After successful surgery for colorectal cancer, patients over 70 years of age are less likely to receive postoperative (adjuvant) chemotherapy than younger patients, even though it prolongs life. The ...underuse of chemotherapy relates to the belief that it is excessively toxic in the elderly. This analysis of data from seven randomized trials of adjuvant chemotherapy for resected colorectal cancer found that selected older patients not only benefit from such treatment but tolerate it almost as well as their younger counterparts.
Older patients not only benefit from such treatment but tolerate it almost as well as their younger counterparts.
By 2030, one in five Americans will be over 65 years of age.
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Physicians will be seeing increasing numbers of elderly patients with colorectal cancer and other cancers whose incidence increases with age. Currently, 60 percent of malignant disease occurs in persons over 65 years of age. More than half of these patients are over 70 years old, and one fourth of them are over 80 years old.
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In some clinical trials, the elderly have been excluded by design. More often, their outcomes have been pooled in results that have not been analyzed according to age. Consequently, only . . .
Recent studies demonstrated that the performance of InGaN/GaN quantum well (QW) light emitting diodes (LEDs) can be significantly improved through the insertion of an InGaN underlayer (UL). The ...current working hypothesis is that the presence of the UL reduces the density of non-radiative recombination centers (NRCs) in the QW itself: during the growth of the UL, surface defects are effectively buried in the UL, without propagating towards the QW region. Despite the importance of this hypothesis, the concentration profile of defects in the quantum wells of LEDs with and without the UL was never investigated in detail. This paper uses combined capacitance-voltage and steady-state photocapacitance measurements to experimentally identify the defects acting as NRCs and to extract a depth-profile of the traps, thus proving the incorporation upon indium-reaction. Specifically: (i) we demonstrate that LEDs without UL have a high density (9.2 × 1015 cm−3) of defects, compared to samples with UL (0.8 × 1015 cm−3); (ii) defects are located near midgap (EC-1.8 eV, corresponding to Ei-ET ∼ 0.3 eV), thus acting as efficient NRCs; (iii) crucially, the density of defects has a peak within the QWs, indicating that traps are segregated at the first grown InGaN layers; (iv) we propose a model to calculate trap distribution in the QW, and we demonstrate a good correspondence with experimental data. These results provide unambiguous demonstration of the role of UL in limiting the propagation of defects towards the QWs, and the first experimental characterization of the properties of the related traps.
Marfan syndrome (MFS) is a highly variable genetic connective tissue disorder caused by mutations in the calcium binding extracellular matrix glycoprotein fibrillin-1. Patients with the most severe ...form of MFS (neonatal MFS; nMFS) tend to have mutations that cluster in an internal region of fibrillin-1 called the neonatal region. This region is predominantly composed of eight calcium-binding epidermal growth factor-like (cbEGF) domains, each of which binds one calcium ion and is stabilized by three highly conserved disulfide bonds. Crucially, calcium plays a fundamental role in stabilizing cbEGF domains. Perturbed calcium binding caused by cbEGF domain mutations is thus thought to be a central driver of MFS pathophysiology. Using steered molecular dynamics (SMD) simulations, we demonstrate that cbEGF domain calcium binding decreases under mechanical stress (i.e. cbEGF domains are mechanosensitive). We further demonstrate the disulfide bonds in cbEGF domains uniquely orchestrate protein unfolding by showing that MFS disulfide bond mutations markedly disrupt normal mechanosensitive calcium binding dynamics. These results point to a potential mechanosensitive mechanism for fibrillin-1 in regulating extracellular transforming growth factor beta (TGFB) bioavailability and microfibril integrity. Such mechanosensitive "smart" features may represent novel mechanisms for mechanical hemostasis regulation in extracellular matrix that are pathologically activated in MFS.
Subcutaneously injected therapeutics must pass through the interstitial matrix of the skin in order to reach their intended targets. This complex, three-dimensional structure limits the type and ...quantity of drugs that can be administered by local injection. Here we found that depolymerization of the viscoelastic component of the interstitial matrix in animal models with a highly purified recombinant human hyaluronidase enzyme (rHuPH20) increased the dispersion of locally injected drugs, across a broad range of molecular weights without tissue distortion. rHuPH20 increased infusion rates and the pattern and extent of appearance of locally injected drugs in systemic blood. In particular, rHuPH20 changed the pharmacokinetic profiles and significantly augmented the absolute bioavailability of locally injected large protein therapeutics. Importantly, within 24 h of injection, the interstitial viscoelastic barriers were restored without histologic alterations or signs of inflammation. rHuPH20 may function as an interstitial delivery enhancing agent capable of increasing the dispersion and bioavailability of coinjected drugs that may enable subcutaneous administration of therapeutics and replace intravenous delivery.
