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BACKGROUND: Worldwide, hypertensive disorders of pregnancy (HDP) are among the leading causes of maternal and fetal morbidity and mortality. Serum uric acid is a test that can evaluate the severity of HDP and the associated maternal and fetal morbidity and mortality. AIM: To examine the relationship between maternal serum uric acid levels and the severity of HDP and overall pregnancy outcomes. MATERIAL AND METHODS: A retrospective study was conducted on women with a gestational age > 20 weeks and BP >140/90 mmHg over three years. A total of 134 patients were included in the study. Patients with chronic hypertension, hyperuricemia without hypertension, and other major illnesses were excluded. Data were collected from medical records, including age, gravida, parity, weight, height, gestational age, blood pressure at admission, urine albumin, and serum uric acid levels. RESULTS: Of the 134 enrolled women with HDP, 76 had gestational hypertension, 41 had preeclampsia, and 17 had eclampsia. Mean uric acid levels in mg/dL were 6.06±1.651, 6.20±0.824, and 7.38±1.26 in gestational hypertension, preeclampsia, and eclampsia, respectively, which was a significant association (p=0.002). Mean uric acid in mg/dL was 5.86±1.27 in intensive care unit (ICU) patients compared to 6.45±1.39 in ward patients (p=0.015). There was a significantly increased risk of ICU admission and preterm delivery (r=-0.401, p<0.001) in patients with elevated uric acid levels. There was a significantly increased risk of low-birth-weight babies with elevated uric acid levels (r=-0.278, p=0.001). However, there was no statistically significant increased risk of newborn intensive care unit admissions (p=0.264) with elevated uric acid levels. CONCLUSION: Serum uric acid levels vary significantly in HDP and were found to be elevated in severe preeclampsia and eclampsia. It can be considered for risk stratification in HDP based on disease severity; however, its role in determining outcomes is debatable. Using serum uric acid levels in predictive models along with known biomarkers may determine its possible additional value in disease prediction and severity.
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BACKGROUND AND AIMS: Mineralocorticoid receptor antagonists (MRAs) improve cardiovascular outcomes in a variety of settings. This study aimed to assess whether cardioprotective effects of MRAs are modified by heart failure (HF) and atrial fibrillation (AF) status and to study their impact on AF events. METHODS: MEDLINE, Embase, and Cochrane Central databases were searched to 24 March 2023 for randomized controlled trials evaluating the efficacy of MRAs as compared with placebo or usual care in reducing cardiovascular outcomes and AF events in patients with or at risk for cardiovascular diseases. Random-effects models and interaction analyses were used to test for effect modification. RESULTS: Meta-analysis of seven trials (20 741 participants, mean age: 65.6 years, 32% women) showed that the efficacy of MRAs, as compared with placebo, in reducing a composite of cardiovascular death or HF hospitalization remains consistent across patients with HF [risk ratio = 0.81; 95% confidence interval (CI): 0.67-0.98] and without HF (risk ratio = 0.84; 95% CI: 0.75-0.93; interaction P = .77). Among patients with HF, MRAs reduced cardiovascular death or HF hospitalization in patients with AF (hazard ratio = 0.95; 95% CI: 0.54-1.66) to a similar extent as in those without AF (hazard ratio = 0.82; 95% CI: 0.63-1.07; interaction P = .65). Pooled data from 20 trials (21 791 participants, mean age: 65.2 years, 31.3% women) showed that MRAs reduce AF events (risk ratio = 0.76; 95% CI: 0.67-0.87) in both patients with and without prior AF. CONCLUSIONS: Mineralocorticoid receptor antagonists are similarly effective in preventing cardiovascular events in patients with and without HF and most likely retain their efficacy regardless of AF status. Mineralocorticoid receptor antagonists may also be moderately effective in preventing incident or recurrent AF events.
