Search

Background: Motor neuron diseases (MNDs) encompass amyotrophic lateral sclerosis (ALS), pure/predominant upper (pUMN) and lower motor neuron (pLMN) phenotypes. However respiratory studies have mainly focused on bulbar (B-ALS) and spinal (S-ALS) onset ALS, while little is known in other MNDs. In this study we therefore aimed at characterizing baseline and longitudinal patterns of respiratory involvement and their clinical management in MND patients stratified by their clinical phenotype., Methods: Serial pulmonary function tests (PFTs) (spirometry, arterial blood gas analysis, overnight pulse oximetry and peak cough expiratory flow) records of the MND patients hospitalized between 2020 and 2024 were reviewed. Using longitudinal examinations, deltas of variation in respiratory measures were generated and frequency and timings of non-invasive ventilation (NIV) adaptation were evaluated. Data were compared between phenotypes using the Kruskal-Wallis test with Bonferroni adjustment., Results: 42 S-ALS, 105 B-ALS, 42 pLMN and 31 pUMN patients were included. Both at baseline and longitudinally, B-ALS showed the worst respiratory parameters, followed by pLMN, S-ALS and pUMN. NIV adaptation was equally frequent between groups, but earlier in B-ALS compared to pUMN (p = 0.01). At baseline, B-ALS showed worse spirometry and PCEF only, but compared to all the other phenotypes (p from <0.0001 to 0.03). Longitudinally, they conversely exhibited more severe decline in all PFTs, but only relative to pUMN (p from 0.0009 to 0.04), with deltas of variation comparable to the ones observed in S-ALS and pLMN. Among NIV users, more severe PCEF and spirometry impairment further emerged in S-ALS compared to pUMN (p from 0.01 to 0.04)., Conclusions: We evidenced convergent trajectories of respiratory decline across B-ALS, S-ALS and pLMN, highlighting the utility of multimodal assessments for tracking progressing respiratory disturbances. These findings have potential to accelerate earlier and more tailored respiratory management across diverse MND phenotypes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Developmental and epileptic encephalopathies (DEEs) comprise a complex spectrum of neurological disorders characterized by neurodevelopmental delay and early-onset seizures primarily caused by diverse genetic mutations. Traditional treatments have largely been symptomatic, focusing on seizure control without addressing the underlying genetic causes. The advent of gene therapy, particularly through antisense oligonucleotides (ASOs), offers a promising avenue toward targeted therapeutic interventions. ASOs by virtue of their ability to modulate gene expression at the mRNA level represent a sophisticated approach to counteract the effects of pathogenic mutations. This review delves into the recent advancements in ASO technology, highlighting its application in preclinical and clinical settings for DEEs. We present evidence of the efficacy of ASOs in ameliorating disease phenotypes in vitro and in vivo, alongside promising outcomes from ongoing clinical trials. The therapeutic landscape for DEEs is on the cusp of significant transformation, underscored by the potential of ASOs to offer precise, personalized, treatments that extend beyond symptomatic relief to potentially rectify the genetic underpinnings of these disorders., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Antimicrobial resistance is a silent pandemic harming human health, and Pseudomonas aeruginosa is the most common bacterium responsible for chronic pulmonary and eye infections. Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics. In this review, the in vitro/in vivo activities of the frog skin-derived AMP Esc(1-21) are shown. Esc(1-21) rapidly kills both the planktonic and sessile forms of P. aeruginosa and stimulates migration of epithelial cells, likely favoring repair of damaged tissue. However, to undertake preclinical studies, some drawbacks of AMPs (cytotoxicity, poor biostability, and limited delivery to the target site) must be overcome. For this purpose, the stereochemistry of two amino acids of Esc(1-21) was changed to obtain the diastereomer Esc(1-21)-1c, which is more stable, less cytotoxic, and more efficient in treating P. aeruginosa -induced lung and cornea infections in mouse models. Incorporation of these peptides (Esc peptides) into nanoparticles or immobilization to a medical device (contact lens) was revealed to be an effective strategy to ameliorate and/or to prolong the peptides' antimicrobial efficacy. Overall, these data make Esc peptides encouraging candidates for novel multifunctional drugs to treat lung pathology especially in patients with cystic fibrosis and eye dysfunctions, characterized by both tissue injury and bacterial infection., Competing Interests: The authors declare no conflicts of interest.

