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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.

Asunto(s)

Antineoplásicos , Compuestos de Bifenilo , Resistencia a Antineoplásicos , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ligando Inductor de Apoptosis Relacionado con TNF , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/uso terapéutico , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Especies Reactivas de Oxígeno/metabolismo , Distribución Tisular , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología

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BACKGROUND: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an apoptosis inducer that exhibits an ideal therapeutic safety profile with less adverse effects than conventional chemotherapy. However, the occurrence of TRAIL resistance has been reported in various cancers including colorectal cancer (CRC). Substantial efforts have been channelled towards managing TRAIL resistance including identifying molecular targets. Interleukins (ILs) have been recently shown to play critical roles in modulating TRAIL sensitivity in cancer cells. METHODS AND RESULTS: This study investigated the roles of two ILs, IL-8 and IL⍺, in TRAIL resistance in CRC. TRAIL-resistant HT-29 and TRAIL-sensitive HCT 116 cells, were treated with human recombinant IL-8 and IL-1⍺. The results indicated that treatment with IL-8 (2.5 ng/mL) significantly protected TRAIL-sensitive HCT 116 cells from TRAIL-induced cell death (p < 0.05). However, IL-1⍺ did not play a role in modulating CRC cells' responses to TRAIL. Data from RT-qPCR and Western blotting revealed the molecular regulations of IL-8 on TRAIL decoy receptor genes (OPG) and autophagy-related genes (BECN1 and LC3B) expression. The activation of the phosphoinositide 3-kinase (PI3K) pathway was shown to counteract TRAIL-induced cell death. By inhibiting its activation with wortmannin, the protective role of IL-8 against TRAIL treatment was reversed, suggesting the involvement of the PI3K pathway. CONCLUSION: Collectively, findings from this study identified the role of IL-8 and PI3K in modulating CRC cells' sensitivity to TRAIL. Further validation of these two potential molecular targets is warranted to overcome TRAIL resistance in CRC.

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Apoptosis , Neoplasias Colorrectales , Interleucina-8 , Fosfatidilinositol 3-Quinasas , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF , Humanos , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Interleucina-8/metabolismo , Interleucina-8/genética , Células HCT116 , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Células HT29 , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Muerte Celular/efectos de los fármacos

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The performance of photovoltaic (PV) modules is greatly impacted by dust accumulation and defects appearing in photovoltaic (PV) modules. Existing studies primarily focus on the effect of dust on general photovoltaic performance, neglecting the interactions with pre-existing defects such as snail trails. These defects are known to degrade the efficiency of PV modules. However, their interaction with environmental factors like dust accumulation has not been extensively analyzed. This research comprehensively analyzes the impact of dust accumulation on the performance of PV modules affected by snail trails. Using an experimental setup under outdoor conditions, the study incorporates thermal imaging, current-voltage characteristic curve tracing (IV curve tracing), electroluminescence (EL) imaging, and chemical analysis of the accumulated dust, to evaluate the electrical and thermal parameters affecting PV module performance. The study focuses on three types of modules, clean serves as a reference module (PV-R), normal unclean (PV-N), and snail trail-affected unclean PV module (PV-S). Compared to the PV-R module, the study meticulously quantifies the effect of accumulated dust on key performance indicators such as output power, V, and I. The PV-N module exhibits reductions of 17.7 % in current, 3.91 % in voltage, and 18.15 % in power output. The PV-S module experienced a decrease of 7.4 % in current, 7.55 % in voltage, and 14.87 % in power output under the dust deposition density of 6.984 g/m^2 having a mean particle size of 2.2279 µm. The dust deposition reduced the transmittance of glass, which indicates a potentially adverse impact on the PV module's efficiency. The findings highlighted in the current work provide a significant understanding of the detrimental impacts of dust accumulation on defected photo voltaic modules, highlighting the need for regular maintenance and cleaning to ensure optimal performance.

