High baseline perivascular space volume in basal ganglia is associated with attention and executive function decline in Parkinson's disease.

BACKGROUND: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. OBJECTIVES: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. METHODS: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. RESULTS: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. CONCLUSIONS: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.

Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).

Increased perivascular space volume in white matter and basal ganglia is associated with cognition in Parkinson's Disease.

Perivascular spaces (PVS), fluid-filled compartments surrounding brain vasculature, are an essential component of the glymphatic system responsible for transport of waste and nutrients. Glymphatic system impairment may underlie cognitive deficits in Parkinson's disease (PD). Studies have focused on the role of basal ganglia PVS with cognition in PD, but the role of white matter PVS is unknown. This study examined the relationship of white matter and basal ganglia PVS with domain-specific and global cognition in individuals with PD. Fifty individuals with PD underwent 3T T1w magnetic resonance imaging (MRI) to determine PVS volume fraction, defined as PVS volume normalized to total regional volume, within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of global cognitive function (Montreal Cognitive Assessment, and global cognitive composite score), and cognitive-specific domains (executive function, memory, visuospatial function, attention, and language). Higher white matter rostral middle frontal PVS was associated with lower scores in both global cognitive and visuospatial function. In the basal ganglia higher PVS was associated with lower scores for memory with a trend towards lower global cognitive composite score. While previous reports have shown that greater amount of PVS in the basal ganglia is associated with decline in global cognition in PD, our findings suggest that increased white matter PVS volume may also underlie changes in cognition.

Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition.

Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor-positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.

Neonatal and early childhood outcomes following early vs later preterm premature rupture of membranes.

OBJECTIVE: Data regarding long-term outcomes of neonates reaching viability following early preterm premature rupture of membranes (PPROM; <25.0 weeks at rupture) are limited. We hypothesized that babies delivered after early PPROM would have increased rates of major childhood morbidity compared with those with later PPROM (≥25.0 weeks at rupture). STUDY DESIGN: This was a secondary analysis of a multicenter randomized controlled trial of magnesium sulfate vs placebo for cerebral palsy prevention. Women with singletons and PPROM of 15-32 weeks were included. All women delivered at 24.0 weeks or longer. Those with PPROM less than 25.0 weeks (cases) were compared with women with PPROM at 25.0-31.9 weeks (controls). Composite severe neonatal morbidity (sepsis, severe intraventricular hemorrhage, periventricular leukomalacia, severe necrotizing enterocolitis, bronchopulmonary dysplasia, and/or death) and composite severe childhood morbidity at age 2 years (moderate or severe cerebral palsy and/or Bayley II Infant and Toddler Development scores greater than 2 SD below the mean) were compared. RESULTS: A total of 1531 women (275 early PPROM cases) were included. Demographics were similar between the groups. Cases delivered earlier (26.6 vs 30.1 weeks, P < .001) and had a longer rupture-to-delivery interval (20.0 vs 10.4 days, P < .001). Case neonates had high rates of severe composite neonatal morbidity (75.6% vs 21.8%, P < .001). Children with early PPROM had higher composite severe childhood morbidity (51.6% vs 22.5%, P < .001). Early PPROM remained associated with composite severe childhood morbidity in multivariable models, even when controlling for delivery gestational age and other confounders. CONCLUSION: Early PPROM is associated with high rates of neonatal morbidity. Early childhood outcomes at age 2 years remain poor compared with those delivered after later PPROM.

The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

Delivery of monochorionic twins in the absence of complications: analysis of neonatal outcomes and costs.

OBJECTIVE: We sought to estimate the optimal time to deliver uncomplicated monochorionic-diamnionic (MCDA) twins. STUDY DESIGN: Data were retrospectively obtained from twin pregnancies from 2000 through 2009. The gestational week-specific prospective perinatal mortality risk was calculated. A cohort of MCDA twins with nonindicated deliveries was analyzed separately. Neonatal outcomes and costs were compared between MCDA twins with nonindicated deliveries born at specific weeks of gestation, and those born the subsequent week. RESULTS: There were 5894 dichorionic-diamnionic twins and 1704 MCDA twins. After 28 weeks, the gestational week-specific prospective risk of perinatal mortality did not differ between groups. There were 948 MCDA twins with nonindicated deliveries. Until 37 weeks, the risk of severe neonatal morbidity, perinatal mortality, and hospital costs were greater for fetuses delivered compared to fetuses born in a subsequent week. CONCLUSION: To optimize neonatal outcome and decrease hospital costs, MCDA twins should not be delivered <37 weeks unless medically indicated.

