Discordant Behavior Research Articles

Opposed evolution of the osseous and soft parts of progestin-associated osteomeningioma after progestin intake discontinuation.

Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed. Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated. For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study. These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.

Discordant calls across genotype discovery approaches elucidate variants with systematic errors.

Large-scale high-throughput sequencing data sets have been transformative for informing clinical variant interpretation and for use as reference panels for statistical and population genetic efforts. Although such resources are often treated as ground truth, we find that in widely used reference data sets such as the Genome Aggregation Database (gnomAD), some variants pass gold-standard filters, yet are systematically different in their genotype calls across genotype discovery approaches. The inclusion of such discordant sites in study designs involving multiple genotype discovery strategies could bias results and lead to false-positive hits in association studies owing to technological artifacts rather than a true relationship to the phenotype. Here, we describe this phenomenon of discordant genotype calls across genotype discovery approaches, characterize the error mode of wrong calls, provide a list of discordant sites identified in gnomAD that should be treated with caution in analyses, and present a metric and machine learning classifier trained on gnomAD data to identify likely discordant variants in other data sets. We find that different genotype discovery approaches have different sets of variants at which this problem occurs, but there are characteristic variant features that can be used to predict discordant behavior. Discordant sites are largely shared across ancestry groups, although different populations are powered for the discovery of different variants. We find that the most common error mode is that of a variant being heterozygous for one approach and homozygous for the other, with heterozygous in the genomes and homozygous reference in the exomes making up the majority of miscalls.

PD16-04 DIFFERENTIAL TREATMENT RESPONSE OF PROSTATE AND METASTATIC LESIONS IN PATIENTS WITH NEWLY DIAGNOSED METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD16-04 DIFFERENTIAL TREATMENT RESPONSE OF PROSTATE AND METASTATIC LESIONS IN PATIENTS WITH NEWLY DIAGNOSED METASTATIC PROSTATE CANCER Baris Esen, Hulya Seymen, Okan Falay, Kayhan Tarim, Mert Kilic, Sevil Bavbek, Yakup Kordan, Derya Tilki, Tarik Esen, and Mehmet Onur Demirkol Baris EsenBaris Esen More articles by this author , Hulya SeymenHulya Seymen More articles by this author , Okan FalayOkan Falay More articles by this author , Kayhan TarimKayhan Tarim More articles by this author , Mert KilicMert Kilic More articles by this author , Sevil BavbekSevil Bavbek More articles by this author , Yakup KordanYakup Kordan More articles by this author , Derya TilkiDerya Tilki More articles by this author , Tarik EsenTarik Esen More articles by this author , and Mehmet Onur DemirkolMehmet Onur Demirkol More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003271.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We aimed to evaluate the response of primary tumor to systemic treatment in patients with newly diagnosed mPCa with serial PSMA PET/CT scans. METHODS: A total of 43 patients with newly diagnosed mPCa who had significant prostatic PSMA uptake at baseline PSMA PET/CT (bPSMA) and underwent at least one follow-up PSMA PET/CT (fPSMA) after receiving systemic treatment were included in the study. Those who received any definitive treatment at localized stage and those who underwent radiotherapy to prostate before fPSMA were excluded. Prostatic and metastatic PSMA responses after systemic treatment were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) as recommended by guidelines. Discordant behavior between prostate and metastases was defined as the condition when metastatic lesions are responding (CR or PR) to systemic treatment while prostate had progressed or vice versa. CHAARTED criteria was applied to categorize patients according to the volume of metastatic disease. RESULTS: The mean age of patients at bPSMA was 67.7±8.5 years. The median PSA at bPSMA was 31.7 ng/dL (IQR: 11.3 – 106.0). Patient characteristics and treatments were summarized in Table 1. The median time interval between bPSMA and the first fPSMA was 5.7 months (IQR: 4.6 – 7.5). Nine patients (20.9%) had CR, 25 (58.1%) had PR, 5 (11.6%) had SD and 4 (9.3%) had PD at prostate following systemic treatment. Patients with low-volume disease had prostatic CR twice more commonly than those with high-volume disease (27.3% vs 14.3%). In 6 (13%) cases, a significant PSMA uptake at prostate was detected despite a complete response of all metastatic sites. Discordant treatment responses at the prostate and metastatic sites were observed in 6 out of 43 (16%) patients. CONCLUSIONS: Discordant behavior between prostate and metastases are not rare in mPCa. Almost one-fourth of patients with low-volume mPCa achieved a complete prostatic response with systemic treatment only. Prostatic response on PSMA PET/CT following systemic treatment can be used to select ideal patients for the treatment of the primary tumor in patients with mPCa. Source of Funding: Baris Esen is supported by European Urological Scholarship Programme through a 1-year research scholarship © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e490 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Baris Esen More articles by this author Hulya Seymen More articles by this author Okan Falay More articles by this author Kayhan Tarim More articles by this author Mert Kilic More articles by this author Sevil Bavbek More articles by this author Yakup Kordan More articles by this author Derya Tilki More articles by this author Tarik Esen More articles by this author Mehmet Onur Demirkol More articles by this author Expand All Advertisement PDF downloadLoading ...

