Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers.

In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan et al. (Oncogenesis 2020) and Wang et al. (Cancer Cell Int 2022) demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib. The studies also identified hyaluronic acid synthase -3 (HAS3) as a bonafide target of Sorafenib in RCC cells. The studies demonstrate that an over-the-counter drug Hymecromone (4-methylumbelliferone) blocks inactivation of Sorafenib in RCC cells and improves its efficacy against mRCC through the inhibition of HAS3 expression and HA signaling. In the broader context, improving the efficacy of "old and failed drugs" that have favorable safety profiles should increase the availability of effective treatments for patients with advanced cancers.

Phytoremediation Performance with Ornamental Plants in Monocultures and Polycultures Conditions Using Constructed Wetlands Technology.

The assessment of constructed wetlands (CWs) has gained interest in the last 20 years for wastewater treatment in Latin American regions. However, the effects of culture systems with different ornamental species in CWs for phytoremediation are little known. In this study, some chemical parameters such as total suspended solids (TSS), chemical oxygen demand (COD), phosphate (PO4-P), and ammonium (NH4-N) were analyzed in order to prove the removal of pollutants by phytoremediation in CWs. The environmental impact index based on eutrophication reduction (EI-E) was also calculated to estimate the cause-effect relationship using CWs in different culture conditions. C. hybrids and Dieffenbachia seguine were used in monoculture and polyculture (both species mixed) mesocosm CWs. One hundred eighty days of the study showed that CWs with plants in monoculture/polyculture conditions removed significant amounts of organic matter (TSS and COD) (p > 0.05; 40-55% TSS and 80-90% COD). Nitrogen and phosphorous compounds were significantly lower in the monoculture of D. seguine (p < 0.05) than in monocultures of C. hybrids, and polyculture systems. EI-E indicator was inversely proportional to the phosphorous removed, showing a smaller environmental impact with the polyculture systems (0.006 kg PO43- eq removed) than monocultures, identifying the influence of polyculture systems on the potential environmental impacts compared with the phytoremediation function in monocultures (0.011-0.014 kg PO43- eq removed). Future research is required to determine other types of categories of environmental impact index and compare them with other wastewater treatment systems and plants. Phytoremediation with the ornamental plants studied in CWs is a good option for wastewater treatment using a plant-based cleanup technology.

Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention.

The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, and became moribund. Lung tissues from these mice and bronchoalveolar lavage and lung tissues from patients with COVID-19 showed elevated levels of hyaluronic acid (HA), HA-family members, an inflammatory signature, and immune cell infiltration. 4-methylumbelliferone (4-MU), an oral drug for biliary-spasm treatment, inhibits HA-synthesis. At the human equivalent dose, 4-MU prevented/inhibited COVID-19-like pathologies and long-term morbidity; 4-MU and metabolites accumulated in mice lungs. Therefore, these versatile SARS-COV-2 ribo-oligonucleotide oropharyngeal models recapitulate COVID-19 pathology, with HA as its critical mediator and 4-MU as a potential therapeutic for COVID-19.

Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.

BACKGROUND: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. METHODS: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RESULTS: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. CONCLUSION: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

Molecular Oncology of Bladder Cancer from Inception to Modern Perspective.

Within the last forty years, seminal contributions have been made in the areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes seminal discoveries and advances in the molecular oncology of BC. Starting with the concept of divergent molecular pathways for the development of low- and high-grade bladder tumors, field cancerization versus clonality of bladder tumors, cancer driver genes/mutations, genetic polymorphisms, and bacillus Calmette-Guérin (BCG) as an early form of immunotherapy are some of the conceptual contributions towards improving patient care. Although beginning with a promise of predicting prognosis and individualizing treatments, "-omic" approaches and molecular subtypes have revealed the importance of BC stem cells, lineage plasticity, and intra-tumor heterogeneity as the next frontiers for realizing individualized patient care. Along with urine as the optimal non-invasive liquid biopsy, BC is at the forefront of the biomarker field. If the goal is to reduce the number of cystoscopies but not to replace them for monitoring recurrence and asymptomatic microscopic hematuria, a BC marker may reach clinical acceptance. As advances in the molecular oncology of BC continue, the next twenty-five years should significantly advance personalized care for BC patients.

Partial Trisomy 13q/Monosomy 3p Resulting from a Paternal Reciprocal 3p;13q Translocation in a Boy with Facial Dysmorphism and Hypertrophic Cardiomyopathy.

Individuals with 3p deletion show a great clinical variability. Apparently, a 1.5-Mb terminal deletion, including the CRBN and CNTN4 genes, is sufficient to cause this syndrome. Partial trisomy 13q is a rare chromosomal abnormality with a variable phenotypic expression, but in most cases, patients have a phenotype resembling complete trisomy 13. The aim of the present study is to describe a 9-month-old Mexican male patient with 3p deletion/13q duplication and a novel clinical finding. He presented with facial dysmorphism and multiple congenital alterations. Echocardiogram revealed cardiac insufficiency with hypertrophic cardiomyopathy and pulmonary hypertension, not previously reported. Karyotype from the patient and his father were 46,XY,add(3)(p26) and 46,XY,t(3;13), respectively. Microarray assay of the proband exhibited an approximately 2.6-Mb loss at terminal 3p26.3 and a 27.7-Mb gain of the long arm in terminal chromosome 13 at q31.1q34. A chromosomal imbalance with a partial trisomy 13q31.1q34 and monosomy 3p26.3 of paternal origin were detected. Microarray assay of both parents were normal. The proband has a cardiomyopathy not previously reported. These data enrich the spectrum of clinical manifestations in 3p deletion/3q duplication chromosomopathy.

