Rhinovirus (RV), a ssRNA virus of the picornavirus family, is a major cause of the common cold as well as asthma and chronic obstructive pulmonary disease exacerbations. Viral dsRNA produced during ...replication may be recognized by the host pattern recognition receptors TLR-3, retinoic acid-inducible gene (RIG)-I, and melanoma differentiation-associated gene (MDA)-5. No study has yet identified the receptor required for sensing RV dsRNA. To examine this, BEAS-2B human bronchial epithelial cells were infected with intact RV-1B or replication-deficient UV-irradiated virus, and IFN and IFN-stimulated gene expression was determined by quantitative PCR. The separate requirements of RIG-I, MDA5, and IFN response factor (IRF)-3 were determined using their respective small interfering RNAs (siRNA). The requirement of TLR3 was determined using siRNA against the TLR3 adaptor molecule Toll/IL-1R homologous region-domain-containing adapter-inducing IFN-beta (TRIF). Intact RV-1B, but not UV-irradiated RV, induced IRF3 phosphorylation and dimerization, as well as mRNA expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, 10-kDa IFN-gamma-inducible protein/CXCL10, IL-8/CXCL8, and GM-CSF. siRNA against IRF3, MDA5, and TRIF, but not RIG-I, decreased RV-1B-induced expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, and inflammatory protein-10/CXCL10 but had no effect on IL-8/CXCL8 and GM-CSF. siRNAs against MDA5 and TRIF also reduced IRF3 dimerization. Finally, in primary cells, transfection with MDA5 siRNA significantly reduced IFN expression, as it did in BEAS-2B cells. These results suggest that TLR3 and MDA5, but not RIG-I, are required for maximal sensing of RV dsRNA and that TLR3 and MDA5 signal through a common downstream signaling intermediate, IRF3.
PVD and FLP sensory neurons envelope the body of the C. elegans adult with a highly branched network of thin sensory processes. Both PVD and FLP neurons are mechanosensors. PVD is known to mediate ...the response to high threshold mechanical stimuli. Thus PVD and FLP neurons are similar in both morphology and function to mammalian nociceptors. To better understand the function of these neurons we generated strains lacking them. Behavioral analysis shows that PVD and FLP regulate movement under normal growth conditions, as animals lacking these neurons demonstrate higher dwelling behavior. In addition, PVD—whose thin branches project across the body-wall muscles—may have a role in proprioception, as ablation of PVD leads to defective posture. Moreover, movement-dependent calcium transients are seen in PVD, a response that requires MEC-10, a subunit of the mechanosensory DEG/ENaC channel that is also required for maintaining wild-type posture. Hence, PVD senses both noxious and innocuous signals to regulate C. elegans behavior, and thus combines the functions of multiple mammalian somatosensory neurons. Finally, strong mechanical stimulation leads to inhibition of egg-laying, and this response also depends on PVD and FLP neurons. Based on all these results we suggest that noxious signals perceived by PVD and FLP promote an escape behavior consisting of increased speed, reduced pauses and reversals, and inhibition of egg-laying.
Marine invertebrates harbour a complex suite of bacterial and archaeal symbionts, a subset of which are probably linked to host health and homeostasis. Within a complex microbiome it can be difficult ...to tease apart beneficial or parasitic symbionts from nonessential commensal or transient microorganisms; however, one approach is to detect strong cophylogenetic patterns between microbial lineages and their respective hosts. We employed the Procrustean approach to cophylogeny (PACo) on 16S rRNA gene derived microbial community profiles paired with COI, 18S rRNA and ITS1 host phylogenies. Second, we undertook a network analysis to identify groups of microbes that were co‐occurring within our host species. Across 12 coral, 10 octocoral and five sponge species, each host group and their core microbiota (50% prevalence within host species replicates) had a significant fit to the cophylogenetic model. Independent assessment of each microbial genus and family found that bacteria and archaea affiliated to Endozoicomonadaceae, Spirochaetaceae and Nitrosopumilaceae have the strongest cophylogenetic signals. Further, local Moran's I measure of spatial autocorrelation identified 14 ASVs, including Endozoicomonadaceae and Spirochaetaceae, whose distributions were significantly clustered by host phylogeny. Four co‐occurring subnetworks were identified, each of which was dominant in a different host group. Endozoicomonadaceae and Spirochaetaceae ASVs were abundant among the subnetworks, particularly one subnetwork that was exclusively comprised of these two bacterial families and dominated the octocoral microbiota. Our results disentangle key microbial interactions that occur within complex microbiomes and reveal long‐standing, essential microbial symbioses in coral reef invertebrates.
To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery.
...Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m
and G 50 mg/m
were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0.
Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% 90% CI, 61 to 83) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment.
Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.
•Thermodynamic model of MEA system developed with uncertainty quantification.•Reaction kinetics should be consistent with thermodynamic model for electrolytes.•Model is simultaneously predictive of ...VLE, heat of absorption, and heat capacity.•Uncertainty in the VLE model of MEA-H2O-CO2 system can have significant effect.•Bayesian approach is very useful for quantifying parametric uncertainty.
