The applications of CRISPR/Cas-mediated microRNA and lncRNA editing in plant biology: shaping the future of plant non-coding RNA research.

MAIN CONCLUSION: CRISPR/Cas technology has greatly facilitated plant non-coding RNA (ncRNA) biology research, establishing itself as a promising tool for ncRNA functional characterization and ncRNA-mediated plant improvement. Throughout the last decade, the promising genome editing tool clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas; CRISPR/Cas) has allowed unprecedented advances in the field of plant functional genomics and crop improvement. Even though CRISPR/Cas-mediated genome editing system has been widely used to elucidate the biological significance of a number of plant protein-coding genes, this technology has been barely applied in the functional analysis of those non-coding RNAs (ncRNAs) that modulate gene expression, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Nevertheless, compelling findings indicate that CRISPR/Cas-based ncRNA editing has remarkable potential for deciphering the biological roles of ncRNAs in plants, as well as for plant breeding. For instance, it has been demonstrated that CRISPR/Cas tool could overcome the challenges associated with other approaches employed in functional genomic studies (e.g., incomplete knockdown and off-target activity). Thus, in this review article, we discuss the current status and progress of CRISPR/Cas-mediated ncRNA editing in plant science in order to provide novel prospects for further assessment and validation of the biological activities of plant ncRNAs and to enhance the development of ncRNA-centered protocols for crop improvement.

Decoding Angiotensin Receptors: TOMAHAQ-Based Detection and Quantification of Angiotensin Type-1 and Type-2 Receptors.

Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the angiotensin type-1 and type-2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type-1 and type-2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non-antibody-based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type-1 and type-2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type-1 and type-2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin-angiotensin system activation, including oxidative stress, inflammation, amyloid-ß load, and paired helical filament-tau tangle burden. Conclusions These robust high-throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.

Applications of nanotechnologies for miRNA-based cancer therapeutics: current advances and future perspectives.

MicroRNAs (miRNAs) are short (18-25 nt), non-coding, widely conserved RNA molecules responsible for regulating gene expression via sequence-specific post-transcriptional mechanisms. Since the human miRNA transcriptome regulates the expression of a number of tumor suppressors and oncogenes, its dysregulation is associated with the clinical onset of different types of cancer. Despite the fact that numerous therapeutic approaches have been designed in recent years to treat cancer, the complexity of the disease manifested by each patient has prevented the development of a highly effective disease management strategy. However, over the past decade, artificial miRNAs (i.e., anti-miRNAs and miRNA mimics) have shown promising results against various cancer types; nevertheless, their targeted delivery could be challenging. Notably, numerous reports have shown that nanotechnology-based delivery of miRNAs can greatly contribute to hindering cancer initiation and development processes, representing an innovative disease-modifying strategy against cancer. Hence, in this review, we evaluate recently developed nanotechnology-based miRNA drug delivery systems for cancer therapeutics and discuss the potential challenges and future directions, such as the promising use of plant-made nanoparticles, phytochemical-mediated modulation of miRNAs, and nanozymes.

Investigation of the enhanced antitumour potency of STING agonist after conjugation to polymer nanoparticles.

Intravenously administered cyclic dinucleotides and other STING agonists are hampered by low cellular uptake and poor circulatory half-life. Here we report the covalent conjugation of cyclic dinucleotides to poly(ß-amino ester) nanoparticles through a cathepsin-sensitive linker. This is shown to increase stability and loading, thereby expanding the therapeutic window in multiple syngeneic tumour models, enabling the study of how the long-term fate of the nanoparticles affects the immune response. In a melanoma mouse model, primary tumour clearance depends on the STING signalling by host cells-rather than cancer cells-and immune memory depends on the spleen. The cancer cells act as a depot for the nanoparticles, releasing them over time to activate nearby immune cells to control tumour growth. Collectively, this work highlights the importance of nanoparticle structure and nano-biointeractions in controlling immunotherapy efficacy.

Optimal evaluation of re-opening policies for COVID-19 through the use of metaheuristic schemes.

