RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies.

Combined therapies play a key role in the fight against complex pathologies, such as cancer and related drug-resistance issues. This is particularly relevant in targeted therapies where inhibition of the drug target can be overcome by cross-activating complementary pathways. Unfortunately, the drug combinations approved to date -mostly based on small molecules- face several problems such as toxicity effects, which limit their clinical use. To address these issues, we have designed a new class of RNase H-sensitive construct (3ASO) that can be disassembled intracellularly upon cell entry, leading to the simultaneous release of three different therapeutic oligonucleotides (ONs), tackling each of them the mRNA of a different protein. Here, we used Escherichia coli RNase H1 as a model to study an unprecedented mode of recognition and cleavage, that is mainly dictated by the topology of our RNA·DNA-based hybrid construct. As a model system for our technology we have created 3ASO constructs designed to specifically inhibit the expression of HER2, Akt and Hsp27 in HER2+ breast cancer cells. These trifunctional ON tools displayed very low toxicity and good levels of antiproliferative activity in HER2+ breast cancer cells. The present study will be of great potential in the fight against complex pathologies involving multiple mRNA targets, as the proposed cleavable designs will allow the efficient single-dose administration of different ON drugs simultaneously.

Radiological and functional outcomes of Reverdin Isham osteotomy in moderate Hallux Valgus: a systematic review and meta-analysis.

This systematic review and meta-analysis addresses the effects of minimally invasive surgical techniques, specifically the Reverdin Isham osteotomy, on functional and radiological outcomes in patients with moderate Hallux Valgus, a common foot deformity. The review included randomized and non-randomized controlled trials, as well as case reports, assessing the osteotomy in adults with moderate to severe Hallux Valgus. Searches were conducted in electronic databases such as MEDLINE and Web of Science up until July 2023, and the Joanna Briggs Institute's critical appraisal tool was used to assess the risk of bias. Meta-analytical analyses employed a random-effects model with small-sample correction, presenting results as standardized mean differences and mean differences with 95% confidence intervals. Seven studies involving 554 patients and 643 operated feet were included, showing significant improvements in AOFAS scores (an average improvement of 36 points from 28.61 to 45.16) and reductions in radiological angles such as the distal metatarsal angle and hallux valgus angle post-surgery (IMA improved by - 3.07° from - 4.68 to - 1.46, DMAA by - 6.12° from - 9.52 to - 2.71, and HVangle by - 15.27° from - 17.98 to - 12.57). Despite these positive outcomes, most studies exhibited risks of bias and other methodological limitations, impacting the generalizability of the results. Overall, the findings highlight the efficacy of the Reverdin Isham osteotomy in improving both functional and radiological parameters in patients with moderate Hallux Valgus, although further research is warranted to solidify these results. No specific funding was received for this study, and the protocol was registered on PROSPERO with the number CRD-42023445886.

A framework to reduce energy consumption in a press shop floor based on industrializable IIoT (I3oT).

This article presents a framework to reduce energy consumption in a floor shop press based on Industrializable Industrial Internet of Things (I3oT). The I3oT proposes the development of IIoT tools using the information available in the system, without adding any additional sensors. Based on this philosophy, we proposed to develop the C360 criterion in our previous works, which allowed to extract all the information available in the stamping presses for the development of I3oT applications. In this article, we propose the development of a framework to optimize the parameters accessible from the C360 criterion for energy saving in the stamping process. Regarding the three parameters that can be modified and that affect energy consumption, that is, counterbalance pressure, tonnage and press speed, we will work with the first two in this paper. At the end of the article, the results obtained from the presses installed at Ford factory in Almussafes (Valencia) are shown based on their adjustment.

Complete mitochondrial genome of the introduced Indian walking stick Carausius morosus (Lonchodidae, Insecta) from California.

We present the complete mitochondrial genome of Carausius morosus from Salinas, CA. The mitochondrial genome of C. morosus is circular, AT rich (78.1%), and 16,671 bp in length. It consists of 13 protein-coding, 22 transfer RNA, and 2 ribosomal RNA genes and is identical in gene content to Carausius sp.

Enhancing employee wellbeing and happiness management in the wine industry: unveiling the role of green human resource management.