The accurate characterization of the thermodynamic models of a reactive solvent-based CO2 capture system is essential for adequately capturing system behavior in a process model. Moreover, uncertainty in these models can significantly affect simulation results, although it is often neglected. With this incentive, a model of thermodynamic properties, including vapor-liquid equilibrium (VLE), enthalpy, and solution chemistry, has been developed using a rigorous methodology for the aqueous monoethanolamine (MEA) system as a baseline. The final thermodynamic framework consists of both a deterministic and stochastic model. The deterministic model is developed by regressing parameters of the e-NRTL activity coefficient model in Aspen Plus® to VLE, heat capacity, and heat of absorption data while downselecting the model’s large parameter space through use of information-theoretic criteria. The stochastic model is developed through an uncertainty quantification (UQ) procedure, using the results of the deterministic regression to determine a prior parameter distribution. This prior distribution and the experimental VLE data are used to derive a posterior distribution through Bayesian inference, which is used to represent the final stochastic model. A reaction model in which the kinetics are written in terms of the reaction equilibrium constants, to ensure consistency with the thermodynamics model, is developed. These new thermodynamic and reaction models are incorporated into an existing MEA system process model from the open literature, and the prior and posterior parameter distributions are propagated through the models. This provides valuable insight into the extent to which uncertainty in thermodynamic models affects key process variables, including CO2 capture efficiency and energy requirement for solvent regeneration.
This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as second-line therapy in patients with unresectable endometrial cancer. The primary end point was the ...objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes.
An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinum-based chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle.
There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8–21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3–46.4). Median PFS was 5.6 months (95% CI: 3.7–6.3), and median OS was 10.6 months (95% CI: 8.9–14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR.
Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies.
A compact and portable open-path sensor for simultaneous detection of atmospheric N(2)O and CO has been developed with a 4.5 μm quantum cascade laser (QCL). An in-line acetylene (C(2)H(2)) gas ...reference cell allows for continuous monitoring of the sensor drift and calibration in rapidly changing field environments and thereby allows for open-path detection at high precision and stability. Wavelength modulation spectroscopy (WMS) is used to detect simultaneously both the second and fourth harmonic absorption spectra with an optimized dual modulation amplitude scheme. Multi-harmonic spectra containing atmospheric N(2)O, CO, and the reference C(2)H(2) signals are fit in real-time (10 Hz) by combining a software-based lock-in amplifier with a computationally fast numerical model for WMS. The sensor consumes ~50 W of power and has a mass of ~15 kg. Precision of 0.15 ppbv N(2)O and 0.36 ppbv CO at 10 Hz under laboratory conditions was demonstrated. The sensor has been deployed for extended periods in the field. Simultaneous N(2)O and CO measurements distinguished between natural and fossil fuel combustion sources of N(2)O, an important greenhouse gas with poorly quantified emissions in space and time.
Surgical evaluation of lymph node metastasis is paramount in the treatment of cervical cancer. We sought to explore the outcomes of patients with and without para-aortic lymphadenectomy undergoing ...curative-intent radical hysterectomy for stage IA-IIA cervical cancer.
Institutional data were retrospectively reviewed to identify women undergoing curative-intent radical hysterectomy with concurrent lymphadenectomy for stage IA-IIA cervical carcinoma from 2004 to 2021. Any carcinoma histology was allowed. Clinical risk stratification was performed according to GOG 92 and GOG 109 protocols. Disease outcomes, patterns of recurrence, and survival were analyzed with Chi square, t-test, Kaplan-Meier, and Cox proportional hazards multivariable statistics.
300 patients were identified, 265 met inclusion criteria. Median follow up was 56 months. Pelvic lymphadenectomy (PLND) was performed in 71%, with the remainder undergoing combined para-aortic dissection (PPaLND). Baseline patient demographics and presence of clinical risk factors were well balanced between groups. PPaLND was more common in patients undergoing open surgery (OR 10.58, p <.0001), and tumors were larger in this group (2.96 vs 2.12 cm, p = .0002) and more likely non-squamous histology (OR 2.02, p = .017). Recurrence of disease was present in 13% of cases, with no difference between PLND and PPaLND regardless of histology. There were zero cases of isolated PaLN recurrence in either group. Neither progression free nor overall survival was different between groups. Prophylactic extended field radiation (EFRT) was not prescribed.
Omission of PaLN dissection, in the absence of suspicious nodes, did not decrease survival. There were no isolated PaLN recurrences after PLND alone.
•Omission of routine para-aortic lymphadenectomy did not worsen survival for surgically managed early stage cervical cancer.•Patients undergoing combined PPaLND had higher pre-operative risk factors.•There were no isolated PaLN recurrences in patients omitting PaLND.
Purpose We examined the frequency of followup prostate specific antigen testing and prostate biopsy among men treated with active surveillance in the academic and community urology practices ...comprising MUSIC (Michigan Urological Surgery Improvement Collaborative). Materials and Methods MUSIC is a consortium of 42 practices that maintains a prospective clinical registry with validated clinical data on all patients diagnosed with prostate cancer at participating sites. We identified all patients in MUSIC practices who entered active surveillance and had at least 2 years of continuous followup. After determining the frequency of repeat prostate specific antigen testing and prostate biopsy, we calculated rates of concordance with NCCN Guidelines® recommendations (ie at least 3 prostate specific antigen tests and 1 surveillance biopsy) collaborative-wide and across individual practices. Results We identified 513 patients who entered active surveillance from January 2012 through September 2013 and had at least 2 years of followup. Among the 431 men (84%) who remained on active surveillance for 2 years 132 (30.6%) underwent followup surveillance testing at a frequency that was concordant with NCCN® (National Comprehensive Cancer Network®) recommendations. At the practice level, the median rate of guideline concordant followup was 26.5% (range 10% to 67.5%, p <0.001). Among patients with discordant followup, the absence of followup biopsy was common and not significantly different across practices (median rate 82.0%, p = 0.35). Conclusions Among diverse community and academic practices in Michigan, there is wide variation in the proportion of men on active surveillance who meet guideline recommendations for followup prostate specific antigen testing and repeat biopsy. These data highlight the need for standardized active surveillance pathways that emphasize the role of repeat surveillance biopsies.
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