Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth ...regulation that could serve as an important target for cancer therapy.
We evaluated FRα expression in breast cancers by genomic (
= 3,414) and IHC (
= 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1),
, and in human TNBC xenograft models.
FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death
by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth.
FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses.
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Ischemia-reperfusion (IR) injury is the main cause of delayed graft function in solid organ transplantation. Hypoxia-inducible factors (HIFs) control the expression of genes related to ...preconditioning against IR injury. During normoxia, HIF-α subunits are marked for degradation by the egg-laying defective nine homolog (EGLN) family of prolyl-4-hydroxylases. The inhibition of EGLN stabilizes HIFs and protects against IR injury. The aim of this study was to determine whether the EGLN inhibitors sodium (
)-2-hydroxyglutarate (
)-2HG and succinic acid (SA) have a nephroprotective effect against renal IR injury in Wistar rats.
(
)-2HG was synthesized in a 22.96% yield from commercially available L-glutamic acid in a two-step methodology (diazotization/alkaline hydrolysis), and its structure was confirmed by nuclear magnetic resonance and polarimetry. SA was acquired commercially. (
)-2HG and SA were independently evaluated in male and female Wistar rats respectively after renal IR injury. Rats were divided into the following groups: sham (SH), nontoxicity (
)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg, IR, and compound+IR (
)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg; independent SH and IR groups were used for each assessed compound. Markers of kidney injury (BUN, creatinine, glucose, and uric acid) and liver function (ALT, AST, ALP, LDH, serum proteins, and albumin), proinflammatory cytokines (IL-1β, IL-6, and TNF-α), oxidative stress biomarkers (malondialdehyde and superoxide dismutase), and histological parameters (tubular necrosis, acidophilic casts, and vascular congestion) were assessed. Tissue HIF-1α was measured by ELISA and Western blot, and the expression of Hmox1 was assessed by RT-qPCR.
(
)-2HG had a dose-dependent nephroprotective effect, as evidenced by a significant reduction in the changes in the BUN, creatinine, ALP, AST, and LDH levels compared with the IR group. Tissue HIF-1α was only increased in the IR group compared to SH; however, (
)-2HG caused a significant increase in the expression of Hmox1, suggesting an early accumulation of HIF-1α in the (
)-2HG-treated groups. There were no significant effects on the other biomarkers. SA did not show a nephroprotective effect; the only changes were a decrease in creatinine level at 12.5 mg/kg and increased IR injury at 50 mg/kg. There were no effects on the other biochemical, proinflammatory, or oxidative stress biomarkers.
None of the compounds were hepatotoxic at the tested doses. (
)-2HG showed a dose-dependent nephroprotective effect at the evaluated doses, which involved an increase in the expression of Hmox1, suggesting stabilization of HIF-1α. SA did not show a nephroprotective effect but tended to increase IR injury when given at high doses.
The main purpose of this study was to describe a group of Colombian physical therapists' beliefs and attitudes towards Evidence-Based Practice (EBP), their education, knowledge and skills for ...implementing EBP, the use of relevant literature in clinical practice, access to and availability of scientific information and perceived barriers to including EBP in practice.
This was a cross-sectional study which involved 1,064 Colombian physical therapists. The study used a 50-item screening questionnaire EBP developed to estimate attitudes, beliefs, knowledge and skills regarding. This instrument has been adapted and was validated previously in Colombia by Flórez-López et al.
The population mostly consisted of young females (77.2%) aged 22 to 29 years old (79.4%). Most respondents had an undergraduate degree (87.7%). The physical therapists stated that they had positive attitudes and beliefs regarding EBP, most of them answering that they agreed or strongly agreed that EBP is necessary (71.6%), the relevant literature is useful for practice (61.3%), EBP improves the quality of patient care (64.1%) and evidence helps in decision-making (44.5%). Forty-one percent of the respondents indicated that a lack of research skills was the most important barrier to the use of evidence in practice.
The physical therapists reported that they had a positive attitude to EBP and were interested in learning about or improving the skills necessary to adopt EBP in their clinical practice.
