Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations.

Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations

The role of acculturation on sense of fairness of the division of family labor and marital quality among Brazilian immigrants in the U.S.

Over 1 million people are admitted into the United States each year with the status of legal permanent residents. Brazilian immigrants in the US are a relatively small population; however, their numbers are growing to approximately 800,000 to 1 million. Among immigrant couples, partners may acculturate using different attitudes and at different paces. Also, acculturation involves changes in many domains, including the perceptions of fairness in the division of family labor, which may have implications for marital quality. The current study aimed to evaluate the relationships among acculturation, sense of fairness of the division of family labor, and marital quality among Brazilian immigrants in the US. An additional purpose of this study was to address this growing and yet under studied population. Results suggest that there is a significant relationship between sense of fairness of the division of family labor and marital quality among Brazilian immigrant married women, in that perceptions of unfairness in the division of labor contribute to decrease marital quality. However, the associations involving acculturation were not confirmed. There are two possible explanations for these non-significant findings. First, it is possible that Brazilian women are more similar to their American counterparts in regards to sense of fairness than previously thought. Therefore, being more or less acculturated would not be predictive of sense of fairness among this particular sample. Second, the findings of the current study also point to the need to look more closely at the instrumentation used to measure acculturation, to review its concept and indicators. It is recommended that instruments measuring acculturation among Brazilian immigrants should be specifically designed to address the uniqueness of this specific population. In addition, acculturation measure should be updated to assess the possibility that remote acculturation may occur by mean of mass communication between geographically separated groups. It is important for counselors who work with Brazilian immigrant couples to be knowledgeable of the demographic realities these couples face (e.g., decreased career mobility and lower rates of domestic help), as well as marital dynamics involving partners sense of fairness with changing expectations of the division of family labor and marital quality

How predation and landscape fragmentation affect vole population dynamics

Background: Microtine species in Fennoscandia display a distinct north-south gradient from regular cycles to stable populations. The gradient has often been attributed to changes in the interactions between microtines and their predators. Although the spatial structure of the environment is known to influence predator-prey dynamics of a wide range of species, it has scarcely been considered in relation to the Fennoscandian gradient. Furthermore, the length of microtine breeding season also displays a north-south gradient. However, little consideration has been given to its role in shaping or generating population cycles. Because these factors covary along the gradient it is difficult to distinguish their effects experimentally in the field. The distinction is here attempted using realistic agent-based modelling. Methodology/Principal Findings: By using a spatially explicit computer simulation model based on behavioural and ecological data from the field vole (Microtus agrestis), we generated a number of repeated time series of vole densities whose mean population size and amplitude were measured. Subsequently, these time series were subjected to statistical autoregressive modelling, to investigate the effects on vole population dynamics of making predators more specialised, of altering the breeding season, and increasing the level of habitat fragmentation. We found that fragmentation as well as the presence of specialist predators are necessary for the occurrence of population cycles. Habitat fragmentation and predator assembly jointly determined cycle length and amplitude. Length of vole breeding season had little impact on the oscillations. Significance: There is good agreement between our results and the experimental work from Fennoscandia, but our results allow distinction of causation that is hard to unravel in field experiments. We hope our results will help understand the reasons for cycle gradients observed in other areas. Our results clearly demonstrate the importance of landscape fragmentation for population cycling and we recommend that the degree of fragmentation be more fully considered in future analyses of vole dynamics

Cerebellar Transcranial Direct Current Stimulation Applied over Multiple Days Does Not Enhance Motor Learning of a Complex Overhand Throwing Task in Young Adults

