The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors.
In vitro
studies demonstrated that everolimus inhibited ...pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a β-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of β-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%,
p
< 0.001
vs
. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold,
p
< 0.01,
vs
. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold,
p
< 0.001
vs
. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%,
p
< 0.001
vs
. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%,
p
< 0.001
vs
. basal and
p
< 0.05
vs
. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%,
p
< 0.001
vs
. basal and
p
< 0.05
vs
. cabergoline alone). To test β-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in β-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.
Autoimmune Addison's disease (AAD) entails a chronic adrenal insufficiency and is associated with an increased risk of severe infections. It is, however, unknown how patients with AAD were affected ...by the coronavirus disease 2019 (COVID-19) pandemic of 2020-2021. This study was aimed at investigating the incidence of COVID-19 in patients with AAD in Sweden, the self-adjustment of medications during the disease, impact on social aspects, and treatment during hospitalization. Additionally, we investigated if there were any possible risk factors for infection and hospitalization.
Questionnaires were sent out from April to October 2021 to 813 adult patients with AAD in the Swedish Addison Registry. The questionnaires included 55 questions inquiring about COVID-19 sickness, hospital care, medications, and comorbidities, focusing on the pre-vaccine phase.
Among the 615 included patients with AAD, COVID-19 was reported in 17% of which 8.5% required hospital care. Glucocorticoid treatment in hospitalized patients varied. For outpatients, 85% increased their glucocorticoid dosage during sickness. Older age (P = .002) and hypertension (P = .014) were associated with an increased risk of hospital care, while younger age (P < .001) and less worry about infection (P = .030) were correlated with a higher risk of COVID-19.
In the largest study to date examining AAD during the COVID-19 pandemic, we observed that although one-fifth of the cohort contracted COVID-19, few patients required hospital care. A majority of the patients applied general recommended sick rules despite reporting limited communication with healthcare during the pandemic.
Pediatric headaches have been linked to adverse life events or psychological factors in children and their families, with a complex and bidirectional association. Moreover, it is well-known that ...psychological stress can trigger headaches.
We searched three databases for studies focusing on headaches and adverse events or psychological factors in children up to 12 years old or in their caregivers.
We included 28 studies. Child psychological factors, including internal and external symptoms, were commonly associated with all types of headaches. Sleep disturbances showed a positive association with headaches in 3 out of 5 studies. Family conflict and unhappiness were frequently found in children suffering with headaches, while single-parent families and divorce were not associated. Stressful environments and adverse life events, particularly bullying, were also found to be linked with headaches.
Childhood headaches represent an alarm bell for clinicians to investigate and treat psychological or psychiatric disorders in children and their family. Further studies are needed to elucidate the role of early-life adverse events in children and their families.
•Evidences show connections between childhood headache and adverse childhood experiences.•Headache is associated to school-related stress and being bullied.•Family conflict and unhappiness are associated with headache.•Single-parent family and divorce are not connected with headache.•Internalising symptoms were frequently found in children with headache.
Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients treated with EGFR-tyrosine kinase inhibitors (TKIs) inevitably develop resistance through several biological ...mechanisms. However, little is known on the molecular mechanisms underlying acquired resistance to suboptimal EGFR-TKI doses, due to pharmacodynamics leading to inadequate drug exposure. To evaluate the effects of suboptimal EGFR-TKI exposure on resistance in NSCLC, we obtained HCC827 and PC9 cell lines resistant to suboptimal fixed and intermittent doses of gefitinib and compared them to cells exposed to higher doses of the drug. We analyzed the differences in terms of EGFR signaling activation and the expression of epithelial-mesenchymal transition (EMT) markers, whole transcriptomes byRNA sequencing, and cell motility. We observed that the exposure to low doses of gefitinib more frequently induced a partial EMT associated with an induced migratory ability, and an enhanced transcription of cancer stem cell markers, particularly in the HCC827 gefitinib-resistant cells. Finally, the HCC827 gefitinib-resistant cells showed increased secretion of the EMT inducer transforming growth factor (TGF)-β1, whose inhibition was able to partially restore gefitinib sensitivity. These data provide evidence that different levels of exposure to EGFR-TKIs in tumor masses might promote different mechanisms of acquired resistance.
The comparative benefits and harms of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) for patients with aortic stenosis are unclear.
To compare clinical ...outcomes, including early (≤30-day) and midterm (≤1-year) mortality, in adults with severe aortic stenosis undergoing either TAVI or SAVR.
