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High Mechanical Conditioning by Tumor Extracellular Matrix Stiffness Is a Predictive Biomarker for Antifibrotic Therapy in HER2-Negative Breast Cancer.
No full textTumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis. Cancer cells can be mechanically conditioned by stiff extracellular matrix, exhibiting a 1,004-gene signature [mechanical conditioning (MeCo) score]. Nintedanib has demonstrated antifibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib's antifibrotic effect on breast cancer outcomes. We present long-term follow-up and analysis of a neoadjuvant randomized phase II trial in early HER2-negative breast cancer. Patients (N = 130) underwent a baseline biopsy and received 12 paclitaxel courses alone (control arm) or in combination with nintedanib (experimental arm). The tumor MeCo score was determined by RNA sequencing. The primary aim was to assess nintedanib's impact on event-free survival based on MeCo scores. Follow-up data were retrieved from 111 patients; 75 baseline and 24 post-run-in phase samples were sequenced. After median follow-up of 9.67 years, median event-free survival was not statistically different between arms (P = 0.37). However, in the control arm, high- versus low-MeCo patients had a statistically higher relapse risk: HR = 0.21; P = 0.0075. This risk was corrected by nintedanib in the experimental arm: HR = 0.37; P = 0.16. Nintedanib demonstrated pharmacodynamic engagement, reducing the MeCo score by 25% during the run-in phase (P High MeCo is predictive of poor outcomes in HER2-negative early breast cancer, although this risk can be mitigated by nintedanib, which is able to specifically reduce MeCo
Regenerative medicine: Hydrogels and mesoporous silica nanoparticles.
No full textHydrogels, that are crosslinked polymer networks, can absorb huge quantities of water and/or biological fluids. Their physical properties, such as elasticity and soft tissue, together with their biocompatibility and biodegradability, closely resemble living tissues. The versatility of hydrogels has fuelled their application in various fields, such as agriculture, biomaterials, the food industry, drug delivery, tissue engineering, and regenerative medicine. Their combination with nanoparticles, specifically with Mesoporous Silica Nanoparticles (MSNs), have elevated these composites to the next level, since MSNs could improve the hydrogel mechanical properties, their ability to encapsulate and controlled release great amounts of different therapeutic agents, and their responsiveness to a variety of external and internal stimuli. In this review, the main features of both MSNs and hydrogels are introduced, followed by the discussion of different hydrogels-MSNs structures and an overview of their use in different applications, such as drug delivery technologies and tissue engineering
Immigrant Health and Early-Onset Colorectal Cancer Disparities: Results From the Spanish Early-Onset Colorectal Cancer Consortium.
No full text20.500.12530/87854To better understand immigration disparities among a Spanish Early-Onset Colorectal Cancer (SECOC) subset, according to the country of origin. We selected 250 consecutive participants from the SECOC consortium. Data on baseline patient and tumor characteristics, family history of colorectal cancer (CRC), and follow-up were collected. The presence of mismatch repair deficiency was also assessed. Special data regarding country of origin, time of stay in Spain in case of other different country, and a 10-year cutoff that specifies the obtaining of Spanish nationality defined the variables of interest for comparison. Seventy-five percent of patients with early-onset CRC (EOCRC) (188) were born in Spain, whereas the other 25% were born outside of Spain. The mean time of living in Spain until the EOCRC diagnosis was 16.5 years. Comparatively, most of the analyzed features showed equivalent proportions between cohorts. Only Spanish patients appeared to have more familial cancer component in first degree in general (32.3%; P = .01), compared with non-Spaniards, which showed a predominant sporadic component (56.4%; P Although there were few differences between Spanish and non-Spanish EOCRC, the most remarkable difference was that linked with the situation of those immigrants who have recently arrived in Spain, in relation to their lower health coverage, which could be associated with the delay in the diagnosis and their subsequent worse prognosis
Giant thigh hemosiderotic/aneurysmal dermatofibroma: Case report with radiologic-pathologic correlation.
No full text20.500.12530/87857Hemosiderotic/aneurysmal variant of dermatofibroma (DF) is infrequent and may be misdiagnosed with malignant lesions. We report the case of a giant (7.6cm) subcutaneous hemosiderotic/aneurysmal DF (H/ADF) of the thigh in a 53-year-old female patient. Internal arterial and venous hypervascularity was seen by spectral Doppler ultrasound. Magnetic resonance image showed a discrete homogeneous hypointense in T1-weighted images (WI) and T2-WI mass, with hyperintense areas in fat-suppressed T2-WI. The histology revealed a monotonous fusocelular proliferation without atypia, positive for CD163, factor XIIIa and CD10. Widely distributed hemosiderin pigment and two blood-filled pseudovascular spaces lacking endothelial lining were present. H/ADF was diagnosed. The mass was removed but surgical margins were affected. The patient did not present local relapse or distant metastasis. H/ADF are unusual cutaneous soft tissue tumours that can be clinically, radiologically and histopathologically confused with malignant lesions such as melanomas, vascular lesions or sarcomas, especially in giant cases
Radiation necrosis after radiation therapy treatment of brain metastases: A computational approach.