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Outdoor recreation has experienced a boom in recent years and continues to grow. While outdoor recreation provides wide-ranging benefits to human well-being, there are growing concerns about the sustainability of recreation with the increased pressures placed on ecological systems and visitor experiences. These concerns emphasize the need for managers to access accurate and timely recreation data at scales that match the growing extent of the recreation footprint. Here, we compare spatial and temporal patterns of winter and summer recreation using traditional (trail cameras, infrared counters, aerial surveys, participatory mapping) and application-based tools (Strava Metro, Strava Global Heatmap, Wikiloc) across the Columbia and Canadian Rocky Mountains of western Canada. We demonstrate how recreation use can be estimated using traditional and application-based tools, although their accuracy and utility varies across space, season and activity type. We found that trail cameras and infrared counters captured similar broad-scale patterns in count estimates of pedestrians and all recreation activities. Aerial surveys captured areas with low recreation intensity and participatory mapping captured coarser information on the intensity and extent of recreation across large spatial and temporal scales. Application-based data provided detailed spatiotemporal information on recreation use, but datasets were biased towards specific activities. Strava Metro data was more suited for capturing broad-scale spatial patterns in biking than pedestrian recreation. Application-based data should be supplemented with data from traditional tools to identify biases in data and fill in data gaps. We provide a comparison of each tool for measuring recreation use, highlight each tools' strengths and limitations and applications to address real-world monitoring and management scenarios. Our research contributes towards a better understanding of which tool, or combinations of tools, to use that can expand the rigor and scope of recreation research. These findings support decision-making to mitigate pressures on wildlife and their habitats while allowing for high-quality recreation experiences.

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Recreación , Humanos , Estaciones del Año , Canadá , Análisis Espacio-Temporal

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Background: Death Receptor 5 (DR5) is expressed on the surface of primary bone and soft tissue sarcoma cells, and its activation induces cell death primarily through apoptosis. The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death. Currently, clinical trials are investigating the effectiveness of DR5 activation using new biological agents, such as bi-specific or tetravalent antibodies, in improving the survival of patients with relapsed or refractory cancers. Furthermore, investigations continue into the use of novel combination therapies to enhance DR5 response, for example, with inhibitor of apoptosis protein (IAP) antagonist agents [such as the second mitochondria-derived activator of caspase (SMAC) mimetics] and with immune checkpoint inhibitor anti-programmed death-ligand 1 (anti-PD-L1) or anti-programmed cell death-1 (anti-PD-1) antibodies. Other therapies include nanoparticle-mediated delivery of TRAIL plasmid DNA or TRAIL mRNA and stem cells as a vehicle for the targeted delivery of anti-cancer agents, such as TRAIL, to the tumor. Methods: scoping review of the literature from November 2017 to March 2024, utilizing PubMed and Google Scholar. Results: New agents under investigation include nanoTRAIL, anti-Kv10.1, multimeric IgM, and humanized tetravalent antibodies. Developments have been made to test novel agents, and imaging has been used to detect DR5 in preclinical models and patients. The models include 3D spheroids, genetically modified mouse models, a novel jaw osteosarcoma model, and patient-derived xenograft (PDX) animal models. There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies. Conclusion: In vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.

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Background: This study evaluates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon-γ-induced protein-10 (IP-10) in pregnant women with COVID-19 and their newborns, exploring the effects of antiviral treatments and vaccine-induced neutralizing antibody (Nab) inhibition on these key viral infection biomarkers. Methods: We studied 61 pregnant women with past COVID-19 and either three (n=56) or four (n=5) doses of vaccination, and 46 without COVID-19 but vaccinated. We analyzed them and their newborns' blood for TRAIL, IP-10, and Nab levels using enzyme-linked immunosorbent assays (ELISA), correlating these with other clinical factors. Results: Our study found lower TRAIL but higher IP-10 levels in maternal blood than neonatal cord blood, irrespective of past COVID-19 diagnosis. Cases diagnosed with COVID-19 < 4 weeks previously had higher maternal blood TRAIL levels (16.49 vs. 40.81 pg/mL, p=0.0064) and IP-10 (154.68 vs. 225.81 pg/mL, p=0.0170) than those never diagnosed. Antiviral medication lowered TRAIL and IP-10 in maternal blood without affecting Nab inhibition (TRAIL: 19.24 vs. 54.53 pg/mL, p=0.028; IP-10: 158.36 vs. 255.47 pg/mL, p=0.0089). TRAIL and IP-10 levels were similar with three or four vaccine doses, but four doses increased Nab inhibition (p=0.0363). Previously COVID-19 exposed pregnant women had higher Nab inhibition (p < 0.0001). No obvious correlation was found among TRAIL, IP-10, and Nab inhibition level. Conclusions: Our study suggests that lower maternal TRAIL and higher IP-10 levels compared to neonatal cord blood coupled with a rise in both markers following COVID-19 diagnosis that could be reduced by antivirals indicates a correlation to infection severity. Higher vaccine doses enhance Nab inhibition, irrespective of antiviral medication use and independent of TRAIL or IP-10 levels, highlighting the significance and safety of adequate vaccination and antiviral use post-diagnosis in pregnant women.

