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1.
ACS Appl Eng Mater ; 2(4): 1170-1189, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38693992

ABSTRACT

The expansion of the Internet of Things market and the proliferation of wearable technologies have generated a significant demand for textile-based energy storage systems. This work reports the engineered design of hybrid electrode nanomaterials of N-doped carbon nanotubes (CNT-N) functionalized with two types of manganese oxides (MOs)-birnessite (MnO2) and hausmannite (Mn3O4)-and their application in solid-state textile-based hybrid supercapacitors (SCs). A versatile citric acid-mediated eco-friendly one-pot aqueous precipitation process is proposed for the fabrication of the hybrids. Remarkably, different types of MOs were obtained by simply changing the reaction temperature from room temperature to 100 °C, without any post-thermal treatment. Asymmetric textile SCs were developed using cotton fabrics coated with CNT-N and the hybrids as textile electrodes, and poly(vinyl) alcohol/orthophosphoric acid as the solid-gel electrolyte. The asymmetric devices presented enhanced energy storage performance relative to the symmetric device based on CNT-N and excellent cycling stability (>96%) after 8000 charge/discharge cycles owing to synergistic effects between CNT-N and the MOs, which endowed nonfaradaic and pseudocapacitive features to the SCs. The asymmetric SC based on CNT-N@MnO2 featured 47% higher energy density and comparable power density to the symmetric CNT-N-based device (8.70 W h cm-2 at 309.01 µW cm-2 vs. 5.93 W h cm-2 at 346.58 µW cm-2). The engineered hybrid CNT-N@MO nanomaterials and the eco-friendly citric acid-assisted one-pot precipitation route open promising prospects not only for energy storage, but also for (photo)(electro)catalysis, wastewater treatment, and (bio)sensing.

2.
Cell Rep ; 43(4): 114080, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38581677

ABSTRACT

Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. Recent evidence suggests diversity in dopamine signaling, yet it remains poorly understood how heterogeneous signals might be organized to facilitate the role of downstream circuits mediating distinct aspects of behavior. Here, we investigated the organizational logic of dopaminergic signaling by recording and labeling individual midbrain dopamine neurons during associative behavior. Our findings show that reward information and behavioral parameters are not only heterogeneously encoded but also differentially distributed across populations of dopamine neurons. Retrograde tracing and fiber photometry suggest that populations of dopamine neurons projecting to different striatal regions convey distinct signals. These data, supported by computational modeling, indicate that such distributional coding can maximize dynamic range and tailor dopamine signals to facilitate specialized roles of different striatal regions.


Subject(s)
Dopaminergic Neurons , Mesencephalon , Dopaminergic Neurons/physiology , Dopaminergic Neurons/metabolism , Animals , Mesencephalon/physiology , Mesencephalon/cytology , Male , Mice , Reward , Dopamine/metabolism , Association Learning/physiology , Mice, Inbred C57BL
3.
Clin Oral Investig ; 28(3): 201, 2024 Mar 08.
Article in English | MEDLINE | ID: mdl-38453706

ABSTRACT

OBJECTIVES: The aim of this study was to assess cone beam computed tomography (CBCT) as a root canal anatomy diagnostic tool by comparison with micro-CT gold-standard. MATERIALS AND METHODS: 216 two-rooted mandibular molars were first scanned in a CBCT device (200 µm voxel size) and posteriorly in a micro-CT scanner (19.61 µm). The volumes were sequentially screened to classify main root canal anatomy according to Vertucci classification, and for the presence of lateral canals and apical deltas, in both mesial and distal roots. RESULTS: Both methods revealed a higher prevalence of Vertucci Type II and IV in the mesial root, and Vertucci Type I in the distal root. The percentage of agreement for main root canal anatomy classification between CBCT and micro-CT scores was high (85.2%). CONCLUSION: Sensibility to detect both lateral canals and apical deltas with CBCT was low. These results attest to the fact that minor anatomical changes might be difficult to identify with CBCT imaging, hampering its diagnostic value.


