From accurate sound to breakthrough technologies, JBL has a history of transporting superior audio experiences to fans across the globe; and its headphones are no exception. The team’s unwavering commitment to delivering unmatched experiences and unique...

Armed with drones, helicopters and military-grade software, a British photographer has developed a new way to remember glaciers

A cache of Denisovan tools shows how these extinct humans moved from using sharp stone flakes 150,000 years ago to stone blades and chisels around 60,000 years ago

Title: Provenge Approved for Advanced Prostate Cancer
Category: Health News
Created: 4/29/2010 2:10:00 PM
Last Editorial Review: 4/30/2010 12:00:00 AM

Title: Drugs Show Promise for Some Advanced Lung Cancers
Category: Health News
Created: 4/29/2015 12:00:00 AM
Last Editorial Review: 4/30/2015 12:00:00 AM

Title: Most States Restrict Pregnant Women's Advance Directives: Study
Category: Health News
Created: 4/26/2019 12:00:00 AM
Last Editorial Review: 4/29/2019 12:00:00 AM

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5–25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.

Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (n = 27) and/or immunofluorescence in circulating tumor cells (CTC; n = 20). Cox regression and Kaplan–Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (N = 38) or platinum monotherapy (N = 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56–8.87; P < 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77–20.86; P = 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.

Clinical teaching is a cornerstone of health sciences education; it is also the most challenging aspect. The University of Pittsburgh Schools of Dental Medicine, Nursing, and Pharmacy developed a new evidence-based interprofessional course framed as a faculty learning community (FLC) around the principles of learning in a clinical environment. The aim of this study was to assess the overall effectiveness of this two-semester FLC at four health professions schools in academic year 2014-15. The assessment included anonymous participant surveys in each session and an anonymous end-of-course survey. Thirty-five faculty members from dental, health and rehabilitation sciences, nursing, and pharmacy enrolled in the FLC, with six to 32 enrollees attending each session. All attendees at each session completed the session evaluation surveys, but the attendance rate at each session ranged from 17.1% to 91.4%. Sixteen participants (46%) completed the end-of-course survey. The results showed overall positive responses to the FLC and changes in the participants’ self-reported knowledge. Session surveys showed that the participants found the FLC topics helpful and appreciated the opportunity to learn from each other and the interprofessional nature of the FLC. Responses to the end-of-course survey were in alignment with the individual session surveys and cited specific benefits as being the content, teaching materials, and structured discussions. In additional feedback, participants reported interest to continue as a cohort and to extend the peer-support system beyond the FLC. This outcomes assessment of the first round of the FLC confirmed that this cohort-based faculty development in an interprofessional setting was well received by its participants. Their feedback provided valuable insights for changes to future offerings.

ABSTRACT

All enterococci produce a complex polysaccharide called the enterococcal polysaccharide antigen (EPA). This polymer is required for normal cell growth and division and for resistance to cephalosporins and plays a critical role in host-pathogen interaction. The EPA contributes to host colonization and is essential for virulence, conferring resistance to phagocytosis during the infection. Recent studies revealed that the "decorations" of the EPA polymer, encoded by genetic loci that are variable between isolates, underpin the biological activity of this surface polysaccharide. In this work, we investigated the structure of the EPA polymer produced by the high-risk enterococcal clonal complex Enterococcus faecalis V583. We analyzed purified EPA from the wild-type strain and a mutant lacking decorations and elucidated the structure of the EPA backbone and decorations. We showed that the rhamnan backbone of EPA is composed of a hexasaccharide repeat unit of C2- and C3-linked rhamnan chains, partially substituted in the C3 position by α-glucose (α-Glc) and in the C2 position by β-N-acetylglucosamine (β-GlcNAc). The so-called "EPA decorations" consist of phosphopolysaccharide chains corresponding to teichoic acids covalently bound to the rhamnan backbone. The elucidation of the complete EPA structure allowed us to propose a biosynthetic pathway, a first essential step toward the design of antimicrobials targeting the synthesis of this virulence factor.

