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Purpose Obesity has been shown to be strongly associated with the development of breast and gynecologic cancers. PIK3CA is one of the most commonly altered genes in solid tumors, and patients who have alterations are routinely initiated on therapies that target this pathway. However, response can vary greatly between patients, and the reason for differences in response has yet to be completely understood. Obesity has been shown to alter cancer metabolism and further dysregulate the PI3K/AKT/mTOR pathway which may affect response to target therapy. L. Cantley and colleagues suggest that the state of consistent hyperinsulinemia, which is common in obesity, can compromise the clinical benefit of PI3K-pathway targeted therapy, as insulin is a known potent stimulator of this pathway. Therefore, the purpose of this study was to compare clinical outcomes between obese and non-obese patients on pathway-directed therapy. Methods A retrospective analysis was performed on 140 patients with breast, ovarian, cervical, or endometrial malignancies at Avera Cancer Institute. Female patients with a documented oncogenic PIK3CA alteration were included in the study. Overall survival (OS) and progression free survival (PFS) were the primary endpoints. BMI groups were determined by using existing clinical categories of obesity as defined by the CDC. Patients were stratified into 2 BMI groups: Group A 25 kg/m2 and Group B 25 kg/m2. The Kaplan-Meier method was used to derive time-to-event estimates and test for significance. A cox proportional-hazard model was utilized to determine the association between survival time for patients with BMI being the predictor variable. Results Of the 140 patients, 106 patients had breast cancer, 21 patients had endometrial cancer, 9 patients had ovarian cancer, 3 patients had cervical cancer, and 1 patient had vaginal melanoma. There were 52 patients in Group A and 88 patients in Group B. 25 of the 140 patients had documented PIK3CA alterations but were never initiated on targeted therapy. Group B was found to reduce the hazard by a factor of 0.63 (p=0.09). The subset of Group B with PI3K/mTOR targeted therapy was found to reduce the hazard by a factor of 0.43 (p=0.008). Among the 43 patients who were included in PFS analysis, it was found that there was no statistically significant (p=0.6) improved PFS between the two groups. Conclusion In this analysis, patients with a PIK3CA mutation and who had a higher BMI had an improved response rate from targeted therapy and overall survival than compared to patients with a lower BMI. Treatment lines prior to initiation of targeted therapy varied greatly, and differences in the multiple types of malignancies studied in this analysis was a limitation. More prospective studies that are statistically powered are warranted in order to assess the true impact of obesity on improved OS compared to patients with a BMI 25. Citation Format: Diana Kim, Bing Xu, Rachel Elsey, Tobias Meissner, Casey Williams. Clinical outcomes between obese and non-obese breast and gynecological cancer patients with alterations in the PI3K/AKT/mTOR pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1385.

Vascular endothelial cells (ECs) differentiated from pluripotent stem cells have enormous potential to be used in a variety of therapeutic areas such as tissue engineering of vascular grafts and re-vascularization of ischemic tissues. To date, various protocols have been developed to differentiate stem cells toward vascular ECs. However, current methods are still not sufficient to drive the distinct arterial venous differentiation. Therefore, developing refined method of arterial-venous differentiation is critically needed to address this gap. Here, we developed a biomaterial platform to mimic multivalent ephrin-B2/EphB4 signaling and investigated its role in the early arterial and venous specification of pluripotent stem cells. Our results show immobilized ephrinB2 or EphB4 on hydrogel substrates have a distinct effect on arterial venous differentiation by regulating several arterial venous markers. When in combination with Wnt pathway agonist or BMP4 signaling, the ephrin-B2/EphB4 biomaterial platform can create diverging EC progenitor populations, demonstrating differential gene expression pattern across a wide range of arterial and venous markers, as well as phenotypic markers such as anti-thrombotic, pro-atherogenic and osteogenic genes, that are consistent with the in vivo expression patterns of arterial and venous ECs. Importantly, this distinct EC progenitor population cannot be achieved by current methods of applying soluble factors or hemodynamic stimuli alone, illustrating that fine-tuning of developmental signals using the biomaterial platform offers a new approach to better control the arterial venous differentiation of stem cells.

We investigate a novel mechanism to interpret each coordinate of Deep Neural Network (DNN) activations with concepts aligned with art principles such as light, shape, pattern, line, and textures. After training state-of-the-art DNN architectures as paintings' style classifiers, we collect activations from the second to last layer of DNN and conduct a data analysis. Based on the interpretation results, we can demonstrate which art principles are essential when machines understand styles and also can decipher each coordinates value in the context of relatedness to specific art principles.