Subject(s)
Dental Pulp Cavity , Mandible , Dental Pulp Cavity/diagnostic imaging , Dental Pulp Cavity/anatomy & histology , X-Ray Microtomography , Mandible/diagnostic imaging , Cone-Beam Computed Tomography/methods , Tooth Root/diagnostic imaging , Tooth Root/anatomy & histology
4.
Odontology ; 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38514512

ABSTRACT

To evaluate the impact on the quality of filling with of low-fusion and conventional gutta-percha cones. Thirty-six maxillary canines were prepared and divided into three groups: I-conventional cone with Downpack at 200 °C at 4 mm from the WL; II-low-fusion cone with Downpack at 100 °C up to 4 mm from the WL; III-low-fusion cone with Downpack at 100 °C up to 7 mm from the WL. Temperature variations were measured in thirds on the external surface of the root. The bond strength was evaluated using the push-out test. The adhesive interface was analyzed by scanning electron microscopy. The bond strength and the temperature variation data were analyzed using analysis of variance and the failure type using the chi-square test. The low-fusion cone group with 7 mm Downpack showed higher bond strength (4.2 ± 2.7) compared with conventional cones (2.8 ± 1.6) and low-fusion cones with 4 mm Downpack (2.9 ± 1.6) (p < 0.05), with occurrence of a higher number of adhesive failures to the filling material and mixed failures. Relative to temperature variation, there was less temperature change in the apical third, in the low-fusion cone with Downpack 7 mm (1.0 ± 1.0) (p < 0.05). The use of low-fusion cones allowed the continuous wave condensation technique to be performed at a lower depth of Downpack at 100 °C at 7 mm, with less heating in the apical third, without compromising the quality of filling. Using gutta-percha cones with low fusion, which permits a lower condensation temperature and reduced Downpack depth, maintains the quality of filling, in order to minimize possible damage to the periapical tissues.

5.
Cell Rep ; 43(4): 113958, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38520691

ABSTRACT

The brain can generate actions, such as reaching to a target, using different movement strategies. We investigate how such strategies are learned in a task where perched head-fixed mice learn to reach to an invisible target area from a set start position using a joystick. This can be achieved by learning to move in a specific direction or to a specific endpoint location. As mice learn to reach the target, they refine their variable joystick trajectories into controlled reaches, which depend on the sensorimotor cortex. We show that individual mice learned strategies biased to either direction- or endpoint-based movements. This endpoint/direction bias correlates with spatial directional variability with which the workspace was explored during training. Model-free reinforcement learning agents can generate both strategies with similar correlation between variability during training and learning bias. These results provide evidence that reinforcement of individual exploratory behavior during training biases the reaching strategies that mice learn.


Subject(s)
Forelimb , Animals , Forelimb/physiology , Mice , Exploratory Behavior/physiology , Mice, Inbred C57BL , Learning/physiology , Male , Movement , Reinforcement, Psychology , Female , Behavior, Animal
6.
Cell Rep ; 43(4): 113993, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38551963

ABSTRACT

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, with notable exceptions that suggest that these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive highly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior.


Subject(s)
Forelimb , Pyramidal Tracts , Animals , Forelimb/physiology , Pyramidal Tracts/physiology , Spinal Cord/physiology , Spinal Cord/cytology , Mice , Motor Cortex/physiology , Neurons/physiology , Motor Neurons/physiology , Female , Male , Axons/physiology , Synapses/physiology
7.
Antioxidants (Basel) ; 13(3)2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38539858

ABSTRACT

The historical use of plants as sources of natural compounds has persisted over time. Increasing the intake of bioactive substances shows significant potential for promoting overall well-being and health. This study delves into the pigments, phenolic composition, and profile, along with antioxidant properties, of leaf extracts rich in bioactives from plants in the Azores region, contributing to sustainable primary food production. Analyses encompassed chlorophylls, carotenoids, total phenols, ortho-diphenols, and flavonoids, as well as antioxidant capacity assessment, polyphenolic profiling, and quantification. Psidium guajava L. and Smallanthus sonchifolius (Poepp.) H.Rob. exhibited elevated chlorophyll content, while Colocasia esculenta (L.) Schott displayed the highest carotenoid levels. Annona cherimola Mill., Eriobotrya japonica (Thunb.) Lindl, and Psidium guajava L. demonstrated pronounced total phenols, ortho-diphenols, and flavonoids. These findings align with heightened antioxidant capacity. HPLC-DAD (high-performance liquid chromatography with diode-array detection) characterization unveiled elevated hydroxycinnamic acids in E. japonica and Ipomea batatas (L.) Lam. compared to A. cherimola Mill., while C. esculenta exhibited increased flavone content. Among the quantified compounds, flavonols were the ones that predominantly demonstrated contribution to the antioxidant capacity of these leaves. This research highlights Azorean leaf plants' antioxidant potential, fostering natural product development for better health.