IMPORTANCE Enterococci are opportunistic pathogens responsible for hospital- and community-acquired infections. All enterococci produce a surface polysaccharide called EPA (enterococcal polysaccharide antigen) required for biofilm formation, antibiotic resistance, and pathogenesis. Despite the critical role of EPA in cell growth and division and as a major virulence factor, no information is available on its structure. Here, we report the complete structure of the EPA polymer produced by the model strain E. faecalis V583. We describe the structure of the EPA backbone, made of a rhamnan hexasaccharide substituted by Glc and GlcNAc residues, and show that teichoic acids are covalently bound to this rhamnan chain, forming the so-called "EPA decorations" essential for host colonization and pathogenesis. This report represents a key step in efforts to identify the structural properties of EPA that are essential for its biological activity and to identify novel targets to develop preventive and therapeutic approaches against enterococci.

ABSTRACT

Recent advances in the analysis of microbial communities colonizing the human body have identified a resident microbial community in the human urinary tract (UT). Compared to many other microbial niches, the human UT harbors a relatively low biomass. Studies have identified many genera and species that may constitute a core urinary microbiome. However, the contribution of the UT microbiome to urinary tract infection (UTI) and recurrent UTI (rUTI) pathobiology is not yet clearly understood. Evidence suggests that commensal species within the UT and urogenital tract (UGT) microbiomes, such as Lactobacillus crispatus, may act to protect against colonization with uropathogens. However, the mechanisms and fundamental biology of the urinary microbiome-host relationship are not understood. The ability to measure and characterize the urinary microbiome has been enabled through the development of next-generation sequencing and bioinformatic platforms that allow for the unbiased detection of resident microbial DNA. Translating technological advances into clinical insight will require further study of the microbial and genomic ecology of the urinary microbiome in both health and disease. Future diagnostic, prognostic, and therapeutic options for the management of UTI may soon incorporate efforts to measure, restore, and/or preserve the native, healthy ecology of the urinary microbiomes.

Peanut allergy is one of the most common food allergies in children, with increasing prevalence over time. The dual-allergen exposure hypothesis now supports transcutaneous sensitization to peanut as a likely pathophysiologic mechanism for peanut allergy development. As a result, there is emerging evidence that early peanut introduction has a role in peanut allergy prevention. Current first-line diagnostic tests for peanut allergy have limited specificity, which may be enhanced with emerging tools such as component-resolved diagnostics. Although management of peanut allergy includes avoidance and carrying an epinephrine autoinjector, risk of fatal anaphylaxis is extremely low, and there is minimal risk related to cutaneous or inhalational exposure. Quality of life in children with peanut allergy requires significant focus. Moving forward, oral and epicutaneous immunotherapy are emerging and exciting tools that may have a role to play in desensitization to peanut.

Key Points

A Yersinia pestis mutant synthesizing an adjuvant form of lipid A (monophosphoryl lipid A, MPLA) displayed increased biogenesis of bacterial outer membrane vesicles (OMVs). To enhance the immunogenicity of the OMVs, we constructed an Asd-based balanced-lethal host-vector system that oversynthesized the LcrV antigen of Y. pestis, raised the amounts of LcrV enclosed in OMVs by the type II secretion system, and eliminated harmful factors like plasminogen activator (Pla) and murine toxin from the OMVs. Vaccination with OMVs containing MPLA and increased amounts of LcrV with diminished toxicity afforded complete protection in mice against subcutaneous challenge with 8 x 10⁵ CFU (80,000 50% lethal dose [LD₅₀]) and intranasal challenge with 5 x 10³ CFU (50 LD₅₀) of virulent Y. pestis. This protection was significantly superior to that resulting from vaccination with LcrV/alhydrogel or rF1-V/alhydrogel. At week 4 postimmunization, the OMV-immunized mice showed more robust titers of antibodies against LcrV, Y. pestis whole-cell lysate (YPL), and F1 antigen and more balanced IgG1:IgG2a/IgG2b-derived Th1 and Th2 responses than LcrV-immunized mice. Moreover, potent adaptive and innate immune responses were stimulated in the OMV-immunized mice. Our findings demonstrate that self-adjuvanting Y. pestis OMVs provide a novel plague vaccine candidate and that the rational design of OMVs could serve as a robust approach for vaccine development.