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Fibrilação Atrial , Insuficiência Cardíaca , Idoso , Feminino , Humanos , Masculino , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Ensaios Clínicos como AssuntoRESUMO
Objective. Brain-computer interface (BCI) technology is poised to play a prominent role in modern work environments, especially a collaborative environment where humans and machines work in close proximity, often with physical contact. In a physical human robot collaboration (pHRC), the robot performs complex motion sequences. Any unexpected robot behavior or faulty interaction might raise safety concerns. Error-related potentials, naturally generated by the brain when a human partner perceives an error, have been extensively employed in BCI as implicit human feedback to adapt robot behavior to facilitate a safe and intuitive interaction. However, the integration of BCI technology with error-related potential for robot control demands failure-free integration of highly uncertain electroencephalography (EEG) signals, particularly influenced by the physical and cognitive state of the user. As a higher workload on the user compromises their access to cognitive resources needed for error awareness, it is crucial to study how mental workload variations impact the error awareness as it might raise safety concerns in pHRC. In this study, we aim to study how cognitive workload affects the error awareness of a human user engaged in a pHRC.Approach. We designed a blasting task with an abrasive industrial robot and manipulated the mental workload with a secondary arithmetic task of varying difficulty. EEG data, perceived workload, task and physical performance were recorded from 24 participants moving the robot arm. The error condition was achieved by the unexpected stopping of the robot in 33% of trials.Main results. We observed a diminished amplitude for the prediction error negativity (PEN) and error positivity (Pe), indicating reduced error awareness with increasing mental workload. We further observed an increased frontal theta power and increasing trend in the central alpha and central beta power after the unexpected robot stopping compared to when the robot stopped correctly at the target. We also demonstrate that a popular convolution neural network model, EEGNet, could predict the amplitudes of PEN and Pe from the EEG data prior to the error.Significance. This prediction model could be instrumental in developing an online prediction model that could forewarn the system and operators of the diminished error awareness of the user, alluding to a potential safety breach in error-related potential-based BCI system for pHRC. Therefore, our work paves the way for embracing BCI technology in pHRC to optimally adapt the robot behavior for personalized user experience using real-time brain activity, enriching the quality of the interaction.
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Interfaces Cérebro-Computador , Robótica , Humanos , Carga de Trabalho/psicologia , Eletroencefalografia/métodos , CogniçãoRESUMO
Ectopic variceal bleeding is a potentially under recognized source of gastrointestinal (GI) hemorrhage. While vascular complications following pancreatic transplant are relatively common, the development of symptomatic ectopic venous varices has rarely been reported. We report two patients with a remote history of simultaneous kidney pancreas transplant (SPK) presenting two decades after transplant with an occult GI bleed. In both cases, a lengthy diagnostic course was required. The varices were treated with coil embolization via transhepatic approach. Our findings add to the limited literature on this topic and aid in the recognition, diagnosis, and management of this unusual presentation.
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Embolização Terapêutica , Varizes Esofágicas e Gástricas , Transplante de Pâncreas , Varizes , Humanos , Varizes Esofágicas e Gástricas/diagnóstico , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/terapia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Varizes/complicações , Varizes/terapia , Transplante de Pâncreas/efeitos adversosRESUMO
NHC-Pd(II) pincer catalyzed oxidative amination and hydroamination of olefins is developed under solvent-free aerobic conditions. Reaction offered a temperature-controlled synthesis of (Z)-enamine and ß-amino esters to provide easy access and remarkable functional group tolerance for a variety of enamines. The developed approach renders an opportunity of scalability and flexibility, and besides this, the produced enamines can be transformed into many N-containing heterocycles, underscoring its potential usage in synthetic and pharmaceutical chemistry. Moreover, it is the first report for coupling of aniline with styrene.
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Nephrotoxicity is a significant concern during the development of new drugs or when assessing the safety of chemicals in consumer products. Traditional methods for testing nephrotoxicity involve animal models or 2D in vitro cell cultures, the latter of which lack the complexity and functionality of the human kidney. 3D in vitro models are created by culturing human primary kidney cells derived from urine in a 3D microenvironment that mimics the fluid shear stresses of the kidney. Thus, 3D in vitro models provide more accurate and reliable predictions of human nephrotoxicity compared to existing 2D models. In this review, we focus on precision nephrotoxicity testing using 3D in vitro models with human autologous urine-derived kidney cells as a promising approach for evaluating drug safety.
