Here, we outline our current understanding of the human gut virome, in particular the phage component of this ecosystem, highlighting progress, and challenges in viral discovery in this arena. We ...reveal how developments in high-throughput sequencing technologies and associated data analysis methodologies are helping to illuminate this abundant 'biological dark matter.' Current evidence suggests that the human gut virome is a highly individual but temporally stable collective, dominated by phages exhibiting a temperate lifestyle. This viral community also appears to encode a surprisingly rich functional repertoire that confers a range of attributes to their bacterial hosts, ranging from bacterial virulence and pathogenesis to maintaining host-microbiome stability and community resilience. Despite the significant advances in our understanding of the gut virome in recent years, it is clear that we remain in a period of discovery and revelation, as new methods and technologies begin to provide deeper understanding of the inherent ecological characteristics of this viral ecosystem. As our understanding increases, the nature of the multi-partite interactions occurring between host and microbiome will become clearer, helping us to more rationally define the concepts and principles that will underpin approaches to using human gut virome components for medical or biotechnological applications.
Insulators are multiprotein-DNA complexes thought to affect gene expression by mediating inter- and intrachromosomal interactions. Drosophila insulators contain specific DNA-binding proteins plus ...common components, such as CP190, that facilitate these interactions. Here, we examine changes in the distribution of Drosophila insulator proteins during the heat-shock and ecdysone responses. We find that CP190 recruitment to insulator sites is the main regulatable step in controlling insulator function during heat shock. In contrast, both CP190 and DNA-binding protein recruitment are regulated during the ecdysone response. CP190 is necessary to stabilize specific chromatin loops and for proper activation of transcription of genes regulated by this hormone. These findings suggest that cells may regulate recruitment of insulator proteins to DNA to activate insulator activity at specific sites and create distinct patterns of nuclear organization that are necessary to achieve proper gene expression in response to different stimuli.
► CP190 recruitment to DNA is dramatically reduced during the heat-shock response ► DNA localization of CP190, Su(Hw), CTCF, and BEAF is regulated during 20HE treatment ► CP190 mediates chromatin looping after 20HE treatment ► CP190 is necessary for proper regulation of 20HE nonresponsive genes
Reconstructing past sea levels can help constrain uncertainties surrounding the rate of change, magnitude, and impacts of the projected increase through the 21st century. Of significance is the ...mid-Holocene relative sea-level highstand in tectonically stable and remote (far-field) locations from major ice sheets. The east coast of Australia provides an excellent arena in which to investigate changes in relative sea level during the Holocene. Considerable debate surrounds both the peak level and timing of the east coast highstand. The southeast Australian site of Bulli Beach provides the earliest evidence for the establishment of a highstand in the Southern Hemisphere, although questions have been raised about the pretreatment and type of material that was radiocarbon dated for the development of the regional sea-level curve. Here we undertake a detailed morpho- and chronostratigraphic study at Bulli Beach to better constrain the timing of the Holocene highstand in eastern Australia. In contrast to wood and charcoal samples that may provide anomalously old ages, probably due to inbuilt age, we find that short-lived terrestrial plant macrofossils provide a robust chronological framework. Bayesian modelling of the ages provide improved dating of the earliest evidence for a highstand at 6,880±50 cal BP, approximately a millennium later than previously reported. Our results from Bulli now closely align with other sea-level reconstructions along the east coast of Australia, and provide evidence for a synchronous relative sea-level highstand that extends from the Gulf of Carpentaria to Tasmania. Our refined age appears to be coincident with major ice mass loss from Northern Hemisphere and Antarctic ice sheets, supporting previous studies that suggest these may have played a role in the relative sea-level highstand. Further work is now needed to investigate the environmental impacts of regional sea levels, and refine the timing of the subsequent sea-level fall in the Holocene and its influence on coastal evolution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women ...with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. Methods HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov ( NCT00045032 ). Findings Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09–11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68–0·86) and death (0·74, 0·64–0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89–1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. Interpretation 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. Funding F Hoffmann-La Roche (Roche).
