The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to ...degradation. In this Review we highlight recent advances in formulation and delivery strategies--such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs--and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.
The primary objective was to determine if vaginal cuff brachytherapy and chemotherapy (VCB/C) increases recurrence-free survival (RFS) compared with pelvic radiation therapy (RT) in high-intermediate ...and high-risk early-stage endometrial carcinoma.
A randomized phase III trial was performed in eligible patients with endometrial cancer. Eligible patients had International Federation of Gynecology and Obstetrics (2009) stage I endometrioid histology with Gynecologic Oncology Group protocol 33-based high-intermediate-risk criteria, stage II disease, or stage I to II serous or clear cell tumors. Treatment was randomly assigned between RT (45 to 50.4 Gy over 5 weeks) or VCB followed by intravenous paclitaxel 175 mg/m
(3 hours) plus carboplatin (area under the curve, 6) every 21 days for three cycles.
The median age of the 601 patients was 63 years, and 74% had stage I disease. Histologies included endometrioid (71%), serous (15%), and clear cell (5%). With a median follow-up of 53 months, the 60-month RFS was 0.76 (95% CI, 0.70 to 0.81) for RT and 0.76 (95% CI, 0.70 to 0.81) for VCB/C (hazard ratio, 0.92; 90% confidence limit, 0.69 to 1.23). The 60-month overall survival was 0.87 (95% CI, 0.83 to 0.91) for RT and 0.85 (95% CI, 0.81 to 0.90) for VCB/C (hazard ratio, 1.04; 90% confidence limit, 0.71 to 1.52). Vaginal and distant recurrence rates were similar between arms. Pelvic or para-aortic nodal recurrences were more common with VCB/C (9%
4%). There was no heterogeneity of treatment effect with respect to RFS or overall survival among clinical or pathologic variables evaluated.
Superiority of VCB/C compared with pelvic RT was not demonstrated. Acute toxicity was greater with VCB/C; late toxicity was similar. Pelvic RT alone remains an effective, well-tolerated, and appropriate adjuvant treatment in high-risk early-stage endometrial carcinomas of all histologies.
Many patients with oncogene-driven non–small-cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors experience limited sites of disease progression. This study investigated retrospectively ...the benefits of local ablative therapy (LAT) to central nervous system (CNS) and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively.
Patients with metastatic ALK+ NSCLC treated with crizotinib (n = 38) and EGFR-MT NSCLC treated with erlotinib (n = 27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression-free survival (PFS1), and site of first progression were recorded. A subset of patients with either nonleptomeningeal CNS and/or four sites or fewer of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same tyrosine kinase inhibitors. The subsequent median progression-free survival from the time of first progression (PFS2) and pattern of progression were recorded.
Median progression-free survival in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. Twenty-five of 51 patients (49%) who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, one with surgery) and continuation of the same targeted therapy. Post-LAT, 19 of 25 patients progressed again, with median PFS2 of 6.2 months.
Oncogene-addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with more than 6 months of additional disease control.
SUMMARY
The ability to quantify structural uncertainty in geological models that incorporate geophysical data is affected by two primary sources of uncertainty: geophysical parameter uncertainty and ...uncertainty in the relationship between geophysical parameters and geological properties of interest. Here, we introduce an open-source, trans-dimensional Bayesian Markov chain Monte Carlo (McMC) algorithm GeoBIPy—Geophysical Bayesian Inference in Python—for robust uncertainty analysis of time-domain or frequency-domain airborne electromagnetic (AEM) data. The McMC algorithm provides a robust assessment of geophysical parameter uncertainty using a trans-dimensional approach that lets the AEM data inform the level of model complexity necessary by allowing the number of model layers itself to be an unknown parameter. Additional components of the Bayesian algorithm allow the user to solve for parameters such as data errors or corrections to the measured instrument height above ground. Probability distributions for a user-specified number of lithologic classes are developed through posterior clustering of McMC-derived resistivity models. Estimates of geological model structural uncertainty are thus obtained through the joint probability of geophysical parameter uncertainty and the uncertainty in the definition of each class. Examples of the implementation of this algorithm are presented for both time-domain and frequency-domain AEM data acquired in Nebraska, USA.
Establishing a permanent human presence on the Moon or Mars requires a secure supply of oxygen for life support and refueling. The electrolysis of water has attracted significant attention in this ...regard as water-ice may exist on both the Moon and Mars. However, to date there has been no study examining how the lower gravitational fields on the Moon and Mars might affect gas-evolving electrolysis when compared to terrestrial conditions. Herein we provide experimental data on the effects of gravitational fields on water electrolysis from 0.166 g (lunar gravity) to 8 g (eight times the Earth's gravity) and show that electrolytic oxygen production is reduced by around 11% under lunar gravity with our system compared to operation at 1 g. Moreover, our results indicate that electrolytic data collected using less resource-intensive ground-based experiments at elevated gravity (>1 g) may be extrapolated to gravitational levels below 1 g.
