FAK-inhibition opens the door to checkpoint immunotherapy in Pancreatic Cancer

Immunotherapy has had remarkable success in the treatment of some cancer types. However, pancreatic cancer has remained largely refractory to immunotherapy, including immune checkpoint inhibitors. Recently, Jiang and colleagues identified a key role for FAK in regulating the composition of the fibrotic and immuno-suppressive pancreatic tumour niche, and showed that FAK inhibitors can be used in combination with immune checkpoint blockade and gemcitabine chemotherapy to significantly delay pancreatic tumour progression. This study further supports the use of FAK inhibitors in combination with immunotherapy

How do financial constraints affect creativity?

This paper investigates the effects of financial constraints on the outcome of different types of creative tasks such as product ideation and product repair. Four experimental studies examine the effect of financial constraints on creativity of the outcome of a product ideation task, and compare the effect of financial constraints with the effect of another type of constraint (i.e., input restrictions) on creativity of products ideated and on the amount of resources invested in the development of the creative solution. Furthermore, these studies explore the type of creative process ignited by financial constraints and analyze the effect of financial constraints in interaction with an individual difference such as novelty seeking, which embraces more remote determinants of creative performance, on the creativity of the outcomes to a product ideation task, as well as on the creativity of the outcomes to a more constrained task such as repairing an existing product. The results suggest that constrained financial resources may be beneficial to creativity. Financial constraints lead to the ideation of more creative products. Yet these products are generated using fewer inputs and a lower budget than products generated in an unconstrained condition. Furthermore, while yielding outcomes as creative as the ones generated under input constraints, financial constraints induce a parsimonious mindset reflected in the use of less costly resources. More interestingly, financial constraints activate a top-down rather than a bottom-up processing strategy in approaching the creative task. Finally, the results show that the effect of financial constraints is stronger for individuals with inherent tendencies toward novelty seeking, because their stock of experiences and perspectives puts them under stress when facing an unconstrained problem space. This interaction effect holds not only for product ideation tasks, but also when the problem space is already constrained in nature, as in the case of repairing a product. These findings, which are quite counterintuitive from the perspective of classic new product development literature, suggest that, at least under certain conditions, the use of financial constraints might constitute a promising approach to foster new ideas' generation, one that leads to more creative outcomes despite using less costly inputs. In addition, our results suggest that, when dealing with a creative task, companies should modulate the adoption of this kind of constraint on the individual characteristics of their employees, specifically on their innate tendency to seek novelty

5-α reductase inhibitors and prostate cancer prevention: where do we turn now?

With the lifetime risk of being diagnosed with prostate cancer so great, an effective chemopreventive agent could have a profound impact on the lives of men. Despite decades of searching for such an agent, physicians still do not have an approved drug to offer their patients. In this article, we outline current strategies for preventing prostate cancer in general, with a focus on the 5-α-reductase inhibitors (5-ARIs) finasteride and dutasteride. We discuss the two landmark randomized, controlled trials of finasteride and dutasteride, highlighting the controversies stemming from the results, and address the issue of 5-ARI use, including reasons why providers may be hesitant to use these agents for chemoprevention. We further discuss the recent US Food and Drug Administration ruling against the proposed new indication for dutasteride and the change to the labeling of finasteride, both of which were intended to permit physicians to use the drugs for chemoprevention. Finally, we discuss future directions for 5-ARI research

Effect of local cold-pack application on systemic anabolic and inflammatory response to sprint-interval training: a prospective comparative trial

We evaluated the effect of cold ice-pack application following a brief sprint-interval training on the balance between anabolic mediators [growth hormone (GH), insulin-like growth factor-I (IGF-I), testosterone], catabolic markers (cortisol, IGFBP-1), and circulating pro [Interlukin-6 (IL-6) and IL-1β]- and anti-inflammatory cytokines [IL-1 receptor antagonist (IL-1ra)]. Twelve males, elite junior handball players performed 4 × 250 m treadmill run, at 80% of each individual’s maximal speed, followed by a rest period with and without local cold-pack application. Pre, immediately post, and 60-min post-exercise blood samples were drawn. Exercise was associated with a significant increase in IL-6, GH, IGFBP-3, and testosterone levels. Local cold-pack application was associated with significant decreases in IL-1β, IL-1ra, IGF-I, and IGFBP-3 and a greater increase of IGFBP-1 during recovery. Local ice therapy immediately following sprint-interval training was associated with greater decreases in both pro- and anti-inflammatory cytokines and anabolic hormones supporting some clinical evidence for possible negative effects on athletic performance

Timing of Favorable Conditions, Competition and Fertility Interact to Govern Recruitment of Invasive Chinese Tallow Tree in Stressful Environments