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Anticuerpos Neutralizantes , COVID-19 , Quimiocina CXCL10 , Complicaciones Infecciosas del Embarazo , SARS-CoV-2 , Ligando Inductor de Apoptosis Relacionado con TNF , Humanos , Femenino , Embarazo , Quimiocina CXCL10/sangre , COVID-19/inmunología , COVID-19/prevención & control , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Adulto , Ligando Inductor de Apoptosis Relacionado con TNF/sangre , SARS-CoV-2/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/sangre , Recién Nacido , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Biomarcadores/sangre , Sangre Fetal/inmunología , Vacunación

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Introduction: The vestibular system's contribution to spatial learning and memory abilities may be clarified using the virtual Morris Water Maze Task (vMWMT). This is important because of the connections between the vestibular system and the hippocampus area. However, there is ongoing debate over the role of the vestibular system in developing spatial abilities. This study aimed to evaluate the relationship between Dynamic Visual Acuity (DVA) across three planes and spatial abilities. Methods: This cross-sectional study was conducted with 50 healthy adults aged 18 to 55 with normal stress levels and mental health and no neurological, audiological, or vestibular complaints. The Trail-Making Test (TMT) Forms A and B for the assessment of executive functions, the DVA test battery for the evaluation of visual motor functions, and the Virtual Morris Water Maze Test (vMWMT) for the assessment of spatial learning and spatial memory were performed. All participants also underwent the Benton Face Recognition Test (BFRT) and Digit Symbol Substitution Tests (DSST) to assess their relation with spatial memory. Results: DVA values in horizontal (H-DVA), vertical (V-DVA), and sagittal (S-DVA) planes ranged from (-0.26) to 0.36 logMAR, (-0.20) to 0.36 logMAR, and (-0.28) to 0.33 logMAR, respectively. The latency of three planes of DVA was affected by vMWMT (Horizontal, Vertical, and Sagittal; Estimate: 22.733, 18.787, 13.341, respectively p < 0.001). Moreover, a moderately significant correlation was also found, with a value of 0.571 between the Virtual MWM test and BFRT and a value of 0.539 between the DSST (p < 0.001). Conclusion: Spatial abilities in healthy adults were significantly influenced by dynamic visual functions across horizontal, vertical, and sagittal planes. These findings are expected to trigger essential discussions about the mechanisms that connect the vestibular-visual system to the hippocampus. The original vMWMT protocol is likely to serve as a model for future studies utilizing this technology.

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In the realm of modern healthcare, Electronic Health Records EHR serve as invaluable assets, yet they also pose significant security challenges. The absence of EHR access auditing mechanisms, which includes the EHR audit trails, results in accountability gaps and magnifies security vulnerabilities. This situation effectively paves the way for unauthorized data alterations to occur without detection or consequences. Inadequate EHR compliance auditing procedures, particularly in verifying and validating access control policies, expose healthcare organizations to risks such as data breaches, and unauthorized data usage. These vulnerabilities result from unchecked unauthorized access activities. Additionally, the absence of EHR audit logs complicates investigations, weakens proactive security measures, and raises concerns to put healthcare institutions at risk. This study addresses the pressing need for robust EHR auditing systems designed to scrutinize access to EHR data, encompassing who accesses it, when, and for what purpose. Our research delves into the complex field of EHR auditing, which includes establishing an immutable audit trail to enhance data security through blockchain technology. We also integrate Purpose-Based Access Control (PBAC) alongside smart contracts to strengthen compliance auditing by validating access legitimacy and reducing unauthorized entries. Our contributions encompass the creation of audit trail of EHR access, compliance auditing via PBAC policy verification, the generation of audit logs, and the derivation of data-driven insights, fortifying EHR access security.