Background:

Patient identification is an important step for advance care planning (ACP) discussions.

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.

Negative circumferential resection margins (CRM) are the cornerstone for the curative treatment of locally advanced rectal cancer (LARC). However, in up to 18.6% of patients, tumor-positive resection margins are detected on histopathology. In this proof-of-concept study, we investigated the feasibility of optical molecular imaging as a tool for evaluating the CRM directly after surgical resection to improve tumor-negative CRM rates. Methods: LARC patients treated with neoadjuvant chemoradiotherapy received an intravenous bolus injection of 4.5 mg of bevacizumab-800CW, a fluorescent tracer targeting vascular endothelial growth factor A, 2–3 d before surgery (ClinicalTrials.gov identifier: NCT01972373). First, for evaluation of the CRM status, back-table fluorescence-guided imaging (FGI) of the fresh surgical resection specimens (n = 8) was performed. These results were correlated with histopathology results. Second, for determination of the sensitivity and specificity of bevacizumab-800CW for tumor detection, a mean fluorescence intensity cutoff value was determined from the formalin-fixed tissue slices (n = 42; 17 patients). Local bevacizumab-800CW accumulation was evaluated by fluorescence microscopy. Results: Back-table FGI correctly identified a tumor-positive CRM by high fluorescence intensities in 1 of 2 patients (50%) with a tumor-positive CRM. For the other patient, low fluorescence intensities were shown, although (sub)millimeter tumor deposits were present less than 1 mm from the CRM. FGI correctly identified 5 of 6 tumor-negative CRM (83%). The 1 patient with false-positive findings had a marginal negative CRM of only 1.4 mm. Receiver operating characteristic curve analysis of the fluorescence intensities of formalin-fixed tissue slices yielded an optimal mean fluorescence intensity cutoff value for tumor detection of 5,775 (sensitivity of 96.19% and specificity of 80.39%). Bevacizumab-800CW enabled a clear differentiation between tumor and normal tissue up to a microscopic level, with a tumor-to-background ratio of 4.7 ± 2.5 (mean ± SD). Conclusion: In this proof-of-concept study, we showed the potential of back-table FGI for evaluating the CRM status in LARC patients. Optimization of this technique with adaptation of standard operating procedures could change perioperative decision making with regard to extending resections or applying intraoperative radiation therapy in the case of positive CRM.

Among the emerging techniques to detect the real footprint of buried ore deposits is isotope tracing. Novel and automated preparation systems such as continuous flow isotope ratio mass spectrometry, off-axis integrated cavity output spectroscopy for isotopic compositions of selected molecules, multi-collector inductively coupled-plasma mass spectrometry (ICP-MS), triple quadrupole ICP-MS, laser ablation ICP-MS, and a multitude of inline preparation systems have facilitated the use of isotopes as tracers in mineral exploration, as costs for isotope analyses have decreased and the time required for the analyses has improved. In addition, the isotope systems being used have expanded beyond the traditional light stable and Pb isotopes to include a multitude of elements that behave differently during processes that promote the mobilization of elements during both primary and secondary dispersion. Isotopes are also being used to understand barren areas that lack a critical process to form an ore deposit and to reveal precise redox mechanisms. The goal is to be able to use isotopes to reflect a definitive process that occurs in association with the deposit and not in barren systems, and then to relate these to something that is easier to measure, namely elemental concentrations. As new generations of exploration and environmental scientists are becoming more comfortable with the application of isotopes to effectively trace processes involved in geoscience, and new technologies for rapid and inexpensive analyses of isotopes are continually being developed, novel applications of isotope tracing are becoming more mainstream.