The rate of new exotic recruitment following removal of adult invaders (reinvasion pressure) influences restoration outcomes and costs but is highly variable and poorly understood. We hypothesize that broad variation in average reinvasion pressure of Triadica sebifera (Chinese tallow tree, a major invader) arises from differences among habitats in spatiotemporal availability of realized recruitment windows. These windows are periods of variable duration long enough to permit establishment given local environmental conditions. We tested this hypothesis via a greenhouse mesocosm experiment that quantified how the duration of favorable moisture conditions prior to flood or drought stress (window duration), competition and nutrient availability influenced Triadica success in high stress environments. Window duration influenced pre-stress seedling abundance and size, growth during stress and final abundance; it interacted with other factors to affect final biomass and germination during stress. Stress type and competition impacted final size and biomass, plus germination, mortality and changes in size during stress. Final abundance also depended on competition and the interaction of window duration, stress type and competition. Fertilization interacted with competition and stress to influence biomass and changes in height, respectively, but did not affect Triadica abundance. Overall, longer window durations promoted Triadica establishment, competition and drought (relative to flood) suppressed establishment, and fertilization had weak effects. Interactions among factors frequently produced different effects in specific contexts. Results support our ‘outgrow the stress’ hypothesis and show that temporal availability of abiotic windows and factors that influence growth rates govern Triadica recruitment in stressful environments. These findings suggest that native seed addition can effectively suppress superior competitors in stressful environments. We also describe environmental scenarios where specific management methods may be more or less effective. Our results enable better niche-based estimates of local reinvasion pressure, which can improve restoration efficacy and efficiency by informing site selection and optimal Management

Ice-stream stability on a reverse bed slope

Marine-based ice streams whose beds deepen inland are thought to be inherently unstable. This instability is of particular concern because significant portions of the marine-based West Antarctic and Greenland ice sheets are losing mass and their retreat could contribute significantly to future sea-level rise. However, the present understanding of ice-stream stability is limited by observational records that are too short to resolve multi-decadal to millennial-scale behaviour or to validate numerical models8. Here we present a dynamic numerical simulation of Antarctic ice-stream retreat since the Last Glacial Maximum (LGM), constrained by geophysical data, whose behaviour is consistent with the geomorphological record. We find that retreat of Marguerite Bay Ice Stream following the LGM was highly nonlinear and was interrupted by stabilizations on a reverse-sloping bed, where theory predicts rapid unstable retreat. We demonstrate that these transient stabilizations were caused by enhanced lateral drag as the ice stream narrowed. We conclude that, as well as bed topography, ice-stream width and long-term retreat history are crucial for understanding decadal- to centennial-scale ice-stream behaviour and marine ice-sheet vulnerability

Fibroblast Growth Factor-2 Primes Human Mesenchymal Stem Cells for Enhanced Chondrogenesis

Human mesenchymal stem cells (hMSCs) are multipotent cells capable of differentiating into a variety of mature cell types, including osteoblasts, adipocytes and chondrocytes. It has previously been shown that, when expanded in medium supplemented with fibroblast growth factor-2 (FGF-2), hMSCs show enhanced chondrogenesis (CG). Previous work concluded that the enhancement of CG could be attributed to the selection of a cell subpopulation with inherent chondrogenic potential. In this study, we show that FGF-2 pretreatment actually primed hMSCs to undergo enhanced CG by increasing basal Sox9 protein levels. Our results show that Sox9 protein levels were elevated within 30 minutes of exposure to FGF-2 and progressively increased with longer exposures. Further, we show using flow cytometry that FGF-2 increased Sox9 protein levels per cell in proliferating and non-proliferating hMSCs, strongly suggesting that FGF-2 primes hMSCs for subsequent CG by regulating Sox9. Indeed, when hMSCs were exposed to FGF-2 for 2 hours and subsequently differentiated into the chondrogenic lineage using pellet culture, phosphorylated-Sox9 (pSox9) protein levels became elevated and ultimately resulted in an enhancement of CG. However, small interfering RNA (siRNA)-mediated knockdown of Sox9 during hMSC expansion was unable to negate the prochondrogenic effects of FGF-2, suggesting that the FGF-2-mediated enhancement of hMSC CG is only partly regulated through Sox9. Our findings provide new insights into the mechanism by which FGF-2 regulates predifferentiation hMSCs to undergo enhanced CG

Identification and Characterization of the Host Protein DNAJC14 as a Broadly Active Flavivirus Replication Modulator

Viruses in the Flavivirus genus of the Flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. To identify cellular factors with antiviral activity against flaviviruses, we screened a cDNA library using an iterative approach. We identified a mammalian Hsp40 chaperone protein (DNAJC14) that when overexpressed was able to mediate protection from yellow fever virus (YFV)-induced cell death. Further studies revealed that DNAJC14 inhibits YFV at the step of viral RNA replication. Since replication of bovine viral diarrhea virus (BVDV), a member of the related Pestivirus genus, is also known to be modulated by DNAJC14, we tested the effect of this host factor on diverse Flaviviridae family members. Flaviviruses, including the pathogenic Asibi strain of YFV, Kunjin, and tick-borne Langat virus, as well as a Hepacivirus, hepatitis C virus (HCV), all were inhibited by overexpression of DNAJC14. Mutagenesis showed that both the J-domain and the C-terminal domain, which mediates self-interaction, are required for anti-YFV activity. We found that DNAJC14 does not block YFV nor HCV NS2-3 cleavage, and using non-inhibitory mutants demonstrate that DNAJC14 is recruited to YFV replication complexes. Immunofluorescence analysis demonstrated that endogenous DNAJC14 rearranges during infection and is found in replication complexes identified by dsRNA staining. Interestingly, silencing of endogenous DNAJC14 results in impaired YFV replication suggesting a requirement for DNAJC14 in YFV replication complex assembly. Finally, the antiviral activity of overexpressed DNAJC14 occurs in a time- and dose-dependent manner. DNAJC14 overexpression may disrupt the proper stoichiometry resulting in inhibition, which can be overcome upon restoration of the optimal ratios due to the accumulation of viral nonstructural proteins. Our findings, together with previously published work, suggest that the members of the Flaviviridae family have evolved in unique and important ways to interact with this host Hsp40 chaperone molecule