Most cancers depend on a high rate of aerobic glycolysis for their continued growth and survival. Paradoxically, some cancer cell lines also display addiction to glutamine despite the fact that ...glutamine is a nonessential amino acid that can be synthesized from glucose. The high rate of glutamine uptake exhibited by glutamine-dependent cells does not appear to result solely from its role as a nitrogen donor in nucleotide and amino acid biosynthesis. Instead, glutamine plays a required role in the uptake of essential amino acids and in maintaining activation of TOR (target of rapamycin) kinase. Moreover, in many cancer cells, glutamine is the primary mitochondrial substrate and is required for maintenance of mitochondrial membrane potential and integrity and for support of the NADPH production needed for redox control and macromolecular synthesis.
Background
In the absence of treatment, endometrial hyperplasia (EH) can progress to endometrial cancer, particularly in the presence of histologic nuclear atypia. The development of EH results from ...exposure of the endometrium to oestrogen unopposed by progesterone. Oral progestogens have been used as treatment for EH without atypia, and in some cases of EH with atypia in women who wish to preserve fertility or who cannot tolerate surgery. EH without atypia is associated with a low risk of progression to atypia and cancer; EH with atypia is where the cells are structurally abnormal, and has a higher risk of developing cancer. Oral progestogen is not always effective at reversing the hyperplasia, can be associated with side effects, and depends on patient adherence. The levonorgestrel‐intrauterine system (LNG‐IUS) is an alternative method of administration of progestogen and may have some advantages over non‐intrauterine progestogens.
Objectives
To evaluate the effectiveness and safety of the levonorgestrel intrauterine system (LNG‐IUS) in women with endometrial hyperplasia (EH) with or without atypia compared to medical treatment with non‐intrauterine progestogens, placebo, surgery or no treatment.
Search methods
We searched the following databases: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO, and conference proceedings of 10 relevant organisations. We handsearched references in relevant published studies. We also searched ongoing trials in ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry, and other trial registries. We performed the final search in May 2020.
Selection criteria
Randomised controlled trials (RCTs) and cross‐over trials of women with a histological diagnosis of endometrial hyperplasia with or without atypia comparing LNG‐IUS with non‐intrauterine progestogens, placebo, surgery or no treatment.
Data collection and analysis
Two review authors independently performed study selection, risk of bias assessment and data extraction. Our primary outcome measures were regression of EH and adverse effects associated with the LNG‐IUS device (such as pelvic inflammatory disease, device expulsion, uterine perforation) when compared to treatment with non‐intrauterine progestogens, placebo, surgery or no treatment. Secondary outcomes included hysterectomy, hormone‐related adverse effects (such as bleeding/spotting, pelvic pain, breast tenderness, ovarian cysts, weight gain, acne), withdrawal from treatment due to adverse effects, satisfaction with treatment, and cost or resource use. We rated the overall quality of evidence using GRADE methods.
Main results
Thirteen RCTs (1657 women aged 22 to 75 years) met the inclusion criteria. Two studies had insufficient data for meta‐analysis, thus the quantitative analysis included 11 RCTs. All trials evaluated treatment duration of six months or less. The evidence ranged from very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding and poor reporting of study methods), inconsistency and imprecision.
LNG‐IUS versus non‐intrauterine progestogens
Primary outcomes
Regression of endometrial hyperplasia
The LNG‐IUS probably improves regression of EH compared with non‐intrauterine progestogens at short‐term follow‐up (up to six months) (OR 2.94, 95% CI 2.10 to 4.13; I² = 0%; 10 RCTs, 1108 participants; moderate‐quality evidence). This suggests that if regression of EH following treatment with a non‐intrauterine progestogen is assumed to be 72%, regression of EH following treatment with LNG‐IUS would be between 85% and 92%. Regression of EH may be improved by LNG‐IUS compared with non‐intrauterine progestogens at long‐term follow‐up (12 months) (OR 3.80, 95% CI 1.75 to 8.23; 1 RCT, 138 participants; low‐quality evidence),
Adverse effects associated with LNG‐IUS
There was insufficient evidence to determine device‐related adverse effects; only one study reported on expulsion with insufficient data for analysis.
