Abstract
Context
Pituitary neuroendocrine tumors (PitNETs) are a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset of patients ...are resistant or poorly responsive to the main current medical treatments i.e., synthetic somatostatin analogs (SSAs) and dopamine agonists. Thus, development and optimization of novel and available medical therapies is necessary. Biguanides (metformin, buformin, and phenformin) are antidiabetic drugs that exert antitumoral actions in several tumor types, but their pharmacological effects on PitNETs are poorly known.
Objective
We aimed to explore the direct effects of biguanides on key functions (cell viability, hormone release, apoptosis, and signaling pathways) in primary cell cultures from human PitNETs and cell lines. Additionally, we evaluated the effect of combined metformin with SSAs on cell viability and hormone secretion.
Design
A total of 13 corticotropinomas, 13 somatotropinomas, 13 nonfunctioning PitNETs, 3 prolactinomas, and 2 tumoral pituitary cell lines (AtT-20 and GH3) were used to evaluate the direct effects of biguanides on cell viability, hormone release, apoptosis, and signaling pathways.
Results
Biguanides reduced cell viability in all PitNETs and cell lines (with phenformin being the most effective biguanide) and increased apoptosis in somatotropinomas. Moreover, buformin and phenformin, but not metformin, reduced hormone secretion in a cell type–specific manner. Combination metformin/SSA therapy did not increase SSA monotherapy effectiveness. Effects of biguanides on PitNETs could involve the modulation of AMP-activated protein kinase–dependent (Ca2+i, PI3K/Akt) and independent (MAPK) mechanisms.
Conclusion
Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening avenues to explore their potential as drugs to treat these pathologies.
Biguanides reduced aggressiveness features (e.g., proliferation, apoptosis) in pituitary neuroendocrine tumors, opening avenues to explore their potential as drugs to treat these pathologies.
The importance of submicroscopic malaria infections in high-transmission areas could contribute to maintain the parasite cycle. Regarding non-endemic areas, its importance remains barely understood ...because parasitaemia in these afebrile patients is usually below the detection limits for microscopy, hence molecular techniques are often needed for its diagnosis. In addition to this, the lack of standardized protocols for the screening of submicroscopic malaria in immigrants from endemic areas may underestimate the infection with Plasmodium spp. The aim of this study was to assess the prevalence of submicroscopic malaria in afebrile immigrants living in a non-endemic area.
A prospective, observational, multicentre study was conducted. Afebrile immigrants were included, microscopic observation of Giemsa-stained thin and thick blood smears, and two different molecular techniques detecting Plasmodium spp. were performed. Patients with submicroscopic malaria were defined as patients with negative blood smears and detection of DNA of Plasmodium spp. with one or both molecular techniques. Demographic, clinical, analytical and microbiological features were recorded and univariate analysis by subgroups was carried out with STATA v15.
A total of 244 afebrile immigrants were included in the study. Of them, 14 had a submicroscopic malaria infection, yielding a prevalence of 5.7% (95% confidence interval 3.45-9.40). In 71.4% of the positive PCR/negative microscopy cases, Plasmodium falciparum alone was the main detected species (10 out of the 14 patients) and in 4 cases (28.6%) Plasmodium vivax or Plasmodium ovale were detected. One patient had a mixed infection including three different species.
The prevalence of submicroscopic malaria in afebrile immigrants was similar to that previously described in Spain. Plasmodium vivax and P. ovale were detected in almost a third of the submicroscopic infections. Screening protocols for afebrile immigrants with molecular techniques could be useful for a proper management of these patients.
With more than 7500 cases reported since April 2022, Spain has experienced the highest incidence of mpox in Europe. From 12 July onward, the modified vaccinia Ankara-Bavaria Nordic (MVA-BN) smallpox ...vaccine was offered as pre-exposure prophylaxis for those receiving pre-exposure prophylaxis for human immunodeficiency virus (HIV-PrEP). Our aim was to assess the effectiveness of 1 dose of MVA-BN vaccine as pre-exposure prophylaxis against mpox virus (MPXV) infection in persons on HIV-PrEP.
National retrospective cohort study between 12 July and 12 December 2022. Individuals aged ≥18 years receiving HIV-PrEP as of 12 July with no previous MPXV infection or vaccination were eligible. Each day, we matched individuals receiving a first dose of vaccine and unvaccinated controls of the same age and region. We used a Kaplan-Meier estimator, calculated risk ratios (RR) and vaccine effectiveness (VE = 1 - RRx100).
