Competing accounts propose that working memory (WM) is subserved either by persistent activity in single neurons or by dynamic (time-varying) activity across a neural population. Here, we compare ...these hypotheses across four regions of prefrontal cortex (PFC) in an oculomotor-delayed-response task, where an intervening cue indicated the reward available for a correct saccade. WM representations were strongest in ventrolateral PFC neurons with higher intrinsic temporal stability (time-constant). At the population-level, although a stable mnemonic state was reached during the delay, this tuning geometry was reversed relative to cue-period selectivity, and was disrupted by the reward cue. Single-neuron analysis revealed many neurons switched to coding reward, rather than maintaining task-relevant spatial selectivity until saccade. These results imply WM is fulfilled by dynamic, population-level activity within high time-constant neurons. Rather than persistent activity supporting stable mnemonic representations that bridge subsequent salient stimuli, PFC neurons may stabilise a dynamic population-level process supporting WM.
To investigate the genetic changes associated withAML relapse, and to determine whether clonal evolution contributes to relapse, we performed whole-genome sequencing of primary tumour-relapse pairs ...andmatched skin samples fromeight patients, including unique patient identifier (UPN) 933124, whose primary tumourmutations were previously reported3. Assuming that all the mutations detected are heterozygous in the primary tumour sample (with a malignant cellular content at 93.72% for the primary bone marrow sample, see Supplementary Information), we were able to calculate the fraction of total malignant cells in each clone.
Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level (1,2). To determine the mutational ...spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
Cause of Cambrian Explosion - Terrestrial or Cosmic? Steele, Edward J.; Al-Mufti, Shirwan; Augustyn, Kenneth A. ...
Progress in biophysics and molecular biology,
August 2018, 2018-08-00, 20180801, Letnik:
136
Journal Article
Recenzirano
Odprti dostop
We review the salient evidence consistent with or predicted by the Hoyle-Wickramasinghe (H-W) thesis of Cometary (Cosmic) Biology. Much of this physical and biological evidence is multifactorial. One ...particular focus are the recent studies which date the emergence of the complex retroviruses of vertebrate lines at or just before the Cambrian Explosion of ∼500 Ma. Such viruses are known to be plausibly associated with major evolutionary genomic processes. We believe this coincidence is not fortuitous but is consistent with a key prediction of H-W theory whereby major extinction-diversification evolutionary boundaries coincide with virus-bearing cometary-bolide bombardment events. A second focus is the remarkable evolution of intelligent complexity (Cephalopods) culminating in the emergence of the Octopus. A third focus concerns the micro-organism fossil evidence contained within meteorites as well as the detection in the upper atmosphere of apparent incoming life-bearing particles from space. In our view the totality of the multifactorial data and critical analyses assembled by Fred Hoyle, Chandra Wickramasinghe and their many colleagues since the 1960s leads to a very plausible conclusion – life may have been seeded here on Earth by life-bearing comets as soon as conditions on Earth allowed it to flourish (about or just before 4.1 Billion years ago); and living organisms such as space-resistant and space-hardy bacteria, viruses, more complex eukaryotic cells, fertilised ova and seeds have been continuously delivered ever since to Earth so being one important driver of further terrestrial evolution which has resulted in considerable genetic diversity and which has led to the emergence of mankind.
The coronavirus disease 2019 (COVID-19) pandemic necessitated rapid changes in medical practice. Many of these changes may add value to care, creating opportunities going forward.
To provide an ...evidence-informed, expert-derived review of genitourinary cancer care moving forward following the initial COVID-19 pandemic.
A collaborative narrative review was conducted using literature published through May 2020 (PubMed), which comprised three main topics: reduced in-person interactions arguing for increasing virtual and image-based care, optimisation of the delivery of care, and the effect of COVID-19 in health care facilities on decision-making by patients and their families.
Patterns of care will evolve following the COVID-19 pandemic. Telemedicine, virtual care, and telemonitoring will increase and could offer broader access to multidisciplinary expertise without increasing costs. Comprehensive and integrative telehealth solutions will be necessary, and should consider patients’ mental health and access differences due to socioeconomic status. Investigations and treatments will need to maximise efficiency and minimise health care interactions. Solutions such as one stop clinics, day case surgery, hypofractionated radiotherapy, and oral or less frequent drug dosing will be preferred. The pandemic necessitated a triage of those patients whose treatment should be expedited, delayed, or avoided, and may persist with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in circulation. Patients whose demographic characteristics are at the highest risk of complications from COVID-19 may re-evaluate the benefit of intervention for less aggressive cancers. Clinical research will need to accommodate virtual care and trial participation. Research dissemination and medical education will increasingly utilise virtual platforms, limiting in-person professional engagement; ensure data dissemination; and aim to enhance patient engagement.