Differential treatment response of prostate and metastatic lesions in patients with newly diagnosed metastatic prostate cancer.

56 Background: We aimed to evaluate the response of primary tumor to systemic treatment in patients with newly diagnosed mPCa with serial PSMA PET/CT scans. Methods: A total of 43 patients with newly diagnosed mPCa who had significant prostatic PSMA uptake at baseline PSMA PET/CT (bPSMA) and underwent at least one follow-up PSMA PET/CT (fPSMA) after receiving systemic treatment were included in the study. Those who received any definitive treatment at localized stage and those who underwent radiotherapy to prostate before fPSMA were excluded. Prostatic and metastatic PSMA response after systemic treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) as recommended by guidelines. Discordant behavior between prostate and metastases was defined as the condition when metastatic lesions are responding (CR or PR) to systemic treatment while prostate had progressed or vice versa. CHAARTED criteria was applied to categorize patients according to the volume of metastatic disease. Results: The mean age of patients at bPSMA was 67.7 ± 8.5 years. The median PSA at bPSMA was 31.7 ng/dL (IQR: 11.3 – 106.0). Patient characteristics and treatments are summarized. The median time interval between bPSMA and the first fPSMA was 5.7 months (IQR: 4.6 – 7.5). Nine patients (20.9%) had CR, 25 (58.1%) had PR, 5 (11.6%) had SD and 4 (9.3%) had PD at prostate following systemic treatment. Patients with low-volume disease had prostatic CR twice more commonly than those with high-volume disease (27.3% vs 14.3%). In 6 (13%) cases, a significant PSMA uptake at prostate was detected despite a complete response of all metastatic sites. Discordant treatment responses at the prostate and metastatic sites were observed in 6 out of 43 (16%) patients. Conclusions: Discordant behavior between prostate and metastases are not rare in mPCa. Almost one-fourth of patients with low-volume mPCa achieved a complete prostatic response with systemic treatment only. Prostatic response on PSMA PET/CT following systemic treatment can be used to select ideal patients for the treatment of the primary tumor in patients with mPCa. [Table: see text]

Valence Disproportionation of GeS in the PbS Matrix Forms Pb5Ge5S12 Inclusions with Conduction Band Alignment Leading to High n-Type Thermoelectric Performance.

Converting waste heat into useful electricity using solid-state thermoelectrics has a potential for enormous global energy savings. Lead chalcogenides are among the most prominent thermoelectric materials, whose performance decreases with an increase in chalcogen amounts (e.g., PbTe > PbSe > PbS). Herein, we demonstrate the simultaneous optimization of the electrical and thermal transport properties of PbS-based compounds by alloying with GeS. The addition of GeS triggers a complex cascade of beneficial events as follows: Ge2+ substitution in Pb2+ and discordant off-center behavior; formation of Pb5Ge5S12 as stable second-phase inclusions through valence disproportionation of Ge2+ to Ge0 and Ge4+. PbS and Pb5Ge5S12 exhibit good conduction band energy alignment that preserves the high electron mobility; the formation of Pb5Ge5S12 increases the electron carrier concentration by introducing S vacancies. Sb doping as the electron donor produces a large power factor and low lattice thermal conductivity (κlat) of ∼0.61 W m-1 K-1. The highest performance was obtained for the 14% GeS-alloyed samples, which exhibited an increased room-temperature electron mobility of ∼121 cm2 V-1 s-1 for 3 × 1019 cm-3 carrier density and a ZT of 1.32 at 923 K. This is ∼55% greater than the corresponding Sb-doped PbS sample and is one of the highest reported for the n-type PbS system. Moreover, the average ZT (ZTavg) of ∼0.76 from 400 to 923 K is the highest for PbS-based systems.

