Revista De Investigacion Clinica-Clinical and Translational Investigation最新文献

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown.

Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling.

Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins.

Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC.

Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling.

The development of hemodialysis (HD) membranes has substantially advanced in the last decade. This has resulted in the manufacturing of medium cut-off membranes (MCO) whose internal architecture is based on greater pore size and a smaller diameter, thus promoting the clearance of particles of greater size as well as retrofiltration. Multiple studies have proven their efficacy in the clearance of uremic mid-sized molecules such as β2-microglobulin, free light chains, and some interleukins; this clearance is far superior with MCO membranes when compared with high-flux HD, and similar to that obtained with online hemodiafiltration. This review summarizes the results of the most relevant clinical studies of this membrane in terms of uremic toxin clearance, as well as the features of some clinical outcomes such as quality of life and hospitalizations.

Membranes and sorbents play a crucial role in extracorporeal blood purification therapies, which aim to remove harmful molecules and toxins from the blood. Over the years, advancements in hemodialysis (HD) membranes and sorbents have significantly enhanced their safety and effectiveness. This review article will summarize the latest breakthroughs in the development and clinical application of HD membranes and sorbents. We will commence with a concise examination of the mechanisms involved in solute transport across membranes and sorbents. Subsequently, we will explore the evolutionary path of HD membranes, from early cellophane membranes to high-flux membranes, including the development of high-cutoff membranes and the emergence of medium- cutoff membranes. We will discuss each type of HD membrane's advantages and limitations, highlighting the most promising advancements in novel biomaterials and biocompatibility, technologies, research in membrane performance, and their clinical applications. Furthermore, we will delve into the evolution and progress of sorbent technology, tracing its historical development, outlining its key characteristics, examining the mechanism involved in the adsorption process, and exploring its clinical application. This review aims to underscore the growth and future landscape of HD membranes and sorbents in extracorporeal blood purification techniques.

Artificial intelligence (AI) generative models driven by the integration of AI and natural language processing technologies, such as OpenAI's chatbot generative pre-trained transformer large language model (LLM), are receiving much public attention and have the potential to transform personalized medicine. Dialysis patients are highly dependent on technology and their treatment generates a challenging large volume of data that has to be analyzed for knowledge extraction. We argue that, by integrating the data acquired from hemodialysis treatments with the powerful conversational capabilities of LLMs, nephrologists could personalize treatments adapted to patients' lifestyles and preferences. We also argue that this new conversational AI integrated with a personalized patient-computer interface will enhance patients' engagement and self-care by providing them with a more personalized experience. However, generative AI models require continuous and accurate updates of data, and expert supervision and must address potential biases and limitations. Dialysis patients can also benefit from other new emerging technologies such as Digital Twins with which patients' care can also be addressed from a personalized medicine perspective. In this paper, we will revise LLMs potential strengths in terms of their contribution to personalized medicine, and, in particular, their potential impact, and limitations in nephrology. Nephrologists' collaboration with AI academia and companies, to develop algorithms and models that are more transparent, understandable, and trustworthy, will be crucial for the next generation of dialysis patients. The combination of technology, patient-specific data, and AI should contribute to create a more personalized and interactive dialysis process, improving patients' quality of life.

Home hemodialysis (HD) and automated peritoneal dialysis (APD) have advantages over HD in hospitals or HD centers. Home therapies are generally less expensive and give patients greater mobility and freedom for work, school, family, and recreational activities. Technological advances have made it possible to complement APD with devices for remote monitoring (RM) of the patient. With them, objective information generated in the APD device is collected and sent to repositories "in the cloud" for analysis or at the time decided by the health team. With APD+RM, it is possible to monitor therapeutic compliance, effective dialysis time, ultrafiltration volumes, inflow and outflow patterns of dialysis fluid, and patient actions to respond to alarms that indicate deviations from the parameters set by the nephrologist. The results of APD+RM show good acceptance by the patient, nephrologists, and nurses, treatment adherence has improved, hospitalizations and technique failure have decreased, and some aspects of quality of life have improved. However, there is a lack of controlled clinical trials that reliably demonstrate lower mortality and comorbidity due to specific causes.

Blood purification as an adjunctive therapy has been studied for several decades. In this review, we will focus on the most recent studies, particularly on adsorption techniques. These include hemofilters with adsorptive membranes, both endotoxin-specific and non-specific. In addition, we will discuss sorbents that target endotoxins, as well as devices that non-selectively capture viruses and bacteria. For each technique, we will also explore the reasons why blood purification methods have thus far failed to improve survival. Conventionally, reasons for the lack of success in blood purification techniques have been attributed to the need for better patient stratification through bedside measurements of interleukins and endotoxins. The choice of assay is also crucial, with endotoxin activity assays being preferable to other forms of limulus amoebocyte lysate assays. Another critical factor is timing, as administering blood purification at the wrong moment can potentially harm the patient. Mechanistic studies are still lacking for most devices, leaving us to treat patients blindly, except in endotoxin cases. In the context of viruses, especially COVID-19, we require a deeper understanding of the complexities involved in viral replication, as this could significantly impact the efficacy of blood purification techniques. The failures highlighted for each device should be viewed as potential areas for improvement. Despite the challenges, we remain hopeful that these techniques will eventually succeed and prove beneficial in the future.