The COVID-19 pandemic will have lasting effects on the delivery of health care. These changes offer opportunities to improve access, delivery, and the value of care for patients with genitourinary cancers but raise concerns that physicians and health administrators must consider in order to ensure equitable access to care.
The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed the care provided to many patients with genitourinary cancers. This has necessitated a transition to telemedicine, changes in threshold or delays in many treatments, and an opportunity to reimagine patient care to maintain safety and improve value moving forward.
The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed the care provided to many patients with genitourinary cancers. This has necessitated a transition to telemedicine, changes in threshold, or delays in many treatments, and an opportunity to reimagine patient care to maintain safety and improve value moving forward.
No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for quantitative analysis.
To ...indirectly compare the efficacy and safety of first-line treatments for mRCC in the intention-to-treat (ITT) population and by clinical risk group.
An updated systematic review from database inception to February 17, 2019 identified all parallel-group randomized controlled trials assessing first-line therapy for mRCC. “Clinically relevant” studies were selected for a network meta-analysis. Progression-free survival (PFS) was the primary outcome. Overall survival (OS), overall response rate (ORR), and grade 3 and 4 adverse events (AEs) were secondary outcomes.
We identified 12 relevant trials: 12 reported outcomes for PFS, nine for OS, 10 for ORR, and nine for AEs. In the ITT population, cabozantinib (surface under the cumulative ranking curves SUCRA 84%), avelumab plus axitinib (SUCRA 68%), and pembrolizumab plus axitinib (SUCRA 82%) were superior to the other agents for PFS; pembrolizumab plus axitinib appeared superior for OS (SUCRA 95%); and atezolizumab demonstrated the lowest likelihood of AEs (SUCRA 100%). Findings were similar in the intermediate/poor-risk subgroup. Based on the limited data available, avelumab plus axitinib may be preferred in patients with favorable-risk disease.
The optimal first-line treatment for mRCC appears to differ by efficacy endpoint, toxicity, and clinical risk group. Direct comparative studies remain important in guiding treatment choice.
Head-to-head comparisons do not exist for the newest treatments of metastatic renal cell carcinoma (mRCC). In an indirect comparison, we found that pembrolizumab plus axitinib and cabozantinib are good options for most patients with mRCC.
The optimal first-line treatment for metastatic renal cell carcinoma differs by clinical risk group and efficacy endpoint. In the intention-to-treat population, cabozantinib, avelumab+axitinib, and pembrolizumab+axitinib are likely preferred for progression-free survival, while pembrolizumab+axitinib combination is preferred for overall survival.
Background
The role of surgical resection for patients with large or multifocal intrahepatic cholangiocarcinoma (ICC) remains unclear. This study evaluated the long-term outcome of patients who ...underwent hepatic resection for large (≥7 cm) or multifocal (≥2) ICC.
Methods
Between 1990 and 2013, 557 patients who underwent liver resection for ICC were identified from a multi-institutional database. Clinicopathologic characteristics, operative details, and long-term survival data were evaluated.
Results
Of the 557 patients, 215 (38.6 %) had a small, solitary ICC (group A) and 342 (61.4 %) had a large or multifocal ICC (group B). The patients in group B underwent an extended hepatectomy more frequently (16.9 vs. 30.4 %;
P
< 0.001). At the final pathology exam, the patients in group B were more likely to show evidence of vascular invasion (22.5 vs. 38.5 %), direct invasion of contiguous organs (6.5 vs. 12.9 %), and nodal metastasis (13.3 vs. 21.0 %) (all
P
< 0.05). Interestingly, the incidences of postoperative complications (39.3 vs. 46.8 %) and hospital mortality (1.1 vs. 3.7 %) were similar between the two groups (both
P
> 0.05). The group A patients had better rates for 5-year overall survival (OS) (30.5 vs. 18.7 %;
P
< 0.05) and disease-free survival (DFS) (22.6 vs. 8.2 %;
P
< 0.05) than the group B patients. For the patients in group B, the factors associated with a worse OS included more than three tumor nodules hazard ratio (HR), 1.56, nodal metastasis (HR, 1.47), and poor differentiation (HR, 1.48).