8.
Curr Biol ; 34(5): 1034-1047.e4, 2024 Mar 11.
Article in English | MEDLINE | ID: mdl-38377999

ABSTRACT

Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson's disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter. However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences. We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.


Subject(s)
Dopaminergic Neurons , Parkinson Disease , Mice , Animals , Dopaminergic Neurons/physiology , Substantia Nigra/physiology , Movement/physiology , Pars Compacta
9.
Nature ; 626(7999): 583-592, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38092040

ABSTRACT

Animals exhibit a diverse behavioural repertoire when exploring new environments and can learn which actions or action sequences produce positive outcomes. Dopamine release after encountering a reward is critical for reinforcing reward-producing actions1-3. However, it has been challenging to understand how credit is assigned to the exact action that produced the dopamine release during continuous behaviour. Here we investigated this problem in mice using a self-stimulation paradigm in which specific spontaneous movements triggered optogenetic stimulation of dopaminergic neurons. Dopamine self-stimulation rapidly and dynamically changes the structure of the entire behavioural repertoire. Initial stimulations reinforced not only the stimulation-producing target action, but also actions similar to the target action and actions that occurred a few seconds before stimulation. Repeated pairings led to a gradual refinement of the behavioural repertoire to home in on the target action. Reinforcement of action sequences revealed further temporal dependencies of refinement. Action pairs spontaneously separated by long time intervals promoted a stepwise credit assignment, with early refinement of actions most proximal to stimulation and subsequent refinement of more distal actions. Thus, a retrospective reinforcement mechanism promotes not only reinforcement, but also gradual refinement of the entire behavioural repertoire to assign credit to specific actions and action sequences that lead to dopamine release.


Subject(s)
Dopamine , Learning , Reinforcement, Psychology , Reward , Animals , Mice , Decision Making/physiology , Dopamine/metabolism , Dopaminergic Neurons/metabolism , Learning/physiology , Optogenetics , Time Factors , Models, Psychological , Models, Neurological
11.
Elife ; 122023 Dec 19.
Article in English | MEDLINE | ID: mdl-38113081

ABSTRACT

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ('Myomatrix arrays') that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a 'motor unit,' during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and identifying pathologies of the motor system.


Subject(s)
Motor Neurons , Primates , Rats , Mice , Animals , Motor Neurons/physiology , Electrodes , Muscle Fibers, Skeletal
12.
Biomarkers ; 28(7): 617-627, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37942654

ABSTRACT

INTRODUCTION: High-risk human papillomavirus (HPV) is the aetiological agent of cervical cancer, which remains the fourth leading cause of cancer death in women worldwide. K14-HPV16 transgenic mice are a model for HPV-induced cancers, which undergo multistep squamous carcinogenesis at the skin, that is histologically and molecularly similar to carcinogenesis of the human cervix. Previous screens of differentially regulated microRNAs (miRs) using K14-HPV16 mice showed a role for miR-21, miR-155, miR-150, miR-146a, miR-125b and miR-223 during carcinogenesis. METHODS: We now aim to translate these observations into the clinical setting, using data provided by The Cancer Genome Atlas (TCGA) to explore whether those microRNAs can influence the survival of cervical cancer patients. RESULTS: Results showed that low miR-150, miR-155 and miR-146a expression levels in primary tumours were associated with poor overall survival. However, only miR-150 and miR-155 were found to be independent predictors, increasing the risk of death. When patients were stratified by clinical stage, low miR-150, miR-155, miR-146a and miR-125b were associated with poor survival for clinical stages I and II. Only low miR-150 expression increased the death risk. CONCLUSION: We conclude that miR-150 and miR-155 may be potentially applied as prognostic biomarkers in cervical cancer patients. However, further investigation is required to determine their applicability.


Subject(s)
MicroRNAs , Papillomavirus Infections , Uterine Cervical Neoplasms , Animals , Female , Humans , Mice , Biomarkers, Tumor/genetics , Carcinogenesis/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Papillomavirus Infections/genetics , Papillomavirus Infections/pathology , Prognosis , Uterine Cervical Neoplasms/genetics
13.
Diagnostics (Basel) ; 13(21)2023 Oct 31.
Article in English | MEDLINE | ID: mdl-37958253