Purpose: The aim of this work was to investigate potential risk factors associated with HPV infection and to determine the HPV genotype prevalence among women from the Southerns areas of Morocco., Methods: A total of n = 308 sexually active women provided their written consent to participate in this study. A detailed questionnaire was used to collect data, related to the age and life style of participants. HPV L1 gene detection was performed by a nested PCR method using consensus primers. HPV genotypes were determined using direct Sanger sequencing method. Statistical analysis of the results obtained was carried out using R software., Results: We detected HPV in 42.5 % of the total investigated samples. HPV infection was significantly associated with the following risk factors: age of the first intercourse (OR = 2.27, 95 % CI: 1.03-5.10, p = 0.044), and previous history of STIs (OR = 3.13, 95 % CI: 1.12-9.63, p = 0.034). High risk-HPV and Low risk-HPV genotypes were found in 26.6 % and 5.5 % of the participants, respectively. The most prevalent genotypes were HPV16 (22 %), HPV18 (2.6 %), HPV11 (1.6 %) and HPV83 (1.3 %). Multiple infections were found in 3.2 %. The genotypes covered by the bivalent, quadrivalent and nonavalent HPV vaccines account for 57.5 %, 62.8 % and 66.6 %, respectively., Conclusion: HPV infection prevalence reported in this study among women from the Southerns areas of Morocco is one of the highest reported in the country so far. Our finding confirm that the current HPV vaccines directed against the most prevalent HPV16 genotype, recently introduced in the country, should offer a good protection to the most vulnerable population if implemented properly. These results highlight the importance of HPV screening and vaccination programs in this region., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: Evidence indicates that human papillomavirus (HPV) and Chlamydia trachomatis (CT) co-infection increases the risk of developing cervical pathogenesis. This study aims to assess the prevalence and possible risk factors of CT and HPV/CT co-infection in women from South of Morocco with normal and abnormal cytology., Methods: Participants were recruited after signing an informed consent. Cervical samples were collected and analysed for the presence of HPV or CT. Detection of genomic DNA of both pathogens was performed by nested polymerase chain reaction. HPV genotypes defined by Sanger sequencing method. The association between demographic features and co-infection status was determined using a logistic regression model. A possible association between the presence of HPV and CT and cytological abnormality patterns was also investigated., Results: We recruited n = 438 women, aged between 18 and 86 years. Around 59% of participants underwent a pap smear test for the first-time. Genomic DNA of HPV, CT and HPV/CT co-infection was detected in 32.3%, 17.7%, and 13.4% of the total samples, respectively. The identified risk factors associated with CT infection were history of sexually transmitted infections and marital status. By contrast, only smoking was found to be associated with HPV/CT co-infection. Evidence showed that co-infection was associated with an increased risk of developing cervical abnormalities (OR 3.18, 95% CI 0.96-9.21; p = 0.040)., Conclusion: HPV and CT rates were high among the studied population. Evidence suggests that HPV/CT co-infected women were more susceptible to developing abnormal cytology., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Worldwide, cervical cancer is a real health issue, however, gaps exist in the public's awareness of the causal role of Human papillomavirus (HPV) in the development of this disease. This study aims to determine the level of awareness, knowledge and the associated factors on HPV among university students in Morocco. A cross-sectional study was conducted with a descriptive and analytical aim, among students attending Ibn Zohr University, in Agadir, Morocco. An interview questionnaire was used to collect information about the participants: demographic data, awareness and level of knowledge on HPV infection, and awareness of cervical cancer. Logistic regression analyses were used to determine the associated factors with awareness and level of knowledge on HPV. A total of 479 students participated in this study (mean age 21.82 ± 2.091). Most participants n = 391 (81.6%) were aware of cervical cancer, while only n = 7 (1.5%) identified HPV as a sexually transmitted infection. Among students, 10.0% (n = 48) were aware of HPV but only half of them n = 23 (47.9%) confirmed that HPV is associated with cervical cancer, and n = 29 (60.4%) showed low knowledge on HPV. Multivariate analysis revealed that HPV awareness has a strong association with a higher level of education (OR 4.04; 95% CI: 1.92-8.52), and with being a biology student (OR 5.20; 95% CI: 2.12-12.73), while high HPV knowledge was only associated with the female gender (OR 3.76; 95% CI: 1.01-13.92). The data suggest that university students in Morocco did not show sufficient knowledge of HPV infection and its consequences. This supports that earlier incorporation of sexual health education programs, especially related to HPV and cervical cancer, must be implemented in the university to reduce the burden of HPV-associated diseases among the population at risk., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: The volume regulated anion channel (VRAC) is known to be involved in different aspects of cancer cell behaviour and response to therapies. For this reason, we investigated the effect of DCPIB, a presumably specific blocker of VRAC, in two types of cancer: pancreatic duct adenocarcinoma (PDAC) and melanoma., Experimental Approach: We used patch-clamp electrophysiology, supported by Ca 2+ imaging, gene expression analysis, docking simulation and mutagenesis. We employed two PDAC lines (Panc-1 and MiaPaCa-2), as well as a primary (IGR39) and a metastatic (IGR37) melanoma line., Key Results: DCPIB markedly increased whole-cell currents in Panc-1, MiaPaca2 and IGR39, but not in IGR37 cells. The currents were mostly mediated by K Ca 1.1 channels, commonly known as BK channels. We confirmed DCPIB activation of BK channels also in HEK293 cells transfected with α subunits of this channel. Further experiments showed that in IGR39, and to a smaller degree also in Panc-1 cells, DCPIB induced a rapid Ca 2+ influx. This, in turn, indirectly potentiated BK channels and, in IGR39 cells, additionally activated other Ca 2+ -dependent channels. However, Ca 2+ influx was not required for activation of BK channels by DCPIB, as such activation involved the extracellular part of the protein and we have identified a residue crucial for binding., Conclusion and Implications: DCPIB directly targeted BK channels and, also, acutely increased intracellular Ca 2+ . Our findings extend the list of DCPIB effects that should be taken into consideration for future development of DCPIB-based modulators of ion channels and other membrane proteins., (© 2022 The British Pharmacological Society.)