Guiding principles for rewilding.

There has been much recent interest in the concept of rewilding as a tool for nature conservation, but also confusion over the idea, which has limited its utility. We developed a unifying definition and 10 guiding principles for rewilding through a survey of 59 rewilding experts, a summary of key organizations' rewilding visions, and workshops involving over 100 participants from around the world. The guiding principles convey that rewilding exits on a continuum of scale, connectivity, and level of human influence and aims to restore ecosystem structure and functions to achieve a self-sustaining autonomous nature. These principles clarify the concept of rewilding and improve its effectiveness as a tool to achieve global conservation targets, including those of the UN Decade on Ecosystem Restoration and post-2020 Global Biodiversity Framework. Finally, we suggest differences in rewilding perspectives lie largely in the extent to which it is seen as achievable and in specific interventions. An understanding of the context of rewilding projects is the key to success, and careful site-specific interpretations will help achieve the aims of rewilding.

Recientemente ha habido mucho interés por el concepto de retorno a la vida silvestre como herramienta para la conservación de la naturaleza, pero también ha habido confusión por la idea que ha limitado su utilidad. Desarrollamos una definición unificadora y diez principios básicos para el retorno a la vida silvestre por medio de encuestas a 59 expertos en retorno a la vida silvestre, un resumen de las visiones de las organizaciones más importantes para el retorno a la vida silvestre y talleres que involucraron a más de 100 participantes de todo el mundo. Los principios básicos transmiten que el retorno a la vida silvestre existe en un continuo de escala, conectividad y nivel de influencia humana y que su objetivo es restaurar la estructura y las funciones del ecosistema para lograr una naturaleza autónoma autosustentable. Estos principios aclaran el concepto del retorno a la vida silvestre e incrementan su efectividad como herramienta para lograr los objetivos mundiales de conservación, incluyendo aquellos de la Década de la ONU para la Restauración de Ecosistemas y el Marco de Trabajo de la Biodiversidad Global post 2020. Finalmente, sugerimos que las diferencias en las perspectivas del retorno a la vida silvestre yacen principalmente en el grado al que es visto como factible y en intervenciones específicas. Un entendimiento del contexto de los proyectos de retorno a la vida silvestre es importante para el éxito, y las interpretaciones específicas de sitio ayudarán a lograr las metas del retorno a la vida silvestre. Principios Básicos para el Retorno a la Vida Silvestre.

Disengagement of motor cortex from movement control during long-term learning.

Motor learning involves reorganization of the primary motor cortex (M1). However, it remains unclear how the involvement of M1 in movement control changes during long-term learning. To address this, we trained mice in a forelimb-based motor task over months and performed optogenetic inactivation and two-photon calcium imaging in M1 during the long-term training. We found that M1 inactivation impaired the forelimb movements in the early and middle stages, but not in the late stage, indicating that the movements that initially required M1 became independent of M1. As previously shown, M1 population activity became more consistent across trials from the early to middle stage while task performance rapidly improved. However, from the middle to late stage, M1 population activity became again variable despite consistent expert behaviors. This later decline in activity consistency suggests dissociation between M1 and movements. These findings suggest that long-term motor learning can disengage M1 from movement control.

Growth, photosynthesis and removal responses of the cyanobacteria Chroococcus sp. to malathion and malaoxon.

Malathion is an organophosphorus pesticide widely used in agricultural crops, despite its toxicity. In addition, malaoxon occurs by oxidation of malathion being more toxic. The toxic effects of malathion and malaoxon in humans include hepatoxicity, breast cancer, genetic damage and endocrine disruption. The aim of this study involved assessing the effect of malathion commercial grade on Chroococcus sp., and its potential as an alternative to the removal of this pesticide and its transformation product such as malaoxon. We evaluated the effect of malathion at different concentrations (1, 25, 50, 75 and 100 ppm) on the biomass of the cyanobacteria Chroococcus sp. grown in medium BG-11; also, we analyse its ability to degrade both malathion and malaoxon into a temperature of 28 ± 2 °C and at pH 6. The results showed that 50 ppm of malathion the cyanobacteria Chroococcus sp. reached the highest removal efficiency of malathion and malaoxon (69 and 65%, respectively); also, the growth rate of Chroococcus sp. increased without inhibiting the production of chlorophyll "a", this can be explained by the hormesis phenomenon. Therefore, we consider that the cyanobacteria Chroococcus sp. may be a good candidate for bioremediation of aquatic systems contaminated with organophosphorus pesticides such as malathion and its transformation product such as malaoxon.