Thematic collection: This article is part of the Exploration 17 collection available at: https://www.lyellcollection.org/cc/exploration-17

In the past decade, significant research efforts have been devoted to mineral chemistry studies to assist porphyry exploration. These activities can be divided into two major fields of research: (1) porphyry indicator minerals (PIMs), which are used to identify the presence of, or potential for, porphyry-style mineralization based on the chemistry of magmatic minerals such as zircon, plagioclase and apatite, or resistate hydrothermal minerals such as magnetite; and (2) porphyry vectoring and fertility tools (PVFTs), which use the chemical compositions of hydrothermal minerals such as epidote, chlorite and alunite to predict the likely direction and distance to mineralized centres, and the potential metal endowment of a mineral district. This new generation of exploration tools has been enabled by advances in and increased access to laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), short-wave length infrared (SWIR), visible near-infrared (VNIR) and hyperspectral technologies. PIMs and PVFTs show considerable promise for exploration and are starting to be applied to the diversity of environments that host porphyry and epithermal deposits globally. Industry has consistently supported development of these tools, and in the case of PVFTs encouraged by several successful blind tests where deposit centres have successfully been predicted from distal propylitic settings. Industry adoption is steadily increasing but is restrained by a lack of the necessary analytical equipment and expertise in commercial laboratories, and also by the ongoing reliance on well-established geochemical exploration techniques (e.g. sediment, soil and rock chip sampling) that have aided the discovery of near-surface resources over many decades, but are now proving less effective in the search for deeply buried mineral resources and for those concealed under cover.

Thematic collection: This article is part of the Exploration 17 collection available at: https://www.lyellcollection.org/cc/exploration-17

There have been several advances in inductively coupled plasma-mass spectrometer (ICP-MS) analytical technologies in the last decade. Collision/reaction cell ICP-MS and triple quadrupole ICP-MS techniques can produce lower detection limits for select elements that experience interferences with a standard quadrupole (e.g. Se and As). Triple quadrupole ICP-MS, in particular, can eliminate virtually all polyatomic or isobaric interferences for highly accurate measurements of some element isotopes systematics that are of great interest in mineral exploration, namely Pb/Pb. Laser ablation ICP-MS has become more popular as an effective analytical tool to measure mineral grain trace elements, which could assist in vectoring to mineralization or exploration drill targets. The ablation of a spot on a Li-borate fused glass disk paired with XRF analysis has also gained popularity as an alternative to total whole rock characterization packages that employ several separate digestions and analytical methods. While there have been several advancements in ICP-MS technologies in exploration geochemistry, they have not been widely accepted or implemented. This slow adaptation could be due to the extended recession in the mining industry between 2012 and 2017. It is also possible that standard ICP-MS data (i.e. no collision/reaction cell) is still fit for purpose. This stands in stark contrast to implementation of ICP-MS in the previous decade (1997–2007), which was transformational for the industry.

Consideration of all elements from large multi-element ICP-MS analytical suites for mineral exploration can be an extremely powerful tool in the exploration toolkit. The discovery of the White Gold District, Yukon, is a prime example of how the utilization of soil geochemical data, when plotted spatially, can vector to gold mineralization. The presence of Au + As + Sb soil anomalies were key to delineating mineralization, especially when accompanied by publicly available geological, geographical and geophysical data. Additionally, elements and element ratios not typically considered in Au exploration, including Ni and U, were utilized to determine the lithological and structural controls on mineralization. The availability of multi-element ICP-MS data was also useful in the discovery of the Cascadero Copper Taron Caesium deposit. Ore-grade Cs was discovered only because Cs was included in the multi-element ICP-MS exploration geochemistry suite. Before the availability of ICP-MS, it is unlikely that this deposit would have been discovered.