Objectives: Novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus has been declared a pandemic by the World Health Organization as of March 11, 2020. Pregnant women naturally have a reduced immune system due to immunological changes and decreased lung capacity due to respiratory adaptations, making them more susceptible to coronavirus complications. Within the Mount Sinai Health system, more than 15,000 deliveries are performed annually. We began to care for pregnant women with known COVID-19 infections in late March of 2020. In early April 2020, a policy was implemented to perform universal COVID-19 testing for all women planning to deliver within the Mount Sinai Health system. We examined the antibody response of postpartum women who delivered at Mount Sinai Hospital with a SARS-CoV-2 infection between the study intervals during March 15, 2020, through April 30, 2020., Study Design: This was a prospective observational study examining the immune response of pregnant women who delivered at Mount Sinai Hospital with a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Women with a SARS-CoV-2 infection were contacted via phone to discuss participation in the study. Patients who consented were scheduled for a phlebotomy visit to assess their antibody titer levels to COVID-19. The COVID-19 enzyme-linked immunosorbent assay (ELISA) immunoglobulin (Ig)-G antibody test was used to evaluate the patients' antibody titers. The assay detects IgG antibodies for the detection of IgG seroconversion in patients following a known recent SARS-CoV-2 infection., Results: A total of 120 patients were identified with a documented SARS-CoV-2 infection who delivered within the prespecified time frame. Of those patients, 25 women agreed to participate and were included. Of them, 64.00% were Caucasian with a mean age of 35 years. The mean body mass index (BMI) was 30 kg/m 2 and the majority of patients had commercial insurance (88.00%). The majority of women were asymptomatic for COVID-19 at the time of admission (80.00%) and the average gestational age of delivery and diagnosis of COVID-19 was 39 weeks' gestation. The later the gestational age at the time of diagnosis, the lower the antibody titer response. When examining the interval from diagnosis to antibody titer analysis, patients with the highest titers (2,880) tended to have a shorter interval between their COVID-19 diagnosis and the time at which the titer level was drawn. Patients with symptoms on admission had similar antibody titer levels when compared with women who were asymptomatic., Conclusion: The antibody response among women infected with COVID-19 during pregnancy appears to be greater when the patients are diagnosed at an earlier gestational age., Key Points: · COVID-19 antibody status appears to be greater when diagnosed at an earlier gestational age.. · Asymptomatic and symptomatic pregnant women had similar antibody responses.. · Patients with the highest titers tended to have a shorter interval between their COVID-19 diagnoses.., Competing Interests: None declared., (Thieme. All rights reserved.)