ABSTRACT

Klotho proteins, αKlotho, ßKlotho, and γKlotho, exert tumor-suppressive activities via the fibroblast growth factor receptors and multiple cell-signaling pathways. There is a growing interest in Klotho proteins as potential diagnostic and prognostic biomarkers for multiple diseases. However, recent advances regarding their roles and potential applications in cancer remain disperse and require an integrated analysis. The present review analyzed research articles published between 2012 and 2022 in the Cochrane and Scopus scientific databases to study the role of Klotho in cancer and their potential as tools for diagnosing specific cancer types, predicting tumor aggressiveness and prognosis. Twenty-six articles were selected, dealing with acute myeloid leukemia and with bladder, breast, colorectal, esophageal, gastric, hepatocellular, ovarian, pancreatic, prostatic, pulmonary, renal, and thyroid cancers. αKlotho was consistently associated with improved prognosis and may be useful in estimating patient survival. A single study reported the use of soluble αKlotho levels in blood serum as a tool to aid the diagnosis of esophageal cancer. γKlotho was associated with increased aggressiveness of bladder, breast, and prostate cancer, and ßKlotho showed mixed results. Further clinical development of Klotho-based assays will require careful identification of specific tumor subtypes where Klotho proteins may be most valuable as diagnostic or prognostic tools.

14.
bioRxiv ; 2023 Nov 17.
Article in English | MEDLINE | ID: mdl-38014164

ABSTRACT

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse group of neurons with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, no studies have mapped the diversity of spinal cell types targeted by CSNs, let alone compare CFA and RFA populations. Here we use anatomical and RNA-sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal cell types, with notable exceptions that suggest these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive surprisingly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior.

16.
Open Vet J ; 13(9): 1223-1227, 2023 09.
Article in English | MEDLINE | ID: mdl-37842105

ABSTRACT

Background: Teratomas are rare types of germ cell neoplasms composed of various differentiated or undifferentiated tissues. Case Description: A 25-week-old female control FVB /n mouse in a 4-week toxicity study presented abdominal distension and poor body condition. It was euthanized, and the necropsy examination revealed a large mass connected to the tip of the right uterine horn, occupying the entire abdominal cavity. Microscopically, this mass showed areas of epidermal differentiation, with laminated keratin and sebaceous glands, differentiation into respiratory and digestive epithelium, cartilage, bone, and extensive areas of differentiation into the nervous tissue, being classified as an ovarian teratoma. Conclusion: As far as authors know, the occurrence of ovarian teratomas in the FVB/n mouse strain has never been previously described.


Subject(s)
Ovarian Neoplasms , Rodent Diseases , Teratoma , Mice , Female , Animals , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/veterinary , Teratoma/diagnosis , Teratoma/veterinary
17.
Molecules ; 28(18)2023 Sep 16.
Article in English | MEDLINE | ID: mdl-37764436

ABSTRACT

The residues generated in the wine industry (pomace, stems, seeds, wine lees, and grapevine shoots) are a potential source of bioactive compounds that can be used in other industries despite being sometimes underestimated. Different extraction methods using various solvents and extraction conditions are currently being investigated. Due to its natural occurrence in wines, safe behavior, and low toxicity when compared to other organic solvents, ethanol is used as an extracting agent. The aim of this study was to identify the winery by-product from the Região Demarcada do Douro and its corresponding extraction solvents that yields the most favorable results in (poly)phenols content and antioxidant capacity. To achieve this, five different ratios of ethanol: water, namely 0:100, 25:75, 50:50, 75:25, and 100:0 (v/v), for extracting the phenolic compounds were employed. Afterwards, the determination of total phenolic content (TPC), ortho-diphenols content (ODC), and flavonoid content (FC) as well as the antioxidant capacity of the obtained extracts using three different methods was performed. Since the best results of the spectrophotometric assays were obtained mostly with hydroethanolic extracts of stems (50:50, v/v), identification by HPLC-DAD has carried out. It was possible to conclude that the Tinta Roriz variety displayed the highest number of identified (poly)phenols.