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Human papillomavirus (HPV) vaccination among adolescents in rural, western North Carolina (NC) remains suboptimal. Data are needed to understand the barriers to HPV vaccination in these communities. We conducted a cross-sectional pilot study of parental attitudes and provider practices regarding HPV vaccination in rural western NC counties with lower HPV vaccination rates. Eight health department clinics were enrolled in the study. Further, 29 provider and 32 parent surveys were analyzed along with environmental scans. Median provider comfort regarding knowledge of HPV-associated diseases was 85% (IQR = 75-95), on a scale of 0-100% (100% representing complete comfort). Median parental comfort level regarding knowledge of HPV-associated diseases and the HPV vaccine was 75% (IQR = 50-89) and 75% (IQR = 49-96), respectively. Less than 25% of parents rated the HPV vaccine as 'extremely effective' against genital (16.7%) and anal cancers (17.9%). Parents were more likely to rate the vaccine as 'extremely effective' to 'very effective' if their child was female. There was no significant difference between parental- and provider-reported comfort with knowledge about HPV-associated diseases (p = 0.0725) and the HPV vaccine (p = 0.167). This study identified multiple opportunities to increase HPV vaccine coverage among unvaccinated adolescents at parental, provider, and clinic levels. Health education of rural NC residents and providers in public health settings may identify future interventions to increase HPV vaccine uptake.
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Few seroprevalence studies have been conducted on coronavirus disease (COVID-19) in Nepal. Here, we aimed to estimate seroprevalence and assess risk factors for infection in the general population of Nepal by conducting two rounds of sampling. The first round was in October 2020, at the peak of the first generalized wave of COVID-19, and the second round in July-August 2021, following the peak of the wave caused by the delta variant of SARS-CoV-2. We used cross-sectional probability-to-size (PPS)-based multistage cluster sampling to estimate the seroprevalence in the general population of Nepal at the national and provincial levels. We tested for anti-SARS-CoV-2 total antibody using the WANTAI SARS-CoV-2 Ab ELISA kit. In Round 1, the overall national seroprevalence was 14.4%, with provincial estimates ranging from 5.3% in Sudurpaschim to 27.3% in Madhesh Province. In Round 2, the estimated national seroprevalence was 70.7%, with the highest in the Madhesh Province (84.8%) and the lowest in the Gandaki Province (62.9%). Seroprevalence was comparable between males and females (Round 1, 15.8% vs. 12.2% and Round 2, 72.3% vs. 68.7%). The seroprevalence in the ecozones-Terai, hills, and mountains-was 76.3%, 65.3%, and 60.5% in Round 2 and 17.7%, 11.7%, and 4.6% in Round 1, respectively. In Nepal, COVID-19 vaccination was introduced in January 2021. At the peak of the first generalized wave of COVID-19, most of the population of Nepal remained unexposed to SARS-CoV-2. Towards the end of the second generalized wave in April 2021, two thirds of the population was exposed.
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COVID-19 , Feminino , Masculino , Humanos , COVID-19/epidemiologia , Nepal/epidemiologia , Vacinas contra COVID-19 , Estudos Transversais , Pandemias , Estudos Soroepidemiológicos , SARS-CoV-2 , Anticorpos AntiviraisRESUMO
Importance: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can give rise to pancreatic cancer (PC). Limited population data exist on their prevalence, natural history, or risk of malignant transformation (IPMN-PC). Objective: To fill knowledge gaps in epidemiology of IPMNs and associated PC risk by estimating population prevalence of IPMNs, associated PC risk, and proportion of IPMN-PC. Design, Setting, and Participants: : This retrospective cohort study was conducted in Olmsted County, Minnesota. Using the Rochester Epidemiology Project (REP), patients aged 50 years and older with abdominal computed tomography (CT) scans between 2000 and 2015 were randomly selected (CT cohort). All patients from the REP with PC between 2000 and 2019 were also selected (PC cohort). Data were analyzed from November 2021 through August 2023. Main outcomes and Measures: CIs for PC incidence estimates were calculated using exact methods with the Poisson distribution. Cox models were used to estimate age, sex, and stage-adjusted hazard ratios for time-to-event end points. Results: The CT cohort included 2114 patients (1140 females [53.9%]; mean [SD] age, 68.6 [12.1] years). IPMNs were identified in 231 patients (10.9%; 95% CI, 9.7%-12.3%), most of which were branch duct (210 branch-duct [90.9%], 16 main-duct [6.9%], and 5 mixed [2.2%] IPMNs). There were 5 Fukuoka high-risk (F-HR) IPMNs (2.2%), 39 worrisome (F-W) IPMNs (16.9%), and 187 negative (F-N) IPMNs (81.0%). After a median (IQR) follow-up of 12.0 (8.1-15.3) years, 