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Foraging for resources is an essential process for the daily life of an ant colony. What makes this process so fascinating is the self-organization of ants into trails using chemical pheromone in the absence of direct communication. Here we present a stochastic lattice model that captures essential features of foraging ant dynamics inspired by recent agent-based models while forgoing more detailed interactions that may not be essential to trail formation. Nevertheless, our model's results coincide with those presented in more sophisticated theoretical models and experiments. Furthermore, it captures the phenomenon of multiple trail formation in environments with multiple food sources. This latter phenomenon is not described well by other more detailed models. We complement the stochastic lattice model by describing a macroscopic PDE which captures the basic structure of lattice model. The PDE provides a continuum framework for the first-principle interactions described in the stochastic lattice model and is amenable to analysis. Linear stability analysis of this PDE facilitates a computational study of the impact various parameters impart on trail formation. We also highlight universal features of the modeling framework that may allow this simple formation to be used to study complex systems beyond ants.

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Hormigas , Conducta Alimentaria , Modelos Biológicos , Procesos Estocásticos , Hormigas/fisiología , Animales , Conducta Alimentaria/fisiología , Feromonas/metabolismo , Feromonas/fisiología , Simulación por Computador , Conceptos Matemáticos

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This case report discusses three developmental vascular anomalies (DVAs) observed in adults and highlights the challenges related to the diagnosis and management. Even though detected at early ages, diagnostic difficulties are observed in the adult age due to the scarcity and diverse clinical features. These cases illustrate the necessity of a multidisciplinary approach involving clinicians and radiologists for precise and prompt diagnosis in adults, where misdiagnosis and delays in intervention are frequent. The cases comprised a 17-year-old female with an absent right pulmonary artery and mitral stenosis, a 46-year-old female with chronic obstructive pulmonary disease (COPD), with an absent left pulmonary artery, and a 60-year-old female with bronchial asthma and tuberculosis exhibiting a rare DVA. This discussion highlights the importance of intensified clinical suspicion and thorough evaluation for the cases of unexplained respiratory symptoms and abnormal image findings in patients, which can further provide the medical community with valuable insights.

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BACKGROUND: Alzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aß) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aß plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aß oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. METHODS: Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aß1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aß-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aß-treated HEBSCs. RESULTS: Neurotoxicity induced by soluble Aß1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aß-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aß neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aß as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aß-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aß-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. CONCLUSION: Microglia are key mediators of both protection and neurodegeneration in response to Aß. Polarizing microglia toward a protective state could be used as a preventative strategy against Aß-induced neurotoxicity.

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Péptidos beta-Amiloides , Microglía , Fragmentos de Péptidos , Ligando Inductor de Apoptosis Relacionado con TNF , Microglía/metabolismo , Microglía/efectos de los fármacos , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Animales , Fragmentos de Péptidos/toxicidad , Fragmentos de Péptidos/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/toxicidad , Ratones , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Corteza Entorrinal/metabolismo , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/patología , Técnicas de Cultivo de Órganos

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PURPOSE: To study whether, during typical-level running, non-rear-foot strikers (non-RFS) or rear-foot strikers (RFS) presented a similar or different extent of neuromuscular fatigue after a prolonged graded run. METHODS: Sixteen experienced male trail runners (8 non-RFS and 8 RFS) performed a 2.5-hour treadmill graded running exercise. Before and after exercise, neuromuscular tests were performed to assess neuromuscular fatigue of the plantar flexors. Biomechanical gait parameters were acquired with an instrumented treadmill, and electromyographic activity of the lower-limb muscles was collected as an index of muscle activation. RESULTS: There were no significant time × foot strike interactions for neuromuscular (all P ≥ .742), muscle activation (all P ≥ .157), or biomechanical (all P ≥ .096) variables. CONCLUSIONS: A dominant level running foot-strike pattern did not directly affect the extent of neuromuscular fatigue during a prolonged graded run. This suggests that no ideal running foot-strike pattern exists to minimize neuromuscular fatigue during prolonged-duration races wherein cumulative uphill and downhill segments are high, such as in trail running.