Exploring mechanisms of protein influence on calcium oxalate kidney stone formation.

Calcium oxalate monohydrate (COM) crystals are the primary constituent of most kidney stones, but urine proteins in stone matrix are believed to be critical elements for stone formation from these crystals. Recent data have shown that hundreds of proteins appear in the stone matrix with no explanation for inclusion of so many proteins. We have proposed a stone formation model with protein stimulated COM aggregation based on polyanion-polycation aggregation, which is supported by finding that matrix is highly enriched in strongly anionic and strongly cationic proteins. Many other proteins may be drawn to such aggregates due to their limited solubility in water or charge effects. Finding similar protein enrichment in both polyarginine (pR) induced aggregates of urine proteins and COM stone matrix would support this hypothesis. Purified proteins (PP) were obtained from random urine samples of six healthy adults by ultradiafiltration. Protein aggregation was induced by adding pR to PP solutions at two concentrations; 0.25 and 0.5µg pR/µg of PP. Samples of each fraction and the original PP mixture were lyophilized and analyzed by tandem mass spectrometry. Aggregates induced by pR addition to PP samples collected a protein mixture that mimicked the protein distribution observed in COM matrix, supporting our hypothesis. The apparently discordant behavior of certain abundant anionic proteins preferentially joining the pR aggregate, when they had demonstrated reduced abundance in COM stone matrix, suggests that this model was overdriven to aggregate. The reversal of aggregate preference of albumin at low pR addition supports this interpretation.

When a smile is a conflict: Affective mismatch between facial displays and group membership induces conflict and triggers cognitive control.

Affective responses to emotional expressions critically depend on the expresser's group membership: Facial displays by in-group members elicit concordant affective behavior in the perceiver whereas out-group expressions elicit discordant behavior. A prominent explanation for this response divergence assumes that initial affective responses are elicited by the social message signaled by facial displays (social intentions account). In this study we tested an alternative account, proposing that specific combinations of group membership and facial expression (i.e., positive expressions by negatively evaluated out-group members or negative expressions by positively evaluated in-group members) result in affective conflict (processing conflict account). In 4 experiments White participants executed simple 2-choice categorization tasks on pictures of emotions expressed by Middle-Eastern (out-group) or White persons (in-group). We observed consistent performance decrements to affectively incongruent compared with congruent faces. Moreover, consistent with the processing conflict account, experienced conflict from affectively incongruent faces reactively induces recruitment of cognitive control resources. Conflict adaptation effects occurred (a) irrespective of the type of conflict and (b) also for emotional facial expressions for which the underlying social message does not vary with group membership. In summary, these results substantiate the processing conflict hypothesis. Consequences for the prominent social intentions account are discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Dynamic Changes of Cardiac Repolarization Instability during Exercise Testing.

Physical exercise triggers efferent cardiac sympathetic activation. Here, we tracked the spatiotemporal properties of cardiac repolarization on a beat-to-beat basis throughout a standardized exercise test and hypothesized a detectable change at the point of the anaerobic threshold (AT). The study included 20 healthy adults (age 35.3 ± 6.7 yr) undergoing a standardized incremental exercise test on a cycle ergometer. During exercise testing, high-resolution (2000 Hz) ECG monitoring in Frank lead configuration was performed. Three-dimensional beat-to-beat repolarization instability (dT°) was assessed by a novel vector-based method according to a previously published technology. In parallel, the lactate threshold (LT) was detected according to Dickhuth and Mader. We could identify a characteristic pattern of dT° signal during exercise testing. With increasing physical activity, dT° increased concordantly to heart rate. At an average of 164 ± 38 W, dT° and heart rate abruptly showed a discordant behavior, characterized by a transient drop of dT°. The maximal discordance between dT° and heart rate was defined as ATdT° and highly significantly correlated with LTDickhuth (r = 0.841, P < 0.001) and LTMader (r = 0.819, P < 0.001), which were at 156 ± 39 and 172 ± 46 W, respectively. The characteristic of dT° could not be provoked by fast atrial pacing in the absence of exercise. Repolarization instability shows a characteristic pattern during standardized exercise in healthy individuals that allows for a noninvasive estimation of AT.