Congenital anomalies of the lower genitourinary (LGU) tract are frequently comorbid due to genetically linked developmental pathways, and are among the most common yet most socially stigmatized ...congenital phenotypes. Genes involved in sexual differentiation are prime candidates for developmental anomalies of multiple LGU organs, but insufficient prospective screening tools have prevented the rapid identification of causative genes. Androgen signaling is among the most influential modulators of LGU development. The present study uses SpDamID technology in vivo to generate a comprehensive map of the pathways actively regulated by the androgen receptor (AR) in the genitalia in the presence of the p300 coactivator, identifying wingless/integrated (WNT) signaling as a highly enriched AR-regulated pathway in the genitalia. Transcription factor (TF) hits were then assayed for sexually dimorphic expression at two critical time points and also cross-referenced to a database of clinically relevant copy number variations to identify 252 TFs exhibiting copy variation in patients with LGU phenotypes. A subset of 54 TFs was identified for which LGU phenotypes are statistically overrepresented as a proportion of total observed phenotypes. The 252 TF hitlist was then subjected to a functional screen to identify hits whose silencing affects genital mesenchymal growth rates. Overlap of these datasets results in a refined list of 133 TFs of both functional and clinical relevance to LGU development, 31 of which are top priority candidates, including the well-documented renal progenitor regulator, Sall1. Loss of Sall1 was examined in vivo and confirmed to be a powerful regulator of LGU development.
Spatial and temporal regulation of chondrocyte maturation in the growth plate drives growth of many bones. One essential event to generate the ordered cell array characterizing growth plate cartilage ...is the formation of chondrocyte columns in the proliferative zone via 90-degree rotation of daughter cells to align with the long axis of the bone. Previous studies have suggested crucial roles for cadherins and integrin β1 in column formation. The purpose of this study was to determine the relative contributions of cadherin- and integrin-mediated cell adhesion in column formation. Here we present new mechanistic insights generated by application of live time-lapse confocal microscopy of cranial base explant cultures, robust genetic mouse models, and new quantitative methods to analyze cell behavior. We show that conditional deletion of either the cell-cell adhesion molecule
or the cell-matrix adhesion molecule
disrupts column formation. Compound mutants were used to determine a potential reciprocal regulatory interaction between the two adhesion surfaces and identified that defective chondrocyte rotation in a N-cadherin mutant was restored by a heterozygous loss of integrin β1. Our results support a model for which integrin β1, and not N-cadherin, drives chondrocyte rotation and for which N-cadherin is a potential negative regulator of integrin β1 function.
Forkhead box class O (FOXO) proteins are transcription factors that function downstream of the PTEN tumor suppressor and directly control the expression of genes involved in apoptosis, cell cycle ...progression, and stress responses. In the present study, we show that FOXO1 interacts with four and a half LIM 2 (FHL2) in prostate cancer cells. This interaction occurred in the nucleus and was enhanced by lysophosphatic acid. FHL2 decreased the transcriptional activity of FOXO1 and the expression of known FOXO target genes and inhibited FOXO1‐induced apoptosis. Interestingly, SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity. FHL2 enhanced the interaction of FOXO1 and SIRT1 and the deacetylation of FOXO1 by Sirtuin‐1 (SIRT1). Overall, our data show that FHL2 inhibits FOXO1 activity in prostate cancer cells by promoting the deacetylation of FOXO1 by SIRT1.