4 patients developed PC (2 patients in F-HR and 2 patients in F-N groups). The PC incidence rate per 100 person years for F-HR IPMNs was 34.06 incidents (95% CI, 4.12-123.02 incidents) and not significantly different for patients with F-N IPMNs compared with patients without IPMNs (0.16 patients; 95% CI, 0.02-0.57 patients vs 0.11 patients; 95% CI, 0.06-0.17 patients; P = .62). The PC cohort included 320 patients (155 females [48.4%]; mean [SD] age, 72.0 [12.3] years), and 9.8% (95% CI, 7.0%-13.7%) had IPMN-PC. Compared with 284 patients with non-IPMN PC, 31 patients with IPMN-PC were older (mean [SD] age, 76.9 [9.2] vs 71.3 [12.5] years; P = .02) and more likely to undergo surgical resection (14 patients [45.2%] vs 60 patients [21.1%]; P = .003) and more-frequently had nonmetastatic PC at diagnosis (20 patients [64.5%] vs 130 patients [46.8%]; P = .047). Patients with IPMN-PC had better survival (adjusted hazard ratio, 0.62; 95% CI, 0.40-0.94; P = .03) than patients with non-IPMN PC. Conclusions and Relevance: In this study, CTs identified IPMNs in approximately 10% of patients aged 50 years or older. PC risk in patients with F-N IPMNs was low and not different compared with patients without IPMNs; approximately 10% of patients with PC had IPMN-PC, and they had better survival compared with patients with non-IPMN PC.
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Neoplasias Císticas, Mucinosas e Serosas , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Neoplasias Intraductais Pancreáticas/diagnóstico por imagem , Neoplasias Intraductais Pancreáticas/epidemiologia , Neoplasias Intraductais Pancreáticas/patologia , Estudos Retrospectivos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
Wearable smart glasses are an emerging technology gaining popularity in the assistive technologies industry. Smart glasses aids typically leverage computer vision and other sensory information to translate the wearer's surrounding into computer-synthesized speech. In this work, we explored the potential of a new technique known as "acoustic touch" to provide a wearable spatial audio solution for assisting people who are blind in finding objects. In contrast to traditional systems, this technique uses smart glasses to sonify objects into distinct sound auditory icons when the object enters the device's field of view. We developed a wearable Foveated Audio Device to study the efficacy and usability of using acoustic touch to search, memorize, and reach items. Our evaluation study involved 14 participants, 7 blind or low-visioned and 7 blindfolded sighted (as a control group) participants. We compared the wearable device to two idealized conditions, a verbal clock face description and a sequential audio presentation through external speakers. We found that the wearable device can effectively aid the recognition and reaching of an object. We also observed that the device does not significantly increase the user's cognitive workload. These promising results suggest that acoustic touch can provide a wearable and effective method of sensory augmentation.
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Acústica , Percepção do Tato , Humanos , Cegueira , Fala , Visão OcularRESUMO
The use of dual-energy computed tomography (CT) allows for reconstruction of energy- and material-specific image series. The combination of low-energy monochromatic images, iodine maps, and virtual unenhanced images can improve lesion detection and disease characterization in the gastrointestinal tract in comparison with single-energy CT.
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The purpose of the paper is to identify factors associated with operational factor (OF), geo-environmental factor (GEF), and managerial factor (MF) from the literature. After identification, the study intended to assess the impact of geo-environmental factors and managerial factors on operational factors of the mining industry. The study also tests the indirect effect of managerial factors between GEF and OF in the Indian environment. The geographical boundary of the study was 06 large mines of Odisha, Jharkhand, and Chhattisgarh of India. Three hundred and twenty nine number of purposive samples were collected via email and filtered and processed through the SPSS package. To find out the complex role and inter-relationship of GEF and MF on OF, the study adopted the structural equation modelling technique. The finding reflects that MF plays a partial mediation among GEF and OF. This phenomenon is completely novel in its field when it comes to the geo-environmental and management difficulties confronting mining operations. This research can aid managers in identifying key geological and environmental concerns in mining operations, as well as providing data for regulatory compliance. Overall, this study's findings can help management create policies and manage the environmental concerns of the mining sector. The study's findings provide important directions for future Indian mining research.
