The burden of epidermal growth factor receptor (EGFR) exon 20 insertion mutation (Exon 20ins) in non-small cell lung cancer is not well understood. A systematic review was conducted to identify ...evidence on mutation frequency, prognostic impact, clinical, patient-reported, and economic outcomes associated with Exon 20ins.
Searches were conducted in Embase and Medline and supplemented with recent conference proceedings. Included studies were not limited by intervention, geography, or publication year.
Seventy-eight unique studies were included; 53 reporting mutation frequency, 13 prognostic impact, 36 clinical outcomes, and one humanistic burden. No economic burden data were identified. The frequency of Exon 20ins mutation ranged from 0.1% to 4% of all NSCLC cases and 1% to 12% of all EGFR mutations. Data on the prognostic impact of Exon 20ins were heterogeneous but highlighted poorer outcomes in patients with Exon 20ins mutation compared with patients with other EGFR mutations and EGFR wildtype across a wide range of therapies and treatment lines. Comparative evidence on the clinical efficacy and safety of currently available therapies were limited, as were sample sizes of studies reporting on real-world effectiveness. Nine single-arm trials and 27 observational studies reported clinical outcomes for patients with Exon 20ins. Trends towards better survival and response were observed for chemotherapy compared with TKIs as first-line treatments. For subsequent treatment lines, novel targeted therapies provided encouraging preliminary responses while results for chemotherapy were less favorable. Limited safety data were reported. One conference abstract described the symptom burden for Exon 20ins patients with fatigue and pain being most common.
Findings of the systematic review show a high unmet need for safe and efficacious treatments for patients with Exon 20ins as well and need for further evidence generation to better understand the patient-level and economic impact for these patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially ...limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.
We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement ...of glucose-dependent insulin release in pancreatic β-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9–39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic β-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.
BACKGROUNDIn transposition flaps, thicker tissue and higher degrees of rotation are associated with increased pivotal restraint; however, limited experimental data exist quantifying the degree to ...which these affect flap biomechanics. The use of artificial skin models in conjunction with digital image correlation technology allows for investigation into biomechanical properties of skin flaps.
OBJECTIVETo quantify the effects of tissue thickness and rotational angles on pivotal restraint within transposition flaps using artificial skin models.
METHODSNinety degree bilobed and trilobed flaps were used to close defects in artificial skin models of increasing thicknesses. Digital image correlation was used to quantify strain. Quantitative and qualitative differences in strain were assessed in increasing flap thicknesses and between flap designs.
RESULTSIncreasing flap thickness was associated with decreasing strain. In the bilobed flap, increasing thickness was associated with displacement of the flap pivot point away from the distal flap edge. Comparatively, lower angles of rotation in the trilobed flap were not associated with migration of the flap pivot point.
CONCLUSIONIncreased pivotal restraint observed in higher degrees of rotation is due to migration of the flap pivot point. This model supports the common practice of decreasing flap angles to compensate for pivotal restraint.
Context
:
An accurate assessment of lumbar spine active range of motion (AROM) is clinically important. Dual inclinometry is recommended as the optimal technique for measuring lumbar flexion AROM; ...however, the procedures differ in the literature.
Objective
:
To compare 2 different handheld digital dual inclinometry (HDDI) techniques for evaluating lumbar flexion AROM.
Design
:
The study was a repeated-measures design consisting of 2 trials.
Setting
:
Laboratory.
Participants
:
A sample of 69 adult volunteers (28 men and 41 women; mean age 23.8 2.4 y) without pain or injury to their back, hips, or abdomen for at least 3 months participated in the study.
Intervention
:
Using standardized methods, 1 trained tester performed 2 different HDDI measurements of standing lumbar flexion AROM on each subject. Each subject performed one repetition of AROM lumbar flexion per HDDI measurement. The HDDI measures differed in the process for placing the upper inclinometer, with one technique identifying the upper landmark by skilled palpation of the T12 spinous process and the other technique by measuring 15-cm cephalad to the S2 region landmark to approximate the location of the T12 spinous process.
Main Outcome Measures
:
A dependent
t
test, Pearson correlation coefficient (
r
), the 95% limits of agreement, and Bland–Altman plots were used to examine agreement between the techniques.
Results
:
Dependent
t
testing showed no significant differences between the techniques (mean difference = 1.2°,
P
= .11). A strong correlation existed between the 2 HDDI techniques (
r
= .80,
P
< .001). The Bland–Altman plot illustrated that 64 of the 69 data points were within the 95% limits of agreement for the 2 techniques.
Conclusions
:
The findings suggest that HDDI measurements of lumbar flexion AROM are comparable when using either of the 2 HDDI techniques described. Clinicians can make an evidence-based choice for using either method of measuring lumbar flexion AROM.