The effects of branched-chain amino acid interactions on growth performance, blood metabolites, enzyme kinetics and transcriptomics in weaned pigs.

The impact of excess dietary leucine (Leu) was studied in two growth assays with pigs (8-25 kg). In each trial, forty-eight pigs were allotted to one of six dietary groups. The dietary Leu supply increased from treatment L100 to L200 (three increments). To guarantee that interactions between the branched-chain amino acids (BCAA) were not cushioned either surpluses of isoleucine (Ile, expt 1) or valine (Val; expt 2) were avoided. In the fifth treatment, the effects of a simultaneous excess of Leu and Val (expt 1), or of Leu and Ile (expt 2) were investigated. The sixth treatment was a positive control. An increase in dietary Leu decreased growth performance, and increased plasma Leu and serum alpha-keto-isocaproate levels in a linear, dose-dependent manner. Levels of plasma Ile and Val, and of serum alpha-keto-beta-methylvalerate and alpha-keto-isovalerate, indicated increased catabolism. Linear increases in the activity of basal branched-chain alpha-keto acid dehydrogenase in the liver confirmed these findings. No major alterations occurred in the mRNA of branched-chain amino acid catabolism genes. In liver tissue from expt 2, however, the mRNA levels of growth hormone receptor, insulin-like growth factor acid labile subunit and insulin-like growth factor 1 decreased significantly with increasing dietary Leu. In conclusion, excess dietary Leu increased the catabolism of BCAA mainly through posttranscriptional mechanisms. The impact of excess Leu on the growth hormone--insulin-like growth factor-1 axis requires further investigation.

1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.

Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.

Computed tomography imaging strategies and perspectives in orbital fractures

OBJECTIVE: The objective of this study was to demonstrate the sensitivity and specificity of multislice computed tomography (CT) for diagnosis of orbital fractures following different protocols, using an independent workstation. MATERIALS AND METHODS: CT images of 36 patients with maxillofacial fractures (symptomatic to orbit region) who were submitted to multislice CT scanning were analyzed, retrospectively. The images were interpreted based on 5 protocols, using an independent workstation: 1) axial (original images); 2) multiplanar reconstruction (MPR); 3) 3D images; 4) association of axial/MPR/3D images and 5) coronal images. The evaluated anatomical sites were divided according to the orbital walls: lateral (with or without zygomatic frontal process fracture); medial; superior (roof) and inferior (anterior, medial). The collected data were analyzed statistically using a validity test (Youden's J index; p<0.05). The clinical and/or surgical findings (medical records) were considered as the gold standard to corroborate the diagnosis of the anatomical localization of the orbital fracture. RESULTS: 3D-CT scanning presented sensitivity of 78.9 percent, which was not superior to that of MPR (84.0 percent), axial/MPR/3D (90.5 percent) and coronal images (86.1 percent). On the other hand, the diagnostic value of axial images was considered limited for orbital fractures region, with sensitivity of 44.2 percent. CONCLUSIONS: Except for the axial images, which presented a low sensitivity, all methods evaluated in this study showed high specificity and sensitivity for the diagnosis of orbital fractures according to the proposed methodology. This protocol can add valuable information to the diagnosis of fractures using the association of axial/MPR/3D with multislice CT.

Computed tomography imaging strategies and perspectives in orbital fractures.