Concordance and Discordance of Sexual Identity, Sexual Experience, and Current Sexual Behavior in 45-Year-Old Men: Results From the German Male Sex-Study.

IntroductionDiscordance of various aspects of sexual orientation has been mostly studied in young adults or in small samples of heterosexual men. Studies focusing on concordance and discordance of aspects of sexual orientation in representative samples of middle-aged men including homosexual men are scarce.AimTo investigate concordant and discordant sexual behavior in 45-year-old German men with a special focus on homosexual identified men.MethodsData for this cross-sectional study were collected within the German Male Sex-Study. Participants were 45-year-old Caucasian males from the general population. Men self-reported on sexual identity, sexual experience, and current sexual behavior. Associations between sexual identity, experience, and behavior were analyzed using the chi-square test.Main Outcome MeasureAssociations of sexual identity with sexual experience and behavior in a community-based sample of men, and discordance of sexual identity and behavior especially in the subgroup of homosexual men.Results12,354 men were included in the study. 95.1% (n = 11.749) self-identified as heterosexual, 3.8% (n = 471) as homosexual, and 1.1% (n = 134) as bisexual. Sexual identity was significantly associated with sexual experience and behavior. 85.5% of all men had recently been sexually active, but prevalence of sexual practices varied. In hetero- and bisexuals, vaginal intercourse was the most common sexual practice, whereas oral sex was the most common in homosexuals. A discordance of sexual identity was especially found in homosexual men: 5.5% of homosexuals only had sexual experiences with women, and 10.3% of homosexuals recently had vaginal intercourse. In this latter subgroup, only one-quarter ever had sexual experience with a man, and three-quarters had only engaged in sexual activity with a woman.ConclusionSexual identity is associated with differences in sexual experience and behavior in German middle-aged men. A considerable proportion of homosexual identified men live a heterosexual life.Goethe VE, Angerer H, Dinkel A, et al. Concordance and Discordance of Sexual Identity, Sexual Experience, and Current Sexual Behavior in 45-Year-Old-Men: Results From the German Male Sex-Study. Sex Med 201;6:282–290.

Extensive Gene Amplification as a Mechanism for Piperacillin-Tazobactam Resistance in Escherichia coli.

ABSTRACTAlthough the TEM-1 β-lactamase (BlaTEM-1) hydrolyzes penicillins and narrow-spectrum cephalosporins, organisms expressing this enzyme are typically susceptible to β-lactam/β-lactamase inhibitor combinations such as piperacillin-tazobactam (TZP). However, our previous work led to the discovery of 28 clinical isolates of Escherichia coli resistant to TZP that contained only blaTEM-1. One of these isolates, E. coli 907355, was investigated further in this study. E. coli 907355 exhibited significantly higher β-lactamase activity and BlaTEM-1 protein levels when grown in the presence of subinhibitory concentrations of TZP. A corresponding TZP-dependent increase in blaTEM-1 copy number was also observed, with as many as 113 copies of the gene detected per cell. These results suggest that TZP treatment promotes an increase in blaTEM-1 gene dosage, allowing BlaTEM-1 to reach high enough levels to overcome inactivation by the available tazobactam in the culture. To better understand the nature of the blaTEM-1 copy number proliferation, whole-genome sequence (WGS) analysis was performed on E. coli 907355 in the absence and presence of TZP. The WGS data revealed that the blaTEM-1 gene is located in a 10-kb genomic resistance module (GRM) that contains multiple resistance genes and mobile genetic elements. The GRM was found to be tandemly repeated at least 5 times within a p1ESCUM/p1ECUMN-like plasmid when bacteria were grown in the presence of TZP.

Benign neck masses showing restricted diffusion: Is there a histological basis for discordant behavior?

