Impact of healthcare inequities on survival in Mexican patients with metastatic renal cell carcinoma.

Introduction: The survival of patients with metastatic renal cell carcinoma (mRCC) has improved dramatically due to novel systemic treatments. However, mRCC mortality continues to rise in Latin America. Methods: A retrospective, multicenter study of patients diagnosed with mRCC between 2010-2018 in Mexico City was conducted. The aim of the study was to evaluate the impact of healthcare insurance on access to treatment and survival in patients with mRCC. Results: Among 924 patients, 55.4%, 42.6%, and 1.9% had no insurance (NI), social security, (SS) and private insurance (PI), respectively. De novo metastatic disease was more common in NI patients (70.9%) compared to SS (47.2%) and PI (55.6%) patients (p<0.001). According to IMDC Prognostic Index, 20.2% were classified as favorable, 49% as intermediate, and 30.8% as poor-risk disease. Access to systemic treatment differed by healthcare insurance: 36.1%, 99.5%, and 100% for the NI, SS, and PI patients, respectively (p<0.001). NI patients received fewer lines of treatment, with 24.8% receiving only one line of treatment (p<0.001). Median overall survival (OS) was 13.9 months for NI, 98.9 months for SS, and 147.6 months for NI patients (p<0.001). In multivariate analysis, NI status, brain metastases, sarcomatoid features, bone metastases, no treatment were significantly associated with worse OS. Conclusion: OS in mRCC was affected by insurance availability in this resource-limited cohort of Mexican patients. These results underscore the need for effective strategies to achieve equitable healthcare access in an era of effective, yet costly systemic treatments.

Low-cost inertial microfluidic device for microparticle separation: A laser-Ablated PMMA lab-on-a-chip approach without a cleanroom.

Although microparticles are frequently used in chemistry and biology, their effectiveness largely depends on the homogeneity of their particle size distribution. Microfluidic devices to separate and purify particles based on their size have been developed, but many require expensive cleanroom manufacturing processes. A cost-effective, passive microfluidic separator is presented, capable of efficiently sorting and purifying particles spanning the size range of 15 µm to 40 µm. Fabricated from Polymethyl Methacrylate (PMMA) substrates using laser ablation, this device circumvents the need for cleanroom facilities. Prior to fabrication, rigorous optimization of the device's design was carried out through computational simulations conducted in COMSOL Multiphysics. To gauge its performance, chitosan microparticles were employed as a test case. The results were notably promising, achieving a precision of 96.14 %. This quantitative metric underscores the device's precision and effectiveness in size-based particle separation. This low-cost and accessible microfluidic separator offers a pragmatic solution for laboratories and researchers seeking precise control over particle sizes, without the constraints of expensive manufacturing environments. This innovation not only mitigates the limitations tied to traditional cleanroom-based fabrication but also widens the horizons for various applications within the realms of chemistry and biology.

Real-world KINDLE-Latin America subset data on treatment patterns and clinical outcomes in patients with stage III non-small-cell lung cancer.

INTRODUCTION: Stage III non-small-cell lung cancer (NSCLC) management is challenging given the heterogeneous nature of the disease. The LATAM subset of the real-world, global KINDLE study reported the treatment patterns and clinical outcomes for LATAM from the pre-immuno-oncology era. METHODS: The study was conducted in seven countries (Argentina, Chile, Colombia, Dominican Republic, Mexico, Peru and Uruguay) in stage III NSCLC (American Joint Committee on Cancer, 7th edition) diagnosed between January 2013 and December 2017. Retrospective data from patients' medical records (index date to the end of follow-up) were collected. Summary statistics, Kaplan-Meier survival estimates and a two-sided 95% confidence interval (CI) were provided. Cox proportional hazard model was used for univariate and multi-variate analyses. RESULTS: A total of 231 patients was enrolled, the median age was 65.0 years (range 21.0-89.0), 60.6% were males, 76.6% had smoking history, 64.0% had adenocarcinoma and 28.7% underwent curative resection. Multiple treatment regimens (>25) were used; chemotherapy alone was the most common (24.8%). The overall median progression-free survival (mPFS) and median overall survival (mOS) were 14.8 months (95% CI, 12.1-18.6) and 48.6 months (95% CI, 34.7 to not calculable). Significantly better mPFS and mOS were observed for stage IIIA with curative surgery and resectable tumours and stage IIIB with an Eastern Cooperative Oncology Group score of 0/1, female gender, resectable tumours, adenocarcinoma and curative surgery (p < 0.05). CONCLUSION: Results show diversity in treatment practices and the corresponding clinical outcomes in stage III NSCLC. There is a need to streamline treatment selection and sequencing to decrease relapse rates after initial therapy.