INTRODUCTIONThere is little evidence regarding the influence of emotional variables on breastfeeding among mothers of very low birth weight infants (VLBWIs). The objective of this study was to ...measure breast milk production (BMP) at two points in time during neonatal hospitalization and its association with anxiety, depression, and breastfeeding self-efficacy levels among mothers of VLBWIs. POPULATION AND METHOSProspective, observational, and multicenter study in mothers of VLBWIs (500-1500 g) from 9 NEOCOSUR Network centers. BMP was obtained by measuring the amount extracted by each mother. The STAI scale was used for anxiety, the BDI scale for depression, and the ALMA pilot scale for selfefficacy. They were administered at 14 days of life and at 36 weeks of postmenstrual age. The biosocial characteristics of mothers and neonates were also recorded. RESULTSA total of 118 mothers participated. Mean BMP was 169 mL (standard deviation SD: ± 132.4) at 14 days and 285 mL (SD: ± 266.9) at 36 weeks, and it was significantly associated with the perception of breastfeeding self-efficacy (p < 0.001), which was maintained during hospitalization. There was a lower production trend among mothers with higher depression indices at 14 days of life, but not at 36 weeks. No association was observed between BMP and anxiety. No consistently significant associations were observed with biosocial variables. CONCLUSIONBMP was positively associated with breastfeeding self-efficacy; no association was observed with anxiety and depression among mothers of VLBWIs.
The birth of a premature baby is a stressful event for parents. The objective of this study was to determine early stress in parents of very low birth weight infants (VLBWIs) hospitalized in 12 ...neonatal intensive care units from a South American Neonatal Network, to identify associated factors, and to compare the level of parental stress in public versus private healthcare facilities.
Cross-sectional study in mothers/fathers of VLBWIs (500 to 1500 g). Early parental stress was measured using the Parental Stressor Scale, with a score from 1 (low stress) to 5 (high stress). The sociodemographic characteristics of parents and newborn infants were collected and associated with levels of parental stress.
The study included 273 fathers/mothers of a total of 218 VLBW preterm infants. The survey was administered at 5.9 ± 2.0 days of life. The average total parental stress was 3.1 ± 0.8, and the highest score was obtained for the parental role subscale (3.6). A lower education level, unemployment, not having held the newborn infant, and respiratory support requirement were associated with higher parental stress levels. Stress was higher among mothers than fathers, and at public facilities versus private ones.
Among parents of VLBWIs, a moderate early parental stress was observed. Parental role alteration was the most relevant factor. Parental stress was higher among mothers and at public healthcare facilities. A greater sensitization, further research and interventions in this area are required.
In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and ...clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20
CD27
IgD
isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine-cytokine receptor interactions, cytotoxic T-cell activation, and T-cell-dependent B-cell activation. TIL-B-upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR-immune complex formation. Expression of genes associated with B lymphocyte recruitment and lymphoid assembly, including CXCL13, CXCR4, and DC-LAMP, was elevated in TNBC compared with other subtypes and normal breast. TIL-B-rich tumors showed expansion of IgG but not IgA isotypes, and IgG isotype switching positively associated with survival outcomes in TNBC. Clonal expansion was biased toward IgG, showing expansive clonal families with specific variable region gene combinations and narrow repertoires. Stronger positive selection pressure was present in the complementarity determining regions of IgG compared with their clonally related IgA in tumor samples. Overall, class-switched B lymphocyte lineage traits were conspicuous in TNBC, associated with improved clinical outcomes, and conferred IgG-biased, clonally expanded, and likely antigen-driven humoral responses. SIGNIFICANCE: Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor-driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers.
Human B cells and their expressed antibodies are crucial in conferring immune protection. Identifying pathogen-specific antibodies following infection is possible due to enhanced humoral immunity ...against well-described molecules on the pathogen surface. However, screening for cancer-reactive antibodies remains challenging since target antigens are often not identified a priori and the frequency of circulating B cells recognizing cancer cells is likely very low. We investigated whether combined ex vivo culture of human B cells with three innate stimuli, interleukin-17 (IL-17), B-cell activation factor (BAFF), and the toll-like receptor 9 (TLR-9) agonist DNA motif CpG ODN 2006 (CpG), each known to activate B cells through different signalling pathways, promote cell activation, proliferation, and antibody production. Combined IL-17+BAFF+CpG prolonged B-cell survival and increased proliferation compared with single stimuli. IL-17+BAFF+CpG triggered higher IgG secretion, likely by activating differentiated, memory and class-switched CD19+CD20+CD27+IgD- B cells. Regardless of anti-FOLR antibody seropositive status, IL-17+BAFF+CpG combined with a monovalent tumour-associated antigen (folate receptor alpha FOLR) led to secreted antibodies recognizing the antigen and the antigen-expressing IGROV1 cancer cells. In a seropositive individual, FOLR stimulation favoured class-switched memory B-cell precursors (CD27-CD38-IgD-), class-switched memory B cells and anti-FOLR antibody production, while IL-17+BAFF+CpG combined with FOLR, promoted class-switched memory B-cell precursors and antibody-secreting (CD138+IgD-) plasma cells. Furthermore, IL-17+BAFF+CpG stimulation of peripheral blood B cells from patients with melanoma revealed tumour cell-reactive antibodies in culture supernatants. These findings suggest that innate signals stimulate B-cell survival and antibody production and may help identify low-frequency antigen-reactive humoral responses.