Thematic collection: This article is part of the Exploration 17 collection available at: https://www.lyellcollection.org/cc/exploration-17

Mineral exploration under relatively young, exotic cover still presents a major challenge to discovery. Advances and future developments can be categorized in four key areas, (1) understanding metal mobility and mechanisms, (2) rapid geochemical analyses, (3) data access, integration and interoperability and (4) innovation in laboratory-based methods.

Application of ‘regolith-style' surface mapping in covered terrains outside of conventional lateritic terrains is achieving success in terms of reducing background noise and improving geochemical contrasts. However, process models for anomaly generation are still uncertain and require further research. The interaction between the surface environment, microbes, hydrocarbons and chemistry is receiving greater attention. While significant progress has been achieved in understanding the role of vegetation, interaction with the water table and cycling of metals in the near surface environment in Australia, other regions of the world, for example, the till-covered terrains in the northern hemisphere and arid colluvium-covered areas of South America, have seen less progress. In addition to vegetation, the influence of bacteria, fungi and invertebrates is not as well studied with respect to metal mobilization in cover. Field portable XRF has become a standard field technique, though more often used in a camp setting. Apart from a tweaking of analytical quality, instruments have probably reached their peak of analytical development with add-ons, such as cameras, beam-limiters, wireless transmission and GPS as the main differences between instrument suppliers. Their future rests in automated application in unconventional configurations, for example, core scanning and better integration of analytical data with other information such as spectral analyses. Pattern drilling that persists in industry, however, has benefited from innovative application of field-portable tools along with rock and mineral chemistry to provide near real-time results and assist in a shift toward more flexible and targeted drilling in greenfields settings.

Innovation in the laboratory continues to progress. More selective geochemical analysis, imaging of fine particle size fractions and resistate mineral phases and isotope analysis are faster and more accessible than ever before. The application of genomics (and data analysis) as mineral exploration tools is on the horizon. A continuing problem in geoscience, the supply to industry of suitably trained geochemists, persists although some needs, particularly at junior level, will be met by recent initiatives at various universities at graduate level. Unfortunately, the current economic climate has had a significant impact on R&D and retention of geochemistry skills by the industry. Whilst the future is positive, significant investment is required to develop the next generation of geochemical exploration tools and concepts.

Thematic collection: This article is part of the Exploration 17 collection available at: https://www.lyellcollection.org/cc/exploration-17

The bioprocessing industry uses recombinant mammalian cell lines to generate therapeutic biologic drugs. To ensure consistent product quality of the therapeutic proteins, it is imperative to have a controlled production process. Regulatory agencies and the biotechnology industry consider cell line "clonal origin" an important aspect of maintaining process control. Demonstration of clonal origin of the cell substrate, or production cell line, has received considerable attention in the past few years, and the industry has improved methods and devised standards to increase the probability and/or assurance of clonal derivation. However, older production cell lines developed before the implementation of these methods, herein referred to as "legacy cell lines," may not meet current regulatory expectations for demonstration of clonal derivation. In this article, the members of the IQ Consortium Working Group on Clonality present our position that the demonstration of process consistency and product comparability of critical quality attributes throughout the development life cycle should be sufficient to approve a license application without additional genetic analysis to support clonal origin, even for legacy cell lines that may not meet current day clonal derivation standards. With this commentary, we discuss advantages and limitations of genetic testing methods to support clonal derivation of legacy cell lines and wish to promote a mutual understanding with the regulatory authorities regarding their optional use during early drug development, subsequent to Investigational New Drug (IND) application and before demonstration of product and process consistency at Biologics License Applications (BLA) submission.

PURPOSE

Online programs may help to engage patients in advance care planning in outpatient settings. We sought to implement an online advance care planning program, PREPARE (Prepare for Your Care; http://www.prepareforyourcare.org), at home and evaluate the changes in advance care planning engagement among patients attending outpatient clinics.

