Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. ...Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer.
Objective
To present a novel case of perinatal bilateral exophthalmos and corneal ulcers in a neonate Antillean manatee and describe the medical treatment that led to the resolution of the observed ...clinical signs and vision restoration.
Animal studied
A manatee stranded alone in Puerto Rico on July 5, 2020.
Results
The manatee was found in critical condition with pronounced exophthalmos, lagophthalmos, and corneal opacification of both eyes (OU). Vision impairment was evident due to the lack of ocular menace reflex and bumping into the tank's walls. Biomicroscopy revealed conjunctival hyperemia and chemosis, limited third eyelid movement, but had viscous tears present OU. Dense, full‐thickness, white to cream‐colored cellular infiltrates affected 70% of the cornea with peripheral active vascularization OU. Rubeosis iridis was also present OU. Treatment consisted of supportive medical management, including nutritional support and topical treatment for ulcerative keratitis. Resolution of the corneal ulcers and functional vision were achieved after 6 weeks of therapy. Currently, bilateral, mild, intermittent exophthalmos is observed with no adverse clinical signs, and the calf is in good health.
Conclusions
The extent of bilateral corneal disease on a neonatal calf may be a result of an intrauterine infection or possible trauma at or right after birth. While the latter may have led to exophthalmia and consequent corneal disease, the exact cause could not be determined. Supportive therapy and medical management of infectious keratitis were successful and led to vision recovery. This is the first report of ocular pathology in a neonatal manatee.
Sorghum, a competitive crop due to its agronomical advantages, has gained interest as functional food. Sorghum contains phytochemicals with health benefits and presents some antinutritional compounds ...such as condensed tannins (CTs). However, it is well known that CTs exhibit antioxidant capacity. This study evaluated the effect of Mexican nixtamalization on total phenols, CTs and antioxidant capacity using two varieties of sorghum. Different conditions of lime (0, 1 and 2%) and cooking time (20, 30 and 40 min) were tested to obtain the best treatment after optimization using multiple linear regression analysis, aiming to minimize the CTs content and maximize the antioxidant capacity. CTs were reduced at 27% in white sorghum and 90%, in red sorghum. Total phenols, flavonoids and antioxidant capacity had an inverse correlation with lime concentration and cooking time. The best conditions for preserving antioxidant capacity with low content of tannins were 1.13% of lime and 31.11 min cooking. The phenolic profile obtained by HPLC showed reductions in gallic and chlorogenic acids only in white sorghum, whereas catechin and quercetin decreased in both varieties. We concluded that nixtamalization effectively reduced CTs to safety intake values, allowing to preserve other phenolic compounds and antioxidant capacity.
•Mexican nixtamalization process reduced condensed tannins in sorghum.•Total phenols had an inverse correlation with lime concentration in the nixtamalization process.•Nixtamalization was used to preserve the antioxidant capacity in sorghum.
In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint ...inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1-2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3-4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies.
Although Ras genes are frequently mutated in human tumors, these mutations are uncommon in breast cancer. However, many breast tumors show evidences of Ras pathway activation. In this manuscript, we ...have analyzed and characterized mouse mammary tumors generated by random Sleeping Beauty transposon mutagenesis and identify ERAS -a member of the RAS family silenced in adult tissues- as a new gene involved in progression and malignancy of breast cancer. Forced expression of ERAS in human non-transformed mammary gland cells induces a process of epithelial-to-mesenchymal transition and an increase in stem cells markers; these changes are mediated by miR-200c downregulation. ERAS expression in human tumorigenic mammary cells leads to the generation of larger and less differentiated tumors in xenotransplant experiments. Immunohistochemical, RT-qPCR and bioinformatics analysis of human samples show that ERAS is aberrantly expressed in 8-10% of breast tumors and this expression is associated with distant metastasis and reduced metastasis-free survival. In summary, our results reveal that inappropriate activation of ERAS may be important in the development of a subset of breast tumors. These findings open the possibility of new specific treatments for this subset of ERAS-expressing tumors.
Cancer stem cells (CSC) are considered responsible for tumor initiation, therapeutic resistance, and metastasis. A comprehensive knowledge of the mechanisms governing the acquisition and maintenance ...of cancer stemness is crucial for the development of new therapeutic approaches in oncology. E2A basic helix-loop-helix (bHLH) transcription factors are associated with epithelial-mesenchymal transition (EMT) and tumor progression, but knowledge of their functional contributions to cancer biology is still limited. Using a combination of
and
analyses in a novel PyMT-E2A conditional knockout mouse model and derived primary tumor cell lines, we report here an essential role of E2A in stemness, metastasis, and therapeutic resistance in breast cancer. Targeted deletion of E2A in the mammary gland impaired tumor-initiating ability and dedifferentiation potential and severely compromised metastatic competence of PyMT-driven mammary tumors. Mechanistic studies in PyMT-derived cell lines indicated that E2A actions are mediated by the upregulation of Snai1 transcription. Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A-Snail1 axis in metastatic breast cancer. In addition, E2A factors contributed to the maintenance of genomic integrity and resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support the potential for E2A transcription factors as novel targets worthy of translational consideration in breast cancer. SIGNIFICANCE: These findings identify key functions of E2A factors in breast cancer cell stemness, metastasis, and drug resistance, supporting a therapeutic vulnerability to targeting E2A proteins in breast cancer.