Falls and balance difficulties remain a major source of morbidity in Parkinson's Disease (PD) and are stubbornly resistant to therapeutic interventions. The mechanisms of gait impairment in PD are incompletely understood but may involve changes in the Pedunculopontine Nucleus (PPN) and its associated connections. We utilized fMRI to explore the modulation of PPN connectivity by Galvanic Vestibular Stimulation (GVS) in healthy controls (n = 12) and PD subjects even without overt evidence of Freezing of Gait (FOG) while on medication (n = 23). We also investigated if the type of GVS stimuli (i.e., sinusoidal or stochastic) differentially affected connectivity. Approximate PPN regions were manually drawn on T1 weighted images and 58 other cortical and subcortical Regions of Interest (ROI) were obtained by automatic segmentation. All analyses were done in the native subject's space without spatial transformation to a common template. We first used Partial Least Squares (PLS) on a subject-by-subject basis to determine ROIs across subjects that covaried significantly with the voxels within the PPN ROI. We then performed functional connectivity analysis on the PPN-ROI connections. In control subjects, GVS did not have a significant effect on PPN connectivity. In PD subjects, baseline overall magnitude of PPN connectivity was negatively correlated with UPDRS scores (p < 0.05). Both noisy and sinusoidal GVS increased the overall magnitude of PPN connectivity (p = 6 × 10−5, 3 × 10−4, respectively) in PD, and increased connectivity with the left inferior parietal region, but had opposite effects on amygdala connectivity. Noisy stimuli selectively decreased connectivity with basal ganglia and cerebellar regions. Our results suggest that GVS can enhance deficient PPN connectivity seen in PD in a stimulus-dependent manner. This may provide a mechanism through which GVS assists balance in PD, and may provide a biomarker to develop individualized stimulus parameters.

Heart failure (HF) is a common clinical syndrome caused by a variety of cardiac diseases. The morbidity and mortality have increased in the last decades. The pathophysiology of HF is exceedingly complex. It has developed from the simplistic model of pump failure to that of a multisystemic disorder that affects not only the cardiovascular system but also the musculoskeletal, neuroendocrine and immune systems. Apart from myocardial hypertrophy, the pathogenetic mechanisms of HF also include deregulation of the neurohormonal system, with disturbance of the balance between sympathetic and parasympathetic tone, and disruption of the rennin-angiotensin-aldosterone system. Activation of neurohormones and pro-inflammatory cytokines has been recognized in HF progression after an initial cardiac injury. It is becoming increasingly apparent that inflammatory mediators play a crucial role in the development of HF. The purpose of this chapter is to give a brief overview of the role of inflammation in heart failure from animal models to clinical disease.

Since 2008, the housing finance industry has initiated a wide array of mortgage modification programs that have had varying degrees of success. With a significant portion of loans that are currently performing having already received modifications and the prospect for further modifications on distressed mortgages, it is important for investors, servicers, and risk managers (in both the private and public sectors) to have a robust framework for thinking about the future performance of modified mortgages. This article highlights the authors’ research on loan modification performance, which looks at loan and modification characteristics as well as the timing of the modifications to identify key drivers of the redefault rate. The authors find evidence to support the widely held view that modifications that include principal forgiveness and result in significant reductions in payment requirements produce lower re-default rates. They also find evidence suggesting the better performance of recently initiated modifications is not just a function of more effective modification terms but also of the improving macroeconomic climate.

Tenascin-C (TNC) is highly expressed in melanoma; however, little is known about its functions. Recent studies indicate that TNC has a role within the stem cell niche. We hypothesized that TNC creates a specific environment for melanoma cells to show a stem cell-like phenotype, promoting tumor growth and evading conventional therapies. TNC expression was strongly upregulated in melanoma cells grown as 3D spheres (enriched for stem-like cells) when compared to adherent cells. Downmodulation of TNC by shRNA lentiviruses significantly decreased the growth of melanoma spheres. The incidence of pulmonary metastases after intravenous injection of TNC knockdown cells was significantly lower in NOD/SCID IL2Rγ(null) mice compared with control cells. Melanoma spheres contain an increased number of side population (SP) cells, which show stem cell characteristics, and have the potential for drug resistance due to their high efflux capacity. Knockdown of TNC dramatically decreased the SP fraction in melanoma spheres and lowered their resistance to doxorubicin treatment, likely because of the downregulation of multiple ATP-binding cassette (ABC) transporters, including ABCB5. These data suggest that TNC is critical in melanoma progression as it mediates protective signals in the therapy-resistant population of melanoma.