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Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here we identify a role of CNT1 in the renal reabsorption of nucleosides. Deletion of CNT1 in mice increases the urinary excretion of endogenous pyrimidine nucleosides with compensatory alterations in purine nucleoside metabolism. In addition, CNT1 KO mice exhibits high urinary excretion of the nucleoside analog gemcitabine (dFdC), which results in poor tumor growth control in CNT1 KO mice harboring syngeneic pancreatic tumors. Interestingly, increasing the dFdC dose to attain an area under the concentration-time curve level equivalent to that achieved by wild-type (WT) mice rescues antitumor efficacy. The findings provide new insights into how CNT1 regulates reabsorption of endogenous and synthetic nucleosides in murine kidneys and suggest that the functional status of CNTs may account for the optimal action of pyrimidine nucleoside analog therapeutics in humans.
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Nucleosídeos , Nucleosídeos de Pirimidina , Humanos , Camundongos , Animais , Nucleosídeos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Eliminação Renal , Proteínas de Transporte/metabolismo , Antimetabólitos , Proteínas de Transporte de Nucleosídeos/metabolismo , Rim/metabolismoRESUMO
Head and neck squamous cell carcinoma (HNSCC) accounts for over 10,000 deaths in the United States annually. Approximately 80% of HNSCC are human papillomavirus (HPV)-negative which have an overall poorer prognosis compared to the HPV-positive disease. Treatment options are mainly nontargeted chemotherapy, radiation, and surgery. The cyclin-d-CDK4/6-RB pathway, which regulates cell cycle progression, is often deregulated in HNSCC, making it an attractive therapeutic target. In the current study, we investigated the therapeutic effects of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in preclinical models of HNSCCs. Our results show that the specific CDK4/6 inhibitor, abemaciclib, inhibited cell growth, and induced apoptosis in HNSCC cell lines. We also demonstrated that both the pro-survival autophagy pathway and the ERK pathway in HNSCC cells were activated with abemaciclib treatment through the generation of reactive oxygen species (ROS). Coinhibition of CDK4/6 and autophagy synergistically decreased cell viability, induced apoptosis, and inhibited tumor growth in both in vitro and in vivo preclinical HNSCC models. These results reveal a potential therapeutic strategy that supports the rationale for further clinical development of a combination of CDK4/6 and autophagy inhibitors in HNSCC.
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Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Apoptose , Autofagia , Linhagem Celular TumoralRESUMO
Photon-counting detector (PCD) CT is an emerging technology that has led to continued innovation and progress in diagnostic imaging after it was approved by the U.S. Food and Drug Administration for clinical use in September 2021. Conventional energy-integrating detector (EID) CT measures the total energy of x-rays by converting photons to visible light and subsequently using photodiodes to convert visible light to digital signals. In comparison, PCD CT directly records x-ray photons as electric signals, without intermediate conversion to visible light. The benefits of PCD CT systems include improved spatial resolution due to smaller detector pixels, higher iodine image contrast, increased geometric dose efficiency to allow high-resolution imaging, reduced radiation dose for all body parts, multienergy imaging capabilities, and reduced artifacts. To recognize these benefits, diagnostic applications of PCD CT in musculoskeletal, thoracic, neuroradiologic, cardiovascular, and abdominal imaging must be optimized and adapted for specific diagnostic tasks. The diagnostic benefits and clinical applications resulting from PCD CT in early studies have allowed improved visualization of key anatomic structures and radiologist confidence for some diagnostic tasks, which will continue as PCD CT evolves and clinical use and applications grow. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material. See the invited commentary by Ananthakrishnan in this issue.