A new contagious disease or unidentified COVID-19 variants could provoke a new collapse in the global economy. Under such conditions, companies, factories, and organizations must adopt reopening policies that allow their operations to reduce economic effects. Effective reopening policies should be designed using mathematical models that emulate infection chains through individual interactions. In contrast to other modeling approaches, agent-based schemes represent a computational paradigm used to characterize the person-to-person interactions of individuals inside a system, providing accurate simulation results. To evaluate the optimal conditions for a reopening policy, authorities and decision-makers need to conduct an extensive number of simulations manually, with a high possibility of losing information and important details. For this reason, the integration of optimization and simulation of reopening policies could automatically find the realistic scenario under which the lowest risk of infection was attained. In this paper, the metaheuristic technique of the Whale Optimization Algorithm is used to find the solution with the minimal transmission risk produced by an agent-based model that emulates a hypothetical re-opening context. Our scheme finds the optimal results of different generical activation scenarios. The experimental results indicate that our approach delivers practical knowledge and essential estimations for identifying optimal re-opening strategies with the lowest transmission risk.

A systematic review and meta-analysis of e-cigarette use among cancer survivors.

PURPOSE: We conducted a systematic review and meta-analysis to determine the use of e-cigarettes among cancer survivors, factors associated with their use, and prevalence of e-cigarette use as a quit attempt. METHODS: We searched five electronic databases until June 2022. Two authors independently selected studies, appraised their quality, and collected data. RESULTS: Twenty-three publications from eight data sources (national surveys) met our eligibility criteria. The pooled rate of lifetime e-cigarette use among cancer survivors was 15% (95% CI 6-27%); current use was 3% (95% CI 0-8%). Among survivors who currently used traditional cigarettes, 63% (95% CI 57-69%) also used e-cigarettes. The reported rates of weighted lifetime e-cigarette use differed between age groups (18-44 years, up to 46.7%; 45-64, up to 27.2%; ≥65, up to 24.8%). Nine publications reported factors associated with lifetime e-cigarette use (i.e., active use of traditional cigarettes; heavy drinking; poor mental health; younger age; being male, non-Hispanic White, or single; having less than high school education or income ≤$25,000 USD; and living in the South regions of the US or urban areas). E-cigarettes were used as a quit resource by 75% of survivors reporting dual use of electronic and traditional cigarettes (95% CI 63%, 85%). CONCLUSION: More than two-thirds of survivors currently using traditional cigarettes also use e-cigarettes. Higher use rates of e-cigarettes were reported among young cancer survivors compared to older survivors. Future studies are needed to assess the impact of e-cigarettes on long-term health and improve screening of smoking behaviors. IMPLICATIONS FOR CANCER SURVIVORS: Our study provides an overview of the prevalence of e-cigarette use and sociodemographic risk factors associated with e-cigarette use among cancer survivors. The findings can assist providers in supporting attempts to quit among cancer survivors.

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases.

Neurodegenerative diseases (NDDs) are characterized by the progressive degeneration and/or loss of neurons belonging to the central nervous system, and represent one of the major global health issues. Therefore, a number of immunotherapeutic approaches targeting the non-functional or toxic proteins that induce neurodegeneration in NDDs have been designed in the last decades. In this context, due to unprecedented advances in genetic engineering techniques and molecular farming technology, pioneering plant-based immunogenic antigen expression systems have been developed aiming to offer reliable alternatives to deal with important NDDs, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Diverse reports have evidenced that plant-made vaccines trigger significant immune responses in model animals, supported by the production of antibodies against the aberrant proteins expressed in the aforementioned NDDs. Moreover, these immunogenic tools have various advantages that make them a viable alternative for preventing and treating NDDs, such as high scalability, no risk of contamination with human pathogens, cold chain free production, and lower production costs. Hence, this article presents an overview of the current progress on plant-manufactured vaccines for NDDs and discusses its future prospects.

Patient Engagement With Early Stage Advance Care Planning at a Comprehensive Cancer Center.