Arteries and veins have very different susceptibility to certain vascular diseases such as atherosclerosis and vascular calcification. The molecular mechanisms of these differences are not fully understood. In this study, we discovered that COUP-TFII, a transcription factor critical for establishing the venous identity during embryonic vascular development, also regulates the pathophysiological functions of adult blood vessels, especially those directly related to vascular diseases. Specifically, we found that suppression of COUP-TFII in venous ECs switched its phenotype toward pro-atherogenic by up-regulating the expression of inflammatory genes and down-regulating anti-thrombotic genes. ECs with COUP-TFII knockdown also readily undergo endothelial-to-mesenchymal transition (EndoMT) and subsequent osteogenic differentiation with dramatically increased osteogenic transcriptional program and calcium deposition. Consistently, over-expression of COUP-TFII led to the completely opposite effects. In vivo validation of these pro-atherogenic and osteogenic genes also demonstrates a broad consistent differential expression pattern in mouse aorta vs. vena cava ECs, which cannot be explained by the difference in hemodynamic flow. These data reveal phenotypic modulation by different levels of COUP-TFII in arterial and venous ECs and suggest COUP-TFII may play an important role in the different susceptibilities of arteries and veins to vascular diseases such as atherosclerosis and vascular calcification.

SummaryMany genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

s / Brain Stimulation 8 (2015) 395e411 401 through direct or indirect approach has shown promising results in relieving tinnitus in both human and animal subjects. Among the structures stimulated include the cochlear nucleus, auditory cortex, basal ganglion, and prefrontal cortex. However, there remains a large variability in therapeutic effects across different brain stimulation modalities. In order to achieve effective therapy, our lab has established animalmodels of brain stimulation to suppress tinnitus. We have been searching for optimal stimulation strategies and to delineate the underlyingmechanisms of brain-stimulation-induced tinnitus suppression. In this conference, I will present the latest development on tinnitus suppression through brain stimulation and discuss the underlying mechanisms and technological development.

People often change their behavior and beliefs when confronted with deviating behavior and beliefs of others, but the mechanisms underlying such phenomena of conformity are not well understood. Here we suggest that people cognitively represent their own actions and others’ actions in comparable ways (theory of event coding), so that they may fail to distinguish these two categories of actions. If so, other people’s actions that have no social meaning should induce conformity effects, especially if those actions are similar to one’s own actions. We found that female participants adjusted their manual judgments of the beauty of female faces in the direction consistent with distracting information without any social meaning (numbers falling within the range of the judgment scale) and that this effect was enhanced when the distracting information was presented in movies showing the actual manual decision-making acts. These results confirm that similarity between an observed action and one’s own action matters. We also found that the magnitude of the standard conformity effect was statistically equivalent to the movie-induced effect.

Hemitruncus arteriosus is a rare congenital deformity that results in early infant mortality. Persistence into adulthood is very unusual and is associated with pulmonary hypertension. We report a case in an adult male with the associated clinical issues.

Reduced myocardial flow reserve (MFR) is an independent predictor of future risk of major adverse coronary events. Positron emission tomography (PET) is an accepted method for quantifying MFR noninvasively. Cardiac rehabilitation (CR) has been shown to have numerous beneficial effects including

Two studies examined the extent to which different cognitive assessment procedures yield similar data in pre-adolescent children. In Study 1, situationally anxious children reported their self-talk via think-aloud and verbal thought-listing procedures (N = 88). Half of the children reported their self-talk using both think-aloud and thought-listing while the remainder engaged in thought-listing only. Prior participation in think-aloud did not influence the self-talk subsequently reported by children during verbal thought-listing. Compared with thought-listing, more problem-solving (analytical) self-talk and less valenced self-talk was reported during think-aloud. In Study 2, 41 children reported their self-talk via both verbal thought-listing and video-mediated recall (own and other's perspective) procedures. Video-mediated recall generated self-talk of a similar valence to that obtained by thought-listing. More self-talk was generated when the children viewed their own perspective videotape compared with observer perspective videotape and thought-listing. While pre-adolescent children were able to respond to all three cognitive assessment methods, the self-talk produced was not identical. In choosing a cognitive assessment method, researchers and clinicians should be guided by the purpose of the assessment and the setting in which it occurs.