OBJECTIVE: The objective of this study was to demonstrate the sensitivity and specificity of multislice computed tomography (CT) for diagnosis of orbital fractures following different protocols, using an independent workstation. MATERIALS AND METHODS: CT images of 36 patients with maxillofacial fractures (symptomatic to orbit region) who were submitted to multislice CT scanning were analyzed, retrospectively. The images were interpreted based on 5 protocols, using an independent workstation: 1) axial (original images); 2) multiplanar reconstruction (MPR); 3) 3D images; 4) association of axial/MPR/3D images and 5) coronal images. The evaluated anatomical sites were divided according to the orbital walls: lateral (with or without zygomatic frontal process fracture); medial; superior (roof) and inferior (anterior, medial). The collected data were analyzed statistically using a validity test (Youden's J index; p<0.05). The clinical and/or surgical findings (medical records) were considered as the gold standard to corroborate the diagnosis of the anatomical localization of the orbital fracture. RESULTS: 3D-CT scanning presented sensitivity of 78.9%, which was not superior to that of MPR (84.0%), axial/MPR/3D (90.5%) and coronal images (86.1%). On the other hand, the diagnostic value of axial images was considered limited for orbital fractures region, with sensitivity of 44.2%. CONCLUSIONS: Except for the axial images, which presented a low sensitivity, all methods evaluated in this study showed high specificity and sensitivity for the diagnosis of orbital fractures according to the proposed methodology. This protocol can add valuable information to the diagnosis of fractures using the association of axial/MPR/3D with multislice CT.

Validity of multislice computerized tomography for diagnosis of maxillofacial fractures using an independent workstation.

OBJECTIVE: The purpose of this study was to demonstrate the sensitivity and specificity of multislice computerized tomography (CT) for diagnosis of maxillofacial fractures following specific protocols using an independent workstation. STUDY DESIGN: The study population consisted of 56 patients with maxillofacial fractures who were submitted to a multislice CT. The original data were transferred to an independent workstation using volumetric imaging software to generate axial images and simultaneous multiplanar (MPR) and 3-dimensional (3D-CT) volume rendering reconstructed images. The images were then processed and interpreted by 2 examiners using the following protocols independently of each other: axial, MPR/axial, 3D-CT images, and the association of axial/MPR/3D images. The clinical/surgical findings were considered the gold standard corroborating the diagnosis of the fractures and their anatomic localization. The statistical analysis was carried out using validity and chi-squared tests. RESULTS: The association of axial/MPR/3D images indicated a higher sensitivity (range 95.8%) and specificity (range 99%) than the other methods regarding the analysis of all regions. CONCLUSION: CT imaging demonstrated high specificity and sensitivity for maxillofacial fractures. The association of axial/MPR/3D-CT images added important information in relationship to other CT protocols.

CT-based analysis of malignant tumor volume and localization: a preliminary study

O propósito desta pesquisa foi correlacionar medidas volumétricas de lesões malignas em reconstruções tridimensionais (TC-3D) com a resposta ao tratamento e verificar o grau de envolvimento ósseo dessas lesões, aplicando-se protocolos de imagem específicos associados à computação gráfica. Foram estudados 17 indivíduos portadores de lesões malignas maxilofaciais que haviam sido submetidos à tomografia computadorizada espiral (TC-2D). Os dados originais foram transferidos para uma estação de trabalho independente, utilizando um programa para imagens volumétricas, com o qual dois observadores obtiveram medidas de área e volume das lesões, independentemente, 3 vezes cada um, no pré e pós-tratamento. O protocolo de segmentação foi aplicado para avaliação do comprometimento ósseo. A diferença entre os valores obtidos na análise da TC e no padrão ouro não foi considerada significante (p > 0,05). Considerando o envolvimento ósseo, obtiveram-se três falsos-negativos em análise das reconstruções multiplanares (TC-RMP) e nenhum falso-negativo em análise da TC-3D por meio do protocolo de segmentação. A utilização de recursos como reconstrução em TC-3D pode ser um fator diferencial e de grande valia para aumentar opções quanto a localização, dimensões e esclarecimento de componentes de diversas lesões.

CT-based analysis of malignant tumor volume and localization. A preliminary study.

The purpose of this study was to correlate 3D-CT (3D computed tomography) volume measurements of malignant tumors with the response to treatment, and to observe bone invasion in these lesions applying a specific imaging protocol. We analyzed 17 individuals with maxillofacial malignant lesions who were submitted to spiral CT (2D-CT). The original data were transferred to an independent workstation using a 3D volume rendering package software, which was used by two examiners to obtain area and volume measurements of the lesions, independently, three times each, prior to and after treatment. The segmentation protocol was applied for the assessment of bone involvement. The difference between imaging and gold standard values was not considered significant (p > 0.05). Regarding bone invasion, three false-negatives were obtained using MPR-CT (multiplanar reconstruction) and no false-negatives were obtained using the 3D segmentation protocol. The use of 3D-CT may be a differential and important factor for expanding options regarding the localization, dimension, and clarification of lesion components.