BACKGROUND: Establishing care preferences and selecting a prepared medical decision-maker (MDM) are basic components of advance care planning (ACP) and integral to treatment planning. Systematic ACP in the cancer setting is uncommon. We evaluated a systematic social work (SW)-driven process for patient selection of a prepared MDM. METHODS: We used a pre/post design, centered on SW counseling incorporated into standard-of-care practice. New patients with gynecologic malignancies were eligible if they had an available family caregiver or an established Medical Power of Attorney (MPOA). Questionnaires were completed at baseline and 3 months to ascertain MPOA document (MPOAD) completion status (primary objective) and evaluate factors associated with MPOAD completion (secondary objectives). RESULTS: Three hundred and sixty patient/caregiver dyads consented to participate. One hundred and sixteen (32%) had MPOADs at baseline. Twenty (8%) of the remaining 244 dyads completed MPOADs by 3 months. Two hundred and thirty-six patients completed the values and goals survey at both baseline and follow-up: at follow-up, care preferences were stable in 127 patients (54%), changed toward more aggressive care in 60 (25%), and toward the focus on the quality of life in 49 (21%). Correlation between the patient's values and goals and their caregiver's/MPOA's perception was very weak at baseline, improving to moderate at follow-up. Patients with MPOADs by study completion had statistically significant higher ACP Engagement scores than those without. CONCLUSION: A systematic SW-driven intervention did not engage new patients with gynecologic cancers to select and prepare MDMs. Change in care preferences was common, with caregivers' knowledge of patients' treatment preferences moderate at best.

Polymeric microneedles enable simultaneous delivery of cancer immunomodulatory drugs and detection of skin biomarkers.

Background: Immune-modulating therapies impart positive outcomes in a subpopulation of cancer patients. Improved delivery strategies and non-invasive monitoring of anti-tumor effects can help enhance those outcomes and understand the mechanisms associated with the generation of anti-tumor immune responses following immunotherapy. Methods: We report on the design of a microneedle (MN) platform capable of simultaneous delivery of immune activators and collection of interstitial skin fluid (ISF) to monitor therapeutic responses. While either approach has shown promise, the integration of the therapy and diagnostic arms into one MN platform has hardly been explored before. MNs were synthesized out of crosslinked hyaluronic acid (HA) and loaded with a model immunomodulatory nanoparticle-containing drug, CpG oligodinucleotides (TLR9 agonist), for cancer therapy in melanoma and colon cancer models. The therapeutic response was monitored by longitudinal analysis of entrapped immune cells in the MNs following patch retrieval and digestion. Results: Transdermal delivery of CpG-containing NPs with MNs induced anti-tumor immune responses in multiple syngeneic mouse cancer models. CpG-loaded MNs stimulated innate immune cells and reduced tumor growth. Intravital microscopy showed deposition and spatiotemporal co-localization of CpG-NPs within the tumor microenvironment when delivered with MNs. Analysis of MN-sampled ISF revealed similar immune signatures to those seen in the bulk tumor homogenate, such as increased populations of macrophages and effector T cells following treatment. Conclusions: Our hydrogel-based MNs enable effective transdermal drug delivery into immune cells in the tumor microenvironment, and upon retrieval, enable studying the immune response to the therapy over time. This platform has the theranostic potential to deliver a range of combination therapies while detecting biomarkers.

Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma.

PURPOSE: Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset. METHODS: We enrolled 60 patients with newly diagnosed non-germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322). Patients were treated with rituximab 375 mg/m2 intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed. RESULTS: The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively. CONCLUSION: Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.

Body mass index and survival after cancer diagnosis: A pan-cancer cohort study of 114 430 patients with cancer.

The recommendation encouraging patients with cancer to keep a normal body mass index (BMI) is largely extrapolated from data on risk of developing cancer. We tested the prospective association between peri-diagnostic (within 1 year post-diagnosis) BMI and all-cause mortality in patients with incident cancers. During 7.2 years of follow-up, 42% (48,340) of the 114 430 patients with cancer died. Spline analysis revealed that compared with a BMI of 22.5, a BMI lower than 22.5 was associated with increased risk of all-cause mortality across 24 cancer types. A BMI higher than 22.5 was associated with reduced all-cause mortality, while a non-linear association was observed; the lowest risk was found at a BMI of 29.6-34.2, and the risk started to return to and above unity at very high BMI values. The reduced mortality risk of high BMI was observed in 23 of 24 cancer types and maintained after attempts to remove potential selection bias, confounding by smoking and comorbidities, and reserve causality. Compared with a normal BMI of 18.5-24.9, the hazard ratios were 0.85 (95% confidence interval [CI], 0.83-0.87) for an overweight BMI (25-29.9) and 0.82 (0.80-0.85) for an obese BMI (≥30), and the associations were generally consistent across cancer types and various subgroups. Obese BMI was associated with increased life expectancy, up to 6 years among men and 3 years among women. In conclusion, while overweight/obese BMI increases the risk of developing cancer in the general population, overweight/obese peri-diagnostic BMI was associated with longer survival in cancer patients.