No full text20.500.12530/87913Metastasis is the process through which cancer cells break away from a primary tumor, travel through the blood or lymph system, and form new tumors in distant tissues. One of the preferred sites for metastatic dissemination is the brain, affecting more than 20% of all cancer patients. This figure is increasing steadily due to improvements in treatments of primary tumors. Stereotactic radiosurgery (SRS) is one of the main treatment options for patients with a small or moderate number of brain metastases (BMs). A frequent adverse event of SRS is radiation necrosis (RN), an inflammatory condition caused by late normal tissue cell death. A major diagnostic problem is that RNs are difficult to distinguish from BM recurrences, due to their similarities on standard magnetic resonance images (MRIs). However, this distinction is key to choosing the best therapeutic approach since RNs resolve often without further interventions, while relapsing BMs may require open brain surgery. Recent research has shown that RNs have a faster growth dynamics than recurrent BMs, providing a way to differentiate the two entities, but no mechanistic explanation has been provided for those observations. In this study, computational frameworks were developed based on mathematical models of increasing complexity, providing mechanistic explanations for the differential growth dynamics of BMs relapse versus RN events and explaining the observed clinical phenomenology. Simulated tumor relapses were found to have growth exponents substantially smaller than the group in which there was inflammation due to damage induced by SRS to normal brain tissue adjacent to the BMs, thus leading to RN. ROC curves with the synthetic data had an optimal threshold that maximized the sensitivity and specificity values for a growth exponent β* = 1.05, very close to that observed in patient datasets
Reconstruction of Segmental Mandibular Defects with Double-Barrel Fibula Flap and Osseo-Integrated Implants: A Systematic Review.
No full text20.500.12530/87855Background: Mandibular defects resulting from oncological treatment pose significant aesthetic and functional challenges due to the involvement of bone and soft tissues. Immediate reconstruction is crucial to address complications such as malocclusion, mandibular deviation, temporomandibular joint (TMJ) changes, and soft tissue retraction. These issues can lead to functional impairments, including difficulties in chewing, swallowing, and speech. The fibula flap is widely used for mandibular reconstruction due to its long bone segment and robust vascular supply, though it may not always provide adequate bone height for optimal dental rehabilitation. This systematic review aims to determine if the double-barreled fibula flap (DBFF) configuration is a viable alternative for mandibular reconstruction and to evaluate the outcomes of dental implants placed in this type of flap. Materials and Methods: This study adhered to the Cochrane Collaboration criteria and PRISMA guidelines and was registered on the International Platform of Registered Systematic Review and Meta-Analysis Protocols Database (INPLASY2023120026). We included clinical studies published in English, Spanish, or French that focused on adult patients undergoing segmental mandibulectomy followed by DBFF reconstruction and dental rehabilitation. Data sources included Medline/PubMed, the Cochrane Library, EMBASE, Scopus, and manual searches. Two reviewers independently screened and selected studies, with discrepancies resolved by a third reviewer. Data extraction captured variables such as publication year, patient demographics, number of implants, follow-up duration, flap survival, implant failure, and aesthetic outcomes. The risk of bias was assessed using the JBI appraisal tool, and the certainty of evidence was evaluated using the GRADE approach. Results: A total of 17 clinical studies were included, evaluating 245 patients and 402 dental implants. The average patient age was 43.7 years, with a mean follow-up period of 34.3 months. Flap survival was high, with a 98.3% success rate and only four flap losses. The implant failure rate was low at 1.74%. Esthetic outcomes were varied, with only three studies using standardized protocols for evaluation. The overall certainty of evidence for flap survival was moderate, low for implant failure, and very low for aesthetics due to the subjective nature of assessments and variability in reporting. Conclusions: The primary limitations of the evidence included in this review are the observational design of the studies, leading to an inherent risk of bias, inconsistency in reporting methods, and imprecision in outcome measures. Additionally, the subjective nature of aesthetic evaluations and the variability in assessment tools further limit the reliability of the findings. The DBFF technique demonstrates excellent outcomes for mandibular reconstruction, with high flap survival and low implant failure rates, making it a viable option for dental rehabilitation. However, the evidence for aesthetic outcomes is less certain, highlighting the need for more rigorous and standardized research. This review supports the DBFF as a good alternative for mandibular reconstruction with successful dental implant integration, although further studies are needed to enhance the reliability of aesthetic evaluations
A plasmid-chromosome crosstalk in multidrug resistant enterobacteria.
