Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are essential fatty acids with antagonistic inflammatory functions that play vital roles in metabolic health and immune response. ...Current commercial swine diets tend to over-supplement with n-6 PUFAs, which may increase the likelihood of developing inflammatory diseases and affect the overall well-being of the animals. However, it is still poorly understood how n-6/n-3 PUFA ratios affect the porcine transcriptome expression and how messenger RNAs (mRNAs) and microRNAs (miRNAs) might regulate biological processes related to PUFA metabolism. On account of this, we selected a total of 20 Iberian × Duroc crossbred pigs with extreme values for n-6/n-3 FA ratio (10 high vs 10 low), and longissimus dorsi muscle samples were used to identify differentially expressed mRNAs and miRNAs. The observed differentially expressed mRNAs were associated to biological pathways related to muscle growth and immunomodulation, while the differentially expressed microRNAs (ssc-miR-30a-3p, ssc-miR-30e-3p, ssc-miR-15b and ssc-miR-7142-3p) were correlated to adipogenesis and immunity. Relevant miRNA-to-mRNA regulatory networks were also predicted (i.e., mir15b to ARRDC3; mir-7142-3p to METTL21C), and linked to lipolysis, obesity, myogenesis, and protein degradation. The n-6/n-3 PUFA ratio differences in pig skeletal muscle revealed genes, miRNAs and enriched pathways involved in lipid metabolism, cell proliferation and inflammation.
Purpose
Medicines in special situations (MSS) refer to off‐label or to unlicensed drugs under investigation (compassionate use). Our objectives were to evaluate characteristics and to estimate ...overall survival (OS), event‐free survival (EFS), and the duration of treatment (DT) of MSS used for cancer treatment at a multicentre comprehensive cancer institution.
Methods
Retrospective cohort study on adult cancer patients for whom an MSS treatment was requested (January 2011–December 2020). A descriptive analysis was performed and median OS and EFS and 95% confidence intervals (CIs) were estimated. Survival curves were stratified by type of tumor, ECOG (Eastern Cooperative Oncology Group) performance status (PS), age, sex, treatment stage and type of drug (mechanism of action and target).
Results
Treatment was initiated in 2092 episodes (1930 patients) out of 2377 MSS episodes (2189 patients) requested, 33% for hematological treatment and 87% for advanced stage cancer. Median OS (months) was 21.1 (95% CI 19.4–22.7), median EFS was 5.6 (95% CI 5.1–6.0) months, and median DT was 4.5 0.0; 115.3 months.
OS and EFS statistically significantly favored female patients, ECOG PS ≥2 episodes showed worse OS and EFS outcomes (p < 0.0001). Statistically significant differences in survival were found within solid and hematological cancer, disease stage, drug mechanism of action, and type of cancer (p < 0.001) but not for age. Survival outcomes by tumor subtype and drug are presented both globally and separately based on disease stage.
Conclusion
MSS uses are practiced across almost all cancer types, mostly for advanced disease. ECOG PS ≥2, along with advanced disease, was related to worse survival. Information about real‐world outcomes is valuable and contributes to better decision‐making regarding MSS and our experience in this field could be of interest for other colleagues.
The study provides a real world data analysis of outcomes of off‐label and compassionate uses in a large cohort of oncology and hematology patients from a comprehensive and multicenter cancer institution. Main findings showed that survival outcomes differ between hematology and oncology, and a higher ECOG and advanced disease stage were associated with worse survival. Enhancing our understanding of real‐world outcomes associated with off‐label and compassionate offers valuable insights that can improve clinical decision‐making and contribute to the expanding body of knowledge in this field.
Summary
Imbalances in the composition of BCL2 family proteins contribute to tumourigenesis and therapy resistance of mantle cell lymphoma (MCL), making these proteins attractive therapy targets. We ...studied the efficiency of dual targeting the NOXA/MCL1 axis by combining fatty acid synthase inhibitors (NOXA stabilization) with the CDK inhibitor Dinaciclib (MCL1 reduction). This combination synergistically induced apoptosis in cell lines and primary MCL cells and led to almost complete inhibition of tumour progression in a mouse model. Apoptosis was NOXA‐dependent and correlated with the NOXA/MCL1 ratio, highlighting the importance of the NOXA/MCL1 balance for effective cell death induction in MCL.