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The liver requires careful handling intra-operatively owing to its vital functions and complexity. Traditional open hepatectomy, while standard, is invasive and requires long recovery periods. Laparoscopic hepatectomy is a less invasive option, with its own challenges. The rise of robotic surgery, such as the da Vinci® system, improves precision and control, addressing the limitations of conventional methods, but brings new concerns, such as costs and training. This review focuses on the latest advancements in robotic hepatectomy from 2022/23 articles, delving into topics like "robotic surgery in liver transplantation," "robotic hepatectomy for hilar cholangiocarcinoma," "robotic vascular reconstruction following hepatectomy," "robotic repeat hepatectomy," and "prospective trials in robotic hepatectomy." To retrieve articles, a focused literature search was conducted using PubMed for articles from 2022/23 with a 5-year filter, excluding reviews. Initially, abstracts were screened, and relevant articles on robotic surgery were examined in full for inclusion in this review. Although all the above items are cutting-edge, and many of the references are necessarily at the level of case reports, recent articles are still accompanied by surgical videos, which are useful to readers, especially surgeons who are considering imitating the procedures. In summary, we examined the recent advancements in robotic liver resection. The inclusion of videos that present new techniques aids in knowledge transfer. We anticipate the continued growth of this field of research.

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Background and aim The deltoid is a common site for intramuscular injections, but guidelines for administration lack standardization. Global researchers propose various techniques, and recent study reports indicate a 1.5-15% incidence of nerve palsies due to injections. This pilot cadaveric study aimed to standardize the deltoid intramuscular injection sites in the Southeast Asian population. Methods This cadaveric study of a two-year duration was conducted in the Department of Anatomy as an intramural research project in collaboration with the Departments of Anatomy and Orthopedics. In the first year of study, which was the pilot phase of the project, the available six cadavers, i.e., 12 upper extremity specimens were dissected. Anthropometric measurements of deltoid muscle along with the distance of underlying neurovascular structures like the axillary nerve and posterior circumflex humeral artery were measured from neighboring bony landmarks. This article presents the observations of the six cadavers studied in the pilot phase and shall be followed up by another article after the project. Results In adults, in anatomical position, the mean distances of the axillary nerve and posterior circumflex humeral artery from the mid-acromial point are 8.19±0.616 and 8.66±0.968 cm, respectively. The deltoid thickness at 3, 5, and 7 cm from mid-acromial point was observed to be 1.079±0.13 cm (0.5-1.78 cm), 1.599±0.12 cm (1-2.96 cm), and 1.815±1.0 cm (1.2-2.5 cm), respectively. The acquired qualitative and quantitative data were tabulated, graphically represented, and statistically analyzed. Conclusions The deltoid intramuscular injection (IMI) must be given at or below the level of the midpoint of the deltoid muscle, but never in the upper half. We recommend a site, 4 fingerbreadths/9 cm below the mid-acromion point as the safest site to avoid injury to any underlying neurovascular structures.

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as APO2L, has emerged as a highly potential anticancer agent because of its capacity to effectively trigger apoptosis in tumor cells by specifically binding to either of its death receptors (DR4 or DR5) while having no adverse effects on normal cells. Nevertheless, its practical use has been hindered by its inefficient pharmacokinetics characteristics, the challenges involved in its administration and delivery to targeted cells, and the resistance exhibited by most cancer cells towards TRAIL. Gene therapy, as a promising approach would be able to potentially circumvent TRAIL-based cancer therapy challenges mainly through localized TRAIL expression and generating a bystander impact. Among different strategies, using nanoparticles in TRAIL gene delivery allows for precise targeting, and overcoming TRAIL resistance by combination therapy. In this review, we go over potential mechanisms by which cancer cells achieve resistance to TRAIL and provide an overview of different carriers for delivering of the TRAIL gene to resistant cancer cells, focusing on different types of nanoparticles utilized in this context. We will also explore the challenges, and investigate future perspectives of this nanomedicine approach for cancer therapy.