Cerebellar transcranial direct current stimulation (tDCS) enhances motor skill and learning in relatively simple motor tasks, but it is unclear if c-tDCS can improve motor performance in complex motor tasks. The purpose of this study was to determine the influence of c-tDCS applied over multiple days on motor learning in a complex overhand throwing task. In a double-blind, randomized, between-subjects, SHAM-controlled, experimental design, 30 young adults were assigned to either a c-tDCS or a SHAM group. Participants completed three identical experiments on consecutive days that involved overhand throwing in a pre-test block, five practice blocks with concurrent c-tDCS, and a post-test block. Overhand throwing endpoint accuracy was quantified as the endpoint error. The first dorsal interosseous muscle motor evoked potential (MEP) amplitude elicited by transcranial magnetic stimulation was used to quantify primary motor cortex (M1) excitability modulations via c-tDCS. Endpoint error significantly decreased over the 3 days of practice, but the magnitude of decrease was not significantly different between the c-tDCS and SHAM group. Similarly, MEP amplitude slightly increased from the pre-tests to the post-tests, but these increases did not differ between groups. These results indicate that multi-day c-tDCS does not improve motor learning in an overhand throwing task or increase M1 excitability

Transcranial direct current stimulation of primary motor cortex over multiple days improves motor learning of a complex overhand throwing task

Transcranial direct current stimulation (tDCS) applied to the primary motor cortex (M1) improves motor learning in relatively simple motor tasks performed with the hand and arm. However, it is unknown if tDCS can improve motor learning in complex motor tasks involving whole-body coordination with significant endpoint accuracy requirements. The primary purpose was to determine the influence of tDCS on motor learning over multiple days in a complex over-hand throwing task. This study utilized a double-blind, randomized, SHAM-controlled, between-subjects experimental design. Forty-six young adults were allocated to either a tDCS group or a SHAM group and completed three experimental sessions on three consecutive days at the same time of day. Each experimental session was identical and consisted of overhand throwing trials to a target in a pre-test block, five practice blocks performed simultaneously with 20 min of tDCS, and a post-test block. Overhand throwing performance was quantified as the endpoint error. Transcranial magnetic stimulation was used to obtain motor-evoked potentials (MEPs) from the first dorsal interosseus muscle to quantify changes in M1 excitability due to tDCS. Endpoint error significantly decreased over the three days of practice in the tDCS group but not in the SHAM group. MEP amplitude significantly increased in the tDCS group, but the MEP increases were not associated with increases in motor learning. These findings indicate that tDCS applied over multiple days can improve motor learning in a complex motor tasks in healthy young adults

Imaging cervical cytology with scanning near-field optical microscopy (SNOM) coupled with an IR-FEL

Cervical cancer remains a major cause of morbidity and mortality among women, especially in the developing world. Increased synthesis of proteins, lipids and nucleic acids is a pre-condition for the rapid proliferation of cancer cells. We show that scanning near-field optical microscopy, in combination with an infrared free electron laser (SNOM-IR-FEL), is able to distinguish between normal and squamous low-grade and high-grade dyskaryosis, and between normal and mixed squamous/glandular pre-invasive and adenocarcinoma cervical lesions, at designated wavelengths associated with DNA, Amide I/II and lipids. These findings evidence the promise of the SNOM-IR-FEL technique in obtaining chemical information relevant to the detection of cervical cell abnormalities and cancer diagnosis at spatial resolutions below the diffraction limit (?0.2 \ensuremathμm). We compare these results with analyses following attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy; although this latter approach has been demonstrated to detect underlying cervical atypia missed by conventional cytology, it is limited by a spatial resolution of ~3 \ensuremathμm to 30 \ensuremathμm due to the optical diffraction limit

Tracking the Impact of Excisional Cervical Treatment on the Cervix using Biospectroscopy

Local excisional treatment for cervical intra-epithelial neoplasia (CIN) is linked to significant adverse sequelae including preterm birth, with cone depth and radicality of treatment correlating to the frequency and severity of adverse events. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy can detect underlying cervical disease more accurately than conventional cytology. The chemical profile of cells pre- and post-treatment may differ as a result of altered biochemical processes due to excision, or treatment of the disease. Since pre-treatment cervical length varies amongst women, the percentage of cervix excised may correlate more accurately to risk than absolute dimensions. We show that treatment for CIN significantly alters the biochemistry of the cervix, compared with women who have not had treatment; this is due to the removal of cervical tissue rather than the removal of the disease. However, the spectra do not seem to correlate to the cone depth or proportion of cervical length excised. Future research should aim to explore the impact of treatment in a larger cohort