The mRNA expression of insulin receptor isoforms (IR-A and IR-B) and IGFR-2 in the bovine corpus luteum during the estrous cycle, pregnancy, and induced luteolysis.

Isoform A of the human insulin receptor and the IGF-receptor type 2 (IGFR-2) are both receptors for insulin- like growth factor II (IGF II), which plays a major role in luteal development and function in bovine species. The objective of this study was to determine if both insulin receptor isoforms and IGFR-2 were expressed in the bovine corpus luteum (CL) and if they were regulated during the estrous cycle, pregnancy, and induced luteolysis. CL were collected at the slaughterhouse. For induced luteolysis, CL were obtained by transvaginal ovariectomy at 2, 4, 12, 48, and 64 h after prostaglandin (PG) F2alpha-injection. Real-time RT-PCR was applied to investigate mRNA expression. Two alternatively spliced transcripts encoding the insulin receptor were detected in bovine CL. These two isoforms corresponded to the known isoforms A (IR-A) and B (IR-B) in humans. IR-A mRNA predominated in bovine CL and was significantly down-regulated on d 5-7. IR-B mRNA was significantly up-regulated in the late luteal stage and during early pregnancy. IR-A showed a significant down-regulation at 48 h after PGF2. IGFR-2 mRNA was significantly up-regulated in mid and late luteal stages (d 8-18). It is proposed that the differential mRNA expression of IR-A and IGFR-2, both binding IGF II, may play a role in the development and function of the bovine corpus luteum.

3D-CT vascular setting protocol using computer graphics for the evaluation of maxillofacial lesions / Protocolo vascular por meio da 3D-Tc utilizando a computaçäo gráfica para avaliaçäo de lesöes maxilo-faciais

Neste trabalho, demonstramos os aspectos de um granuloma central de células gigantes por meio da tomografia computadorizada (TC) em espiral baseada na reconstruçäo de imagem em três dimensöes (3D), utilizando a computaçäo gráfica, e a importância do protocolo vascular permitindo um melhor diagnóstico, visualizaçäo e contendo dimensöes da lesäo. Foram analisados 21 pacientes com lesöes maxilo-faciais de origens neoplásicas e proliferativas. Dois radiologistas analisaram as imagens. A utilidade da interaçäo da reconstruçäo da imagem por meio da computaçäo gráfica, especialmente utilizando o protocolo vascular para análises qualitativas e quantitativas para o diagnóstico, planejamento de tratamento e evoluçäo, assim como para a localizaçäo da extensäo da lesäo foi demonstrada. Isto é um importante adjunto para a evoluçäo destas lesöes em relaçäo a cortes axiais em TC e para imagens por meio de 3D-TC para estruturas ósseas

Three dimensional spiral computed tomography for maxillofacial tumors: quantitative assessment by a computer graphics-aided system / Tomografia computadorizada tridimensional em espiral para tumores maxilo-faciais: análise quantitativa por meio de um sistema de computaçäo gráfica

O trabalho apresenta aspectos radiográficos da reconstruçäo em @D e em 3D por meio da tomografia computadorizada em espiral em um paciente com linfoma com origem no seio maxilar do lado esquerdo. Foi demonstrado que 3D-TC é um importante método na localizaçäo e na determinaçäo da extensäo de tumores maxilo-faciais, considerando-se principalmente a obtençäo área, medidas volumétricas e lineares dos mesmos. A nova tecnologia proveniente da computaçäo gráfica por meio da 3D-TC utilizando sistemas de imagens interativos demonstraram uma grande melhoria na qualidade da imagem e em resultados finais quando utilizadas propriedades do programa por diferentes protocolos em 3D. Essas imagens por 3D-TC säo consideradas importantes para a análise da destruiçäo óssea e do envolvimento de tecidos moles para o planejamento e acompanhamento do tratamento. Nós concluímos que é importante analisar neoplasias que afetam o complexo maxilo-facial pela computaçäo gráfica utilizando a reconstruçäo em 3D