BACKGROUND: In today's business environment, where sustainability has emerged as a strategic axis of business practices, the study of the link between human resources management and environmental management becomes increasingly necessary. In this sense, the present research focuses on analyzing the impact of Green Human Resource Management (GHRM) on the Sustainable Performance (SP) of Spanish wineries, as well as the mediating effect of Employee Wellbeing (EW) and Work Engagement (WE) on this linkage. In addition, age, size and membership in a Protected Designation of Origin (PDO) are introduced as control variables to increase the precision of the cause-effect relationships examined. METHODS: The study proposes a conceptual model based on previous studies, which is tested using structural equations (PLS-SEM) with data collected from 196 Spanish wineries between September 2022 and January 2023. RESULTS: The findings of the research reveal the existence of a positive and significant relationship between the GHRM development and the SP of Spanish wineries, as well as the partial mediation of EW and WE in this association. CONCLUSIONS: The uniqueness and significance of this study can be attributed to several crucial factors. First, it enhances the understanding and knowledge regarding the advantages associated with GHRM development. Second, no prior research has conducted a comprehensive study on GHRM as a catalyst for SP within the context of Spanish wineries. Third, to the best of the authors' knowledge, no previous study has analyzed the mediating role of EW and WE as mediators in the relationship between GHRM and SP of wineries.

Impact of Minimally Invasive Intra-Capsular Metatarsal Osteotomy on Plantar Pressure Decrease: A Cross-Sectional Study.

Background: Metatarsalgia is a common pathology that is initially treated conservatively, but failure to do so requires surgery, such as the minimally invasive distal metatarsal osteotomy (DICMO). Methods: In this prospective study of 65 patients with primary metatarsalgia who underwent DICMO, plantar pressures, American Orthopaedic Foot and Ankle Society MetaTarsoPhalangeal-InterPhalangeal scale (AOFAS-MTP-IP) and Visual Analog Scale (VAS) were evaluated pre-operatively and post-operatively and there was a subgroup in which an inclinometer was used to observe the importance of the inclination of the osteotomy. Results: The results show a significant reduction in plantar pressures after DICMO surgery without overloading the adjacent radii, especially in the subgroup with an inclinometer to guide the osteotomy. The AOFAS-MTP-IP scale evidenced a marked improvement in metatarsal function and alignment with scores close to normal. The VAS scale showed a substantial decrease in pain after DICMO osteotomy. Conclusions: DICMO, with an inclinometer for a 45° osteotomy, proved to be a safe and effective procedure for primary metatarsalgia, although further comparative studies are needed to confirm its superiority.

Targeting Bacterial Nanocellulose Properties through Tailored Downstream Techniques.

Bacterial nanocellulose (BNC) is a biodegradable polysaccharide with unique properties that make it an attractive material for various industrial applications. This study focuses on the strain Komagataeibacter medellinensis ID13488, a strain with the ability to produce high yields of BNC under acidic growth conditions and a promising candidate to use for industrial production of BNC. We conducted a comprehensive investigation into the effects of downstream treatments on the structural and mechanical characteristics of BNC. When compared to alkaline-treated BNC, autoclave-treated BNC exhibited around 78% superior flexibility in average, while it displayed nearly 40% lower stiffness on average. An SEM analysis revealed distinct surface characteristics, indicating differences in cellulose chain compaction. FTIR spectra demonstrated increased hydrogen bonding with prolonged interaction time with alkaline solutions. A thermal analysis showed enhanced thermal stability in alkaline-treated BNC, withstanding temperatures of nearly 300 °C before commencing degradation, compared to autoclaved BNC which starts degradation around 200 °C. These findings provide valuable insights for tailoring BNC properties for specific applications, particularly in industries requiring high purity and specific mechanical characteristics.

Interactions between maternal parity and feed additives drive the composition of pig gut microbiomes in the post-weaning period.