IMPORTANCE: The public health success of diabetic retinopathy (DR) screening programs depends on patients’ adherence to the timetable of follow-up eye care recommended by the screening program. ...African Americans are among those at highest risk for DR and have one of the lowest rates of eye care use. OBJECTIVES: To assess the rate of adhering to recommended follow-up eye care in a DR screening program administered in a safety-net health care facility and to examine factors associated with follow-up eye care use. DESIGN, SETTING, AND PARTICIPANTS: Prospective follow-up study of persons with type 1 or type 2 diabetes. The setting was an internal medicine clinic of a publicly funded health system in Alabama, serving a population largely uninsured and African American, that had implemented a DR screening program using a nonmydriatic camera for ocular imaging and remote reading centers for evaluation of images. Patients with physician appointments between January 26 and July 24, 2012, were eligible for screening if they had a diagnosis of type 1 or type 2 diabetes and were 19 years or older. Data from the county health system’s administrative database were obtained from January 26, 2012 (date of first enrollee), through May 1, 2015, to establish participants’ eye care use in the ophthalmology clinic after screening. MAIN OUTCOMES AND MEASURES: Adherence to the recommended interval of follow-up eye appointments in the facility’s ophthalmology service as determined by administrative records, as well as factors associated with adherence. RESULTS: Diabetic retinopathy screening was completed in 949 adults with diabetes, of whom 84.5% (802 of 949) were African American, 64.5% (612 of 949) were women, and 71.7% (680 of 949) lacked health insurance. Participants ranged in age from 21 to 95 years, and their mean (SD) age was 53.9 (10.4) years. The mean (SD) age at diabetes diagnosis was 44.3 (12.5) years, and the mean (SD) duration of diabetes was 9.6 (9.4) years. Across interval recommendation types, 29.9% (284 of 949) adhered to obtaining comprehensive follow-up eye care within the recommended time frame. Two years after a participant’s screening date, 50.9% (483 of 949) had no record of having received eye care. Factors associated with adhering to interval appointments were having an advanced age (odds ratio, 1.02; 95% CI, 1.01-1.04) and knowing one’s glycated hemoglobin level (odds ratio, 2.00; 95% CI, 1.34-2.97). Agreeing to assistance in making a follow-up eye care appointment was associated with nonadherence (odds ratio, 0.67; 95% CI, 0.45-0.99). CONCLUSIONS AND RELEVANCE: After a DR screening program in a public clinic largely serving an African American population, only one-third of participants adhered to interval recommendations for follow-up eye appointments, even though cost and accessibility were minimized as barriers to care. Our findings suggest that DR screening programs are not likely to meet their public health goals without incorporation of eye health education initiatives successfully promoting adherence to recommended comprehensive eye care for preventing vision loss.
Purpose
To examine children’s experiences of chemotherapy-induced cognitive impairment––colloquially “chemobrain”––and the impact on children’s social, academic, and daily living skills via a ...qualitative systematic review. Experiencing chemotherapy as a child, when the brain is still developing, may cause lifelong detriment to survivors’ lives. There is a significant gap in understanding their lived experience, including the self-identified barriers that children face following treatment. Such a gap can only be fully bridged by listening to the child’s own voice and/or parent proxy report through an exploration of the qualitative research literature.
Methods
A search of MEDLINE, Embase, PsycINFO, and CINAHL databases was conducted. Inclusion criteria were qualitative studies with a focus on children (0–18 years) during and/or following chemotherapy treatment and explored children’s experiences of chemobrain.
Results
Two synthesized findings were identified from six studies. (1) Chemobrain has an academic and psychosocial impact, which may not be understood by education providers. (2) Children and their parents have concerns about their reintegration and adaptation to school, social lives, and their future selves as independent members of society. Children’s experiences primarily related to changes in their academic and social functioning.
Conclusion
This review highlights two important considerations: (1) the lived experiences of pediatric childhood cancer survivors guiding where future interventions should be targeted, and (2) a need to perform more qualitative research studies in this area, as well as to improve the quality of reporting among the existing literature, given that this is a current gap in the field.
: Porcine xenografts have been used successfully in partial thickness burn treatment for many years. Their disappearance from the market led to the search for effective and efficient alternatives. In ...this article, we examine the synthetic epidermal skin substitute Suprathel
as a substitute in the treatment of partial thickness burns.
: A systematic review following the PRISMA guidelines has been performed. Sixteen Suprathel
and 12 porcine xenograft studies could be included. Advantages and disadvantages between the treatments and the studies' primary endpoints have been investigated qualitatively and quantitatively.
: Although Suprathel had a nearly six times larger TBSA in their studies (
< 0.001), it showed a significantly lower necessity for skin grafts (
< 0.001), and we found a significantly lower infection rate (
< 0.001) than in Porcine Xenografts. Nonetheless, no significant differences in the healing time (
= 0.67) and the number of dressing changes until complete wound healing (
= 0.139) could be found. Both products reduced pain to various degrees with the impression of a better performance of Suprathel
on a qualitative level. Porcine xenograft was not recommended for donor sites or coverage of sheet-transplanted keratinocytes, while Suprathel
was used successfully in both indications.
: The investigated parameters indicate that Suprathel
to be an effective replacement for porcine xenografts with even lower subsequent treatment rates. Suprathel
appears to be usable in an extended range of indications compared to porcine xenograft. Data heterogeneity limited conclusions from the results.
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