Rosaceae species are economically highly relevant crops. Their cultivation systems are constrained by phytopathogens causing severe losses. Plants respond to invading pathogens through signaling ...mechanisms, a component of which are of them being plant elicitor peptides (Peps). Exogenous application of Peps activates defense mechanisms and reduces the symptoms of pathogen infection in various pathosystems. We have previously identified the Rosaceae Peps and showed, in an ex vivo system, that their topical application efficiently enhanced resistance to the bacterial pathogen Xanthomonas arboricola pv. pruni (Xap).
Here we demonstrate the effectiveness of Prunus persica peptides PpPep1 and PpPep2 in protecting peach plants in vivo at nanomolar doses, with 40% reduction of the symptoms following Xap massive infection. We used deep sequencing to characterize the transcriptomic response of peach plants to preventive treatment with PpPep1 and PpPep2. The two peptides induced highly similar massive transcriptomic reprogramming in the plant. One hour, 1 day and 2 days after peptide application there were changes in expression in up to 8% of peach genes. We visualized the transcriptomics dynamics in a background knowledge network and detected the minor variations between plant responses to PpPep1 and PpPep2, which might explain their slightly different protective effects. By designing a P. persica Pep background knowledge network, comparison of our data and previously published immune response datasets was possible.
Topical application of P. persica Peps mimics the PTI natural response and protects plants against massive Xap infection. This makes them good candidates for deployment of natural, targeted and environmental-friendly strategies to enhance resistance in Prunus species and prevent important biotic diseases.
Metastatic colorectal cancer (mCRC) currently lacks reliable biomarkers for precision medicine, particularly for chemotherapy-based treatments. This study examines the behavior of 11 CXC chemokines ...in the blood of 104 mCRC patients undergoing first-line oxaliplatin-based treatment to pinpoint predictive and prognostic markers. Serum samples were collected before treatment, at response evaluation (EVAR), and at disease progression or last follow-up. Chemokines were assessed in all samples using a Luminex® custom panel. CXCL13 levels increased at EVAR in responders, while in non-responders it decreased. Increasing levels of CXCL13 at EVAR, independently correlated with improved progression-free survival (PFS) and overall survival (OS). Nanostring® analysis in primary tumor samples showed CXCL13 gene expression's positive correlation not only with gene profiles related to an immunogenic tumor microenvironment, increased B cells and T cells (mainly CD8+) but also with extended OS. In silico analysis using RNAseq data from liver metastases treated or not with neoadjuvant oxaliplatin-based combinations, and deconvolution analysis using the MCP-counter algorithm, confirmed CXCL13 gene expression's association with increased immune infiltration, improved OS, and Tertiary Lymphoid Structures (TLSs) gene signatures, especially in neoadjuvant-treated patients. CXCL13 analysis in serum from 36 oxaliplatin-treated patients from the METIMMOX study control arm, reported similar findings. In conclusion, the increase of CXCL13 levels in peripheral blood and its association with the formation of TLSs within the metastatic lesions, emerges as a potential biomarker indicative of the therapeutic efficacy in mCRC patients undergoing oxaliplatin-based treatment
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•In CRC, Oxalipatin-based combinations often fail due to resistance and/or toxicity.•Lack of biomarkers complicates treatment decision-making. .•We examined serum levels of 11 CXC chemokines in patients on oxaliplatin.•Increased CXCL13 levels correlate with response, prognosis, tumor immunity and TLSs.•CXCL13 may serve as a predictive and prognostic biomarker for treatment efficacy.
Mechanisms involved in stroke progression are incompletely understood. Ischemic brain injury is characterized by acute local inflammatory response mediated by cytokines. Anti-inflammatory cytokines ...act in a feedback loop to inhibit continued proinflammatory cytokine production. We assessed the implication of interleukin (IL)-10 and IL-4 in deteriorating ischemic stroke.
Two hundred thirty-one patients with ischemic stroke within the first 24 hours from onset were included. Neurological worsening was defined when the Canadian Stroke Scale score fell at least 1 point during the first 48 hours after admission. Anti-inflammatory cytokines were determined in plasma obtained on admission.