Particle-based model of mechanosensory contractility kit assembly.

Cell shape change processes, such as proliferation, polarization, migration, and cancer metastasis, rely on a dynamic network of macromolecules. The proper function of this network enables mechanosensation, the ability of cells to sense and respond to mechanical cues. Myosin II and cortexillin I, critical elements of the cellular mechanosensory machinery, preassemble in the cytoplasm of Dictyostelium cells into complexes that we have termed contractility kits (CKs). Two IQGAP proteins then differentially regulate the mechanoresponsiveness of the cortexillin I-myosin II elements within CKs. To investigate the mechanism of CK self-assembly and gain insight into possible molecular means for IQGAP regulation, we developed a coarse-grained excluded volume molecular model in which all protein polymers are represented by nm-sized spheres connected by spring-like links. The model is parameterized using experimentally measured parameters acquired through fluorescence cross-correlation spectroscopy and fluorescence correlation spectroscopy, which describe the interaction affinities and diffusion coefficients for individual molecular components, and which have also been validated via several orthogonal methods. Simulations of wild-type and null-mutant conditions implied that the temporal order of assembly of these kits is dominated by myosin II dimer formation and that IQGAP proteins mediate cluster growth. In addition, our simulations predicted the existence of "ambiguous" CKs that incorporate both classes of IQGAPs, and we confirmed this experimentally using fluorescence cross-correlation spectroscopy. The model serves to describe the formation of the CKs and how their assembly enables and regulates mechanosensation at the molecular level.

An agent-based transmission model of COVID-19 for re-opening policy design.

The global pandemic caused by the coronavirus (COVID-19) disease has collapsed the worldwide economy. Elements such as non-obligatory vaccination, new strain variants and lack of discipline to follow social distancing measures suggest the possibility that COVID-19 may continue to exist, exhibiting the behavior of a seasonal disease. As the socio-economic crisis has become unsustainable, all countries are planning strategies to gradually restart their economic and social activities. Initially, several containment measures have been adopted involving social distancing, infection detection tests, and ventilation systems. Despite the implementation of such policies, there exists a lack of evaluation of their performance to reduce the contagion index. This means there are no appropriate indicators to decide which intervention or set of interventions present the most effective result. Under these conditions, the development of models that provide useful information in the design and evaluation of containment measures and re-opening policies is of prime concern. In this paper, a novel approach to model the transmission process of COVID-19 in closed environments is proposed. The proposed model can simulate the effects that result from the complex interaction among individuals when they follow a particular containment measure or re-opening policy. With the proposed model, different hypothetical re-opening policies, that are otherwise impossible to analyze in real conditions, can be tested. Computer experiments demonstrate that the proposed model provides suitable information and realistic predictions, which are appropriate for designing strategies that allow a safe return to economic activities.

Hydrogen Sulfide Subchronic Treatment Improves Hypertension Induced by Traumatic Brain Injury in Rats through Vasopressor Sympathetic Outflow Inhibition.

