Hepatocellular carcinoma (HCC) is a vascular tumor with poor prognosis. Given the reported activity of gemcitabine and oxaliplatin (GEMOX) in HCC and the potential benefits of targeting the vascular ...endothelial growth factor pathway with bevacizumab (B), a phase II study of GEMOX-B was undertaken to define efficacy and toxicity profiles in HCC patients.
Eligible patients had pathologically proven measurable unresectable or metastatic HCC. For cycle 1 (14 days), bevacizumab 10 mg/kg was administered alone intravenously on day 1. For cycle 2 and beyond (28 days/cycle), bevacizumab 10 mg/kg was administered on days 1 and 15, gemcitabine 1,000 mg/m2 was administered as a dose rate infusion at 10 mg/m2/min followed by oxaliplatin at 85 mg/m2 on days 2 and 16.
Thirty-three patients were enrolled and 30 patients were assessable for efficacy. The objective response rate was 20%, and 27% of patients had stable disease. Median overall survival was 9.6 months (95% CI, 8.0 months to not available) and median progression-free survival (PFS) was 5.3 months (95% CI, 3.7 to 8.7 months); the PFS rate at 3 and 6 months was 70% (95% CI, 54% to 85%) and 48% (95% CI, 31% to 65%), respectively. The most common treatment-related grade 3 to 4 toxicities included leukopenia/neutropenia, transient elevation of aminotransferases, hypertension, and fatigue.
GEMOX-B could be safely administered with close monitoring and had moderate antitumor activity for patients with advanced HCC. The high 6-month PFS rate is encouraging, and this regimen is worthy of further investigation.
Cilia-related proteins are believed to be involved in a broad range of cellular processes. Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a ciliary protein required ...for ciliogenesis in many cell types, including epidermal keratinocytes. Here we report that RPGRIP1L is also involved in the maintenance of desmosomal junctions between keratinocytes. Genetically disrupting the Rpgrip1l gene in mice caused intraepidermal blistering, primarily between basal and suprabasal keratinocytes. This blistering phenotype was associated with aberrant expression patterns of desmosomal proteins, impaired desmosome ultrastructure, and compromised cell-cell adhesion in vivo and in vitro. We found that disrupting the RPGRIP1L gene in HaCaT cells, which do not form primary cilia, resulted in mislocalization of desmosomal proteins to the cytoplasm, suggesting a cilia-independent function of RPGRIP1L. Mechanistically, we found that RPGRIP1L regulates the endocytosis of desmogleins such that RPGRIP1L-knockdown not only induced spontaneous desmoglein endocytosis, as determined by AK23 labeling and biotinylation assays, but also exacerbated EGTA- or pemphigus vulgaris IgG-induced desmoglein endocytosis. Accordingly, inhibiting endocytosis with dynasore or sucrose rescued these desmosomal phenotypes. Biotinylation assays on cell surface proteins not only reinforced the role of RPGRIP1L in desmoglein endocytosis, but also suggested that RPGRIP1L may be more broadly involved in endocytosis. Thus, data obtained from this study advanced our understanding of the biological functions of RPGRIP1L by identifying its role in the cellular endocytic pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Motivated increases in free will belief help justify punishing others.•Due to this justification, free will beliefs reduce remorse over punitive harm.•Highly punitive free will skeptics experience ...heightened anxiety.•Punishers feel more anxious when punished partner had no choice but to be unfair.•Punitive desires increase anxiety only when free will beliefs are reduced.
Punishing wrongdoers is beneficial for group functioning, but can harm individual well-being. Building on research demonstrating that punitive motives underlie free will beliefs, we propose that free will beliefs help justify punitive impulses, thus alleviating the associated distress. In Study 1, trait-level punitiveness predicted heightened levels of anxiety only for free will skeptics. Study 2 found that higher state-level incarceration rates predicted higher mental health issue rates, only in states with citizens relatively skeptical about free will. In Study 3, participants who punished an unfair partner experienced greater distress than non-punishers, only when their partner did not have free choice. Studies 4 and 5 confirmed experimentally that punitive desires led to greater anxiety only when free will beliefs were undermined by an anti-free will argument. These results suggest that believing in free will permits holding immoral actors morally responsible, thus justifying punishment with diminished negative psychological consequences for punishers.
Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on ...immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.
Parasites with low host specificity (e.g. infecting a large diversity of host species) are of special interest in disease ecology, as they are likely more capable of circumventing ecological or ...evolutionary barriers to infect new hosts than are specialist parasites. Yet for many parasites, host specificity is not fixed and can vary in response to environmental conditions. Using data on host associations for avian malaria parasites (Apicomplexa: Haemosporida), we develop a hierarchical model that quantifies this environmental dependency by partitioning host specificity variation into region‐ and parasite‐level effects. Parasites were generally phylogenetic host specialists, infecting phylogenetically clustered subsets of available avian hosts. However, the magnitude of this specialisation varied biogeographically, with parasites exhibiting higher host specificity in regions with more pronounced rainfall seasonality and wetter dry seasons. Recognising the environmental dependency of parasite specialisation can provide useful leverage for improving predictions of infection risk in response to global climate change.