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Iodo , Tomografia Computadorizada por Raios X , Humanos , Imagens de Fantasmas , Tomografia Computadorizada por Raios X/métodos , Intensificação de Imagem Radiográfica/métodos , FótonsRESUMO
Indoor superspreading events are significant drivers of transmission of respiratory diseases. In this work, we study the dynamics of airborne transmission in consecutive meetings of individuals in enclosed spaces. In contrast to the usual pairwise-interaction models of infection where effective contacts transmit the disease, we focus on group interactions where individuals with distinct health states meet simultaneously. Specifically, the disease is transmitted by infected individuals exhaling droplets (contributing to the viral load in the closed space) and susceptible ones inhaling the contaminated air. We propose a modeling framework that couples the fast dynamics of the viral load attained over meetings in enclosed spaces and the slow dynamics of disease progression at the population level. Our modeling framework incorporates the multiple time scales involved in different setups in which indoor events may happen, from single-time events to events hosting multiple meetings per day, over many days. We present theoretical and numerical results of trade-offs between the room characteristics (ventilation system efficiency and air mass) and the group's behavioral and composition characteristics (group size, mask compliance, testing, meeting time, and break times), that inform indoor policies to achieve disease control in closed environments through different pathways. Our results emphasize the impact of break times, mask-wearing, and testing on facilitating the conditions to achieve disease control. We study scenarios of different break times, mask compliance, and testing. We also derive policy guidelines to contain the infection rate under a certain threshold.
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Poluição do Ar em Ambientes Fechados , Poluição do Ar , HumanosRESUMO
Wnt ligands are critical for tissue homeostasis and form a complex with LRP6 and frizzled coreceptors to initiate Wnt/ß-catenin signaling. Yet, how different Wnts achieve various levels of signaling activation through distinct domains on LRP6 remains elusive. Developing tool ligands that target individual LRP6 domains could help elucidate the mechanism of Wnt signaling regulation and uncover pharmacological approaches for pathway modulation. We employed directed evolution of a disulfide constrained peptide (DCP) to identify molecules that bind to the third ß-propeller domain of LRP6. The DCPs antagonize Wnt3a while sparing Wnt1 signaling. Using PEG linkers with different geometries, we converted the Wnt3a antagonist DCPs to multivalent molecules that potentiated Wnt1 signaling by clustering the LRP6 coreceptor. The mechanism of potentiation is unique as it occurred only in the presence of extracellular secreted Wnt1 ligand. While all DCPs recognized a similar binding interface on LRP6, they displayed different spatial orientations that influenced their cellular activities. Moreover, structural analyses revealed that the DCPs exhibited new folds that were distinct from the parent DCP framework they were evolved from. The multivalent ligand design principles highlighted in this study provide a path for developing peptide agonists that modulate different branches of cellular Wnt signaling.
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Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Proteínas Wnt , Ligantes , Proteínas Wnt/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , beta Catenina/metabolismo , Ligação Proteica , Via de Sinalização Wnt , Peptídeos/farmacologia , Peptídeos/metabolismoRESUMO
Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatment-dependent. In preclinical models of MM, synergy was observed in anti-tumor activity when poly (ADPribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan-sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.
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Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Melfalan/uso terapêutico , Prognóstico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Transplante Autólogo , Transplante de Células-Tronco , Estudos Retrospectivos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/uso terapêutico , DNA Polimerase IIIRESUMO
BACKGROUND: We assessed the change in obstetric management after implementation of a quality improvement intervention, the Nepal Perinatal Quality Improvement Package (NePeriQIP). METHODS: The Nepal Perinatal Quality Improvement Package was a stepped-wedge cluster-randomized controlled trial conducted in 12 public hospitals in Nepal between April 2017 and October 2018. In this study, three hospitals allocated at different time points to the intervention were selected for a nested before-after analysis. We used bivariate and multivariate analyses to compare obstetric management in the control vs intervention group. RESULTS: There were 25 977 deliveries in the three hospitals during the study period: 10 207 (39%) in the control and 15 770 (61%) in the intervention group. After adjusting for maternal age, ethnicity, education, gestational age, stage of labor at admission, complications during labor, and birthweight, the intervention group had a higher proportion of fetal heart rate monitoring performed as per protocol (adjusted odds ratio [aOR] 1.19, 95% confidence interval [CI] 1.12-1.27), shorter time intervals between each fetal heart rate monitoring (aOR 2.09, 95% CI 1.96-2.23), a higher likelihood of abnormal fetal heart rate being detected (aOR 1.53, 95% CI 1.25-1.68), progress of labor more often being recorded immediately after per vaginal examination (aOR 2.73, 95% CI 2.55-2.93), and partograph filled as per standards (aOR 3.18, 95% CI 2.98-3.50). The cesarean birth rate was 2.5% in the control group and 8.2% in the intervention group (aOR 3.12, 95% CI 2.64-3.68). CONCLUSIONS: The NePeriQIP intervention has potential to improve obstetric care, especially intrapartum fetal surveillance, in similar low-resource settings.