Eighty-three patients (35.9%) worsened within the first 48 hours after stroke onset. Significantly lower concentrations of IL-10 were found in patients with neurological worsening (P<0.05), but IL-4 levels were similar in patients with or without deterioration. Lower plasma concentrations of IL-10 (<6 pg/mL) were associated with clinical worsening on multivariate analysis (odds ratio=3.1, 95% CI=1.1 to 8.9) independently of hyperthermia, hyperglycemia, or neurological condition on admission. Further analysis disclosed that early worsening was independently associated with lower IL-10 plasma levels in patients with subcortical infarcts or lacunar stroke but not in patients with cortical lesions.
Anti-inflammatory cytokine IL-10 is associated with the early clinical course of patients with acute ischemic stroke, especially in patients with small vessel disease or subcortical infarctions.
Fatty acids (FAs) play an essential role as mediators of cell signaling and signal transduction, affecting metabolic homeostasis and determining meat quality in pigs. However, FAs are transformed by ...the action of several genes, such as those encoding desaturases and elongases of FAs in lipogenic tissues. The aim of the current work was to identify candidate genes, biological processes, and pathways involved in the modulation of intramuscular FA profile from longissimus dorsi muscle. FA profile by gas chromatography of methyl esters and gene expression by RNA-Seq were determined in 129 Iberian × Duroc backcrossed pigs. An association analysis between the muscle transcriptome and its FA profile was performed, followed by a concordance and functional analysis. Overall, a list of well-known (e.g., PLIN1, LEP, ELOVL6, SC5D, NCOA2, ACSL1, MDH1, LPL, LGALS12, TFRC, GOT1, and FBP1) and novel (e.g., TRARG1, TANK, ENSSSCG00000011196, and ENSSSCG00000038429) candidate genes was identified, either in association with specific or several FA traits. Likewise, several of these genes belong to biological processes and pathways linked to energy, lipid, and carbohydrate metabolism, which seem determinants in the modulation of FA compositions. This study can contribute to elucidate the complex relationship between gene expression and FA profile in pig muscle.
To evaluate the influence of the result of a rapid streptococcal antigen test in paediatric pharyngotonsillitis infections, in terms of improvement of antibiotic therapy adherence.
Randomized ...community clinical trial with two study groups.
Primary Care Centers in Central Catalonia.
Patients aged from 3 to 15 years, who were attended at paediatric consultations on suspicion of pharyngotonsillitis caused by an infection between November 2010 and February 2011 (both included), were included in the study on a consecutive basis. 557 patients met the inclusion criteria and 519 were evaluated.
The control group received the usual diagnostic-therapeutic algorithm. Rapid streptococcal antigen test was additionally performed to experimental group participants and it was indicated the more convenient treatment.
Antibiotic adherence, non-adherence causes and socio-demographic risk factors were evaluated via telephone survey.
Antibiotics were prescribed to 65.6% and paediatricians of the control group were more likely to prescribe antibiotic than the ones in the intervention group (88.5% vs 45.5%, p< 0.0001). 64.8% followed doctor's treatment orders, being failure following medication scheduling the main cause of non-adherence (25.6%). Medication adherence was higher in the experimental group (68%) than in the control group (62.9%) but no significant differences were found.
Rapid strep test, complementing the use of Centor Criteria avoids unnecessary antibiotics prescriptions, but had not been proven to be effective in increasing medication adherence.
Approximately 20% of lung adenocarcinomas harbor activating mutations at
KRAS
, an oncogene with the ability to alter the tumor immune microenvironment. In this retrospective study, we examined 103 ...patients with
KRAS
-mutant lung adenocarcinoma who were treated with immunotherapy-based regimens and we evaluated the clinical outcomes according to PD-L1 expression and the type of
KRAS
mutation. Among all patients included, 47% carried
KRAS G12C
mutation whereas 53% harbored
KRAS
non-G12C mutations. PD-L1 status was available for 77% of cases, with higher expression among KRAS G12C tumors (p = 0.01). Better overall survival and progression-free survival were observed in high PD-L1 expression tumors, regardless of
KRAS
mutation type. The heterogeneous nature of KRAS-mutant tumors and the presence of other co-mutations may contribute to different outcomes to immunotherapy-based strategies.
Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus ...accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.
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