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease. Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity. In this study, by means of electrophysiological techniques and computational studies we discovered their ability to increase the CFTR-controlled ion currents, by direct interaction with the F508del-CFTR mutant. Remarkably, this property was not explored previously with any AMPs or peptides in general. More interestingly, in contrast with clinically used CFTR modulators, Esc peptides would give particular benefit to CF patients by combining their capability to eradicate lung infections and to act as promoters of airway wound repair with their ability to ameliorate the activity of the channel with conductance defects. Overall, our findings not only highlighted Esc peptides as the first characterized AMPs with a novel property, that is the potentiator activity of CFTR, but also paved the avenue to investigate the functions of AMPs and/or other peptide molecules, for a new up-and-coming pharmacological approach to address CF lung disease., (© 2021. The Author(s).)

Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca 2+ -activated K + channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca 2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents.

Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca 2+ ] i ) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K + currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline-a specific inhibitor of large-conductance Ca 2+ -activated BK channels. The TEA-insensitive component was inhibited by senicapoc-a specific inhibitor of the Ca 2+ -activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca 2+ ] i induced by Chl-T. Both KROS and [Ca 2+ ] i increase were inhibited by ACA and clotrimazole-two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca 2+ ] i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.

Finding angiogenic prognostic markers in advanced non-small-cell lung cancer is still an unmet medical need. We explored a set of genetic variants in the VEGF-pathway as potential biomarkers to predict clinical outcomes of patients with non-small-cell lung cancer treated with chemotherapy plus bevacizumab. We prospectively analyzed the relationship between VEGF-pathway components with both pathological and prognostic variables in response to chemotherapy plus bevacizumab in 168 patients with non-squamous non-small-cell lung cancer. Circulating levels of VEGF and VEGFR2 and expression of specific endothelial surface markers and single-nucleotide polymorphisms in VEGF-pathway genes were analyzed. The primary clinical endpoint was progression-free survival. Secondary endpoints included overall survival and objective tumor response. VEGFR-1 rs9582036 variants AA/AC were associated with increased progression-free survival ( p = 0.012 and p = 0.035, respectively), and with improved overall survival ( p = 0.019) with respect to CC allele. Patients with VEGF-A rs3025039 harboring allele TT had also reduced mortality risk ( p = 0.049) compared with the CC allele. The VEGF-A rs833061 variant was found to be related with response to treatment, with 61.1% of patients harboring the CC allele achieving partial treatment response. High pre-treatment circulating levels of VEGF-A were associated with shorter progression-free survival ( p = 0.036). In conclusion, in this prospective study, genetic variants in VEGFR-1 and VEGF-A and plasma levels of VEGF-A were associated with clinical benefit, progression-free survival, or overall survival in a cohort of advanced non-squamous non-small-cell lung cancer patients receiving chemotherapy plus antiangiogenic therapy., Competing Interests: DR-A declares having received honoraria for lectures and advisory boards from Bristol-Myers-Squibb, Merck Sharp & Dohme, Hoffmann-La Roche, Pierre-Fabre, Novartis, Boehringer, Pfizer, Lilly, and AstraZeneca. OJ declares that he has received payment for advisory services from Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche/Genetech, AstraZeneca, Pfizer, Eli Lilly, Abbvie, and Takeda. MP reports having received payments from Bristol-Myers Squibb, AstraZeneca, Takeda, Merck Sharp & Dohme, Hoffmann-La Roche, and Novartis for advisory services. JC received fees for advisory services from Hoffman-La Roche. CR declares having received lecture fees from Merck Sharp & Dohme and AstraZeneca, advisory board payments from Archer, Iceivafa, Merck Sharp & Dohme and Laboratorios Serono, and honoraria for consultancy roles from Mylan and Oncompass. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jantus-Lewintre, Massutí Sureda, González Larriba, Rodríguez-Abreu, Juan, Blasco, Dómine, Provencio Pulla, Garde, Álvarez, Maestu, Pérez de Carrión, Artal, Rolfo, de Castro, Guillot, Oramas, de las Peñas, Ferrera, Martínez, Serra, Rosell and Camps.)