Background and objectives

Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study.

Background and objectives

Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11–13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9–11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan.

Purpose:

KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET).

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus. As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.

Dalbavancin offers a possible treatment option for infectious peritonitis associated with peritoneal dialysis (PD) due to its coverage of Gram-positive bacteria and pharmacokinetic properties. We aimed to evaluate the clinical pharmacokinetics (PK) and pharmacodynamics of dalbavancin in a prospective, randomized, open-label, crossover PK study of adult patients with end-stage renal disease ESRD who were receiving PD. Sampling occurred prior to a single 30-min infusion of dalbavancin at 1,500 mg and at 1, 2, 3, 4, and 6 h and 7 and 14 days postadministration. Concentration-time data were analyzed via noncompartmental analysis. Pharmacodynamic parameters against common infectious peritonitis-causing pathogens were evaluated. Ten patients were enrolled. Patients were a median of 55 years old and had a median weight of 78.2 kg, 50% were female, and 70% were Caucasian. The terminal plasma half-life of dalbavancin was 181.4 ± 35.5 h. The day 0 to day 14 dalbavancin mean area under the curve (AUC) was 40,573.2 ± 9,800.3 mg·h/liter. The terminal-phase half-life of dalbavancin within the peritoneal fluid was 4.309 x 10⁸ ± 1.140 x 10⁹ h. The day 0 to day 14 dalbavancin mean peritoneal fluid AUC was 2,125.0 ± 1,794.3 mg·h/liter. The target plasma AUC/MIC was attained with the intravenous dose in all 10 patients for all Staphylococcus and Streptococcus species at the recommended MIC breakpoints. The intraperitoneal arm of the study was stopped early, because the first 3 patients experienced moderate to severe pain and bloating within 1 h following the administration of dalbavancin. Dalbavancin at 1,500 mg administered intravenously can be utilized without dose adjustment in peritoneal dialysis patients and will likely achieve the necessary peritoneal fluid concentrations to treat peritonitis caused by typical Gram-positive pathogens.

Enterococcus faecium strains are commonly resistant to vancomycin and β-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors.

Inhibition of BET protein bromodomains BD1 and BD2 produces unique phenotypes in disease models.

BACKGROUND AND PURPOSE:

Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma.

Công ty BĐS Khang Điền Nam, thành lập tháng 03 năm 2014

Lĩnh vực hoạt động: môi giới bất động sản Khu Nam, chủ yếu môi giới đất nền về dự án, thổ cư.

Danh sách các dự án bất động sản đã môi giới thành công: Đại Phúc, T30, Phong Phú 4, 6B Intresco, và một số căn hộ khu vực Bình Chánh...

Khu vực môi giới tốt nhất: Bình Chánh, Quận 7, Quận 8 (TP. Hồ Chí Minh); Bến Lức (Long An)

Liên hệ:

Địa chỉ: 142/34 Đường Nguyễn Thị Thập, Phường Bình Thuận, Quận 7, TP. Hồ Chí Minh.

Văn phòng giao dịch: 10 đường số 10, KDC T30, Bình Hưng, Bình Chánh, TP. Hồ Chí Minh.

Hotline: 0908260209

Hotmail: tamnguyen.khangdiennam@gmail.com

Trân trọng cảm ơn quý khách và hy vọng sự hợp tác tốt đẹp!
 

Chuyên môi giới - đầu tư bất động sản phân khúc đa dạng:

• Nhà, đất thổ cư đẹp 
• Đất nền dự án 
• Bán căn hộ chung cư dự án 

Khu vực môi giới tốt nhất: Sơn Trà (Đà Nẵng), Điện Bàn (Quảng Nam), Quy Nhơn (Bình Định), Thừa Thiên Huế

Danh sách dự án BĐS đã thực hiện: Dự án Apec Mandala Wyndham Huế, dự án Nhơn Hội New City, dự án Ngọc Dương Riverside, dự án Mường Thanh Sơn Trà Đà Nẵng...