Participatory health research (PHR) as a research paradigm, guides the research process and strives to achieve positive change in society in the interest of people's health. In this scoping review, ...PHR will be used as an umbrella term considering a wide range of collaborative research approaches in the health context. PHR is conducted 'with' or 'by' those it intends to benefit, as opposed to 'on' and 'for' them. Their involvement throughout the research process seeks to shift power and decision-making from where they traditionally lay within academia toward community, patient and public end-users. Research cannot be truly participatory without concurrently addressing power dynamics within the partnership and power imbalances in decision making. Therefore, power sharing can be defined as a major factor in building effective academic-community collaborations. This scoping review aims to identify, clarify, and map existing literature on power and power sharing in PHR from both theoretical and practical perspectives. Specifically, we will explore how power is conceptualised throughout the literature, and how power and power sharing are applied and addressed in real-life PHR partnerships. This scoping review will be conducted in accordance with the guidelines outlined in the Joanna Briggs Institute (JBI) Reviewer's Manual. This scoping review will consider both empirical and non-empirical research that report on understanding power and power sharing in participatory health research partnerships. All appropriate studies will be retrieved from the following five electronic databases: PubMed, Scopus, Embase, PsycINFO, SocIndex. This review will be limited to articles published in English and from January 1998 to March 2024. As the scoping review aims to capture more than peer-reviewed and published literature, it will also include grey literature such as theses and dissertations, reports, conference proceedings, and editorials. Data from the included literature will be extracted based on the data extraction tool, defined in advance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SummaryImagine being tasked with measuring the distance between two points in a city, but you can only use a taxicab’s odometer which displays only whole-number values (the integer part) of its ...distance traveled so far—such is the display of modern digital measuring devices. This coarse measurement between two points might be called, tongue in cheek, a taxicab metric, but clearly of a different sort from the taxicab metric on a discrete grid that we encounter in combinatorics. We will explore how we might apply probability to our taxicab’s inherent randomness, and along with limit theorems, indeed measure arbitrary distances with any desired accuracy.
To determine the incidence, outcomes, and current strategies for management of brain metastases in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
A literature ...review was performed to obtain data on central nervous system metastases in patients with breast cancer.
HER2 amplification/overexpression is a prognostic and predictive factor for the development of CNS metastases. Autopsy data show that the incidence rate for CNS metastases in patients with breast cancer is approximately 30%; this may be higher (ie, 30% to 50%) in patients with HER2-positive disease. Treatment with trastuzumab is not associated with an increased incidence of CNS metastases. Data from three phase III adjuvant trials showed the incidence was similar between patients who received trastuzumab and those who did not. Furthermore, trastuzumab can significantly improve overall survival in HER2-positive patients who already have CNS metastases compared with patients who do not receive trastuzumab or those who have HER2-negative brain metastases. This survival advantage is conferred via systemic control of the disease. The current standard of care for patients with CNS metastases is whole-brain radiotherapy (WBRT), with or without surgery, or stereotactic radiosurgery. In the future, novel therapies or combinations of therapies may additionally improve survival in these patients.
The incidence of CNS metastases in trastuzumab-treated patients is similar to that in all patients with HER2-positive disease. Trastuzumab can improve survival in patients with HER2-positive disease with CNS metastases.
The care of patients undergoing long-term urethral catheterization is frequently complicated by Proteus mirabilis infection. This organism forms dense, crystalline biofilms, which block catheters ...leading to serious clinical conditions. However, there are currently no truly effective approaches to control this problem. Here, we describe the development of a novel theranostic catheter coating, to simultaneously provide early warning of blockage, and actively delay crystalline biofilm formation.
