Background
Cutaneous squamous‐cell carcinoma (CSCC) is among the most frequent malignancies worldwide. For those not amenable to treatment with curative intent, immune checkpoint inhibition (ICI) ...with anti‐programmed death receptor 1 (PD‐1) antibodies has emerged as a novel therapeutic option. In this study, the authors sought to investigate the activity of the anti‐PD‐1 agent nivolumab in patients with advanced CSCC (aCSCC).
Methods
CA209‐9JC was an open‐label, single‐arm, phase 2 study to evaluate the safety and/or efficacy of nivolumab in systemic treatment‐naive patients with aCSCC. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or 12 months of treatment. The primary end point was the best objective response rate (BORR) as per RECIST 1.1 criteria. Secondary end points included safety, progression‐free survival (PFS), and overall survival (OS).
Results
Twenty‐four patients with aCSCC were enrolled with a median age of 74 years (range, 48–93). Among the 24 patients evaluable for response, the BORR was 58.3% (14/24); there were no complete responses. With a median follow‐up of 17.6 months, median duration of response has not been reached, and the estimated median PFS and OS were 12.7 and 20.7 months, respectively. Prior exposure to radiotherapy was associated with worse outcomes (p = .035, univariate analysis). Treatment‐related adverse events of any grade and grade ≥ 3 occurred in 21 (87.5%) and six (25%) patients, respectively, and one patient discontinued nivolumab due to toxicities.
Conclusions
Nivolumab resulted in robust antitumor activity, sustained responses, and good tolerability in systemic treatment‐naive patients with aCSCC. These data provide further evidence to support the use of ICI as the standard treatment of aCSCC.
In CA209‐9JC, a single‐arm, phase 2 study, 24 systemic treatment‐naive patients with advanced cutaneous squamous‐cell carcinoma were treated with nivolumab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity, or 12 months of treatment. Nivolumab resulted in significant antitumor activity, prolonged responses, and a good tolerability in patients with advanced cutaneous squamous‐cell carcinoma in the first‐line setting.
The comparison of chemical and histopathological data obtained from the analysis of excised tumor fragments oral squamous cell carcinoma (OSCC) with the demographic and clinical evolution data is an ...effective strategy scarcely explored in OSCC studies. The aim was to analyze OSCC tissues for protein expression of enzymes related to oxidative stress and DNA repair and trace elements as candidates as markers of tumor aggressiveness and prognosis. Tumor fragments from 78 OSCC patients that had undergone ablative surgery were qualitatively analyzed by synchrotron micro-X-ray fluorescence for trace elements. Protein expression of SOD-1, Trx, Ref-1 and OGG1/2 was performed by immunohistochemistry. Sociodemographic, clinical, and histopathological data were obtained from 4-year follow-up records. Disease relapse was highest in patients with the presence of chlorine and chromium and lowest in those with tumors with high OGG1/2 expression. High expression of SOD-1, Trx, and Ref-1 was determinant of the larger tumor. Presence of trace elements can be markers of disease prognosis. High expression of enzymes related to oxidative stress or to DNA repair can be either harmful by stimulating tumor growth or beneficial by diminishing relapse rates. Interference on these players may bring novel strategies for the therapeutic management of OSCC patients.
Small water systems are important hotspots of greenhouse gas (GHG) emission, but estimates are poorly constrained as data are scarce. Small ponds are often constructed in urban areas, where they ...receive large amounts of nutrients and therefore tend to be highly productive. Here, we investigated GHG emissions, seasonal and diel variation, and net ecosystem production (NEP) from an urban pond. In monthly 24-h field campaigns during 11 months, diffusive water–atmosphere methane (CH₄) and carbon dioxide (CO₂) fluxes and CH₄ ebullition and oxidation were quantified. With oxygen (O₂) measurements, NEP was assessed. The pond was a net GHG source the entire year, with an emission of 3.4 kg CO₂ eq m−2 yr−1. The dominant GHG emission pathway was CH₄ ebullition (bubble flux, 50%), followed by diffusive emissions of CO₂ (38%) and CH₄ (12%). Sediment CH₄ release was primarily driven by temperature and especially ebullition increased exponentially above a temperature threshold of 15°C. The pond’s atmospheric CO₂ exchange was not related to NEP or temperature but likely to a high allochthonous carbon (C) input via runoff and anaerobic mineralization of C. We expect urban ponds to show a large increase in GHG emission with increasing temperature, which should be considered carefully when constructing ponds in urban areas. Emissions may partly be counteracted by pond management focusing on a reduction of nutrient and organic matter input.
