Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances
. Recent molecular characterization has defined new (epi)genetic drivers and potential targets ...for bladder cancer
. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients
. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten
; Trp53
; Rb1
; Rbl1
) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
Uncontrolled donation after circulatory death (uDCD) increases organ availability for kidney transplant (KT) with short‐term outcomes similar to those obtained from donation after brain death (DBD) ...donors. However, heterogeneous results in the long term have been reported. We compared 10‐year outcomes between 237 KT recipients from uDCD donors maintained by normothermic extracorporeal membrane oxygenation (nECMO) and 237 patients undergoing KT from standard criteria DBD donors during the same period at our institution. We further analyzed risk factors for death‐censored graft survival in the uDCD group. Delayed graft function (DGF) was more common in the uDCD group (73.4% vs 46.4%; P < .01), although glomerular filtration rates at the end of follow‐up were similar in the 2 groups. uDCD and DBD groups had similar rates for 10‐year death‐censored graft (82.1% vs 80.4%; P = .623) and recipient survival (86.2% vs 87.6%; P = .454). Donor age >50 years was associated with graft loss in the uDCD group (hazard ratio: 1.91; P = .058), whereas the occurrence of DGF showed no significant effect. uDCD KT under nECMO support resulted in similar graft function and long‐term outcomes compared with KT from standard criteria DBD donors. Increased donor age could negatively affect graft survival after uDCD donation.
Kidney transplant recipients from uncontrolled donation after circulatory death donors preserved with normothermic extracorporeal membrane oxygenation have long‐term outcomes comparable to recipients from standard criteria donation after brain death donors.
Chicha morada, also known as purple corn drink (PCD), is a traditional noncarbonated beverage commonly prepared at homes and restaurants in Peru. However, in recent years, it is being produced at an ...industrial scale aiming to extend its shelf life, expand its marketing, and make it known worldwide. Traditionally, this beverage, whose main component is purple corn (Zea mays L.), was made and consumed quickly and in some cases, stored under refrigeration until consumption, but never beyond 24 to 48 h. With its industrialization, factories are presented with challenges to design and provide adequate protection of the beverage, assuring its quality and safety. Although its production at an industrial level is similar to that of other noncarbonated drinks containing fruit juice, several processing factors could affect the microbiological stability desired for this beverage, such as the storage of the purple corn drink extract. In this document, a critical review of the production process (raw materials, production stages, and forms of commercialization) that can directly affect the contamination of the beverage is made. Recommendations are made for improving the control points in the industrial process and to avoid potential microbiological problems.
El presente artículo analiza, desde una perspectiva cuantitativa y cualitativa, el activismo académico y sociocultural de los profesionales quechuas en la revaloración y fortalecimiento del quechua ...en Áncash, Perú. El quechua ancashino es una de las variedades mayores del quechua central, tanto geográfica como demográficamente; sin embargo, los estudios reportan la disminución progresiva de quechuahablantes. Sobre la base del desarrollo de la educación intercultural bilingüe, los académicos quechuas organizados en colectivos quechuas empezaron con un trabajo integral en el estudio lingüístico y sociolingüístico del quechua, enseñanza de la lengua, producción de materiales y desarrollo de eventos académicos. Estas acciones han posibilitado un inusitado interés de los quechuas ancashinos y sus descendientes por retomar la lengua originaria, así como de los castellanohablantes por aprender el quechua e identificarse con las manifestaciones culturales quechuas. Hoy en Áncash, en el escenario de la globalización y modernización, se vive una coyuntura de mayor visibilización, revaloración y fortalecimiento del quechua.
Bladder cancer is a current clinical and social problem. At diagnosis, most patients present with nonmuscle-invasive tumors, characterized by a high recurrence rate, which could progress to ...muscle-invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in bladder cancer is still unclear.
Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed
by experiments with bladder cancer cell lines and peripheral blood monocyte-derived macrophages.
We observed
expression is associated and favored type II macrophage differentiation.
experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL10. Using a series of human bladder cancer patient samples, we also observed increased expression of
in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced
expression.
These findings suggest that BMP4 secretion by bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of
by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth.
.
The risk of fungal spoilage of sports drinks produced in the beverage industry was assessed using quantitative microbial spoilage risk assessment (QMSRA). The most relevant pathway was the ...contamination of the bottles during packaging by mould spores in the air. Mould spores' concentration was estimated by longitudinal sampling for 6 years (936 samples) in different production areas and seasons. This data was analysed using a multilevel model that separates the natural variability in spore concentration (as a function of sampling year, season, and area) and the uncertainty of the sampling method. Then, the expected fungal contamination per bottle was estimated by Monte Carlo simulation, considering their settling velocity and the time and exposure area. The product's shelf life was estimated through the inoculation of bottles with mould spores, following the determination of the probability of visual spoilage as a function of storage time at 20 and 30 °C using logistic regression. The Monte Carlo model estimated low expected spore contamination in the product (1.7 × 10−6 CFU/bottle). Nonetheless, the risk of spoilage is still relevant due to the large production volume and because, as observed experimentally, even a single spore has a high spoilage potential. The applicability of the QMSRA during daily production was made possible through the simplification of the model under the hypothesis that no bottle will be contaminated by more than one spore. This simplification allows the calculation of a two-dimensional performance objective that combines the spore concentration in the air and the exposure time, defining “acceptable combinations” according to an acceptable level of spoilage (ALOS; the proportion of spoiled bottles). The implementation of the model at the operational level was done through the representation of the simplified model as a two-dimensional diagram that defines acceptable and unacceptable areas. The innovative methodology employed here for defining and simplifying QMSRA models can be a blueprint for future studies aiming to quantify the risk of spoilage of other beverages with a similar scope.