 

Chúng tôi mong muốn xây dựng cộng đồng bất động sản hiện đại, chuyên nghiệp, giàu tính nhân văn. Chính vì đó, Công ty Vạn Gia Phát ra đời đáp ứng mọi yêu cầu cung cấp giải pháp, dịch vụ bất động sản toàn diện, hợp lý giúp khách hàng tiết kiệm thời gian, chi phí và góp phần tạo lập cuộc sống ưu việt cho khách hàng.

Vạn Gia Phát hướng đến triết lý kinh doanh là phải bền vững. Vì thế các sản phẩm, dịch vụ do công ty cung cấp luôn xét tới yếu tố lợi ích lâu dài, bền vững cho khách hàng và nhà đầu tư.

Bằng khát vọng dẫn đầu và chiến lược phát triển bền vững, Vạn Gia Phát phấn đấu trở thành công ty kinh doanh, đầu tư, cung cấp dịch vụ bất động sản nằm trong top của khu vực và cả nước.

Danh sách các dự án đã đầu tư, thi công xây dựng: Vạn Phát Sông Hậu, Vạn Phát Garden, Vạn Phát Cái Tắc…

Quý khách có nhu cầu tìm hiểu và đầu tư BĐS  tại Cần Thơ vui lòng liên hệ chúng tôi để được tư vấn tốt nhất!

Công ty bất động sản Vạn Hưng Phát – Ninh Thuận thành lâp ngày 16/09/2019, với triết lý kinh doanh “Niềm tin của bạn, tương lai của chúng tôi”.

Với chiến lược xây dựng đội ngũ nhân viên kinh doanh bất động sản ưu tú, chuyên nghiệp, hướng tới một công ty môi giới đạt chuẩn, chuyên nghiệp, đồng bộ và uy tín, phát triển hệ thống bán hàng một cách hiệu quả kết hợp đầu tư xây dựng và phát triển bất động sản ở nhiều mặt.

Với đội ngũ nhân viên giàu kinh nghiệm, chuyên nghiệp, trung thực, luôn lắng nghe và thấu hiểu được nhu cầu của khách hàng để đáp ứng nhu cầu của khách hàng tốt nhất có thể. Niềm vui và sự tin tưởng, tín nhiệm của khách hàng chính là thành công lớn nhất của công ty chúng tôi.

Lĩnh vực hoạt động: Tư vấn, mua bán, ký gởi, cho thuê đất nền, đất dự án, căn hộ. Dịch vụ làm sổ đỏ, gắn tài sản trên đất, xin giấy phép xây dựng. Tư vấn, thiết kế, thi công biệt thự, nhà phố.

Khu vực môi giới tốt nhất hiện nay: TP. Phan Rang - Tháp Chàm.

Chúng tôi luôn sẵn sàng giúp đỡ các bạn!

Liên hệ:
Hotline: 0931 043 939 – 0982 891 111.

Email: ctyvanhungphat@gmail.com

Địa chỉ: Số 97 Quang Trung, TP Phan Rang – Tháp Chàm, Tỉnh Ninh Thuận.

1. Giới thiệu tư vấn các loại hình bất động sản
2. Tư vấn, hỗ trợ pháp lý liên quan đến BDS, trung tâm thành phố và ven đô
3. Nhận, ký gửi, mua bán tất cả các loại bất động sản trên thị trường TP. Hồ Chí Minh

Slogan: Đối tác trung gian tin cậy - Tư vấn đầu từ hiệu quả 

Sau thời gian hình thành và phát triển, dù trải qua nhiều thử thách nhưng với chiến lược phù hợp cùng tư duy quản trị đúng đắn và tinh thần đoàn kết, nỗ lực của toàn công ty, thương hiệu Saigon Center Real ngày càng được khẳng định một cách vững chắc trên thị trường, được khách hàng xem là một Công ty tư vấn đầu tư uy tín số 1 trong ngành dịch vụ Bất động sản Việt Nam.