18.
An. psicol ; 39(2): 207-222, May-Sep. 2023. tab, ilus
Article in English | IBECS | ID: ibc-219760

ABSTRACT

El miedo generalizado de la COVID-19 parece haber exacerbado el impacto negativo de la pandemia. Por eso, es relevante monitorear el miedo de la COVID-19 y su asociación con la salud mental, el bienestar y los comportamientos de las personas, siendo necesarias medidas válidas y fiables de miedo de la COVID-19. Este estudio tuvo como objetivo evaluar las propiedades psicométricas de una versión en portugués europeo de la escala Fear of COVID-19 (FCV-19S-P). Un objetivo secundario fue evaluar la invariancia de medición transversal multigrupo de FCV-19S-P (mujeres vs. hombres). Una muestra de 572 adultos portugueses (72 % mujeres) completaron el FCV-19S-P y medidas de depresión, ansiedad y estrés. Los resultados del estudio respaldaron la validez de esta versión y fiabilidad (alfa de Cronbach = .84; confiabilidad compuesta = .83) y una estructura factorial similar a de la versión original. El miedo de la COVID-19 se asoció positivamente (.23 < r < .31) con depresión, ansiedad y estrés. Los resultados del análisis transversal de invariancia multigrupo respaldaron la invariancia escalar total de la FCV-19S-P y su invariancia residual parcial, lo que sugiere que esta medida puede usarse para llegar a conclusiones válidas con respecto a las comparaciones de género en muestras de adultos portugueses.(AU)


The novelty and uncertainty of the pandemic nourished a gener-alized fear of the COVID-19, which seems to have exacerbated the pan-demic’s negative impact. It is thus relevant to monitor fear of COVID-19 and its association with individuals’ mental health, well-being, and behav-iors. Valid and reliable measures of fear of COVID-19 are necessary for that purpose. This study aimed at assessing the psychometric properties of a European Portuguese version of the Fear of COVID-19 scale (FCV-19S-P). A secondary aim was to assess FCV-19S-P’s multigroup measurement invariance (female vs.male). A sample of 572 Portuguese adults (72 % fe-male) completed the FCV-19S-P and measures of depression, anxiety, and stress. The study results supported this version validityand reliability (Cronbach’s alpha = .84; Composite Reliability = .83), and a factorial struc-ture similar to the original version. Fear of COVID-19 was positively asso-ciated (.23 < r < .31) with depression, anxiety, and stress. Results of the multigroup invariance analysis supported the FCV-19S-P total scalar invar-iance and its partial residual invariance, suggesting that this measure may be used to reach valid conclusions in respect to gender comparisons in samples of Portuguese adults in regard to group observed composite means.(AU)


Subject(s)
Humans , Male , Female , Coronavirus Infections/epidemiology , Pandemics , Fear , Reproducibility of Results , Portugal
19.
Cancers (Basel) ; 15(16)2023 Aug 11.
Article in English | MEDLINE | ID: mdl-37627099

ABSTRACT

High-risk human papillomavirus (HPV) is etiologically related to cervical cancer, other anogenital cancers and oropharyngeal carcinomas. Low-risk HPV, especially HPV6 and HPV11, cause genital warts and laryngeal papillomas. However, the accumulating data suggests that HPV6 and HPV11 may cause malignant lesions at non-cervical anatomic sites. This review aims to estimate the proportions of single and dual HPV6/11 infections in multiple cancers reported in the last 10 years in the Cochrane, Embasa and PubMed databases. Secondly, the genomes of HPV6/11 were compared with the most common high-risk genotype, HPV16, to determine the similarities and differences. A total of 11 articles were selected, including between one and 334 HPV+ cancer patients. The frequencies of single or dual HPV6/11 infections ranged between 0-5.5% for penile and 0-87.5% for laryngeal cancers and were null for vulvar, vaginal and oral cancers. The genomic similarities between HPV6/11 and HPV16 mainly involved the E7 gene, indicating a limited ability to block cell differentiation. The presence of single or dual HPV6/11 infections in variable proportions of penile and laryngeal cancers support the vaccination strategies that cover these genotypes, not only for preventing genital warts but also for cancer prevention. Other risk factors and co-carcinogens are likely to participate in epithelial carcinogenesis associated with low-risk HPV.

20.
Mol Oncol ; 17(12): 2709-2727, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37533407

ABSTRACT

Most patients with muscle-invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up-regulation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF-κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF-κB signaling and patient survival. The efficacy of cisplatin plus the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum-naive claudin-low MIBC showed constitutive NF-κB signaling and this was associated with reduced disease-specific survival in TCGA patients. Chemotherapy up-regulated NF-κB signaling and chemoresistance-associated genes, including SPHK1, PLAUR, and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL-6 serum levels, and did not aggravate immuno-hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF-κB inhibition with platinum-based chemotherapy and conducting a clinical trial in MIBC patients.


Subject(s)
Antineoplastic Agents , Urinary Bladder Neoplasms , Humans , Mice , Animals , NF-kappa B/genetics , Cisplatin/pharmacology , Cisplatin/therapeutic use , Drug Resistance, Neoplasm , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Muscles , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use
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