Plant genomes encode a unique group of papain-type Cysteine EndoPeptidases (CysEPs) containing a KDEL endoplasmic reticulum (ER) retention signal (KDEL-CysEPs or CEPs). CEPs process the cell-wall ...scaffolding EXTENSIN (EXT) proteins that regulate de novo cell-wall formation and cell expansion. Since CEPs cleave EXTs and EXT-related proteins, acting as cell-wall-weakening agents, they may play a role in cell elongation. The Arabidopsis (Arabidopsis thaliana) genome encodes 3 CEPs (AtCPE1-AtCEP3). Here, we report that the genes encoding these 3 Arabidopsis CEPs are highly expressed in root-hair (RH) cell files. Single mutants have no evident abnormal RH phenotype, but atcep1-3 atcep3-2 and atcep1-3 atcep2-2 double mutants have longer RHs than wild-type (Wt) plants, suggesting that expression of AtCEPs in root trichoblasts restrains polar elongation of the RH. We provide evidence that the transcription factor NAC1 (petunia NAM and Arabidopsis ATAF1, ATAF2, and CUC2) activates AtCEPs expression in roots to limit RH growth. Chromatin immunoprecipitation indicates that NAC1 binds to the promoter of AtCEP1, AtCEP2, and, to a lower extent, AtCEP3 and may directly regulate their expression. Inducible NAC1 overexpression increases AtCEP1 and AtCEP2 transcript levels in roots and leads to reduced RH growth while the loss of function nac1-2 mutation reduces AtCEP1-AtCEP3 gene expression and enhances RH growth. Likewise, expression of a dominant chimeric NAC1-SRDX repressor construct leads to increased RH length. Finally, we show that RH cell walls in the atcep1-3 atcep3-2 double mutant have reduced levels of EXT deposition, suggesting that the defects in RH elongation are linked to alterations in EXT processing and accumulation. Our results support the involvement of AtCEPs in controlling RH polar growth through EXT processing and insolubilization at the cell wall.
Synchronous parathyroid and papillary thyroid carcinoma are extremely rare. To our knowledge, only 15 cases have been reported in the last four decades. We describe a 50-year-old female without ...significant past medical or family history and no previous trauma presented with left heel pain that prompted her to seek medical attention. Physical examination was notable for a painless nodule at the left thyroid lobe. Laboratory evaluation showed a serum calcium level of 14.3 mg/dL (8.6–10.3 mg/dL) and intact parathyroid hormone level of 1160 pg/mL (12–88 pg/mL). 99Tc-sestamibi dual-phase with single-photon emission computed tomography fused images showed increased uptake at the left-sided inferior parathyroid gland. Neck ultrasound showed a 1.4 cm heterogeneous nodule in the middle-third of the left thyroid gland and a solitary 1.9 cm vascularized and hypoechoic oval nodule that was considered likely to represent a parathyroid adenoma. Due to its clinical context (severe hypercalcemia and very high levels of PTH), parathyroid carcinoma (PC) was suspected although imaging studies were not characteristic. The patient underwent en bloc resection of the parathyroid mass and left thyroid lobe and central neck compartment dissection. Pathology analysis revealed classical papillary thyroid carcinoma of classical subtype and parathyroid carcinoma. Immunohistochemical staining was positive for cyclidin D1 and negative for parafibromin. High clinical suspicion is required for parathyroid carcinoma diagnosis in the presence of very high level of parathyroid hormone, marked hypercalcemia, and the existence of any thyroid nodule should be approached and the coexistence of other carcinomas should be considered.
El objetivo de este trabajo es analizar la conformación de las identidades docentes de estudiantes nahua y téenek en una Normal de educación intercultural bilingüe (EIB) de la Huasteca Potosina, ...México. La identidad se problematizó en torno a la nación y cultura como dispositivos coloniales que emergen de los discursos estructurales neoliberales en interpelación con la reflexividad de las/os estudiantes. Suponemos que los procesos de construcción identitaria, en el caso analizado, ocurren en las tensiones entre el nivel de las políticas educativas estructurales del Estado neoliberal y la reflexividad de los/as estudiantes indígenas. La investigación se sustenta en una metodología cualitativa basada en el análisis documental y etnográfico. Encontramos que los/as estudiantes en formación construyen procesos mediacionales de identificación heterogéneos y en tensión: asumen referentes significativos de las políticas estructurales educativas de corte neoliberal que se orientan hacia una ciudadanía cosmopolita hegemónica, y resignifican sus propios valores comunales como pueblo.
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