnitude over the frequency range of mammalian hearing, casting doubt on the hypothesized role of cycle-by-cycle OHC-based amplification in mammalian hearing. Here, we review published data and basic physics to show that t he "RC problem " has bee...
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Analysis of Unmet Information Needs Among Patients With Thyroid Cancer

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This survey study uses mixed-methods analysis to assess p retreatment counseling experiences of survivors of thyroid cancer and to identify their unmet information needs.
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Patterns of Infectious Disease Associated with Injection Drug Use

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Abstract
Background
Since 2014, multiple outbreaks of HIV among people who inject drugs (PWID) have occurred across the United States along with hepatitis C (HCV), skin and soft tissue infections (SSTI) and infective endocarditis (IE), creating a converging public health crisis.
Methods
We analyzed the temporal patterns of infectious disease and overdose (OD) using a hierarchical Bayesian distributed lag logistic regression model examining the probability that a given geographic area experienced at least one HIV case in a given month as a function of the counts/rates of OD, HCV, SSTI, IE and associated medical procedures at different lagged time periods.
Results
Current-month HIV is associated with increasing HCV cases; abscess incision and drainage, and SSTI cases, in distinct temporal patterns. For example, one additional HCV case occurring 5 and 7 months previously is associated with a 4% increase in the odds of observing at least one current-month HIV case in a given locale (odds ratios: 1.04, 1.04; 90% credible intervals: 1.01-1.10, 1.00-1.09). No such associations were observed for echocardiograms, IE, or OD.
Conclusion
Lagged associations in other infections preceding rises in current-month HIV counts cannot be described as predictive of HIV outbreaks but may point towards newly discovered epidemics of injection drug use and associated clinical sequalae, prompting clinicians to screen patients more carefully for substance use disorder and associated infections.
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Τετάρτη 8 Φεβρουαρίου 2023

Gaps in Depression Symptom Management for Patients With Head and Neck Cancer

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Gaps in Depression Symptom Management for Patients With Head and Neck Cancer

We sought to understand practice patterns and identify care gaps within a large-scale depression screening program for patients with head and neck cancer. A high proportion of head and neck patients report depressive symptoms, though this triggers a referral in a small number of cases. These data highlight areas for improvement in depression screening care pathways.


Objective

To understand practice patterns and identify care gaps within a large-scale depression screening program for patients with head and neck cancer (HNC).

Study Design

Retrospective cohort study.

Methods

This was a population-based study of adults diagnosed with a HNC between January 2007 and October 2020. Each patient was observed from time of first symptom assessment until end of study date, or death. The exposure of interest was a positive depressive symptom screen on the Edmonton Symptom Assessment System (ESAS). Outcomes of interest included psychiatry/psychology assessment, social work referral, or palliative care assessment. Cause specific hazard models with a time-varying exposure were used to investigate the exposure-outcome relationships.

Results

Of 14,054 patients with HNC, 9016 (64.2%) reported depressive symptoms on at least one ESAS assessment. Within 60 days of first reporting depressive symptoms, 223 (2.7%) received a psychiatry assessment, 646 (7.9%) a social work referral, and 1131 (13.9%) a palliative care assessment. Rates of psychiatry/psychology assessment (HR 3.15 [95% CI 2.67–3.72]), social work referral (HR 1.83 [95% CI 1.64–2.02]), and palliative care assessment (HR 2.34 [95% CI 2.19–2.50]) were higher for those screening positive for depression. Certain patient populations were less likely to receive an assessment including the elderly, rural residents, and those without a prior psychiatric history.

Conclusion

A high proportion of head and neck patients report depressive symptoms, though this triggers a referral in a small number of cases. These data highlight areas for improvement in depression screening care pathways.

Level of Evidence

3 Laryngoscope, 2023
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Features of cytomegalovirus DNAemia and virus‐specific T‐cell responses in allogeneic hematopoietic stem‐cell transplant recipients during prophylaxis with letermovir

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Features of cytomegalovirus DNAemia and virus-specific T-cell responses in allogeneic hematopoietic stem-cell transplant recipients during prophylaxis with letermovir


Abstract

Background

There is scarce information on the natural kinetics of cytomegalovirus (CMV) DNAemia and dynamics of CMV-specific T-cell reconstitution in allogeneic hematopoietic transplant recipients (allo-HSCT) undergoing letermovir (LMV) prophylaxis.

Methods

Twelve adult CMV-seropositive high-risk recipients (median age, 53 years; 9 males/3 females) undergoing LMV prophylaxis and 13 non-LMV allo-HSCT controls (median age, 58 years; 7 males/6 females) were included. CMV DNAemia in plasma was monitored by real-time polymerase chain reaction. Preemptive antiviral therapy (PET) was administered upon detection of ≥1500 IU/ml. CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T cells were enumerated by flow cytometry around days +30, +60, and +90 after allo-HSCT. Ex vivo experiments assessing of the potential effect of LMV on CMV-specific T-cell expansion in a single CMV-seropositive donor were also conducted.

Results

Five LMV patients (41.6%) developed CMV DNAemia that cleared spontaneously. Four patients (33.3%) developed CMV DNAemia after LMV cessation, of which two required PET. Nine non-LMV patients (69.2%) developed CMV DNAemia (five required PET). The percentage of LMV and non-LMV patients exhibiting detectable CMV-specific T-cell responses was comparable (7/10 vs. 10/13; p = .71). Nevertheless, median CMV-specific CD4+ and CD8+ T-cell counts were lower in LMV patients by days +60 (p = .006 and .02, respectively) and +90 (p = .08 and .02). Ex vivo, CMV-specific CD8+ T cells expanded to the same level either in the presence (19.8%) or in the absence of LMV (20.6%).

Conclusions

In our series, episodes of CMV DNAemia in LMV patients cleared spontaneously. A diminished degree of CMV-specific T-cell reconstitution in LMV patients compared to non-LMV patients was observed.

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Genomic profiling and prognostic factors of H3 K27M‐mutant spinal cord diffuse glioma

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Genomic profiling and prognostic factors of H3 K27M-mutant spinal cord diffuse glioma

In a large cohort (n=77), we characterized the molecular, clinicopathological, and prognostic characteristics of H3 K27M-mutant spinal cord diffuse glioma. ATRX mutation, CDK6 amplification, RB pathway alteration, a higher number of Copy number variant (CNV) events, chromosome (Chr) 9p deletion, and Chr 10p deletion is associated with worse survival. Glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway and PI3K pathway.


Abstract

H3 K27-altered diffuse midline glioma is a highly lethal pediatric-type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27-altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M-mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M-mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M-mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M-mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutation s. The TP53-mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis <18 years old, p = 0.056). Cox regression and Kaplan–Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway, KRAS/PI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M-mutant spinal cord d iffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.
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