Currently, there is a lack of efficient recurrence prediction methods for papillary thyroid carcinoma (PTC). In this study, we enrolled 202 PTC patients submitted to total thyroidectomy and ...radioiodine therapy with long-term follow-up (median = 10.7 years). The patients were classified as having favorable clinical outcome (PTC-FCO, no disease in the follow-up) or recurrence (PTC-RE). Alterations in
, and
were investigated (
= 202) and the transcriptome of 48 PTC (>10 years of follow-up) samples was profiled. Although no mutation was associated with the recurrence risk, 68 genes were found as differentially expressed in PTC-RE compared to PTC-FCO. Pathway analysis highlighted a potential role of cancer-related pathways, including signal transduction and FoxO signaling. Among the eight selected genes evaluated by RT-qPCR,
and
showed down-expression exclusively in the PTC-FCO group compared to non-neoplastic tissues (NT). Increased expression of
was an independent marker of shorter disease-free survival hazard ratio (HR) 2.9; 95% confidence interval (CI95) 1.2-7.0 in our cohort and with overall survival in the TCGA dataset (HR = 4.38, CI95 1.2-15.5). In conclusion,
transcript was identified as a novel prognostic marker candidate in PTC patients treated with total thyroidectomy and radioiodine therapy.
Hypancistrus zebra is a Loricariid endemic to a very limited stretch of the Xingu River and has a high value in the ornamental fish trade. The natural populations have experienced high fishing ...pressure since the late 80s and were recently impacted by the construction of the third largest hydroelectric dam complex in the world, the Belo Monte Project. Since 2004, it has been considered critically endangered and had its capture and trade forbidden. Even with its capture and trade prohibited since 2004, the species continues to be one of the most trafficked fish in the world. The biometric knowledge of the species is essential for monitoring its natural populations and management in ex situ environments. This work aims to establish the weight-length relationship (WLR) and length-length relationship (LLR) of the species and to evaluate the condition factor (K) of H. zebra rescued from trafficking. The study was conducted at the Laboratório de Aquicultura de Peixes Ornamentais do Xingu from February 2022 to June 2022, estimating the parameters of WLR and LLR of 1165 specimens divided into four simple linear regression (SLR) models: all specimens, only juveniles, only females, and only males. The K of 190 specimens rescued from trafficking by the Brazilian Federal Police was evaluated. The WLRs and LLRs were estimated using SLR. The difference between the allometry coefficients (b) and between the residuals of the models (juveniles, females, and males) was evaluated using the ANOVA significance test. The total length of the species ranged from 1.6 to 9.3 cm. The coefficient of allometry (b) of the WLR of the species is 3.22 and of the LLR is 1.04, demonstrating that H. zebra presents positive allometric growth. The evaluation of the residuals of the models showed differences between ontogenetic stages and between sexes. The development of juveniles is isometric until the first sexual maturation phase and differs in negative allometric for females and positive allometric for males, showing sexual dimorphism in the species. Among the specimens rescued from trafficking, 54.74% were underweight, and 13.16% were under 60% of the expected K value, demonstrating the poor conditions in which these animals are transported by trafficking.
The lack of gestational weight gain (GWG) recommendations for low- and middle-income countries is a significant concern.
To identify the ranges on the Brazilian GWG charts associated with lowest ...risks of selected adverse maternal and infant outcomes.
Data from 3 large Brazilian datasets were used. Pregnant individuals aged ≥18, without hypertensive disorders or gestational diabetes were included. Total GWG was standardized to gestational age-specific z-scores according to Brazilian GWG charts. A composite infant outcome was defined as the occurrence of any of small-for-gestationa lage (SGA), large-forgestationa lage (LGA), or preterm birth. In a separate sample, postpartum weight retention (PPWR) was measured at 6 and/or 12 mo postpartum. Multiple logistic and Poisson regressions were performed with GWG z-scores as the exposure and individual and composite outcomes. GWG ranges associated with the lowest risk of the composite infant outcome were identified using noninferiority margins.
For the neonatal outcomes, 9500 individuals were included in the sample. For PPWR, 2602 and 7859 individuals were included at 6 and 12 mo postpartum, respectively. Overall, 7.5% of the neonates were SGA, 17.6% LGA, and 10.5% were preterm. Higher GWG z-scores were positively associated with LGA birth, whereas lower z-scores were positively associated with SGA births. The risk of the selected adverse neonatal outcomes were lowest (within 10% of lowest observed risk) when individuals with underweight, normal weight, overweight, or obesity gained between 8.8–12.6; 8.7–12.4; 7.0–8.9; and 5.0–7.2 kg, respectively. These gains correspond to probabilities of PPWR ≥5 kg at 12 mo of 30% for individuals with under and normal weight, and <20% for overweight and obesity.
