Protein expression of renal uptake and efflux transporters was quantified by quantitative targeted proteomics using the surrogate peptide approach. Renal uptake transporters assessed in this study ...included organic anion transporters (OAT1-OAT4), organic cation transporter 2 (OCT2), organic/carnitine cation transporters (OCTN1 and OCTN2), and sodium-glucose transporter 2 (SGLT2); efflux transporters included P-glycoprotein, breast cancer resistance protein, multidrug resistance proteins (MRP2 and MRP4), and multidrug and toxin extrusion proteins (MATE1 and MATE2-K). Total membrane was isolated from the cortex of human kidneys (N = 41). The isolated membranes were digested by trypsin and the digest was subjected to liquid chromatography-tandem mass spectrometry analysis. The mean expression of surrogate peptides was as follows (given with the standard deviation, in picomoles per milligram of total membrane protein): OAT1 (5.3 ± 1.9), OAT2 (0.9 ± 0.3), OAT3 (3.5 ± 1.6), OAT4 (0.5 ± 0.2), OCT2 (7.4 ± 2.8), OCTN1 (1.3 ± 0.6), OCTN2 (0.6 ± 0.2), P-glycoprotein (2.1 ± 0.8), MRP2 (1.4 ± 0.6), MRP4 (0.9 ± 0.6), MATE1 (5.1 ± 2.3), and SGLT2 (3.7 ± 1.8). Breast cancer resistance protein (BCRP) and MATE2-K proteins were detectable but were below the lower limit of quantification. Interestingly, the protein expression of OAT1 and OAT3 was significantly correlated (r > 0.8). A significant correlation was also observed between expression of multiple other drug transporters, such as OATs/OCT2 or OCTN1/OCTN2, and SGLT2/OCTNs, OCT, OATs, and MRP2. These renal transporter data should be useful in deriving in vitro to in vivo scaling factors to accurately predict renal clearance and kidney epithelial cell exposure to drugs or their metabolites.
The number of cancer survivors is growing steadily and increasingly, clinical trials are being designed to include long-term follow-up to assess not only survival, but also late effects and ...health-related quality of life (HRQOL). Therefore it is is essential to develop patient-reported outcome measures (PROMs) that capture the full range of issues relevant to disease-free cancer survivors. The objectives of this project are: 1) to develop a European Organisation for Research and Treatment of Cancer (EORTC) questionnaire that captures the full range of physical, mental and social HRQOL issues relevant to disease-free cancer survivors; and 2) to determine at which minimal time since completion of treatment the questionnaire should be used.
We reviewed 134 publications on cancer survivorship and interviewed 117 disease-free cancer survivors with 11 different types of cancer across 14 countries in Europe to generate an exhaustive, provisional list of HRQOL issues relevant to cancer survivors. The resulting issue list, the EORTC core questionnaire (QLQ-C30), and site-specific questionnaire modules were completed by a second group of 458 survivors.
We identified 116 generic survivorship issues. These issues covered body image, cognitive functioning, health behaviors, negative and positive outlook, health distress, mental health, fatigue, sleep problems, physical functioning, pain, several physical symptoms, social functioning, and sexual problems. Patients rated most of the acute symptoms of cancer and its treatment (e.g. nausea) as no longer relevant approximately one year after completion of treatment.
Compared to existing cancer survivorship questionnaires, our findings underscore the relevance of assessing issues related to chronic physical side effects of treatment such as neuropathy and joint pain. We will further develop a core survivorship questionnaire and three site-specific modules for disease-free adult cancer survivors who are at least one year post-treatment.
Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained virtually unchanged for many decades. Currently, prevention or early diagnosis at ...a curable stage is exceedingly difficult; patients rarely exhibit symptoms and tumours do not display sensitive and specific markers to aid detection. Pancreatic cancers also have few prevalent genetic mutations; the most commonly mutated genes are KRAS, CDKN2A (encoding p16), TP53 and SMAD4 - none of which are currently druggable. Indeed, therapeutic options are limited and progress in drug development is impeded because most pancreatic cancers are complex at the genomic, epigenetic and metabolic levels, with multiple activated pathways and crosstalk evident. Furthermore, the multilayered interplay between neoplastic and stromal cells in the tumour microenvironment challenges medical treatment. Fewer than 20% of patients have surgically resectable disease; however, neoadjuvant therapies might shift tumours towards resectability. Although newer drug combinations and multimodal regimens in this setting, as well as the adjuvant setting, appreciably extend survival, ∼80% of patients will relapse after surgery and ultimately die of their disease. Thus, consideration of quality of life and overall survival is important. In this Primer, we summarize the current understanding of the salient pathophysiological, molecular, translational and clinical aspects of this disease. In addition, we present an outline of potential future directions for pancreatic cancer research and patient management.
The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the ...disease make a revision necessary.
A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained.
The revised classification of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images.
This international, web-based consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption.
The molecular architecture of cell cycle arrest Stallaert, Wayne; Taylor, Sovanny R; Kedziora, Katarzyna M ...
Molecular systems biology,
September 2022, 2022-09-00, 20220901, 2022-09-01, Letnik:
18, Številka:
9
Journal Article
Recenzirano
Odprti dostop
The cellular decision governing the transition between proliferative and arrested states is crucial to the development and function of every tissue. While the molecular mechanisms that regulate the ...proliferative cell cycle are well established, we know comparatively little about what happens to cells as they diverge into cell cycle arrest. We performed hyperplexed imaging of 47 cell cycle effectors to obtain a map of the molecular architecture that governs cell cycle exit and progression into reversible (“quiescent”) and irreversible (“senescent”) arrest states. Using this map, we found multiple points of divergence from the proliferative cell cycle; identified stress‐specific states of arrest; and resolved the molecular mechanisms governing these fate decisions, which we validated by single‐cell, time‐lapse imaging. Notably, we found that cells can exit into senescence from either G1 or G2; however, both subpopulations converge onto a single senescent state with a G1‐like molecular signature. Cells can escape from this “irreversible” arrest state through the upregulation of G1 cyclins. This map provides a more comprehensive understanding of the overall organization of cell proliferation and arrest.
Synopsis
Certain stresses can induce exit from the proliferative cell cycle into cell cycle arrest states. Mapping fate trajectories following hypomitogenic, replicative, and oxidative stress shows that cell cycle arrest is not a discrete state but a complex and continuous architecture of cell states.
Cell cycle mapping is used to reveal how the cell cycle responds to hypomitogenic, replicative and oxidative stress.
Cells can exit the proliferative cell cycle from different phases (G1 or G2) driven by distinct molecular mechanisms.
Sustained replication stress can generate polyploid cells through mitotic skipping and endoreduplication.
Regardless of the phase of cell cycle exit, cells converge on a single state of senescence with a G1‐like molecular signature.
Certain stresses can induce exit from the proliferative cell cycle into cell cycle arrest states. Mapping fate trajectories following hypomitogenic, replicative and oxidative stress shows that cell cycle arrest is not a discrete state but a complex and continuous architecture of cell states.