Delivery and assessment of a CRISPR/nCas9-based genome editing system on in vitro models of mucopolysaccharidoses IVA assisted by magnetite-based nanoparticles.

Mucopolysaccharidosis IV A (MPS IVA) is a lysosomal disorder caused by mutations in the GALNS gene. Consequently, the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate accumulate in the lysosomal lumen. Although enzyme replacement therapy has shown essential advantages for the patients, several challenges remain to overcome, such as the limited impact on the bone lesion and recovery of oxidative profile. Recently, we validated a CRISPR/nCas9-based gene therapy with promising results in an in vitro MPS IVA model. In this study, we have expanded the use of this CRISPR/nCas9 system to several MPS IVA fibroblasts carrying different GALNS mutations. Considering the latent need to develop more safety vectors for gene therapy, we co-delivered the CRISPR/nCas9 system with a novel non-viral vector based on magnetoliposomes (MLPs). We found that the CRISPR/nCas9 treatment led to an increase in enzyme activity between 5 and 88% of wild-type levels, as well as a reduction in GAGs accumulation, lysosomal mass, and mitochondrial-dependent oxidative stress, in a mutation-dependent manner. Noteworthy, MLPs allowed to obtain similar results to those observed with the conventional transfection agent lipofectamine. Overall, these results confirmed the potential of CRISPR/nCas9 as a genome editing tool for treating MPS IVA. We also demonstrated the potential use of MLPs as a novel delivery system for CRISPR/nCas9-based therapies.

Novel Photo- and Thermo-Responsive Nanocomposite Hydrogels Based on Functionalized rGO and Modified SIS/Chitosan Polymers for Localized Treatment of Malignant Cutaneous Melanoma.

Melanoma is an aggressive type of skin cancer that accounts for over 75% of skin cancer deaths despite comprising less than 5% of all skin cancers. Despite promising improvements in surgical approaches for melanoma resection, the survival of undetectable microtumor residues has remained a concern. As a result, hyperthermia- and drug-based therapies have grown as attractive techniques to target and treat cancer. In this work, we aim to develop a stimuli-responsive hydrogel based on chitosan methacrylate (ChiMA), porcine small intestine submucosa methacrylate (SISMA), and doxorubicin-functionalized reduced graphene oxide (rGO-DOX) that eliminates microtumor residues from surgically resected melanoma through the coupled effect of NIR light-induced photothermal therapy and heat-induced doxorubicin release. Furthermore, we developed an in silico model to optimize heat and mass transport and evaluate the proposed chemo/photothermal therapy in vitro over melanoma cell cultures.

The Tracking of Moist Habitats Allowed Aiphanes (Arecaceae) to Cover the Elevation Gradient of the Northern Andes.

The topographic gradients of the Tropical Andes may have triggered species divergence by different mechanisms. Topography separates species' geographical ranges and offers climatic heterogeneity, which could potentially foster local adaptation to specific climatic conditions and result in narrowly distributed endemic species. Such a pattern is found in the Andean centered palm genus Aiphanes. To test the extent to which geographic barriers and climatic heterogeneity can explain distribution patterns in Aiphanes, we sampled 34 out of 36 currently recognized species in that genus and sequenced them by Sanger sequencing and/or sequence target capture sequencing. We generated Bayesian, likelihood, and species-tree phylogenies, with which we explored climatic trait evolution from current climatic occupation. We also estimated species distribution models to test the relative roles of geographical and climatic divergence in their evolution. We found that Aiphanes originated in the Miocene in Andean environments and possibly in mid-elevation habitats. Diversification is related to the occupation of the adjacent high and low elevation habitats tracking high annual precipitation and low precipitation seasonality (moist habitats). Different species in different clades repeatedly occupy all the different temperatures offered by the elevation gradient from 0 to 3,000 m in different geographically isolated areas. A pattern of conserved adaptation to moist environments is consistent among the clades. Our results stress the evolutionary roles of niche truncation of wide thermal tolerance by physical range fragmentation, coupled with water-related niche conservatism, to colonize the topographic gradient.