Sufficient vascularization of tissue is critical in regenerative medicine and tissue engineering. Embryonic stem cells (ESCs) can act as an unlimited resource in providing vascular tissue given their ability to self-renew and differentiate into any cell type. However, controlled vascular differentiation remains a challenge due to an intricate, coordinated interaction of multiple factors. Soluble factors, extracellular matrices, cell-cell interactions, and hemodynamic forces all contribute to vascular development. We propose to investigate how mouse ESCs respond to the combined stimuli of fluidic shear stress and various extracellular matrices, especially in terms of arterial or venous specification.

We evaluated the performance of tracheal intubation using video laryngoscopy in an obstetric unit. We analyzed airway management details during a 3-year period, and observed 180 intubations. All cases were managed with direct or video laryngoscopy. Direct laryngoscopy resulted in 157 out of 163 (95% confidence interval [CI], 92%-99%) first attempt successful intubations and failed once. Video laryngoscopy resulted in 18 of 18 (95% CI, 81%-100%) successful intubations on first attempt. The failed direct laryngoscopy was rescued with video laryngoscopy. The patients managed with video laryngoscopy frequently required urgent or emergency surgery and had predictors of difficult direct laryngoscopy in 16 of 18 cases. Video laryngoscopy may be a useful adjunct for obstetric airway management, and its role in this difficult airway scenario should be further studied.

Modeling forces applied to scissors during cutting of biological materials is useful for surgical simulation. Previous approaches to haptic display of scissor cutting are based on recording and replaying measured data. This paper presents an analytical model based on the concepts of contact mechanics and fracture mechanics to calculate forces applied to scissors during cutting of a slab of material. The model considers the process of cutting as a sequence of deformation and fracture phases. During deformation phases, forces applied to the scissors are calculated from a torque-angle response model synthesized from measurement data multiplied by a ratio that depends on the position of the cutting crack edge and the curve of the blades. Using the principle of conservation of energy, the forces of fracture are related to the fracture toughness of the material and the geometry of the blades of the scissors. The forces applied to scissors generally include high-frequency fluctuations. We show that the analytical model accurately predicts the average applied force. The cutting model is computationally efficient, so it can be used for real-time computations such as haptic rendering. Experimental results from cutting samples of paper, plastic, cloth, and chicken skin confirm the model, and the model is rendered in a haptic virtual environment.

s / Brain Stimulation 8 (2015) 360e377 368 cognitive deficits in working memory and sustained attention are associated with worse outcomes. A single session of transcranial direct current stimulation (tDCS) when given to the left dorsolateral prefrontal cortex (LDLPFC) has been shown to enhance working memory in healthy and clinical populations. We examined whether a single session of tDCS can similarly enhance working memory or sustained attention in euthymic bipolar disorder patients. Fifteen euthymic bipolar disorder patients were randomized to receive a single session of sham tDCS, anodal tDCS to the LDLPFC with extracephalic cathode (F-EX tDCS) and anodal tDCS to the LDLPFC with cerebellar cathode (F-CE tDCS), in a counterbalanced order. Participants completed a 3-back letter working memory task and an auditory continuous performance test ‘online’ during active or sham tDCS at each session. Active tDCS was administered for 30 minutes at 2 mA. No effect of either active F-EX or F-CE tDCS on working memory or sustained attention was found for the entire group. However, exploratory cluster analyses conducted on performance outcomes for both active conditions relative to sham tDCS revealed 2-cluster solutions for both abilities, suggesting improvement in some individuals but not others. Specifically, working memory improved in 4/15 with F-EX, and 5/15 patients with F-CE tDCS, respectively. Improved sustained attention performance was also found in 4/15 patients with F-CE tDCS, however, no improvement was found with F-EX tDCS. Cognitive enhancing effects of active F-EX and F-CE tDCS were evident only in a minority of participants. The considerable interindividual variability in outcomes observed with active tDCS is consistent with known variability in the motor cortex. This study provides preliminary evidence in support of F-CE tDCS for improving working memory and sustained attention in euthymic bipolar disorder patients.

Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56–/CD16+(CD56–) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory NK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56–NK fraction compared with that of CD56+NK cells was associated with extremely poorin vitrocytotoxic function of this subset. In addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56–, as compared with the CD56+NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56–NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total NK cell population.

Investigations of natural killer (NK) cells in simian models of disease have been hampered by a lack of appropriate phenotypic markers and by an inadequate understanding of the regulation of NK cell activities. In the present study, a panel of monoclonal antibodies (mAbs) specific for various human NK receptors was screened for cross-reactivity with NK cells from rhesus macaques and pigtailed macaques. Flow cytometric analyses using anti-human NKG2A and anti-human NKp80 mAbs individually, and particularly in combination with anti-CD16 mAb, allowed for the identification of the entire NK cell population in both species. NK cells in monkeys were generally identified by negative selection of peripheral blood mononuclear cells (PBMCs) for the absence of T-cell, B-cell, and monocyte markers. mAb-mediated ligation of NKp80 induced NK cell cytotoxicity, while in the case of NKG2A it displayed a clear capability to inhibit the lysis of target cells by NK cells from macaques, as well as from humans. This new phenotypic and functional characterization of NKG2A and NKp80 in rhesus and pigtailed macaque NK cells provides a new approach in the analysis of their innate immune system. (Blood. 2005;106:1718-1725)

A 4-week-old otherwise healthy female infant was brought to the Emergency Department (ED) by her parents with a chief complaint of ‘‘spitting up’’ after feedings. The infant was delivered full-term via cesarean section without complications and discharged home soon after birth. The parents denied any fever, wheezing, stridor, cyanosis, or projectile vomiting for the previous 4 weeks. They did report some episodes of bloodtinged diarrhea about 2 weeks prior, which resolved spontaneously. On physical examination, the infant was well appearing, with a heart rate of 177 beats/min, a respiratory rate of 32 breaths/min, an oxygen saturation of 98% on ambient air, and a rectal temperature of 37.2 C (99.0 F). The infant was not irritable; the abdomen was soft, nontender, and non-distended. The infant tolerated feeding in the ED and did not have any vomiting or drooling after feeding. No respiratory distress or cyanosis during feeding was observed. Chest and abdomen X-ray studies were taken (Figures 1, 2).

Perhaps the most important sociocultural tool that a child can have in Western society is literacy, a skill that can only be learned through social interaction. Consequently, it is widely accepted not only that children should be read to, but also that such readings will benefit their emergent literacy skills (e.g., Whitehurst & Lonigan, 1998). Emergent literacy refers to the knowledge children have about literacy prior to formal schooling. Relevant skills include knowledge about the conventions of print, letter identification, vocabulary, and story skills, as well as an awareness of the conventions and purposes of book reading (e.g., Snow & Dickinson, 1991). All of these skills are potentially learned through shared book reading (Bus, van IJzendoorn, & Pellegrini, 1995; Scarborough & Dobrich, 1994; Wells, 1985; Whitehurst & Lonigan, 1998), as well as other storytelling activities (e.g., Beals, De Temple, & Dickinson, 1994; Low & Durkin, 2001; Reese, 1995). The frequency of shared book reading during the preschool years purportedly accounts for about 8% of the variance in children’s later literacy achievement; this effect decreases in strength as children’s literacy skills increase (Bus et al., 1995; Scarborough & Dobrich, 1994).

Chang et al. ([1][1]) explore the advantages of technetium (Tc-99m) sestamibi and Tc-99m tetrafosmin 1-day stress-only perfusion imaging. This is an invaluable protocol in cardiac nuclear stress testing, especially in light of the growing concern surrounding radiation exposure secondary to physician

Two studies are described which used think-aloud (Study 1) and verbal thought-listing (Studies 1 and 2) procedures to assess preadolescent children's self-talk under conditions of mild anxiety. The self-talk reported was coded into six theoretically meaningful categories and the relationship between self-talk type and anxiety (state and trait) examined. Increased levels of anxiety were associated with higher rates of negative self-talk, but not clearly associated with other types of self-talk. These results suggest negative self-talk plays a role in the generation or maintenance of anxiety in normal children. From the data, it is unclear to what extent perceived task difficulty contributes to the relationship between trait anxiety and negative self-talk. Assessment of self-regulation (Study 1) identified higher levels of anxiety in children reporting awareness of strategies for managing their anxiety.