BACKGROUND: Nursery pigs undergo stressors in the post-weaning period that result in production and welfare challenges. These challenges disproportionately impact the offspring of primiparous sows compared to those of multiparous counterparts. Little is known regarding potential interactions between parity and feed additives in the post-weaning period and their effects on nursery pig microbiomes. Therefore, the objective of this study was to investigate the effects of maternal parity on sow and offspring microbiomes and the influence of sow parity on pig fecal microbiome and performance in response to a prebiotic post-weaning. At weaning, piglets were allotted into three treatment groups: a standard nursery diet including pharmacological doses of Zn and Cu (Con), a group fed a commercial prebiotic only (Preb) based on an Aspergillus oryzae fermentation extract, and a group fed the same prebiotic plus Zn and Cu (Preb + ZnCu). RESULTS: Although there were no differences in vaginal microbiome composition between primiparous and multiparous sows, fecal microbiome composition was different (R2 = 0.02, P = 0.03). The fecal microbiomes of primiparous offspring displayed significantly higher bacterial diversity compared to multiparous offspring at d 0 and d 21 postweaning (P < 0.01), with differences in community composition observed at d 21 (R2 = 0.03, P = 0.04). When analyzing the effects of maternal parity within each treatment, only the Preb diet triggered significant microbiome distinctions between primiparous and multiparous offspring (d 21: R2 = 0.13, P = 0.01; d 42: R2 = 0.19, P = 0.001). Compositional differences in pig fecal microbiomes between treatments were observed only at d 21 (R2 = 0.12, P = 0.001). Pigs in the Con group gained significantly more weight throughout the nursery period when compared to those in the Preb + ZnCu group. CONCLUSIONS: Nursery pig gut microbiome composition was influenced by supplementation with an Aspergillus oryzae fermentation extract, with varying effects on performance when combined with pharmacological levels of Zn and Cu or for offspring of different maternal parity groups. These results indicate that the development of nursery pig gut microbiomes is shaped by maternal parity and potential interactions with the effects of dietary feed additives.

Improving the Accuracy of Metatarsal Osteotomies in Minimally Invasive Foot Surgery Using a Digital Inclinometer: Preliminary Study.

Minimally invasive foot surgery (MIS) has become a common procedure to treat various pathologies, and accuracy in the angle of metatarsal osteotomies is crucial to ensure optimal results. This randomized controlled trial with 37 patients investigates whether the implementation of a digital inclinometer can improve the accuracy of osteotomies compared to traditional freehand techniques. Patients were randomly allocated to group A (n = 15) receiving inclinometer-assisted surgery or group B (n = 22) receiving conventional surgery. Osteotomies were performed and outcomes were evaluated using an inclinometer. The inclinometer group showed a significant decrease in plantar pressure from 684.1 g/cm2 pretreatment to 449.5 g/cm2 post-treatment (p < 0.001, Cohen's d = 5.477). The control group decreased from 584.5 g/cm2 to 521.5 g/cm2 (p = 0.001, Cohen's d = 0.801). The effect size between groups was large (Cohen's d = -2.572, p < 0.001). The findings indicate a significant improvement in accuracy and reduction in outliers when using an inclinometer, suggesting that this technology has the potential to improve surgical practice and patient outcomes in minimally invasive metatarsal osteotomies.

The investigation of dose rate and photon beam energy dependence of optimized PASSAG polymer gel dosimeter using magnetic resonance imaging.

OBJECTIVE: It seems that dose rate (DR) and photon beam energy (PBE) may influence the sensitivity and response of polymer gel dosimeters. In the current project, the sensitivity and response dependence of optimized PASSAG gel dosimeter (OPGD) on DR and PBE were assessed. MATERIALS AND METHODS: We fabricated the OPGD and the gel samples were irradiated with various DRs and PBEs. Then, the sensitivity and response (R2) of OPGD were obtained by MRI at various doses and post-irradiation times. RESULTS: Our analysis showed that the sensitivity and response of OPGD are not affected by the evaluated DRs and PBEs. It was also found that the dose resolution values of OPGD ranged from 9 to 33 cGy and 12 to 34 cGy for the evaluated DRs and PBEs, respectively. Additionally, the data demonstrated that the sensitivity and response dependence of OPGD on DR and PBE do not vary over various times after the irradiation. CONCLUSIONS: The findings of this research project revealed that the sensitivity and response dependence of OPGD are independent of DR and PBE.

Impact of Concurrent Genomic Alterations on Clinical Outcomes in Patients With ALK-Rearranged NSCLC.