Diffusion weighted imaging (DWI) evolved as a complementary tool to morphologic imaging by offering additional functional information about lesions. Although the technique utilizes movement of water molecules to characterize biological tissues in terms of their cellularity, there are other factors related to the histological constitution of lesions which can have a significant bearing on DWI. Benign lesions with atypical histology including presence of lymphoid stroma, inherently increased cellularity or abundant extracellular collagen can impede movement of water molecules similar to malignant tissues and thereby, show restricted diffusion. Knowledge of these atypical entities while interpreting DWI in clinical practice can avoid potential misdiagnosis. This review aims to present an imaging spectrum of such benign neck masses which, owing to their distinct histology, can show discordant behavior on DWI.

Gas burst vs. gas-rich magma recharge: A multidisciplinary study to reveal factors controlling triggering of the recent paroxysmal eruptions at Mt. Etna

Since January 2011, Mt. Etna volcano has been affected by more than forty paroxysmal eruptions at the summit (New South East Crater; NSEC). On the basis of their very variable duration, seven eruptions have been selected among the twenty-five of 2011–2012 in order to decipher potential differences in their triggering mechanism. Paroxysms have been investigated through a multidisciplinary approach that integrates data from volcanic tremor and petrology (textures and micro-analysis on plagioclase crystals). Our results lead to the conclusion that close relationships exist between the duration of the eruptions and the temporal evolution of the volcanic tremor amplitude, especially during the Strombolian phase preceding the paroxysmal activity. In this regard, we distinguished: 1) paroxysms preceded by long-lasting initial Strombolian phases, characterized by low rate of volcanic tremor amplitude increase; and 2) eruptions preceded by short initial Strombolian phases, showing high rate of volcanic tremor amplitude increase. Based on the pattern of volcanic tremor amplitude increase, the former mainly showed a ramp-shaped morphology, while the latter a bell-shaped trend. Location of the volcanic tremor centroid during the quiescent intervals between the paroxysmal eruptions has highlighted the presence of a magmatic volume at 1–2kma.s.l. beneath the North East Crater (NEC). During the syn-eruptive Strombolian and lava fountaining phases, the centroid of volcanic tremor migrates below the NSEC. This leads to the consideration that the magma batch residing beneath NEC played an important role in the volcanic activity at NSEC during the considered period. Also the textures and compositional zoning (anorthite and iron variations) in selected plagioclase crystals of the analyzed lavas suggest relations between duration of the paroxysms and dynamics of pre-eruptive magmatic processes at depth. Particularly, two mechanisms have been accounted for triggering of eruptions at the NSEC on the basis of the concordant or discordant behavior of anorthite and iron in plagioclase coupled with disequilibrium textures at the rim. Concordant anorthite and iron increases in plagioclase crystals with sieve-textured rims indicate recharge by more mafic, gas-rich magma. This textural-compositional behavior has been related to long-lasting eruptions, whose volcanic tremor amplitude evolution produced ramp-shaped increase of the volcanic tremor amplitude before the paroxysmal phase. On the contrary, crystals with sieve-textures at the rim, characterized by increasing iron at rather constant or decreasing anorthite, suggest the prominent role of gas injections into the residing system. In this instance, the compositional behavior has been linked with short-lasting eruptions, whose volcanic tremor amplitude evolution led to a sudden increase of the seismic amplitude before the climax of the eruption. Thus, our work put forward the idea that the evolution and duration of the Strombolian phase preceding the paroxysmal eruptions of 2011–2012 at Mt. Etna are strongly controlled by the eruption triggering mechanism, which can be either gas burst or gas-rich magma recharge.

Heterogeneous drug target expression as possible basis for different clinical and radiological response to the treatment of primary and metastatic renal cell carcinoma: suggestions from bench to bedside

Metastatic disease occurs in a significant percentage of patients with renal cell carcinoma (RCC) and is usually associated with an overall poor prognosis. However, not all of the sites of metastases seem to have the same prognostic significance in patients receiving targeted agents. Indeed, patients with lung-only metastases seem to present a better survival than patients with other sites, whereas liver and bone metastases are associated with a worst prognosis. Some clinical studies suggest that metastatic sites are more responsive than primary tumors. This event may be due to intratumor heterogeneity in terms of somatic mutations, chromosome aberrations, and tumor gene expression, primarily centered around Von Hippel-Lindau (VHL) pathway, such as VHL mutations, HIF levels, vascular endothelial growth factor (VEGF) isoforms, and VEGF receptor levels. Nevertheless, these data do not completely explain the discordant biological behavior between primary tumor and metastatic sites. Understanding the causes of this discordance will have profound consequences on translational research and clinical trials in RCC. In this review, we overview current data on the differences between primary RCC and metastases in terms of drug target expression and clinical/radiological response to targeted agents, thus describing the prognostic role of different metastatic sites in RCC patients.