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BACKGROUND: Among the older population, Parkinson disease (PD) stands out as a leading contributor to disability. Clinically, the foremost objectives in managing PD involve proactively delaying and preventing disability. Understanding the pivotal role of gait and balance in daily functionality holds substantial clinical significance, signaling imminent disability and prompting a reevaluation of management approaches. A key priority lies in identifying novel and effective interventions for symptoms that substantially contribute to disability. OBJECTIVE: This paper presents a systematic review that critically examines the existing body of literature on the use of technology in the rehabilitation of older patients with PD. By synthesizing current evidence, we aim to provide insights into the state of the field, identify gaps in knowledge, and offer recommendations for future research and clinical practice. METHODS: A systematic review of the literature was conducted in September 2023 analyzing manuscripts and papers of the last 5 years from the PubMed, Scopus, Embase, Web of Science, and CINAHL databases following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 14 papers were included. The inclusion criteria are as follows: (1) randomized controlled trial, (2) PD in people aged 65 years and older, and (3) use of technology in the rehabilitation training in the older population. RESULTS: A large portion of effective interventions relies on the incorporation of technology, particularly through virtual reality exergames. This technology appears to have effects not only on the cognitive aspect but also on the physical domain. The analysis of the results clearly indicates that, in terms of gait and balance performance, the technological intervention outperforms the traditional approach, irrespective of the specific technology employed. CONCLUSIONS: This systematic review seeks to shed light on the evolving landscape of technology-assisted rehabilitation for older individuals with PD. As we delve into the available evidence, we will assess the extent to which technology can serve as a valuable adjunct to conventional therapy, offering new avenues for optimized care and improved outcomes in this growing patient demographic. As we sift through the existing evidence, our goal is to evaluate the potential of technology as a valuable supplement to traditional therapy, presenting fresh opportunities for enhanced care and better outcomes in this expanding patient demographic.

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AIMS: Clinical data demonstrate that metformin exhibits antiproliferative, proapoptotic and antimetastatic actions. Here, correlative molecular studies were undertaken to determine the roles of transmembrane tumour necrosis factor-related apoptosis-inducing ligand death receptors (DRs) and CD133, a glycoprotein biomarker of breast cancer (BC) stem cells, in the advantageous action of metformin on pathological and clinical outcomes in BC patients on neoadjuvant chemotherapy. METHODS: We randomly assigned 70 nondiabetic BC patients in a 1:1 ratio to either neoadjuvant AC-T chemotherapy (4 cycles of adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2, followed by 12 cycles of weekly paclitaxel 80 mg/m2) or AC-T with adjunct metformin (850 mg twice/day). The expressions of DR4, DR5 and CD133 were quantified in excised tissue samples with residual tumour cells. RESULTS: The overall clinical response (odds ratio: 22.67 [2.77-185.18], P = .004), breast-conserving surgery (odds ratio: 3.67 [1.303-10.321], P = .014) and pathological complete response (ß = 2.49 ± 1.13 [0.274-4.712], P = .028) rates were significantly improved in the metformin arm. Tissues obtained from the metformin arm had upregulated mRNA expression of DR4 (Mean delta cycle thresholds ± standard error of the mean: 2.68 ± 0.25 vs. 4.87 ± 0.53, P = .0003) and DR5 (0.21 ± 0.25 vs. 4.29 ± 0.95, P = .0004) compared to control arm. The enhanced DR expression negatively correlated with that of CD133 + BC stem cells, which was significantly reduced by metformin at both cytoplasmic/membranous (43.48 vs. 100.00%, P < .0001) and nuclear sites (4.35 vs. 95.00%, P < .0001). CONCLUSION: Metformin improves clinical and pathological responses to neoadjuvant AC-T chemotherapy in BC via prompting directionally opposite changes in DRs (increments) and CD133 + (decrements) expressions. This study was registered in ClinicalTrials.gov (registration number: NCT04170465, https://clinicaltrials.gov/ct2/show/NCT04170465).