Ostriches Sleep like Platypuses

Mammals and birds engage in two distinct states of sleep, slow wave sleep (SWS) and rapid eye movement (REM) sleep. SWS is characterized by slow, high amplitude brain waves, while REM sleep is characterized by fast, low amplitude waves, known as activation, occurring with rapid eye movements and reduced muscle tone. However, monotremes (platypuses and echidnas), the most basal (or ‘ancient’) group of living mammals, show only a single sleep state that combines elements of SWS and REM sleep, suggesting that these states became temporally segregated in the common ancestor to marsupial and eutherian mammals. Whether sleep in basal birds resembles that of monotremes or other mammals and birds is unknown. Here, we provide the first description of brain activity during sleep in ostriches (Struthio camelus), a member of the most basal group of living birds. We found that the brain activity of sleeping ostriches is unique. Episodes of REM sleep were delineated by rapid eye movements, reduced muscle tone, and head movements, similar to those observed in other birds and mammals engaged in REM sleep; however, during REM sleep in ostriches, forebrain activity would flip between REM sleep-like activation and SWS-like slow waves, the latter reminiscent of sleep in the platypus. Moreover, the amount of REM sleep in ostriches is greater than in any other bird, just as in platypuses, which have more REM sleep than other mammals. These findings reveal a recurring sequence of steps in the evolution of sleep in which SWS and REM sleep arose from a single heterogeneous state that became temporally segregated into two distinct states. This common trajectory suggests that forebrain activation during REM sleep is an evolutionarily new feature, presumably involved in performing new sleep functions not found in more basal animals

Ectopic opening of the common bile duct and duodenal stenosis: an overlooked association

<p>Abstract</p> <p>Background</p> <p>Ectopic opening of the common bile duct into the duodenal bulb (EO-CBD-DB) is a rare disease that may be complicated by duodenal ulcer, deformity, stenosis and biliary stones. The aim of this study is to report clinical presentations, endoscopic diagnosis and treatment of this entity as well as to investigate its association with duodenal stenosis.</p> <p>Methods</p> <p>Gastroduodenoscopic findings and radiological imaging were evaluated for ectopic papilla and duodenal stenosis. Diagnostic methods, endoscopic procedures and long-term outcomes of the endoscopic treatment were presented.</p> <p>Results</p> <p>EO-CBD-DB was found in 74 (77.1%) of the 96 patients with duodenal deformity/stenosis (79 male, 17 female, mean age: 58.5, range: 30-87 years). The papilla with normal appearance was retracted to the bulb in 11 while it was at its usual location in the remaining 11. The history of biliodigestive surgery was more common in patients with EO-CBD-DB who were frequently presented with the common bile duct stone-related symptoms than the other patients. Thirteen (17.6%) of the patients with EO-CBD-DB were referred to surgery. Endoscopic treatment was completed in 60 (81.1%) patients after an average of 1.7 (range: 1-6) procedures. These patients were on follow-up for 24.8 (range: 2-46) months. Endoscopic intervention was required in 12 (20%) of them because of recurrent biliary problems. Treatment of the patient who had stricture due to biliary injury during laparoscopic cholecystectomy is still continued.</p> <p>Conclusions</p> <p>The presence of EO-CBD-DB should be considered particularly in middle-aged male patients who have duodenal deformity/stenosis. Endoscopic treatment is feasible in these patients. The long-term outcomes of endoscopic therapy need to be compared with surgical treatment.</p

Plague and Climate: Scales Matter

Plague is enzootic in wildlife populations of small mammals in central and eastern Asia, Africa, South and North America, and has been recognized recently as a reemerging threat to humans. Its causative agent Yersinia pestis relies on wild rodent hosts and flea vectors for its maintenance in nature. Climate influences all three components (i.e., bacteria, vectors, and hosts) of the plague system and is a likely factor to explain some of plague's variability from small and regional to large scales. Here, we review effects of climate variables on plague hosts and vectors from individual or population scales to studies on the whole plague system at a large scale. Upscaled versions of small-scale processes are often invoked to explain plague variability in time and space at larger scales, presumably because similar scale-independent mechanisms underlie these relationships. This linearity assumption is discussed in the light of recent research that suggests some of its limitations