Abstract IA5: Developing therapeutics in mice with ductal pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past 40 years. PDAC frequently harbors somatic mutations in 4 genes (KRAS, P16, Tp53, and SMAD4), and recent exomic and whole genome sequencing efforts have identified a number of less frequent events. Accurate mouse models of PDAC were generated over the last decade, confirming the relevance of these 4 genes and enabling the investigation of fundamental aspects of PDAC tumor biology and therapeutic response. The poor response of pancreatic cancer patients to systemic agents is not predicted by xenograft and other transplanted model systems. An evaluation of this discordant behavior revealed that transplanted tumor models have superior tissue perfusion and delivery of the chemotherapeutic gemcitabine compared to primary murine PDAC, and that this inversely correlates with stromal content. Human PDAC was subsequently confirmed to phenocopy the mouse model as it is also profoundly hypovascular. Stromal depletion with a hedgehog pathway inhibitor increased vascular density and gemcitabine delivery, and prolonged survival to demonstrate a causative role of the hypovascular state in drug responsiveness in PDAC3. The clinical translation of this observation has been encouraging, with several dramatic responses in patients with metastatic PDAC. A randomized trial is currently underway. Alternative methods that target the tumor stroma may also be beneficial in PDAC, including the use of nab-paclitaxel (Abraxane), an albumin-paclitaxel formulation proposed to be sequestered in the intratumoral stroma. Similar to the hedgehog inhibitor, nab-paclitaxel also elevated the gemcitabine levels in the mouse PDAC tumors. However, the mechanism employed was distinct as nab-Paclitaxel did not deplete the stroma and increase the vascular density. Rather, paclitaxel elicits the liberation of reactive oxygen species (ROS), and ROS destabilize and induce the destruction of cytidine deaminase, the major pathway of gemcitabine inactivation in cells4. This novel method of drug synergy was overlooked in the PDX (patient derived xenograft) models, as the chimeric murine stroma is only loosely associated with the human neoplastic cells and they therefore may provide misleading results5. Nab-Paclitaxel treatment with gemcitabine is active in early clinical trials, and genetic variants affecting gemcitabine metabolism may modify this outcome. PDAC is notoriously resistant to VEGF targeted therapeutics despite numerous preclinical experiments that predicted efficacy, and recent approaches in murine PDAC confirmed the prior clinical data6. The hypovascular content of PDAC suggests that the intratumoral endothelial cells are poorly responsive to the available VEGF ligand, and therefore additional pathways may play a more dominant role in vessel proliferation and maintenance. The notch pathway has previously been implicated in vessel morphogenesis, and can be chemically inhibited with gamma secretase inhibitors (GSI). GSI treatment induced the rapid destabilization of the PDAC vasculature, by promoting the death of intratumoral endothelial cells. These effects were exacerbated by concomitant exposure to gemcitabine, resulting in hypoxic necrosis and death of both endothelial cells and neoplastic cells7. A clinical trial has recently begun to evaluate this approach. Although the unique attributes of the PDAC microenvironment participate in the resiliency of PDAC to therapeutics, they also serve as vulnerabilities to exploit for clinical benefit.

Morphofunctional Changes in Goldfish Mauthner Neurons after Application of β-Amyloid

The effects of applying aggregated beta-amyloid peptide fragment 25-35 on the three-dimensional structure and volume of Mauthner neurons (MN) and on motor asymmetry were assessed in goldfish using reconstructions based on serial histological sections. These experiments showed that the motor asymmetry of the fish was stable in the intact state and in controls and correlated tightly with structural asymmetry of neurons. beta-Amyloid produced large changes or inversion in motor asymmetry, which did not coincide with or even contradicted the structural asymmetry of MN. This occurred as a result of marked dystrophy or, conversely, hypertrophy of individual neurons and their individual dendrites, with changes in their proportions. It is suggested that the harmful action of beta-amyloid on MN structure and the discordant ("incorrect") behavior of the fish may result from mechanical deformation evoked by its tape-like fibrils. Overall, the results lead to the conclusion that MN provide a suitable system for studying the structural aspects of amyloidosis.