MEDLINE, Cochrane, and Scopus databases (without language restrictions) from April 2002 to 5 April 2016; multiple registries and Web sites; scientific meeting presentations.
Five randomized trials and 31 observational matched studies comparing mortality outcomes after TAVI or SAVR.
Two investigators independently extracted study data and rated risk of bias.
16 638 patients were analyzed. Overall, there was no statistically significant difference between TAVI and SAVR in early (odds ratio OR, 1.01 95% CI, 0.81 to 1.26) or midterm (OR, 0.96 CI, 0.81 to 1.14) all-cause mortality. Analyses restricted to trials (early: OR, 0.80 CI, 0.51 to 1.25; midterm: OR, 0.90 CI, 0.64 to 1.26) were inconclusive, with wide CIs, whereas analyses of matched studies were similar to the overall results. Transfemoral TAVI provided mortality benefits over SAVR in trials. Analyses restricted to studies of patients at low to intermediate risk showed statistically nonsignificant reductions in early (OR, 0.67 CI, 0.42 to 1.07) and midterm (OR, 0.91 CI, 0.67 to 1.23) mortality with TAVI. Incidence of periprocedural myocardial infarction, major bleeding, acute kidney injury, and new-onset atrial fibrillation was lower with TAVI, but risk for pacemaker implantation, vascular complications, and paravalvular leak increased. Overall, there was a statistically nonsignificant increased risk in long-term (2- to 5-year) all-cause mortality with TAVI (OR, 1.28 CI, 0.97 to 1.69), whereas long-term mortality outcomes in patients at low to intermediate risk were inconclusive, with wide CIs (OR, 1.06 CI, 0.59 to 1.91).
The number of trials was limited, and study designs and patient characteristics were heterogeneous.
Compared with SAVR, TAVI may have similar or better early and midterm outcomes for adults with aortic stenosis, including those at low to intermediate risk.
None.
The spatial–temporal distributions of nitrogen dioxide (NO2) in a rural area of Tiber valley were evaluated over one year (March 2022–February 2023) using remote sensing and in situ measurements. ...Surface concentration monitoring was conducted using a Pandora-2s spectrometer and a chemiluminescence analyzer operated at the Liberti Observatory (CNR-IIA). In spring, when the growing season and the agricultural activities increase, NO2 peaks were detectable by the Pandora but not by the in situ analyzer. The tropospheric Pandora and TROPOMI VCD products showed similar temporal patterns as those of the analyzer at the Observatory. High TROPOMI VCD levels in spring were detected at the Observatory and at six sites selected as representative of rural, residential, and industrial environments. WRF simulations found that high pollution events, observed by the Pandora and analyzer, occurred in calm wind conditions, favouring the accumulation of NO2 locally emitted. The complementary dataset provided by remote sensing and in situ techniques efficiently captured the spatial–temporal NO2 variability in a rural site exposed to low emission sources, thus supporting future decisional policies and actions.
Bleeding is the principal safety concern of antithrombotic therapy and occurs frequently among patients with coronary artery disease (CAD).
We aimed to evaluate the prognostic impact of bleeding on ...mortality compared with that of myocardial infarction (MI) in patients with CAD.
We searched Medline and Embase for studies that included patients with CAD and that reported both the association between the occurrence of bleeding and mortality, and between the occurrence of MI and mortality within the same population. Adjusted hazard ratios (HRs) for mortality associated with bleeding and MI were extracted and ratios of hazard ratios (rHRs) were pooled by using inverse variance weighted random effects meta-analyses. Early events included periprocedural or within 30-day events after revascularisation or acute coronary syndrome (ACS). Late events included spontaneous or beyond 30-day events after revascularisation or ACS.
A total of 141,059 patients were included across 16 studies; 128,660 (91%) underwent percutaneous coronary intervention. Major bleeding increased the risk of mortality to the same extent as MI (rHRsbleedingvsMI 1.10, 95% CI: 0.71-1.71, p=0.668). Early bleeding was associated with a higher risk of mortality than early MI (rHRsbleedingvsMI 1.46, 95% CI: 1.13-1.89, p=0.004), although this finding was not present when only randomised trials were included. Late bleeding was prognostically comparable to late MI (rHRsbleedingvsMI 1.14, 95% CI: 0.87-1.49, p=0.358).
Compared with MI, major and late bleeding is associated with a similar increase in mortality, whereas early bleeding might have a stronger association with mortality.
RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, ...differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.
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