The use of draglines to remove overburden in Queensland opencut mines, results in landscapes that consist of long parallel tertiary overburden spoil-piles that are generally highly saline, ...dispersive, and highly erodible. The height of these spoil-piles may exceed 50–60 m above the original landscapes and the slopes are at the angle of repose of around 75% or 37°. Legislation and public opinion require that these highly disturbed open-cut post-mining landscapes should be satisfactorily rehabilitated into an approved post-mining land use with acceptable erosion rates. Therefore, these slopes must be reduced before the landscape can be rehabilitated. The most expensive component of the rehabilitation process is the re-shaping and preparation of the overburden to create a suitable landscape for vegetation growth. As soils and overburden varies greatly in their erodibilities, the extent and cost of earthworks can be minimized, and rehabilitation failures avoided, if soil erosion from designed landscapes can be predicted using laboratory-based parameters prior to construction of these landscapes. This paper describes the development of a model for that purpose.
A catchment or landscape erosion model MINErosion 4 was developed by upscaling the existing hillslope model MINErosion 3 (So, et al., 2018) and integrate it with both ESRI ArcGIS 10.3 or QGIS 3.16 (freeware), to predict event based and mean annual erosion rate from a postmining catchment or landscape. MINErosion 3 is a model that can be used to predict event and annual erosion rates from field scale hillslopes using laboratory measured erodibility parameters or routinely measured soil physical and chemical properties, and to derive suitable landscape design parameters (slope gradient, slope length and vegetation cover) that will result in acceptable erosion rates. But it cannot be used to predict the sediment delivery from catchments or landscapes. MINErosion 4 was validated against data collected on three instrumented catchments (up to 0.91 ha in size) on the Curragh mine site in Central Queensland. The agreement between predicted (Y) and measured (X) values were very good with the regression equation of Y = 0.92X and an R2 value of 0.81 for individual storm events, and Y = 1.47X and an R2 value of 0.73 for the average annual soil loss. This is probably the first time that a catchment scale erosion is successfully predicted from laboratory measured erodibility parameters.
GPR119 is a rhodopsin-like GPCR expressed in pancreatic β-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a ...highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-4-(3-isopropyl-1,2,4oxadiazol-5-yl)-piperidin-1-yl-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.
This paper presents a simple new method for measuring "wealth effects" on aggregate consumption. The method exploits the stickiness of consumption growth (sometimes interpreted as reflecting ...consumption "habits") to distinguish between immediate and eventual wealth effects. In U.S. data, we estimate that the immediate (next quarter) marginal propensity to consume from a $1 change in housing wealth is about 2 cents, with a final eventual effect around 9 cents, substantially larger than the effect of shocks to financial wealth. We argue that our method is preferable to cointegration-based approaches, because neither theory nor evidence supports faith in the existence of a stable cointegrating vector.
In a model calibrated to match micro- and macroeconomic evidence on household income dynamics, we show that a modest degree of heterogeneity in household preferences or beliefs is sufficient to match ...empirical measures of wealth inequality in the United States. The heterogeneity-augmented model's predictions are consistent with microeconomic evidence that suggests that the annual marginal propensity to consume (MPC) is much larger than the roughly 0.04 im- plied by commonly used macroeconomic models (even ones including some heterogeneity). The high MPC arises because many consumers hold little wealth despite having a strong precautionary motive. Our model also plausibly predicts that the aggregate MPC can differ greatly depending on how the shock is distributed across households (depending, e.g., on their wealth, or employment status).
This review considers the potential influences of the use of cannabis for therapeutic purposes (CTP) on areas of interest to mental health professionals, with foci on adult psychopathology and ...assessment. We identified 31 articles relating to the use of CTP and mental health, and 29 review articles on cannabis use and mental health that did not focus on use for therapeutic purposes. Results reflect the prominence of mental health conditions among the reasons for CTP use, and the relative dearth of high-quality evidence related to CTP in this context, thereby highlighting the need for further research into the harms and benefits of medical cannabis relative to other therapeutic options. Preliminary evidence suggests that CTP may have potential for the treatment of PTSD, and as a substitute for problematic use of other substances. Extrapolation from reviews of non-therapeutic cannabis use suggests that the use of CTP may be problematic among individuals with psychotic disorders. The clinical implications of CTP use among individuals with mood disorders are unclear. With regard to assessment, evidence suggests that CTP use does not increase risk of harm to self or others. Acute cannabis intoxication and recent CTP use may result in reversible deficits with the potential to influence cognitive assessment, particularly on tests of short-term memory.
•Mental health conditions are prominent among the reasons for medical cannabis use.•Cannabis has potential for the treatment of PTSD and substance use disorders.•Cannabis use may influence cognitive assessment, particularly with regard to memory.•Cannabis use does not appear to increase risk of harm to self or others.•More research is needed to characterize the mental health impact of medical cannabis.
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