This study provided evidence to inform new GWG recommendations in Brazil.
Staphylococcal exfoliative toxins (ETs) are glutamyl endopeptidases that specifically cleave the Glu381-Gly382 bond in the ectodomains of desmoglein 1 (Dsg1) via complex action mechanisms. To date, ...four ETs have been identified in different Staphylococcus aureus strains and ETE is the most recently characterized. The unusual properties of ETs have been attributed to a unique structural feature, i.e., the 180° flip of the carbonyl oxygen (O) of the nonconserved residue 192/186 (ETA/ETE numbering), not conducive to the oxyanion hole formation. We report the crystal structure of ETE determined at 1.61 Å resolution, in which P186(O) adopts two conformations displaying a 180° rotation. This finding, together with free energy calculations, supports the existence of a dynamic transition between the conformations under the tested conditions. Moreover, enzymatic assays showed no significant differences in the esterolytic efficiency of ETE and ETE/P186G, a mutant predicted to possess a functional oxyanion hole, thus downplaying the influence of the flip on the activity. Finally, we observed the formation of ETE homodimers in solution and the predicted homodimeric structure revealed the participation of a characteristic nonconserved loop in the interface and the partial occlusion of the protein active site, suggesting that monomerization is required for enzymatic activity.
ABSTRACT
We investigate the prevalence of galactic-scale outflows in post-starburst (PSB) galaxies at high redshift (1 < z < 1.4), using the deep optical spectra available in the UKIDSS Ultra Deep ...Survey (UDS). We use a sample of ∼40 spectroscopically confirmed PSBs, recently identified in the UDS field, and perform a stacking analysis in order to analyse the structure of strong interstellar absorption features such as Mg ii (λ2800 Å). We find that for massive ($M_* \gt 10^{10}\rm \, M_{\odot }$) PSBs at z > 1, there is clear evidence for a strong blue-shifted component to the Mg ii absorption feature, indicative of high-velocity outflows ($v_{\rm out}\sim 1150\pm 160\rm \, km\, s^{-1}$) in the interstellar medium. We conclude that such outflows are typical in massive PSBs at this epoch, and potentially represent the residual signature of a feedback process that quenched these galaxies. Using full spectral fitting, we also obtain a typical stellar velocity dispersion σ* for these PSBs of $\sim 200\rm \, km\, s^{-1}$, which confirms they are intrinsically massive in nature (dynamical mass $M_{\rm d}\sim 10^{11}\rm \, M_{\odot }$). Given that these high-z PSBs are also exceptionally compact (re ∼ 1–$2\rm \, kpc$) and spheroidal (Sérsic index n ∼ 3), we propose that the outflowing winds may have been launched during a recent compaction event (e.g. major merger or disc collapse) that triggered either a centralized starburst or active galactic nuclei (AGN) activity. Finally, we find no evidence for AGN signatures in the optical spectra of these PSBs, suggesting they were either quenched by stellar feedback from the starburst itself, or that if AGN feedback is responsible, the AGN episode that triggered quenching does not linger into the post-starburst phase.
Preliminary methodologically limited studies suggested that taste and smell known as chemosensory impairments and neuropsychiatric symptoms are associated in post-COVID-19. The objective of this ...study is to evaluate whether chemosensory dysfunction and neuropsychiatric impairments in a well-characterized post-COVID-19 sample. This is a cohort study assessing adult patients hospitalized due to moderate or severe forms of COVID-19 between March and August 2020. Baseline information includes several clinical and hospitalization data. Further evaluations were made using several different reliable instruments designed to assess taste and smell functions, parosmia, and neuropsychiatric disorders (using standardized psychiatric and cognitive measures). Out of 1800 eligible individuals, 701 volunteers were assessed on this study. After multivariate analysis, patients reporting parosmia had a worse perception of memory performance (
p
< 0.001). Moderate/severe hypogeusia was significantly associated with a worse performance on the word list memory task (
p
= 0.012); Concomitant moderate/severe olfactory and gustatory loss during the acute phase of COVID-19 was also significantly associated with episodic memory impairment (
p
= 0.006). We found a positive association between reported chemosensory (taste and olfaction) abnormalities and cognition dysfunction in post-COVID-19 patients. These findings may help us identify potential mechanisms linking these two neurobiological functions, and also support the speculation on a possible route through which SARS-CoV-2 may reach the central nervous system.
The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain.
To evaluate the short-term safety of ticagrelor when ...compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy.
We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%.
Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel.
The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days.
The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, -0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57).
In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days.
clinicaltrials.gov Identifier: NCT02298088.
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