The coating comprises of a pH sensitive upper polymer layer (poly(methyl methacrylate-co-methacrylic acid); Eudragit S 100®) and a hydrogel base layer of poly(vinyl alcohol), which is loaded with therapeutic agents (acetohydroxamic acid or ciprofloxacin hydrochloride) and a fluorescent dye, 5(6)-carboxyfluorescein (CF). The elevation of urinary pH due to P. mirabilis urease activity results in the dissolution of the upper layer and release of cargo agents contained in the base layer. Experiments using in vitro models, which were representative of P. mirabilis catheter-associated urinary tract infections, demonstrated that these coatings significantly delay time taken for catheters to block. Coatings containing both CF dye and ciprofloxacin HCl were able to provide an average of ca. 79 h advanced warning of blockage and extend catheter lifespan ca. 3.40-fold.
This study has demonstrated the potential for theranostic, infection-responsive coatings to form a promising approach to combat catheter encrustation and actively delay blockage.
Breast cancer (BC) is the most common women cancer and second most common cause of cancer death in women. A woman living in the United States has 12.3% lifetime risk of being diagnosed with BC. From ...the genomics point of view, the most common three subtypes of BC encountered in clinics are HR+, HER2+, and TNBC or basal-like BC. Estrogen receptor (ER) status or HER2 amplification or chemotherapy is not sufficient to understand the underlying mechanisms of disease progression and resistance (de novo or acquire). Although hormonal therapy and HER2-directed therapies have produced a considerable positive outcome in HR+ and HER2+ BC respectively, there are no established targeted agents for TNBC and basal-like BC. While PARP inhibitors have shown promising activity in BRCA-related cancers, its value in the treatment of TNBC remains to be demonstrated. The PI3K-AKT-mTOR signaling pathway plays a crucial role in the initiation and progress in tumorigenesis including breast tumorigenesis and regulates critical cellular functions including survival, proliferation, and metabolism. This article aims to understand the role of PI3K-mTORC1/C2 alterations in determining the clinical outcome in the specific breast cancer subtypes. The understanding of the tumor cell signaling will help us in the decision-making the process for obtaining the treatment modalities towards further advancement of the precision medicine. In this review, we will restrict our discussion to a basic understanding of the biology of subtype-specific BC and several targeted agents under development for the treatment of BC.
Background Necrotizing enterocolitis (NEC) is a leading cause of death in very low birth weight (VLBW) neonates. The overall mortality of NEC is well documented. However, those requiring surgery ...appear to have increased mortality compared with those managed medically. The objective of this study was to establish national birth-weight-based benchmarks for the mortality of surgical NEC and describe the use and mortality of laparotomy vs peritoneal drainage. Study Design There were 655 US centers that prospectively evaluated 188,703 VLBW neonates (401 to 1,500 g) between 2006 and 2010. Survival was defined as living in-hospital at 1-year or hospital discharge. Results There were 17,159 (9%) patients who had NEC, with mortality of 28%; 8,224 patients did not receive operations (medical NEC, mortality 21%) and 8,935 were operated on (mortality 35%). On multivariable regression, lower birth weight, laparotomy, and peritoneal drainage were independent predictors of mortality (p < 0.0001). In surgical NEC, a plateau mortality of around 30% persisted despite birth weights >750 g; medical NEC mortality fell consistently with increasing birth weight. For example, in neonates weighing 1,251 to 1,500 g, mortality was 27% in surgical vs 6% in medical NEC (odds ratio OR 6.10, 95% CI 4.58 to 8.12). Of those treated surgically, 6,131 (69%) underwent laparotomy only (mortality 31%), 1,283 received peritoneal drainage and a laparotomy (mortality 34%), and 1,521 had peritoneal drainage alone (mortality 50%). Conclusions Fifty-two percent of VLBW neonates with NEC underwent surgery, which was accompanied by a substantial increase in mortality. Regardless of birth weight, surgical NEC showed a plateau in mortality at approximately 30%. Laparotomy was the more frequent method of treatment (69%) and of those managed by drainage, 46% also had a laparotomy. The laparotomy alone and drainage with laparotomy groups had similar mortalities, while the drainage alone treatment cohort was associated with the highest mortality.
PDF