RESUMEN

The trail making test (TMT) is a commonly used tool for evaluating executive functions, and the activation of cerebral oxygenation in the prefrontal cortex (PFC) during the test can reflect the participation of executive function. This study aimed to compare the differences in cerebral oxygenation in the PFC between the computer- and paper-based versions of the TMT and provide a theoretical basis for the optimization and clinical application of the computer-based version. A total of 32 healthy adult participants completed the computer- and paper-based TMT Types A and B. Cerebral oxygenation changes in the PFC were monitored during the experiment using near-infrared spectroscopy. Moreover, average changes in oxyhemoglobin (Δoxy-Hb) levels at the baseline and during activation periods in different types of testing were compared and analyzed. The number of correct connections in the computer-based version Type B was less than that in the paper-based version Type B (p < .001). The task time of the computer-based version was longer than that of the paper-based version (p < .001). The B/A ratio of the number of correct connections in the computer-based version was lower than that in the paper-based version (p < .001). The Δoxy-Hb in the PFC of the paper-based version was higher than that of the computer-based version (p < .001). Significant differences in oxygenation in the PFC were observed between the paper- and computer-based versions of TMT. After further improvement and correction in the subsequent development of the computer-based TMT, and taking into account the psychological feelings and preferences of the participants when performing different versions of the TMTs, the computer-based TMT is expected to play a good auxiliary role in clinical evaluation.

Asunto(s)

Corteza Prefrontal , Espectroscopía Infrarroja Corta , Prueba de Secuencia Alfanumérica , Humanos , Corteza Prefrontal/metabolismo , Masculino , Femenino , Espectroscopía Infrarroja Corta/métodos , Adulto Joven , Adulto , Oxígeno/metabolismo , Oxígeno/sangre , Función Ejecutiva/fisiología , Oxihemoglobinas/metabolismo , Oxihemoglobinas/análisis

RESUMEN

INTRODUCTION: Memory deficits are the primary symptom in amnestic Mild Cognitive Impairment (aMCI); however, executive function (EF) deficits are common. The current study examined EF in aMCI based upon amyloid status (A+/A-) and regional atrophy in signature areas of Alzheimer's disease (AD). METHOD: Participants included 110 individuals with aMCI (A+ = 66; A- = 44) and 33 cognitively healthy participants (HP). EF was assessed using four neuropsychological assessment measures. The cortical thickness of the AD signature areas was calculated using structural MRI data. RESULTS: A + had greater EF deficits and cortical atrophy relative to A - in the supramarginal gyrus and superior parietal lobule. A - had greater EF deficits relative to HP, but no difference in signature area cortical thickness. DISCUSSION: The current study found that the degree of EF deficits in aMCI are a function of amyloid status and cortical thinning in the parietal cortex.

RESUMEN

Decision-making under unpredictable conditions can cause discomfort in autistic persons due to their preference for predictability. Decision-making impairments might furthermore be associated with a dysregulation of sex and stress hormones. This prospective, cross-sectional study investigated decision-making in 32 autistic participants (AP, 14 female) and 31 non-autistic participants (NAP, 20 female) aged 18-64 years. The Iowa Gambling Task (IGT) and the Cambridge Risk Task (CRT) were used to assess decision-making under ambiguity and under risk with known outcome probabilities, respectively. Cortisol, estradiol, and testosterone serum levels were related to decision-making performance. Groups did not differ in overall IGT and CRT performance, but compared with NAP, AP preferred less profitable card decks with predictable outcomes while avoiding those with unpredictable outcomes. AP required more time to reach decisions compared to NAP. Additionally, AP without comorbid depression performed significantly worse than NAP in the IGT. Estradiol and cortisol concentrations were significant predictors of CRT scores in NAP, but not in AP. The study results imply that AP are 'risk-averse' in decision-making under ambiguity as they avoided choice options with unpredictable losses in comparison to NAP. Our findings highlight the intolerance for uncertainty, particularly in ambiguous situations. Thus, we recommend being as transparent and precise as possible when interacting with autistic individuals. Future research should explore decision-making in social situations among individuals with ASD, factoring in person-dependent variables such as depression.