The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report ...the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
A significant portion of the large amount of carbon (C) currently stored in soils of the permafrost region in the Northern Hemisphere has the potential to be emitted as the greenhouse gases CO2 and ...CH4 under a warmer climate. In this study we evaluated the variability in the sensitivity of permafrost and C in recent decades among land surface model simulations over the permafrost region between 1960 and 2009. The 15 model simulations all predict a loss of near‐surface permafrost (within 3 m) area over the region, but there are large differences in the magnitude of the simulated rates of loss among the models (0.2 to 58.8 × 103 km2 yr−1). Sensitivity simulations indicated that changes in air temperature largely explained changes in permafrost area, although interactions among changes in other environmental variables also played a role. All of the models indicate that both vegetation and soil C storage together have increased by 156 to 954 Tg C yr−1 between 1960 and 2009 over the permafrost region even though model analyses indicate that warming alone would decrease soil C storage. Increases in gross primary production (GPP) largely explain the simulated increases in vegetation and soil C. The sensitivity of GPP to increases in atmospheric CO2 was the dominant cause of increases in GPP across the models, but comparison of simulated GPP trends across the 1982–2009 period with that of a global GPP data set indicates that all of the models overestimate the trend in GPP. Disturbance also appears to be an important factor affecting C storage, as models that consider disturbance had lower increases in C storage than models that did not consider disturbance. To improve the modeling of C in the permafrost region, there is the need for the modeling community to standardize structural representation of permafrost and carbon dynamics among models that are used to evaluate the permafrost C feedback and for the modeling and observational communities to jointly develop data sets and methodologies to more effectively benchmark models.
Key Points
Models estimate a loss of near‐surface permafrost area in the Northern Hemisphere between 1960 and 2009
Models estimate that both vegetation and soil C have increased in the permafrost region
Simulated increases in gross primary production are primarily responsible for the modeled increases in C storage
We compared the impact of two different, but commonly consumed, beverages on integrative markers of exercise recovery following a 2 h high intensity interval exercise (i.e., running 70-80%
O
...intervals and interspersed with plyometric jumps). Participants (
= 11 males,
= 6 females) consumed a chocolate flavored dairy milk beverage (CM: 1.2 g carbohydrate/kg BM and 0.4 g protein/kg BM) or a carbohydrate-electrolyte beverage (CEB: isovolumetric with 0.76 g carbohydrate/kg BM) after exercise, in a randomized-crossover design. The recovery beverages were provided in three equal boluses over a 30 min period commencing 1 h post-exercise. Muscle biopsies were performed at 0 h and 2 h in recovery. Venous blood samples, nude BM and total body water were collected before and at 0, 2, and 4 h recovery. Gastrointestinal symptoms and breath hydrogen (H
) were collected before exercise and every 30 min during recovery. The following morning, participants returned for performance assessment. In recovery, breath H
reached clinical relevance of >10 ppm following consumption of both beverages, in adjunct with high incidence of gastrointestinal symptoms (70%), but modest severity. Blood glucose response was greater on CEB vs. CM (
< 0.01). Insulin response was greater on CM compared with CEB (
< 0.01).
lipopolysaccharide stimulated neutrophil function reduced on both beverages (49%). p-GSK-3β/total-GSK-3β was greater on CM compared with CEB (
= 0.037); however, neither beverage achieved net muscle glycogen re-storage. Phosphorylation of mTOR was greater on CM than CEB (
< 0.001). Fluid retention was lower (
= 0.038) on CEB (74.3%) compared with CM (82.1%). Physiological and performance outcomes on the following day did not differ between trials. Interconnected recovery optimization markers appear to respond differently to the nutrient composition of recovery nutrition, albeit subtly and with individual variation. The present findings expand on recovery nutrition strategies to target functionality and patency of the gastrointestinal tract as a prerequisite to assimilation of recovery nutrition, as well as restoration of immunocompetency.
Therapeutic hypothermia (TH) improves survival and confers neuroprotection in out-of-hospital cardiac arrest (OHCA), but TH is underutilized, and regional systems of care for OHCA that include TH are ...needed.
The Cool It protocol has established TH as the standard of care for OHCA across a regional network of hospitals transferring patients to a central TH-capable hospital. Between February 2006 and August 2009, 140 OHCA patients who remained unresponsive after return of spontaneous circulation were cooled and rewarmed with the use of an automated, noninvasive cooling device. Three quarters of the patients (n=107) were transferred to the TH-capable hospital from referring network hospitals. Positive neurological outcome was defined as Cerebral Performance Category 1 or 2 at discharge. Patients with non-ventricular fibrillation arrest or cardiogenic shock were included, and patients with concurrent ST-segment elevation myocardial infarction (n=68) received cardiac intervention and cooling simultaneously. Overall survival to hospital discharge was 56%, and 92% of survivors were discharged with a positive neurological outcome. Survival was similar in transferred and nontransferred patients. Non-ventricular fibrillation arrest and presence of cardiogenic shock were associated strongly with mortality, but survivors with these event characteristics had high rates of positive neurological recovery (100% and 89%, respectively). A 20% increase in the risk of death (95% confidence interval, 4% to 39%) was observed for every hour of delay to initiation of cooling.
A comprehensive TH protocol can be integrated into a regional ST-segment elevation myocardial infarction network and achieves broad dispersion of this essential therapy for OHCA.
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