Traumatic brain injury (TBI) represents a critical public health problem around the world. To date, there are no accurate therapeutic approaches for the management of cardiovascular impairments induce by TBI. In this regard, hydrogen sulfide (H2S), a novel gasotransmitter, has been proposed as a neuro- and cardioprotective molecule. This study was designed to determine the effect of subchronic management with sodium hydrosulfide (NaHS) on hemodynamic, vasopressor sympathetic outflow and sensorimotor alterations produced by TBI. Animals underwent a lateral fluid percussion injury, and changes in hemodynamic variables were measured by pletismographic methods. In addition, vasopressor sympathetic outflow was assessed by a pithed rat model. Last, sensorimotor impairments were evaluated by neuroscore test and beam-walking test. At seven, 14, 21, and 28 days after moderate-severe TBI, the animals showed: (1) a decrease on sensorimotor function in the neuroscore test and beam-walking test; (2) an increase in heart rate, systolic, diastolic, and mean blood pressure; (3) progressive sympathetic hyperactivity; and (4) a decrease in vasopressor responses induced by noradrenaline (α1/2-adrenoceptors agonist) and UK 14,304 (selective α2-adrenoceptor agonist). Interestingly, intraperitoneal daily injections of NaHS, an H2S donor (3.1 and 5.6 mg/kg), during seven days after TBI prevented the development of the impairments in hemodynamic variables, which were similar to those obtained in sham animals. Moreover, NaHS treatment prevented the sympathetic hyperactivity and decreased noradrenaline-induced vasopressor responses. No effects on sensorimotor dysfunction were observed, however. Taken together, our results suggest that H2S ameliorates the hemodynamic and sympathetic system impairments observed after TBI.

A Low-Cost Jamming Detection Approach Using Performance Metrics in Cluster-Based Wireless Sensor Networks.

Wireless Sensor Networks constitute an important part of the Internet of Things, and in a similar way to other wireless technologies, seek competitiveness concerning savings in energy consumption and information availability. These devices (sensors) are typically battery operated and distributed throughout a scenario of particular interest. However, they are prone to interference attacks which we know as jamming. The detection of anomalous behavior in the network is a subject of study where the routing protocol and the nodes increase power consumption, which is detrimental to the network's performance. In this work, a simple jamming detection algorithm is proposed based on an exhaustive study of performance metrics related to the routing protocol and a significant impact on node energy. With this approach, the proposed algorithm detects areas of affected nodes with minimal energy expenditure. Detection is evaluated for four known cluster-based protocols: PEGASIS, TEEN, LEACH, and HPAR. The experiments analyze the protocols' performance through the metrics chosen for a jamming detection algorithm. Finally, we conducted real experimentation with the best performing wireless protocols currently used, such as Zigbee and LoRa.

The impact of cell-of-origin, MYC/Bcl-2 dual expression and MYC rearrangement on disease relapse among early stage diffuse large B-cell lymphoma patients treated with combined modality therapy.

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiation therapy (RT) after a metabolic complete response to immunochemotherapy. With a median follow-up of 31.1 months (95% CI 27.4 - 34.8), 4 relapses occurred. The 3-year progression free survival (PFS), overall survival (OS), and loco-regional relapse free survival (LRFS) for the cohort were 95%, 96%, and 100%, respectively. There were no differences in OS, PFS, or LRFS based on COO or MYC/Bcl-2 dual expression (DE). Similarly, patients with MYC translocations without BCL2 or BCL6 rearrangements did not have worse outcomes. Consolidative RT produced excellent local control, regardless of DLBCL biology, with one late in-field failure.

Quantitative and Functional Analysis of PD-1+ NK Cells in Patients With Autoimmune Thyroid Disease.

CONTEXT: Natural killer (NK) cells have an important role in innate immunity and in the regulation of immune response. The role of NK cells expressing the programmed cell death protein-1 (PD-1) regulatory receptor has not been explored in patients with autoimmune thyroid disease (AITD). PURPOSE: To analyze the levels and function of PD-1+ NK cells in samples from AITD patients. DESIGN: Cases and controls, observational study. SETTING: Hospital Universitario la Princesa, Spain. PATIENTS: Forty patients with AITD, 16 with Hashimoto thyroiditis (HT), 24 with Graves' disease (GD), and 15 healthy controls. INTERVENTION: Multiparametric flow cytometry analysis of peripheral blood NK cells. In vitro assays of cytotoxic activity of NK cells, and synthesis of cytokines. MAIN OUTCOME MEASURES: Levels and function of PD-1+ NK cells in blood samples from AITD patients and controls. RESULTS: Increased levels of NK cells and the CD56dimPD-1+ subset were observed in GD patients. In HT, an enhanced expression of the regulatory receptors NKG2A and NKG2C by CD56brightPD-1+ NK cells was detected. AITD patients showed an increased synthesis of IL-10 by CD56brightPD-1- NK cells, whereas CD56dimPD-1+ cells from GD patients exhibited an enhanced production of interferon-γ. PD-1+ NK cells from patients with GD and HT showed an increased cytotoxic activity. Significant associations were observed in patients with GD or HT between the levels of PD-1+ NK cells and clinical laboratory parameters. CONCLUSIONS: The different abnormalities in NK cell subset levels, in the expression of PD-1 and its function in AITD patients' further support the complex role of these cells in this pathogenesis.