A surface plasmon polariton (SPP) is an excitation resulting from the coupling of light to a surface charge oscillation at a metal-dielectric interface. The excitation and detection of SPPs is ...foundational to the operating mechanism of a number of important technologies, most of which require SPP excitation via direct reflectance, commonly achieved via Attenuated Total Reflection (ATR) using the Kretschmann configuration. As a result, the accessible modes are fundamentally high-loss “leaky modes,” presenting a critical performance barrier. Recently, our group provided the first demonstration of “forbidden,” or guided-wave plasmon polariton modes (GW-PPMs), collective modes of a MIM structure with oscillatory electric field amplitude in the central insulator layer with up to an order of magnitude larger propagation lengths than those of traditional SPPs. However, in that work, GW-PPMs were accessed by indirect reflectance using Otto configuration ATR, making them of limited applied relevance. In this paper, we demonstrate a technique for direct reflectance excitation and detection of GW-PPMs. Specifically, we replace the air gap used in traditional Otto ATR with a low refractive index polymer coupling layer, mirroring a technique previously demonstrated to access Long-Range Surface Plasmon Polariton modes. We fit experimental ATR data using a robust theoretical model to confirm the character of the modes, as well as to explore the potential of this approach to enable advantageous propagation lengths. The ability to excite GW-PPMs using a device configuration that does not require an air gap could potentially enable transformative performance enhancements in a number of critical technologies.
Background
Laparoscopic distal pancreatectomy (LDP) is being increasingly performed with some concerns regarding the cost of the minimally invasive approach. The purpose of this study was to assess ...the cost-effectiveness of LDP versus open distal pancreatectomy (ODP).
Methods
A retrospective clinical and cost-comparison analysis was performed for patients who underwent LDP vs. OPD between 2005 and 2011. Data considered for the comparison analysis were: operative costs (surgical procedure, operative time, blood transfusions), postoperative costs (laboratory testing, hospital stay, complication management, readmissions), and overall costs.
Results
Fifty-one distal pancreatectomies (laparoscopic = 35, open = 16) were performed during the study period. The median operative time was 200 (range, 120–420) min for LDP vs
.
225 (range, 120–460) min for ODP (
p
= 0.93). Median blood loss was 200 (range, 50–900) mL for LDP vs. 394 (range, 75–2000) mL for ODP (
p
= 0.038). Median hospital stay was 7 (range, 3–25) days in the laparoscopic group vs. 11 (range, 5–46) days in the open group (
p
= 0.007). Complication rate was 40% for LDP vs. 69% in ODP (
p
= 0.075). Postoperative intervention was required in 11% of patients after LDP vs. 31% after ODP (
p
= 0.12). The average operative, postoperative, and overall cost was £6039 (range, £4276–£9500), £4547 (range, £1299–£13937), £10587 (range, £6508–£20303) vs. £5231 (range, £3409–£9330), £10094 (range, £2665–£39291), £15324 (range, £7209–£47484) for the LDP and ODP groups, respectively (
p
= 0.033;
p
= 0.006;
p
= 0.197).
Conclusions
We showed that LDP is feasible and safe without having a negative impact on cost. Extensive experience in pancreatic and laparoscopic surgery is required to optimize surgical outcomes.
This study aims to update the 1991 Atlanta Classification of acute pancreatitis, to standardize the reporting of and terminology of the disease and its complications. Important features of this ...classification have incorporated new insights into the disease learned over the last 20 years, including the recognition that acute pancreatitis and its complications involve a dynamic process involving two phases, early and late. The accurate and consistent description of acute pancreatitis will help to improve the stratification and reporting of new methods of care of acute pancreatitis across different practices, geographic areas, and countries.
Epidemiological studies have been published worldwide in recent decades describing the incidence, mortality, aetiology and trends of chronic pancreatitis. Accumulated evidence suggests that chronic ...pancreatitis is increasing in incidence and hospital admission rates are rising accordingly. Alcoholic chronic pancreatitis was previously more common in the developed world than elsewhere, but is now increasing worldwide due to growing per capita alcohol consumption in each nation. Supporting alcohol and smoking cessation in individual patients is essential to slow disease progression and improve overall health, as most patients will die of cirrhosis, cardiovascular disease or smoking related cancers rather than chronic pancreatitis. The socioeconomic impact of chronic pancreatitis is difficult to quantify as little data exists, however given the rising incidence the costs to health care and society are likely to increase. This chapter will describe the epidemiology and aetiology of chronic pancreatitis worldwide and discusses the factors that influence its socioeconomic impact.
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