Nhờ sự đồng lòng, tinh thần đoàn kết và trách nhiệm cao của toàn tập thể công ty cùng sự tín nhiệm, ủng hộ của khách hàng trong suốt thời gian qua, Saigon Center Real đang dần hoàn thiện và phát triển mình.

Đội ngũ SGCR có thu nhập cực cao, trong đó các super sale có doanh số năm 2018 và 2019 là 12 tỷ. Chúng tôi tự hào là tổ chức phát triển nhà lãnh đạo và phát triển các chuyên gia bán hàng xuất sắc nhất Việt Nam, nơi hội tụ nhiều cá nhân tài năng, những người nhân cách lớn và giàu khát vọng, những người luôn sục sôi chí lớn, ngày đêm rèn luyện tài năng, nghiền ngẫm, vận dụng và sáng tạo trong công việc. Luôn ý thức được sứ mệnh của mình như những “thiên sứ” mang lại tổ ấm cho những gia đình khách hàng để họ có thể an cư lạc nghiệp.

Gia nhập vào đại gia đình Saigon Center Real, bạn sẽ có những người bạn, người đồng nghiệp thân thiết gắn bó, chia sẻ những khó khăn trong công việc và cuộc sống. Toàn thể tập thể công ty Saigon Center Real luôn tràn đầy nhiệt huyết - khát vọng, ham học hỏi và không ngừng phấn đấu để vượt qua mọi thách thức, chinh phục mọi thành công.

Với mục tiêu và tầm nhìn tới năm 2025, Saigon Center Real sẽ có mặt tại 63 tỉnh thành trên cả nước với qui mô nhân sự khoảng 10.000 người & trở thành công ty dịch vụ BĐS lớn nhất Việt Nam.

Chúng tôi sẽ làm nên " lịch sử" của ngành dịch vụ BĐS truyền thống Việt Nam & hướng tới mở văn phòng giao dịch tại các nước trên thế giới với qui mô nhân sự khoảng 30 ngàn người vào năm 2030 để trở thành nhà phân phối bất động sản số 1 thế giới, đóng góp vào sự phát triển của ngành bất động sản và nền kinh tế Việt Nam hoà nhập với nền kinh tế thế giới.

Đó là khát vọng, là lý tưởng là "sứ mệnh lịch sử'' của ban lãnh đạo và tất cả mọi thành viên công ty Saigon Center Real cùng nhau hướng tới cuộc sống: “Giàu có - Thành công và Hạnh phúc trọn vẹn”.

Hotline: 0909792352

Danh sách các chi nhánh của Công ty :

• Trụ sở Nguyễn Huệ, Quận 1.
• Chi nhánh Itaxa Quận 3.
• Chi nhánh An Dương Vương, Quận 5.
• Chi nhánh Nguyễn Văn Trỗi, Quận Phú Nhuận.
• Chi nhánh Trần Não, Quận 2.
• Chi nhánh Nguyễn Văn Đậu, Quận Gò Vấp.
• Chi Nhánh Ung Văn Khiêm, Quận Bình Thạnh.
• Chi nhánh Cộng Hòa, Quận Tân Bình.
• Chi Nhánh Quang Trung, Quận 12.
• Chi Nhánh Tô Hiến Thành, Quận 10.

Trân trọng cảm ơn!

Là thiết kế của hãng kiến trúc NBBJ, văn phòng của công ty sản xuất đồ chơi, vật dụng dành cho chó cưng ở Ohio, Mỹ có những ngóc ngách kiểu giường tầng và khu vui chơi để những chú chó có thể chạy nhảy, chơi đùa ngay trong không gian làm việc của nhân viên công ty.