Endothelial progenitor cells in patients with coronary artery disease and left ventricular dysfunction

Endothelial progenitor cells (EPCs) play a key role in maintenance of endothelial integrity and postnatal neovascularization. We verified whether the number of subpopulations of EPCs is different in patients with coronary artery disease (CAD) and normal or impaired left ventricular (LV) function. Sixty-eight consecutive patients (37 men, age 60+/-18 years) with CAD were studied. All patients underwent quantitative coronary angiography and flow cytometric analysis. Patients with LV ejection fraction <45% (n=22) were compared with those with normal function (n=46). The two groups had similar age, sex, cardiovascular risk factors, medical therapy, LV dimension, and number of diseased vessels. Patients with LV dysfunction, by study design, were more symptomatic and had a lower LV ejection fraction. The two groups had similar white cell count and mononuclear cells. The absolute number of CD34 and CD133 cells was significantly (P<0.05) higher in patients with LV dysfunction as compared with patients with normal function or healthy participants. In contrast, CD14 cells were significantly (P=0.005) lower in the former patients than in the latter, whereas no significant difference was noted in the number of cells positive for CD105 among groups. Subpopulations of EPCs have a discordant behavior in CAD patients with or without LV dysfunction, with cells positive for the endothelial markers CD34 and CD133 being increased and cells that promote vasculogenesis and microvascular development being significantly reduced.

Personal Reflections From a Front-Row Seat at the Greatest Show on Earth (Life)

Part I of this discussion of my 65 years since graduating from medical school covered my reasons for being in medicine at all, my explanation for the theatrical terms in the earlier para-scientific document, and finally the effect of World War II on my career.1 Part II will attempt to touch on the privileged life I led in the field of stroke prevention research. In its entirety it is designed as a story or tale about my 50 years in medical practice and does not follow the standard format of a scientific paper. Previously I alluded to the ongoing prejudicial custom of critical attempts to resist new ideas in scientific endeavor. I gave as examples the discordant behavior in Toronto that greeted the discovery of insulin and of less far-reaching consequence my own attempts to convince Canadian and American colleagues that there were 5 distinct causal mechanisms leading to syringomyelia. Surgeons in Cleveland and Boston were adamant that there was but one. Postmortem studies and now routine MR studies prove them wrong. My next contribution of a controversial nature was a description of a group of young patients with stroke whose causes we defined in a study with age and gender-matched controls as being due to emboli associated with mitral valve prolapse and to suggest that this was a clinically overlooked cause of cerebral ischemic events.2 Denials of variable vehemence appeared but the accumulating pathological and surgical data were quite incontrovertible. Ultimately in an Olmstead County prevalence study its occurrence as a cause of stroke was validated.3 Its prevalence is probably less than we suggested in our first report. The difference is probably explained by improvement in the conduct, interpretation and the delineation of newer stroke causes revealed by echocardiography. At times more than one potential cause …

Comparative Gene Profiling of Acute Myeloid Leukemia (AML) and Malignant Melanoma (MEL) Cell Lines Exposed to the MEK Inhibitor PD0325901 Reveals Common Effectors of the MEK/ERK Kinase Module.