We included 5660 matched pairs, with a median follow-up of 62 days (interquartile range, 24-97). Mpox cumulative incidence was 5.6 per 1000 (25 cases) in unvaccinated and 3.5 per 1000 (18 cases) in vaccinated. No effect was found during days 0-6 post-vaccination (VE, -38.3; 95% confidence interval CI, -332.7 to 46.4), but VE was 65% at ≥7 days (95% CI, 22.9 to 88.0) and 79% at ≥14 days (95% CI, 33.3 to 100.0) post-vaccination.
One dose of MVA-BN vaccine offered protection against mpox in most-at-risk population shortly after the vaccination. Further studies need to assess the VE of a second dose and the duration of protection over time.
Hybrid nanocomposites based on Fe3O4 magnetic nanoparticles (MNPs) coated with different types of carbon nanotubes (CNTs) have been studied for the first time as sorbent materials for magnetic solid ...phase extraction (MSPE) for mercury speciation analysis. Monomethylmercury (MMHg) was the target mercury species in water samples and the adsorption and desorption processes were optimized based on this species. Single-walled CNT-MNP showed higher adsorption capacity than double-walled or multi-walled CNTs. Then, the magnetic sorbent was retrieved with an external magnet and MMHg was selectively desorbed from it with dichloromethane (DCM) in two steps with vortex agitation. Inorganic mercury was removed during the desorption stage. The rapid adsorption and desorption equilibrium, the magnetic separation of the sorbent, and the simple and fast synthesis of CNT-MNPs without any additional modification of the CNTs simplified and shortened the extraction procedure. The extract was submitted to derivatization of the mercury species by ethylation (with an optional nitrogen stream evaporation of the organic phase) and injection into a gas chromatograph coupled to an atomic fluorescence detector (GC-pyro-AFS). The overall procedure provides the preconcentration of MMHg up to 150 times and the removal of inorganic mercury at the same time. The procedural limits of detection (LOD) and quantification (LOQ) were 5.4 and 17.9pgmL−1, respectively. Moreover, magnetic nanocomposites can be reused at least 7 times without losing their efficiency. The methodology was validated in tap, dam and river water samples to evaluate the performance under real conditions with recoveries from 79% to 97% of spiked MMHg.
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•Simplified mercury speciation analysis with hybrid magnetic carbon nanotubes is shown for the first time.•Preconcentration of MMHg and removal of inorganic mercury are achieved simultaneously.•Preconcentration factor up to 150 for MMHg is obtained.•No need for functionalization of carbon nanotubes contributes to shorten synthesis.
Somatic mutational mosaicism is a common feature of monogenic genetic disorders, particularly in diseases such as retinoblastoma, with high rates of de novo mutations. The detection and ...quantification of mosaicism is particularly relevant in these diseases, since it has important implications for genetic counseling, patient management, and probably also on disease onset and progression. In order to assess the rate of somatic mosaicism (high- and low-level mosaicism) in sporadic retinoblastoma patients, we analyzed a cohort of 153 patients with sporadic retinoblastoma using ultra deep next-generation sequencing. High-level mosaicism was detected in 14 out of 100 (14%) bilateral patients and in 11 out of 29 (38%) unilateral patients in whom conventional Sanger sequencing identified a pathogenic mutation in blood DNA. In addition, low-level mosaicism was detected in 3 out of 16 (19%) unilateral patients in whom conventional screening was negative in blood DNA. Our results also reveal that mosaicism was associated to delayed retinoblastoma onset particularly in unilateral patients. Finally we compared the level of mosaicism in different tissues to identify the best DNA source to identify mosaicism in retinoblastoma patients. In light of these results we recommended analyzing the mosaic status in all retinoblastoma patients using accurate techniques such as next-generation sequencing, even in those cases in which conventional Sanger sequencing identified a pathogenic mutation in blood DNA. Our results suggest that a significant proportion of those cases are truly mosaics that could have been overlooked. This information should be taking into consideration in the management and genetic counseling of retinoblastoma patients and families.
Black polyethylene (PE) film is used for mulching in processing tomato (
Lycopersicon esculentum
P. Mill.) in Spain achieving a generally high weed control but causing a serious waste problem. Few ...herbicides are available for tomato, so that a biodegradable mulching is the desired solution which should provide high yield, high weed control and be economically available. For 3 years, the same field trial was carried out in four areas of Spain using the following mulch materials in processing tomatoes: (1) untreated control, (2) manual weeding, (3) PE, black, 15 μm thick, (4) and (5) two types of biodegradable plastic mulch, black, 15 μm, (6) oxo-degradable plastic mulch, black, 15 μm, (7) paper mulch, black, 85 g m
−2
, (8) kraft paper mulch, brown, 140 g m
−2
and (9) barley straw, 1 kg m
−2.