Native starch exhibits undesirable properties in the final product when used as an additive. Recently, the effects of the interaction between starch and hydrocolloids on the techno‐functional ...properties of starch have been studied. However, this interaction has not yet been applied to a real food system. Therefore, in this work, the techno‐functional properties of starch–pectin complexes formed by extrusion are investigated. Mixtures of isolated native Pozolero maize starch “HPZ1” and pectin of low degree of methyl‐esterification at four concentrations (0%, 2%, 5%, and 7%) are used. The starch–pectin blends are processed in a single screw extruder with constant variables: temperature, screw speed, and moisture. Morphology, X‐ray diffraction, thermal properties, and techno‐properties are studied. A protective effect of pectin on the starch granules is observed, as evidenced by a matrix involving starch granules. Extrusion results in a partial gelatinization of the starch granules and alters their thermal and pasting properties with the peak temperature increasing with increasing pectin concentration. Extrusion allows both carbohydrates to interact with each other. Finally, the results show that the starch–pectin complexes are ingredients with desirable techno‐functional properties that can be integrated into a food system and add value to Mexican criollo maize.
Extrusion causes a partial gelatinization of starch granules and alters their thermal and pasting properties with the peak temperature increasing with increasing pectin concentration. This thermo‐mechanical process allows both carbohydrates to physically interact with each other.
El cautiverio de animales silvestres produce importantes alteraciones conductuales y fisiológicas, derivadas, entre otras, de la restricción de espacio y limitada variedad alimenticia, por lo que ...resulta necesario el establecimiento continuo de estrategias de compensación como los enriquecimientos. La investigación tuvo como objetivo la evaluación etológica de enriquecimientos con grillos (Acheta domesticus) y gusano rey (Zophobas morio) en especímenes de monos churuco (Lagothrix lagotricha) albergados en la Unidad de Apoyo Hogar de Paso para Fauna Silvestre de la Universidad de la Amazonía, ubicada en el perímetro rural de Florencia - Caquetá, Colombia. Para su desarrollo se implementó un bioterio para la reproducción de los invertebrados utilizados en los enriquecimientos, y se trabajó con 16 especímenes primates (ocho machos y ocho hembras), para cuyo seguimiento conductual se instauraron etogramas durante 11 semanas, de las cuales, en las cuatro primeras no se aplicaron enriquecimientos con el fin de identificar el patrón conductual inicial. El análisis de las interacciones entre las variables conductuales estudiadas (alimentación, locomoción, interacciones sociales, descanso, alerta, cuidado y actividades varias), se realizó mediante la prueba LSD de Fisher (α=0,05); para identificar diferencias entre los factores fijos para cada una de las variables se empleó un análisis de varianza y se desarrolló adicionalmente un análisis de componentes principales. Como resultado principal se encontró que la implementación de los enriquecimientos generó un incremento en el tiempo de inversión para las categorías de alimentación, locomoción, interacciones sociales y actividades varias; y una disminución en la categoría de descanso, logrando así una efectiva motivación para la aparición de conductas naturales de la especie.
Nowadays, orthovanadates are studied because of their unique properties for optoelectronic applications. In this work, the LuVO4:Eu3+, Bi3+ films were prepared by the sol–gel method, using a new ...simple route, and deposited by the dip-coating technique. The obtained films are transparent, fracture-free, and homogenous. The sol–gel process was monitored by Fourier-transform infrared spectroscopy (FTIR), and according to X-ray diffraction (XRD) results, the crystal structure was tetragonal, and films that were highly oriented along the (200) low-energy direction were obtained. The morphological studies by scanning electron microscopy (SEM) showed uniformly distributed circular agglomerations of rice-like particles with nanometric sizes. The luminescence properties of the films were analyzed using a fixed concentration of 2.5 at. % Eu3+ and different concentrations of Bi3+ (0.5, 1.0, and 1.5 at. %); all the samples emit in red, and it has been observed that the light yield of Eu3+ is enhanced as the Bi3+ content increases when the films are excited at 350 nm, which corresponds to the 1S0→3P1 transition of Bi3+. Therefore, a highly efficient energy transfer mechanism between Bi3+ and Eu3+ has been observed, reaching up to 71%. Finally, it was established that this energy transfer process occurs via a quadrupole–quadrupole interaction.
We prepared a series of cinnamoyl-containing furanones by an affordable and short synthesis. The nineteen compounds hold a variety of substituents including electron-donating, electron-withdrawing, ...bulky and meta-substituted phenyls, as well as heterocyclic rings. Compounds showed antibiofilm activity in S. aureus, K. pneumoniae and, more pronounced, against P. aeruginosa. The disruption of quorum sensing (QS) was tested using the violacein test and molecular docking predicted the antagonism of LasR as a plausible mechanism of action. The trimethoxylated and diene derivatives showed the best antibiofilm and anti-QS properties, thus becoming candidates for further modifications.
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