INTRODUCTION: ALK tyrosine kinase inhibitors have exhibited promising activity against advanced ALK-rearranged NSCLC. However, co-occurring genetic alterations, such as CDKN2A/B or TP53, may negatively affect the efficacy of targeted therapies. METHODS: From December 2017 to December 2022, this study cohort analyzed next-generation sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin American cancer centers. Clinicopathologic and molecular features were associated with clinical outcomes and risk of brain metastasis (BrM) in patients with and without concurrent somatic alterations. RESULTS: All patients (N = 116) received a second-generation ALK tyrosine kinase inhibitor, and alectinib was selected in 87.2% of cases. Coalterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). The loss of CDKN2A/B was associated with an increased risk of BrM, with a cumulative incidence of 33.3% versus 7.4% in the non-coaltered subgroup. Compared with patients without coalterations, patients with concurrent CDKN2A/B loss (n = 21) had a shorter median progression-free survival (10.2 versus 34.2 mo, p < 0.001) and overall survival (26.2 versus 80.7 mo, p < 0.001). In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer progression-free survival and OS despite the presence of other somatic coalterations, TP53 mutations, BrM, and Eastern Cooperative Oncology Group Performance Status. CONCLUSIONS: This study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was substantially associated with worse outcomes and a higher risk of brain metastases. The evidence presented in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.

Recent breakthroughs in the management of locally advanced and recurrent/metastatic cervical cancer.

Cervical cancer continues to be a global threat affecting individuals in resource poor communities disproportionately. The treatment paradigm for this disease is ever evolving with recent innovations propelling oncologic outcomes to a new frontier offering survival benefits for patients struggling with locally advanced disease and metastatic/recurrent carcinoma. Immunologic checkpoint inhibitors and anti-body drug conjugates represent two novel drug classes that have demonstrable activity in this disease, particularly in the first-line and second-line treatment paradigm for recurrence. The tolerability of these novel medicines and associated durable responses underscore regulatory approval by the U.S. Food and Drug Administrations and their implementation in clinic.

Blood salvage and autotransfusion during orthotopic liver transplantation for hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a significant cause of oncologic mortality worldwide. Liver transplantation represents a curative option for patients with significant liver dysfunction and absence of metastases. However, this therapeutic option is associated with significant blood loss and frequently requires various transfusions and intraoperative blood salvage for autotransfusion (IBS-AT) with or without a leukocyte reduction filter. This study aimed to analyze available evidence on long-term oncologic outcomes of patients undergoing liver transplantation for HCC with and without IBS-AT. METHODS: Per PRISMA guidelines, a systematic review of keywords "Blood Salvage," "Auto-transfusion," "Hepatocellular carcinoma," and "Liver-transplant" was conducted in PubMed, EMBASE, and SCOPUS. Studies comparing operative and postoperative outcomes were screened and analyzed for review. RESULTS: Twelve studies totaling 1704 participants were included for analysis. Length of stay, recurrence rates, and overall survival were not different between IBS-AT group and non IBS-AT group. CONCLUSION: IBS-AT use is not associated with increased risk of recurrence in liver transplant for HCC even without leukocyte filtration. Both operative and postoperative outcomes are similar between groups. Comparison of analyzed studies suggest that IBS-AT is safe for use during liver transplant for HCC.

Addressing lung cancer screening eligibility in Spain using 2013 and 2021 US Preventive Service Task Force criteria: cross-sectional study.

Objectives: The aim of the study was to ascertain the percentage of Spanish lung cancer cases that would fulfil the lung cancer screening inclusion criteria recommended by the United States Preventive Service Task Force (USPSTF) in 2013 and 2021. Methods: A cross-sectional study was carried out. All lung cancer cases registered in the Thoracic Tumor Registry with data on date of birth, date of diagnosis, smoking habit, number of pack-years and time elapsed since smoking cessation were included. Results: The study included 15 006 patients diagnosed with lung cancer in Spain between 2016 and 2022. Eligibility to participate in screening increased from 53.7% to 63.5% (an increase of 9.8%) according to the 2013 and 2021 recommendations, respectively. The percentage of eligible men rose by 9.2 percentage points with the 2021 versus 2013 recommendations, whereas this rise was 11.5 percentage points in women. Under the 2021 recommendations, 36.6% of women and 5.3% of men would not have fulfilled the screening inclusion criteria due to being never-smokers; 14.9% of women and 11.0% of men would not have fulfilled the age criterion; and 27.0% of ex-smokers among women compared to 35.6% among men would not have been eligible due to >15 years having elapsed since smoking cessation. Conclusions: In Spain, over one-third of lung cancer cases could not be detected through screening, by virtue of not meeting the most recent inclusion criteria stated by the USPSTF. The degree of fulfilment in a potential nationwide screening programme should be analysed, with the aim of establishing inclusion criteria in line with each country's context.