Microfluidic Synthesis and Purification of Magnetoliposomes for Potential Applications in the Gastrointestinal Delivery of Difficult-to-Transport Drugs.

Magnetite nanoparticles (MNPs) have gained significant attention in several applications for drug delivery. However, there are some issues related to cell penetration, especially in the transport of cargoes that show limited membrane passing. A widely studied strategy to overcome this problem is the encapsulation of the MNPs into liposomes to form magnetoliposomes (MLPs), which are capable of fusing with membranes to achieve high delivery rates. This study presents a low-cost microfluidic approach for the synthesis and purification of MLPs and their biocompatibility and functional testing via hemolysis, platelet aggregation, cytocompatibility, internalization, and endosomal escape assays to determine their potential application in gastrointestinal delivery. The results show MLPs with average hydrodynamic diameters ranging from 137 ± 17 nm to 787 ± 45 nm with acceptable polydispersity index (PDI) values (below 0.5). In addition, we achieved encapsulation efficiencies between 20% and 90% by varying the total flow rates (TFRs), flow rate ratios (FRRs), and MNPs concentration. Moreover, remarkable biocompatibility was attained with the obtained MLPs in terms of hemocompatibility (hemolysis below 1%), platelet aggregation (less than 10% with respect to PBS 1×), and cytocompatibility (cell viability higher than 80% in AGS and Vero cells at concentrations below 0.1 mg/mL). Additionally, promising delivery results were obtained, as evidenced by high internalization, low endosomal entrapment (AGS cells: PCC of 0.28 and covered area of 60% at 0.5 h and PCC of 0.34 and covered area of 99% at 4 h), and negligible nuclear damage and DNA condensation. These results confirm that the developed microfluidic devices allow high-throughput production of MLPs for potential encapsulation and efficient delivery of nanostructured cell-penetrating agents. Nevertheless, further in vitro analysis must be carried out to evaluate the prevalent intracellular trafficking routes as well as to gain a detailed understanding of the existing interactions between nanovehicles and cells.

Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial.

PURPOSE: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months). PATIENTS AND METHODS: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods. RESULTS: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96]. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI. CONCLUSIONS: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Design and Manufacture of a Low-Cost Microfluidic System for the Synthesis of Giant Liposomes for the Encapsulation of Yeast Homologues: Applications in the Screening of Membrane-Active Peptide Libraries.

The discovery of new membrane-active peptides (MAPs) is an area of considerable interest in modern biotechnology considering their ample applicability in several fields ranging from the development of novel delivery vehicles (via cell-penetrating peptides) to responding to the latent threat of antibiotic resistance (via antimicrobial peptides). Different strategies have been devised for such discovery process, however, most of them involve costly, tedious, and low-efficiency methods. We have recently proposed an alternative route based on constructing a non-rationally designed library recombinantly expressed on the yeasts' surfaces. However, a major challenge is to conduct a robust and high-throughput screening of possible candidates with membrane activity. Here, we addressed this issue by putting forward low-cost microfluidic platforms for both the synthesis of Giant Unilamellar Vesicles (GUVs) as mimicking entities of cell membranes and for providing intimate contact between GUVs and homologues of yeasts expressing MAPs. The homologues were chitosan microparticles functionalized with the membrane translocating peptide Buforin II, while intimate contact was through passive micromixers with different channel geometries. Both microfluidic platforms were evaluated both in silico (via Multiphysics simulations) and in vitro with a high agreement between the two approaches. Large and stable GUVs (5-100 µm) were synthesized effectively, and the mixing processes were comprehensively studied leading to finding the best operating parameters. A serpentine micromixer equipped with circular features showed the highest average encapsulation efficiencies, which was explained by the unique mixing patterns achieved within the device. The microfluidic devices developed here demonstrate high potential as platforms for the discovery of novel MAPs as well as for other applications in the biomedical field such as the encapsulation and controlled delivery of bioactive compounds.

Genomic Profiling of Premenopausal HR+ and HER2- Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib.

PURPOSE: This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial. METHODS: Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib. RESULTS: Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status. CONCLUSION: In this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

A new method to build multiplex networks using canonical correlation analysis for the characterization of the Alzheimer's disease continuum.