Altered NK cell receptor repertoire and function of natural killer cells in patients with acute myocardial infarction: A three-month follow-up study.

NK cells are important in the onset of acute myocardial infarction (AMI) by their ability to secrete IFN-γ and other inflammatory cytokines. They also participate in regulating pathological cardiac remodeling after myocardial infarction. Mechanisms of regulation, however, are incompletely understood. Herein, the aim of this study is to explore the possible association between the expression pattern of different NK cell receptors (phenotype), as well as the cytotoxic function of NK cells from AMI patients with their myocardial function after three months follow-up. We analyzed the phenotype and function of both CD56dimCD16+ and CD56brightCD16- NK cells from twenty-one patients within the first 72 h after ST-elevation AMI and three-month follow-up, as well as fifteen healthy controls. Clinical characteristics and ventricular function determined by echocardiography were also evaluated. NK cells from AMI patients showed an activated phenotype, characterized by high TNF-α production and low percentages of the activating receptor NKG2D. Interestingly, AMI patients display higher levels of circulating IL-10+ NK cells. Three-month follow-up showed that NK cells exhibit a diminished cytotoxic function. These data show that NK cells may have a role mediating myocardial remodeling by regulating the inflammatory response, mainly by the production of IL-10. We also propose that NKG2D may have a role in the onset of the inflammatory response immediately after AMI. The precise regulation of NK cells function may represent an important step in recovery of myocardial function.

Pre-treatment maximum standardized uptake value predicts outcome after frontline therapy in patients with advanced stage follicular lymphoma.

The impact of pre-treatment maximum standardized uptake value (SUVmax) on the outcome of follicular lymphoma (FL) following specific frontline regimens has not been explored. We performed a retrospective analysis of 346 patients with advanced stage follicular lymphoma (FL) without histological evidence of transformation, and analyzed the impact of SUVmax on outcome after frontline therapy. Fifty-two (15%) patients had a SUVmax >18, and a large lymph node ≥6 cm was the only factor associating with SUVmax >18 on multivariate analysis (odds ratio 2.7, 95% confidence interval [CI]: 1.3-5.3, P=0.006). The complete response rate was significantly lower among patients treated with non-anthracycline-based regimens if SUVmax was >18 (45% vs 92%, P<0.001), but not among patients treated with R-CHOP (P=1). SUVmax >18 was associated with significantly shorter progression-free survival among patients treated with non-anthracycline-based regimens (77 months vs. not reached, P=0.02), but not among patients treated with R-CHOP (P=0.73). SUVmax >18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (8-year OS 70% vs. 90%, P=0.02) and non-anthracycline-based frontline regimens (8-year OS 50% vs 85%, P=0.001). In conclusion, pre-treatment PET scan has prognostic and predictive value in patients with advanced stage FL receiving frontline treatment.

Inventory replenishment decision model for the supplier selection problem using metaheuristic algorithms.

In supply chain management, fast and accurate decisions in supplier selection and order quantity allocation have a strong influence on the company's profitability and the total cost of finished products. In this paper, a novel and non-linear model is proposed for solving the supplier selection and order quantity allocation problem. The model is introduced for minimizing the total cost per time unit, considering ordering, purchasing, inventory, and transportation cost with freight rate discounts. Perfect rate and capacity constraints are also considered in the model. Since metaheuristic algorithms have been successfully applied in supplier selection, and due to the non-linearity of the proposed model, particle swarm optimization (PSO), genetic algorithm (GA), and differential evolution (DE), are implemented as optimizing solvers instead of analytical methods. The model is tested by solving a reference model using PSO, GA, and DE. The performance is evaluated by comparing the solution to the problem against other solutions reported in the literature. Experimental results prove the effectiveness of the proposed model, and demonstrate that metaheuristic algorithms can find lower-cost solutions in less time than analytical methods.