. Weed control, yield and economic aspects were analysed. Most frequent weed species were
Convolvulus arvensis
,
Chenopodium album
and
Amaranthus
spp. Here, we showed that despite differences in weed species, soil type and years, weed competition caused a similar yield decrease in all locations. A common regression coefficient could be estimated indicating that weed competition was responsible for a yield decrease of 3.3 to 4.4 t ha
−1
for each 10% of efficacy loss. Weed control was high for biodegradable plastics, paper mulches and PE ranging between 80% and 100% for all of them; also, yield was similar for all plastic and paper mulching treatments ranging between 72% and 108% of the yield achieved by PE. Here, we demonstrate that technically viable biodegradable alternatives exist for all four locations. From the economic point of view, PE gave highest benefits, mainly due to its low market price and to high yields despite removal costs, showing that its substitution will depend on prohibition. For locations with low-density weed infestations, manual weeding can be an alternative.
A Mediterranean diet (MedDiet)-based intervention reduces the rate of immediate postpartum maternal metabolic disorders. Whether these effects persist long-term remains to be determined. A total of ...2526 normoglycemic women were randomized before the 12th gestational week (GW). IG women followed a MedDiet with extra virgin olive oil (EVOO) (>40 mL/day) and a handful of nuts daily, whereas CG women had to restrict all kinds of dietary fat. At 3 months postpartum, a motivational lifestyle interview was held. The endpoint of the study evaluated the rate of abnormal glucose regulation (AGR) and metabolic syndrome (MetS) at 3 years postpartum in women of the San Carlos cohort. A total of 369/625 (59%) CG women and 1031/1603 (64.3%) IG women were finally analyzed. At 3 months and 3 years postdelivery, the IG women showed higher adherence to the MedDiet, which was associated with lower values of body mass index (BMI) and lipid and glycemic profiles. Body weight change and waist circumference were lower in the IG women. After applying multiple regression analysis, the ORs (95%CI) resulted in AGR (3.18 (2.48-4.08);
< 0.001)/MetS (3.79 (1.81-7.95);
= 0.001) for women with GDM and higher OR for development of MetS in CG women (3.73 (1.77-7.87);
= 0.001). A MedDiet-based intervention early in pregnancy demonstrated persistent beneficial effects on AGR and MetS rates at 3 years postpartum.
Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in ...vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-1,2,3-d,e-1,4-benzoxazin-6-yl-1-naphthalenyl-methanone WIN 55,212-2 (WIN), a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol JWH-133 (JWH), a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium (Ca(2+)(i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl-6,6-dimethyl-bicyclo3.1.1hept-2-ene-2-methanol HU-308 (HU), another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.
The value of minimal residual disease (MRD) status by bone marrow and imaging analysis as independent prognostic factors has been well established in multiple myeloma (MM). Nevertheless data about ...their potential complementarity for a more accurate assessment are limited. With this aim, we retrospectively analyzed the prediction of outcome with the combination of PET‐CT and MRD, assessed by multiparameter flow cytometry (MFC) in 103 patients with newly diagnosed MM. We confirmed the benefit in terms of progression‐free survival (PFS), linked to the achievement of negativity by MFC (hazard ratio HR 0.53; 95% confidence interval CI: 0.28‐0.98), and PET‐CT (HR 0.18; 95% CI: 0.09‐0.36) individually. By combining both techniques, patients who became MRD‐/PET‐, with a median of PFS 92 months, had significant prolonged median PFS (P < .001). This is compared with MRD+/PET‐ and PET+ patients (median PFS of 45 and 28 months, respectively). We observed a significant difference (P = .003) in overall survival (OS) outcomes between MRD‐/PET‐ and MRD+/PET‐ patients (4‐year OS 94.2% and 100%, respectively), vs PET+ patients (4‐year OS 73.8%). All survival results were confirmed in a conditional landmark analysis. These findings support the potential complementarity between PET‐CT and MFC, and highlight their better predictive capability when improving sensitivity.
Aujeszky’s disease in cattle is caused by Suid herpes virus 1. The natural infection has been reported worldwide in bovine species and it is related to direct and indirect contact with infected pigs, ...which represent the main reservoir of the virus. Here, it is reported the first documented outbreak of Aujeszky’s disease in cattle in Sicily (Italy). Severe itching and nonspecific neurological symptoms were the main reported clinical signs. No characteristic gross and histological features were reported other than cutaneous lesions caused by excessive pruritus and hyperaemia, haemorrhages and inflammation in the central nervous system. Diagnosis was confirmed by real time PCR and immunohistochemistry on the nervous tissue. The route of infection remained unknown, but serological data observed in pigs living in close cohabitation with cattle revealed a circulation of a wild strain of the virus in the area. This study contributes to a better knowledge of this disease in a non-conventional host and suggests the need to increase the prophylaxis control plans in specific breeding contexts.
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