Background: Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a novel inflammatory biomarker which has been associated with cardiovascular diseases.

Objective: To study MHR in patients with psoriasis treated with biological agents.

Methods: Between April 2019 and August 2022, MHR was retrospectively evaluated in patients with psoriasis before and 3 months after treatment with infliximab, adalimumab, etanercept, ixekizumab, secukinumab, and ustekinumab in a university hospital in Ankara, Turkey.

Results: This study included 128 patients, 53 females and 75 males. 39 (30.5%) patients were treated with infliximab, 26 (20.3%) with adalimumab, 8 (6.3%) with etanercept, 18 (14.1%) with ixekizumab, 12 (9.4%) with secukinumab, and 25 (19.5%) with ustekinumab. The median MHR was 0.0127 (0.0086-0.0165) in females and 0.0146 (0.0119-0.0200) in males (p = 0.011). The median MHR decreased after treatment with adalimumab, ixekizumab, secukinumab, and ustekinumab, whereas it increased after treatment with infliximab and etanercept (p = 0.790, p = 0.015, p = 0.754, p = 0.221, p = 0.276, p = 0.889, respectively).

Conclusion: MHR significantly decreased in patients with psoriasis after treatment with ixekizumab. Since high MHR levels have been associated with poor clinical outcomes in patients with cardiovascular diseases, ixekizumab might have a positive impact in the treatment of psoriasis patients who had cardiovascular diseases. We suggest that MHR may be useful both in establishing appropriate biological agent treatment and in the follow-up of patients with psoriasis treated with biological agents.

Background: Reduced or null expression of E-cadherin protein is a frequent cause of diffuse gastric cancer (DGC). More than 50% of patients with DGC present somatic variants in CDH1 gene.

Objectives: The objectives of this study were to study E-cadherin expression and identify variants in the CDH1 gene in gastric tumors of patients with DGC.

Methods: We studied 18 Mexican DGC patients who attended a hospital of the Mexican Social Security Institute; E-cadherin expression was determined by immunohistochemistry, and variants were identified by Sanger sequencing in promoter and coding regions. Predictive analysis was performed using PolyPhen-2 and HOPE software.

Results: We found that 56% of DGC patients showed reduced expression of E-cadherin. All patients carried CDH1 variants; overall, 12 different CDH1 variants were identified. Predictive analysis revealed that the rs114265540 variant was probably damaging, with a value of 0.985, indicating a functional impact on the E-cadherin protein. Variants rs34939176 and rs33964119 were identified as risk factors for DGC (odds' ratios [OR] = 31.3, 95% CI 6.3-154.0, p < 0.001; OR = 6.1, 95% CI 2.0-19.0, p < 0.001, respectively) given their elevated frequency and by comparing it with those reported for MXL population in the 1000 Genomes Project database.

Conclusions: In this Mexican population, the percentage of diffuse gastric tumors with reduced expression of E-cadherin was similar to that reported in other populations. All gastric tumors of DGC patients studied had somatic CDH1 gene variants; however, the rs114265540, rs34939176, and rs33964119 variants were importantly related to DGC.

Background: The values of arterial blood gases (ABG) change with altitude above sea level; empirical verification is essential because ventilatory acclimatization varies with ethnicity and a population's adaptation.

Objective: The aim of the study was to describe ABG in a healthy population residing at 2,240 meters above sea level, to identify the mean level of alveolar ventilation (PaCO₂), and to know whether a progressive increase in PaCO₂ occurs with age and the impact of increasing body mass index (BMI).

Methods: We conducted a cross-sectional study in a referral center for respiratory diseases in Mexico City. Associations among variables with correlation coefficient and regression models of PaO₂, SaO₂, and P(A-a)O₂ as dependent variables as a function of age, BMI, minute ventilation, or breathing frequency were explored.

Results: Two hundred and seventeen healthy subjects were evaluated with a mean age of 40 ± 15 years, mean of the PaO₂ was 71 ± 6 mmHg, SaO₂ 94% ± 1.6%, PaCO₂ 30.2 ± 3.4 mmHg, HCO₃ 20 ± 2 mmol/L, BE-2.9 ± 1.9 mmol/L, and the value of pH was 7.43 ± 0.02. In a linear regression, the main results were PaO₂ = 77.5-0.16*age (p < 0.0001) and with aging P(A-a)O₂ tended to increase 0.12 mmHg/year. PaCO₂ in women increased with age by 0.075 mmHg/year (p = 0.0012, PaCO₂ =26.3 + 0.075*age). SaO₂ and PaO₂ decreased significantly in women with higher BMI 0.14% and 0.52 mmHg per kg/m², (p = 0.004 and 0.002 respectively).

Conclusion: Mean PaCO₂ was 30.7 mmHg, implying a mean alveolar ventilation of around 30% above that at sea level.