Objective. The aim of this study was to solve one of the current limitations for the characterization of the brain network in the Alzheimer's disease (AD) continuum. Nowadays, frequency-dependent approaches have reached contradictory results depending on the frequency band under study, tangling the possible clinical interpretations.Approach. To overcome this issue, we proposed a new method to build multiplex networks based on canonical correlation analysis (CCA). Our method determines two basis vectors using the source and electrode-level frequency-specific network parameters for a reference group, and then project the results for the rest of the groups into these hyperplanes to make them comparable. It was applied to: (i) synthetic signals generated with a Kuramoto-based model; and (ii) a resting-state electroencephalography (EEG) database formed by recordings from 51 cognitively healthy controls, 51 mild cognitive impairment subjects, 51 mild AD patients, 50 moderate AD patients, and 50 severe AD patients.Main results. Our results using synthetic signals showed that the interpretation of the proposed CCA-based multiplex parameters (multiplex strength, multiplex characteristic path length and multiplex clustering coefficient) can be analogous to their frequency-specific counterparts, as they displayed similar behaviors in terms of average connectivity, integration, and segregation. Findings using real EEG recordings revealed that dementia due to AD is characterized by a significant increase in average connectivity, and by a loss of integration and segregation.Significance. We can conclude that CCA can be used to build multiplex networks based from frequency-specific results, summarizing all the available information and avoiding the limitations of possible frequency-specific conflicts. Additionally, our method supposes a novel approach for the construction and analysis of multiplex networks during AD continuum.

Recomendaciones de la Sociedad Mexicana de Oncología para la vacunación contra Covid-19 en personas con cáncer en México.

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Design, Screening, and Testing of Non-Rational Peptide Libraries with Antimicrobial Activity: In Silico and Experimental Approaches.

One of the challenges of modern biotechnology is to find new routes to mitigate the resistance to conventional antibiotics. Antimicrobial peptides (AMPs) are an alternative type of biomolecules, naturally present in a wide variety of organisms, with the capacity to overcome the current microorganism resistance threat. Here, we reviewed our recent efforts to develop a new library of non-rationally produced AMPs that relies on bacterial genome inherent diversity and compared it with rationally designed libraries. Our approach is based on a four-stage workflow process that incorporates the interplay of recent developments in four major emerging technologies: artificial intelligence, molecular dynamics, surface-display in microorganisms, and microfluidics. Implementing this framework is challenging because to obtain reliable results, the in silico algorithms to search for candidate AMPs need to overcome issues of the state-of-the-art approaches that limit the possibilities for multi-space data distribution analyses in extremely large databases. We expect to tackle this challenge by using a recently developed classification algorithm based on deep learning models that rely on convolutional layers and gated recurrent units. This will be complemented by carefully tailored molecular dynamics simulations to elucidate specific interactions with lipid bilayers. Candidate AMPs will be recombinantly-expressed on the surface of microorganisms for further screening via different droplet-based microfluidic-based strategies to identify AMPs with the desired lytic abilities. We believe that the proposed approach opens opportunities for searching and screening bioactive peptides for other applications.

Genome-Wide Scan for Five Brain Oscillatory Phenotypes Identifies a New QTL Associated with Theta EEG Band.

Brain waves, measured by electroencephalography (EEG), are a powerful tool in the investigation of neurophysiological traits and a noninvasive and cost-effective alternative in the diagnostic of some neurological diseases. In order to identify novel Quantitative Trait Loci (QTLs) for brain wave relative power (RP), we collected resting state EEG data in five frequency bands (δ, θ, α, ß1, and ß2) and genome-wide data in a cohort of 105 patients with late onset Alzheimer's disease (LOAD), 41 individuals with mild cognitive impairment and 45 controls from Iberia, correcting for disease status. One novel association was found with an interesting candidate for a role in brain wave biology, CLEC16A (C-type lectin domain family 16), with a variant at this locus passing the adjusted genome-wide significance threshold after Bonferroni correction. This finding reinforces the importance of immune regulation in brain function. Additionally, at a significance cutoff value of 5 × 10-6, 18 independent association signals were detected. These signals comprise brain expression Quantitative Loci (eQTLs) in caudate basal ganglia, spinal cord, anterior cingulate cortex and hypothalamus, as well as chromatin interactions in adult and fetal cortex, neural progenitor cells and hippocampus. Moreover, in the set of genes showing signals of association with brain wave RP in our dataset, there is an overrepresentation of loci previously associated with neurological traits and pathologies, evidencing the pleiotropy of the genetic variation modulating brain function.