The field of environmental enrichment for zoo animals, particularly great apes, has been revived by technological advancements such as touchscreen interfaces and motion sensors. However, direct ...animal-computer interaction (ACI) is impractical or undesirable for many zoos. We developed a modular cuboid puzzle maze for the troop of six Western lowland gorillas (
) at Bristol Zoo Gardens, United Kingdom. The gorillas could use their fingers or tools to interact with interconnected modules and remove food rewards. Twelve modules could be interchanged within the frame to create novel iterations with every trial. We took a screen-free approach to enrichment: substituting ACI for tactile, physically complex device components, in addition to hidden automatic sensors, and cameras to log device use. The current study evaluated the gorillas' behavioral responses to the device, and evaluated it as a form of "cognitive enrichment." Five out of six gorillas used the device, during monthly trials of 1 h duration, over a 6 month period. All users were female including two infants, and there were significant individual differences in duration of device use. The successful extraction of food rewards was only performed by the three tool-using gorillas. Device use did not diminish over time, and gorillas took turns to use the device alone or as one mother-infant dyad. Our results suggest that the device was a form of cognitive enrichment for the study troop because it allowed gorillas to solve novel challenges, and device use was not associated with behavioral indicators of stress or frustration. However, device exposure had no significant effects on gorilla activity budgets. The device has the potential to be a sustainable enrichment method in the long-term, tailored to individual gorilla skill levels and motivations. Our study represents a technological advancement for gorilla enrichment, an area which had been particularly overlooked until now. We wholly encourage the continued development of this physical maze system for other great apes under human care, with or without computer logging technology.
Running performance, energy requirements and musculoskeletal stresses are directly related to the action-reaction forces between the limb and the ground. For human runners, the force-time patterns ...from individual footfalls can vary considerably across speed, foot-strike and footwear conditions. Here, we used four human footfalls with distinctly different vertical force-time waveform patterns to evaluate whether a basic mechanical model might explain all of them. Our model partitions the body's total mass (1.0 Mb) into two invariant mass fractions (lower limb=0.08, remaining body mass=0.92) and allows the instantaneous collisional velocities of the former to vary. The best fits achieved (R(2) range=0.95-0.98, mean=0.97 ± 0.01) indicate that the model is capable of accounting for nearly all of the variability observed in the four waveform types tested: barefoot jog, rear-foot strike run, fore-foot strike run and fore-foot strike sprint. We conclude that different running ground reaction force-time patterns may have the same mechanical basis.
Facial emotion processing (FEP) is critical to social cognitive ability. Developmentally, FEP rapidly improves in early childhood and continues to be fine-tuned throughout middle childhood and into ...adolescence. Previous research has suggested that language plays a role in the development of social cognitive skills, including non-verbal emotion recognition tasks. Here we investigated whether language is associated with specific neurophysiological indicators of FEP. One hundred and fourteen children (4–12 years) completed a language assessment and a FEP task including stimuli depicting anger, happiness, fear, and neutrality. EEG was used to record key event related potentials (ERPs; P100, N170, LPP at occipital and parietal sites separately) previously shown to be sensitive to faces and facial emotion. While there were no main effects of language, the P100 latency to negative expressions appeared to increase with language, while LPP amplitude increased with language for negative and neutral expressions. These findings suggest that language is linked to some early physiological indicators of FEP, but this is dependent on the facial expression. Future studies should explore the role of language in later stages of neural processing, with a focus on processes localised to ventromedial prefrontal regions.
•We examine the relationship between language and neurophysiological measures of FEP ERPs across development.•FEP ERPs of interest included P100, N170 and LPP.•Findings suggest relationship between language and neurophysiological measures may differ to behavioural measures of FEP.•Evidence for language playing an interactive role across early and later ERPs.•The interactive role of language appears to be emotion specific.
Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were ...present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Recent Segmental Duplications in the Human Genome Bailey, Jeffrey A.; Gu, Zhiping; Clark, Royden A. ...
Science (American Association for the Advancement of Science),
08/2002, Letnik:
297, Številka:
5583
Journal Article
Recenzirano
Primate-specific segmental duplications are considered important in human disease and evolution. The inability to distinguish between allelic and duplication sequence overlap has hampered their ...characterization as well as assembly and annotation of our genome. We developed a method whereby each public sequence is analyzed at the clone level for overrepresentation within a whole-genome shotgun sequence. This test has the ability to detect duplications larger than 15 kilobases irrespective of copy number, location, or high sequence similarity. We mapped 169 large regions flanked by highly similar duplications. Twenty-four of these hot spots of genomic instability have been associated with genetic disease. Our analysis indicates a highly nonrandom chromosomal and genic distribution of recent segmental duplications, with a likely role in expanding protein diversity.
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