Conclusions
Liver resection can be performed safely for patients with large or multifocal ICC. The long-term outcome for these patients can be stratified on the basis of a prognostic score that includes tumor number, nodal metastasis, and poor differentiation.
Poxviruses carry the enzyme, nucleoside triphosphate phosphohydrolase I (NPH I), required for early viral transcription in the cytoplasm of infected cells. The gene (
nph I) encoding this enzyme from
...Choristoneura fumiferana entomopoxvirus (CfEPV) has been located in the viral genome, cloned and characterized. It has an open reading frame of 1941 nucleotides, potentially encoding a protein with a predicted molecular mass of 76.04 kDa and a pI of 8.83. It has a TAAATG motif where the trinucleotide ATG represents the translational start signal an AT-rich (88%) sequence and an early transcription termination signal (TTTTTAT) upstream of the ATG codon. Northern blot analysis of mRNA from infected larvae showed that a single 4.0 kb transcript which appeared late at day 20 post infection (p.i.) and its transcription continued till day 37 p.i.. Primer extension experiments suggested that the main transcripts started at 15 bases upstream of AUG codon. NPH I homologues have been found in the genomes of other entomopoxviruses and vertebrate poxviruses. Alignment of their amino acid sequences suggested three conserved domains, two of which are considered as ATP binding domains. The most similar homologue is from the closely related entomopoxvirus,
Choristoneura biennis EPV (CbEPV) where 98.2% of nucleotide and 97.2% of amino acid identities are observed, respectively. A single nucleotide difference in CfEPV
nph I was sufficient to distinguish it from CbEPV by PCR amplification and digestion with a restriction enzyme.
Objective To evaluate the effectiveness of a 'single session' group, early intervention, multidisciplinary, education programme (entitled the Fun not Fuss with Food group programme) designed to ...improve children's problem eating and mealtime behaviours.
Design A quasi-experimental time-series design incorporating data collection, twice before and twice following the intervention.
Setting A health district within the southeast region of Queensland, Australia.
Method Data were collected using the Children's Eating and Mealtime Behaviour Inventory - Revised (CEBI-R) and the Family Demographic Questionnaire.
Results Parents who attended the Fun not Fuss with Food group programme reported significant improvements in their child's problem eating and mealtime behaviours and reported reductions in parental concerns regarding their child's eating and mealtime behaviours. Conclusion A single session, early intervention, group education programme for families with children with problem eating and mealtime behaviours is appropriate and effective. Therefore, early intervention group education programmes should be considered as a strategy for this client group.
Recellularization of whole decellularized lung scaffolds provides a novel approach for generating functional lung tissue ex vivo for subsequent clinical transplantation. To explore the potential ...utility of stem and progenitor cells in this model, we investigated recellularization of decellularized whole mouse lungs after intratracheal inoculation of bone marrow-derived mesenchymal stromal cells (MSCs). The decellularized lungs maintained structural features of native lungs, including intact vasculature, ability to undergo ventilation, and an extracellular matrix (ECM) scaffold consisting primarily of collagens I and IV, laminin, and fibronectin. However, even in the absence of intact cells or nuclei, a number of cell-associated (non-ECM) proteins were detected using mass spectroscopy, western blots, and immunohistochemistry. MSCs initially homed and engrafted to regions enriched in types I and IV collagen, laminin, and fibronectin, and subsequently proliferated and migrated toward regions enriched in types I and IV collagen and laminin but not provisional matrix (fibronectin). MSCs cultured for up to 1 month in either basal MSC medium or in a small airways growth media (SAGM) localized in both parenchymal and airway regions and demonstrated several different morphologies. However, while MSCs cultured in basal medium increased in number, MSCs cultured in SAGM decreased in number over 1 month. Under both media conditions, the MSCs predominantly expressed genes consistent with mesenchymal and osteoblast phenotype. Despite a transient expression of the lung precursor TTF-1, no other airway or alveolar genes or vascular genes were expressed. These studies highlight the power of whole decellularized lung scaffolds to study functional recellularization with MSCs and other cells.
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