Exploring Structural-Photophysical Property Relationships in Mitochondria-Targeted Deep-Red/NIR-Emitting Coumarins.

Organic fluorophores operating in the optical window of biological tissues, namely in the deep-red and near-infrared (NIR) region of the electromagnetic spectrum, offer several advantages for fluorescence bioimaging applications owing to the appealing features of long-wavelength light, such as deep tissue penetration, lack of toxicity, low scattering, and reduced interference with cellular autofluorescence. Among these, COUPY dyes based on non-conventional coumarin scaffolds display suitable photophysical properties and efficient cellular uptake, with a tendency to accumulate primarily in mitochondria, which renders them suitable probes for bioimaging purposes. In this study, we have explored how the photophysical properties and subcellular localization of COUPY fluorophores can be modulated through the modification of the coumarin backbone. While the introduction of a strong electron-withdrawing group, such as the trifluoromethyl group, at position 4 resulted in an exceptional photostability and a remarkable redshift in the absorption and emission maxima when combined with a julolidine ring replacing the N,N-dialkylaminobenzene moiety, the incorporation of a cyano group at position 3 dramatically reduced the brightness of the resulting fluorophore. Interestingly, confocal microscopy studies in living HeLa cells revealed that the 1,1,7,7-tetramethyl julolidine-containing derivatives accumulated in the mitochondria with much higher specificity. Overall, our results provide valuable insights for the design and optimization of new COUPY dyes operating in the deep-red/NIR region.

Lung microbiome alterations in patients with anti-Jo1 antisynthetase syndrome and interstitial lung disease.

Aim: To characterize the lung microbiome in the bronchoalveolar lavage fluid (BALF) of patients with Antisynthetase Syndrome (ASSD) according to anti-Jo1 autoantibody positivity and evaluate the correlation with differential cell count and other bacterial genera in BALF. Methods: We sequenced the 16S ribosomal RNA gene in the BALF of anti-Jo1-positive (JoP, n=6) and non-Jo1-positive (NJo, n=17) patients, and the differential cell count in BALF was evaluated. The Spearman's correlation was calculated for the quantitative variables and abundance of bacterial species. Results: The Veillonella genus showed a significant decrease (p<0.01) in JoP (2.2%) in comparison to NJo (4.1%) patients. The correlation analysis showed several high (rho ≥ ± 0.7) and significant (p < 0.05) correlations. We analyzed the results obtained for the Veillonella genera and other study variables. The JoP group showed that the abundance of Veillonella had a high negative correlation with macrophages (rho = - 0.77) and a positive correlation with eosinophils (rho = 0.77), lymphocytes (rho = 0.77), and Prevotella (rho = 1). Conclusions: The lung microbiome in ASSD patients differs and may affect cell composition, contributing to lung damage mechanisms. The presence of anti-Jo1 autoantibodies showed a low abundance of Veillonella. This genus had a strong and positive correlation with Prevotella abundance and levels of eosinophils and lymphocytes, and it showed a strong negative correlation with the percentage of macrophages.

Bilateral Acute Iris Transillumination Syndrome Following Oral Moxifloxacin Overdose.

We report a case of bilateral acute iris transillumination (BAIT) syndrome caused by an overdose of oral moxifloxacin in a Hispanic female patient with no previous respiratory viral infection. A 56-year-old Hispanic female with no history of ocular illness was referred to our glaucoma service to manage her microcystic edema, swelling, and refractory ocular hypertension. Her ocular and systemic symptoms, including progressively worsening bilateral ocular pain, severe photophobia, blurred vision, nausea, and vomiting, started 14 days after an accidental overdose of oral moxifloxacin. Moxifloxacin had been prescribed to treat a complicated urinary tract infection. A slit-lamp examination revealed bilateral microcystic corneal edema and transillumination in the right temporal iris, both consistent with a diagnosis of BAIT syndrome. The existing literature on BAIT syndrome is scarce, and its etiology remains unclear. This case provides clinical evidence supporting moxifloxacin toxicity as a possible cause of BAIT syndrome. We emphasize the importance of conducting extensive research to define the mechanisms involved in moxifloxacin-induced BAIT syndrome and to search for other potential etiologies of this condition.