•A quantitative microbial spoilage risk assessment in a beverage factory was developed.•A Gamma-Poisson model for mould concentration in the air separated measurement error from variability.•Contamination with even a single mould spore should be avoided in the beverage.•The model predicts that less than one bottle per million would be contaminated.•A diagram defining acceptable zones is created to facilitate quality management.
Bacillus Calmette-Guérin (BCG) has been the standard of care for the treatment of high-risk, non-muscle-invasive bladder cancer (NMIBC) for decades, but 49.6% of high-risk and very-high-risk patients ...will experience progression to muscle-invasive disease in five years. Furthermore, cytology and cystoscopy entail a high burden for both patients and health care systems due to the need for very long periods of follow-up. Subsequent adjuvant treatment using intravesical immunotherapy with BCG has been shown to be effective in reducing tumor recurrence and progression, but it is not free of severe adverse effects that ultimately diminish patients' quality of life. Because not all patients benefit from BCG treatment, it is of paramount importance to be able to identify responders and non-responders to BCG as soon as possible in order to offer the best available treatment and prevent unnecessary adverse events. The tumor microenvironment (TME), local immune response, and systemic immune response (both adaptive and innate) seem to play an important role in defining responders, although the way they interact remains unclear. A shift towards a proinflammatory immune response in TME is thought to be related to BCG effectiveness. The aim of this review is to collect the most relevant data available regarding BCG's mechanism of action, its role in modulating innate and adaptive immune responses and the secretion of certain cytokines, and their potential use as immunological markers of response; the aim is also to identify promising lines of investigation.
We aimed to evaluate the oncological and functional outcomes of organ-sparing surgery for testicular germ cell tumors, a procedure that seeks to strike a balance between effective cancer control and ...organ preservation, in the treatment of testicular tumors. We aimed to discuss the surgical technique and complications, and determine the appropriate candidate selection for this approach.
A comprehensive literature search was conducted to identify relevant studies on organ-sparing surgery for testicular tumors. Various databases, including PubMed, Embase, and Cochrane Library, were used. Studies reporting on surgical techniques, complications, and oncologic and functional outcomes were included for analysis.
Current evidence suggests that organ-sparing surgery for testicular germ cell tumors can be considered a safe and efficacious alternative to radical orchiectomy. The procedure is associated with adequate oncological control, as indicated by low recurrence rates and low complication rates. Endocrine testicular function can be preserved in around 80-90% of patients and paternity can be achieved in approximately half of the patients. Candidate selection for this surgery is typically based on the following criteria: pre-surgery normal levels of testosterone and luteinizing hormone, synchronous or metachronous bilateral tumors, tumor in a solitary testis, and tumor size less than 50% of the testis.
Organ-sparing surgery for testicular germ cell tumors offers a promising approach that balances oncological control and preservation of testicular function. Further research, including large-scale prospective studies and long-term follow-ups, is warranted to validate the effectiveness and durability of organ-sparing surgery and to identify optimal patient selection criteria.
Ticks and the diseases they transmit cause great economic losses to livestock in tropical countries. Non-chemical control alternatives include the use of resistant cattle breeds, biological control ...and vaccines. However, the most widely used method is the application of different chemical classes of acaricides and macrocyclic lactones. Populations of the cattle tick, Rhipicephalus (Boophilus) microplus, resistant to organophosphates (OP), synthetic pyrethroids (SP), amitraz and fipronil have been reported in Mexico. Macrocyclic lactones are the most sold antiparasitic drug in the Mexican veterinary market. Ivermectin-resistant populations of R. (B.) microplus have been reported in Brazil, Uruguay and especially in Mexico (Veracruz and Yucatan). Although ivermectin resistance levels in R. (B.) microplus from Mexico were generally low in most cases, some field populations of R. (B.) microplus exhibited high levels of ivermectin resistance. The CHPAT population showed a resistance ratio of 10.23 and 79.6 at lethal concentration of 50% and 99%, respectively. Many field populations of R. (B.) microplus are resistant to multiple classes of antiparasitic drugs, including organophosphates (chlorpyrifos, coumaphos and diazinon), pyrethroids (flumethrin, deltamethrin and cypermethrin), amitraz and ivermectin. This paper reports the current status of the resistance of R. (B.) microplus to acaricides, especially ivermectin, in Mexican cattle.
Este artículo describe y analiza, desde la perspectiva lingüística y literaria, los recursos expresivos, literarios y lingüístico-comunicativos en el huayno ancashino, una manifestación tradicional ...andina en la que se combinan poemas populares quechuas y la música tradicional rural. El estudio de fue nivel descriptivo y abordado con enfoque cualitativo. La data recolectada demuestra que el arte verbal quechua en el huayno ancashino evidencia el uso de diferentes recursos léxicos, expresivo-comunicativos y literarios para manifestar diferentes aspectos de la vida, la muerte y el amor con sus múltiples facetas. En la composición de los versos se evidencia procesos de resemantización y nuevos giros semánticos que adquieren las palabras y expresiones, uso de préstamos lingüísticos y alternancia de códigos, presentadas poética y metafóricamente. De esta manera, el huayno ancashino interpreta poética y artísticamente el sentir y las vivencias de sus gentes y se constituye en la riqueza cultural ancashina.
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