The MEK/ERK kinase module is frequently deregulated in human malignancies, including AML and MEL, and represents a promising therapeutic target. We have recently demonstrated that PD0325901, a selective MEK inhibitor, potently inhibits the growth of both AML and MEL cell lines (IC50 5–20 nM), through a combination of inhibition of cell cycle progression and induction of apoptosis. In order to identify functionally relevant targets of the activity of the MEK/ERK kinase module, we compared the gene expression profiles of the PD0325901-sensitive cell lines OCI-AML3 (AML, harboring a NPM gene mutation) and M14 (MEL, harboring a BRAF mutation), after exposure to vehicle control or 10 nM PD0325901 for 6 and 24h, using the Affymetrix U133A 2.0 and U133 Plus 2.0 gene chips, respectively. All analyses were conducted using the dChip software. In both models, the unsupervised approach showed a tight clustering that was both treatment- and time-dependent; unsupervised and supervised analyses highlighted that the greatest PD0325901-induced variations in gene expression were observed at 24h and 6h in the OCI-AML3 and M14 models, respectively. Comparison of the results obtained in the OCI-AML3 and M14 cell lines showed that 5 genes were consistently modulated after 6h, including CDC25A, cyclin G2, and DUSP6. Cyclin G2 and DUSP6 were also modulated after 24h, together with cyclin D1, TIMP3, and SEMA6A. On the contrary, MAFB, selected in both models, displayed a discordant behavior, being down-regulated upon treatment in OCI-AML3 and up-regulated in M14: this is consistent with the role of MAFB as an important regulator of hematopoiesis, while it does not appear to play a role in melanogenesis. Given the ability of PD0325901 to cause apoptosis, partly through induction of mitochondrial dysfunction in both AML and MEL models, we next investigated whether MEK inhibition specifically modulated the expression of genes related to mitochondrial homeostasis: also in this specific context, the effects were more rapidly induced in M14 than in OCI-AML3, with the greatest changes observed within 6h in the M14 cell line. Two genes were down-regulated after 24h in both models: PPIF, supposedly involved in apoptosis induction, and GRPEL1, on which little is currently known. In addition to mitochondrion-specific changes in gene expression, expression of the mitochondrial protein CPT1A significantly decreased (2-fold), as assessed by WB, after 6 h of exposure of OCI-AML3 cells to 10 nM PD0325901, under which conditions ß-oxidation was also suppressed by the drug. Overall, these results indicate that MEK inhibition by PD0325901 results in the modulation of the expression of a small number of genes that are common to ontogenetically distant tumor models, thereby representing attractive candidates for a shared, functionally relevant, MAPK activation signature; moreover, MEK inhibition results in profound intracellular metabolic changes that might importantly contribute to the anti-neoplastic effect of PD0325901 in AML and, possibly, in other tumor models. MM and SC equally contributed to the work presented.

Place field dissociation and multiple maps in hippocampus

When two sets of visual cues move in discordant fashion, the firing fields of hippocampal place cells can dissociate (follow different sets), split (follow both sets), or remap. This conflicts with views of hippocampus as an associative memory that “completes” patterns given a noisy input. We reconcile these views by treating hippocampus as a collection of independent “maplets”. Normally these act in unison, but under the right conditions they can exhibit discordant behavior. The model also accounts for “barrier cells” [B. Rivard, Y. Li, P.-P. Lenck-Santini, B. Poucet, R.U. Muller, Representation of objects in space by two classes of hippocampal place cells, J. Gen. Physiol. 124 (2004) 9–25], and the occasional temporary cessation of firing of some place cells while others remain active.

The Food Intake of Smokers and Nonsmokers: The Role of Partner's Smoking Behavior

Background. To understand the food patterns of smokers, passive smokers, and nonsmokers is important for health professionals who are assessing disease risks and for those educating individuals regarding healthy lifestyles. This study aimed to investigate the role of smoking behavior on the food intake of men and women, including the smoking habits of their partner.Methods. Information on food intake and smoking behavior was collected by self-administered questionnaires from a cohort of 40- to 70-year-old representatives of the suburban Danish population (n= 2,656), cross-sectionally in 1993–1994.Results. Men and women who smoked were less frequent consumers of fruit, raw vegetables, whole-meal bread, cakes, jam, and tea and were more frequent consumers of white bread, meat, coffee, and beer than nonsmokers. The intake frequencies of meat, fruit, raw vegetables, whole-meal bread, cakes, jam, coffee, and beer among men and of white bread and coffee among women were also associated with their partner's smoking behavior, and for these foods, the intakes of subjects living with a partner with discordant smoking behavior represented a compromise between the food patterns of smokers and nonsmokers. The associations were independent of potential confounders such as age, educational level, and physical exercise.Conclusion. The dietary habits of both men and women are associated with their own and their partner's smoking behavior, independent of age, education, and exercise. Epidemiological studies of smoking and passive smoking-disease relationships should account for the possible confounding by diet.