Volume Conduction Effects on Connectivity Metrics: Application of Network Parameters to Characterize Alzheimer's Disease Continuum.

This study had two main objectives: (i) to study the effects of volume conduction on different connectivity metrics (Amplitude Envelope Correlation AEC, Phase Lag Index PLI, and Magnitude Squared Coherence MSCOH), comparing the coupling patterns at electrode- and sensor-level; and (ii) to characterize spontaneous EEG activity during different stages of Alzheimer's disease (AD) continuum by means of three complementary network parameters: node degree (k), characteristic path length (L), and clustering coefficient (C). Our results revealed that PLI and AEC are weakly influenced by volume conduction compared to MSCOH, but they are not immune to it. Furthermore, network parameters obtained from PLI showed that AD continuum is characterized by an increase in L and C in low frequency bands, suggesting lower integration and higher segregation as the disease progresses. These network changes reflect the abnormalities during AD continuum and are mainly due to neuronal alterations, because PLI is slightly affected by volume conduction effects.

Inter-band Bispectral Analysis of EEG Background Activity to Characterize Alzheimer's Disease Continuum.

The aim of this study was to characterize the EEG alterations in inter-band interactions along the Alzheimer's disease (AD) continuum. For this purpose, EEG background activity from 51 healthy control subjects, 51 mild cognitive impairment patients, 50 mild AD patients, 50 moderate AD patients, and 50 severe AD patients was analyzed by means of bispectrum. Three inter-band features were extracted from bispectrum matrices: bispectral relative power (BispRP), cubic bispectral entropy (BispEn), and bispectral median frequency (BispMF). BispRP results showed an increase of delta and theta interactions with other frequency bands and the opposite behavior for alpha, beta-1, and beta-2. Delta and theta interactions, along with the rest of the spectrum, also experimented a decrease of BispEn with disease progression, suggesting these bands interact with a reduced variety of components in advanced stages of dementia. Finally, BispMF showed a consistent reduction along the AD continuum in all bands, which is reflective of an interaction of the global spectrum with lower frequency bands as the disease develops. Our results indicate a progressive decrease in inter-band interactions with the severity of the disease, especially those involving high frequency components. Since inter-band coupling oscillations are related to complex and multi-scaled brain processes, these alterations likely reflect the neurodegeneration associated with the AD continuum.

Real-World Evidence: Multicenter Efficacy and Toxicity Analysis of Nintedanib With Docetaxel as Second-Line Treatment in Mexican Patients With Advanced Lung Adenocarcinoma.

PURPOSE: The LUME-Lung 1 study has brought consistent evidence of the effective use of nintedanib in lung adenocarcinoma as a second line of treatment; however, differences among ethnicities have been found in some studies. METHODS: This was a retrospective review among 21 medical centers of 150 patients with a confirmed diagnosis of lung adenocarcinoma, included in a compassionate use program of nintedanib from March 2014 to September 2015. The current study aimed to analyze the effectiveness of nintedanib in combination with docetaxel in the Mexican population, using progression-free survival rate and the best objective response to treatment by RECIST 1.1 as a surrogate of effectiveness. In addition, we examined the toxicity profile of our study population as a secondary end point. RESULTS: After exclusion criteria, only 99 patients met the criteria for enrollment in the current study. From the total study population, 53 patients (53.5%) were male and 46 (46.5%) were female, with an average age of 60 years and stage IV as the most prevalent clinical stage at the beginning of the compassionate use program. A total of 48 patients (48.5%) had partial response; 26 (26.3%), stable disease; 4 (4%), complete response; and 16 (16.2%), progression; and 5 (5%) were nonevaluable. We found a median progression-free survival of 5 months (95% CI, 4.3 to 5.7 months). The most common grade 3 or 4 adverse reactions were fatigue (14%) and diarrhea (13%). CONCLUSION: Nintedanib, as part of a chemotherapy regimen, is an effective option with an acceptable toxicity profile for advanced lung adenocarcinoma after first-line treatment progression.