No full text20.500.12530/87908Conjugative plasmids promote the dissemination and evolution of antimicrobial resistance in bacterial pathogens. However, plasmid acquisition can produce physiological alterations in the bacterial host, leading to potential fitness costs that determine the clinical success of bacteria-plasmid associations. In this study, we use a transcriptomic approach to characterize the interactions between a globally disseminated carbapenem resistance plasmid, pOXA-48, and a diverse collection of multidrug resistant (MDR) enterobacteria. Although pOXA-48 produces mostly strain-specific transcriptional alterations, it also leads to the common overexpression of a small chromosomal operon present in Klebsiella spp. and Citrobacter freundii strains. This operon includes two genes coding for a pirin and an isochorismatase family proteins (pfp and ifp), and shows evidence of horizontal mobilization across Proteobacteria species. Combining genetic engineering, transcriptomics, and CRISPRi gene silencing, we show that a pOXA-48-encoded LysR regulator is responsible for the plasmid-chromosome crosstalk. Crucially, the operon overexpression produces a fitness benefit in a pOXA-48-carrying MDR K. pneumoniae strain, suggesting that this crosstalk promotes the dissemination of carbapenem resistance in clinical settings
DUSP1 and SOX2 expression determine squamous cell carcinoma of the salivary gland progression.
No full text20.500.12530/87913Salivary gland squamous cell carcinomas (SG-SCCs) constitute a rare type of head and neck cancer which is linked to poor prognosis. Due to their low frequency, the molecular mechanisms responsible for their aggressiveness are poorly understood. In this work we studied the role of the phosphatase DUSP1, a negative regulator of MAPK activity, in controlling SG-SCC progression. We generated DUSP1 KO clones in A253 human cells. These clones showed a reduced ability to grow in 2D, self-renew in ECM matrices and to form tumors in immunodeficient mice. This was caused by an overactivation of the stress and apoptosis kinase JNK1/2 in DUSP1-/+ clones. Interestingly, RNAseq analysis revealed that the expression of SOX2, a well-known self-renewal gene was decreased at the mRNA and protein levels in DUSP1-/+ cells. Unexpectedly, CRISPR-KO of SOX2 did not recapitulate DUSP1-/+ phenotype, and SOX2-null cells had an enhanced ability to self-renew and to form tumors in mice. Gene expression analysis demonstrated that SOX2-null cells have a decreased squamous differentiation profile -losing TP63 expression- and an increased migratory phenotype, with an enhanced epithelial to mesenchymal transition signature. In summary, our data indicates that DUSP1 and SOX2 have opposite functions in SG-SCC, being DUSP1 necessary for tumor growth and SOX2 dispensable showing a tumor suppressor function. Our data suggest that the combined expression of SOX2 and DUSP1 could be a useful biomarker to predict progression in patients with SG-SCCs
Recuperación de espermatozoides de la orina en hombres con eyaculación retrógrada.
No full text20.500.12530/8791
Screening for HTLV-1 infection should be expanded in Europe.
No full text20.500.12530/87909Human T-cell lymphotropic virus type 1 (HTLV-1) infection is spreading globally at an uncertain speed. Sexual, mother-to-child, and parenteral exposure are the major transmission routes. Neither vaccines nor antivirals have been developed to confront HTLV-1, despite infecting over 10 million people globally and causing life-threatening illnesses in 10% of carriers. It is time to place this long-neglected disease firmly into the 2030 elimination agenda. Current evidence supports once-in-life testing for HTLV-1, as recommended for HIV, hepatitis B and C, along with targeted screening of pregnant women, blood donors, and people who attended clinics for sexually transmitted infections (STIs). Similar targeted screening strategies are already being performed for Chagas disease in some Western countries in persons from Latin America. Given the high risk of rapid-onset HTLV-1-associated myelopathy, universal screening of solid organ donors is warranted. To minimize organ wastage, however, the specificity of HTLV screening tests must be improved. HTLV screening of organ donors in Europe has become mandatory in Spain and the United Kingdom. The advent of HTLV point-of-care kits would facilitate testing. Finally, increasing awareness of HTLV-1 will help those living with HTLV-1 to be tested, clinically monitored, and informed about transmission-preventive measures