Secondary outcomes
The LNG‐IUS may be associated with fewer hysterectomies (OR 0.26, 95% CI 0.15 to 0.46; I² = 19%; 4 RCTs, 452 participants; low‐quality evidence), fewer withdrawals from treatment due to hormone‐related adverse effects (OR 0.41, 95% CI 0.12 to 1.35; I² = 0%; 4 RCTs, 360 participants; low‐quality evidence) and improved patient satisfaction with treatment (OR 5.28, 95% CI 2.51 to 11.10; I² = 0%; 2 RCTs, 202 participants; very low‐quality evidence) compared to non‐intrauterine progestogens. The LNG‐IUS may be associated with more bleeding/spotting (OR 2.13, 95% CI 1.33 to 3.43; I² = 78%; 3 RCTs, 428 participants) and less nausea (OR 0.52, 95% CI 0.28 to 0.95; I² = 0%; 3 RCTs, 428 participants) compared to non‐intrauterine progestogens. Data from single trials for mood swings and fatigue had a similar direction of effect as for bleeding/spotting, nausea and weight gain. There was insufficient evidence to determine cost or resource use.
LNG‐IUS versus no treatment
Regression of endometrial hyperplasia
One study demonstrated that the LNG‐IUS is associated with regression of EH without atypia (OR 78.41, 95% CI 22.86 to 268.97; I² = 0%; 1 RCT, 190 participants; moderate‐quality evidence) compared with no treatment. This study did not report on any other review outcome.
Authors' conclusions
There is moderate‐quality evidence that treatment with LNG‐IUS used for three to six months is probably more effective than non‐intrauterine progestogens at reversing EH in the short term (up to six months) and long term (up to two years). Adverse effects (device‐related and hormone‐related) were poorly and incompletely reported across studies. Very low quality to low‐quality evidence suggests the LNG‐IUS may reduce the risk of hysterectomy, and may be associated with more bleeding/spotting, less nausea, less withdrawal from treatment due to adverse effects, and increased satisfaction with treatment, compared to non‐intrauterine progestogens. There was insufficient evidence to reach conclusions regarding device‐related adverse effects, or cost or resource use.
ABSTRACT
Restrictions to photosynthesis can limit plant growth at high temperature in a variety of ways. In addition to increasing photorespiration, moderately high temperatures (35–42 °C) can cause ...direct injury to the photosynthetic apparatus. Both carbon metabolism and thylakoid reactions have been suggested as the primary site of injury at these temperatures. In the present study this issue was addressed by first characterizing leaf temperature dynamics in Pima cotton (Gossypium barbadense) grown under irrigation in the US desert south‐west. It was found that cotton leaves repeatedly reached temperatures above 40 °C and could fluctuate as much as 8 or 10 °C in a matter of seconds. Laboratory studies revealed a maximum photosynthetic rate at 30–33 °C that declined by 22% at 45 °C. The majority of the inhibition persisted upon return to 30 °C. The mechanism of this limitation was assessed by measuring the response of photosynthesis to CO2 in the laboratory. The first time a cotton leaf (grown at 30 °C) was exposed to 45 °C, photosynthetic electron transport was stimulated (at high CO2) because of an increased flux through the photorespiratory pathway. However, upon cooling back to 30 °C, photosynthetic electron transport was inhibited and fell substantially below the level measured before the heat treatment. In the field, the response of assimilation (A) to various internal levels of CO2 (Ci) revealed that photosynthesis was limited by ribulose‐1,5‐bisphosphate (RuBP) regeneration at normal levels of CO2 (presumably because of limitations in thylakoid reactions needed to support RuBP regeneration). There was no evidence of a ribulose‐1,5‐bisphosphate carboxylase/oxygenase (Rubisco) limitation at air levels of CO2 and at no point on any of 30 A–Ci curves measured on leaves at temperatures from 28 to 39 °C was RuBP regeneration capacity measured to be in substantial excess of the capacity of Rubisco to use RuBP. It is therefore concluded that photosynthesis in field‐grown Pima cotton leaves is functionally limited by photosynthetic electron transport and RuBP regeneration capacity, not Rubisco activity.
Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease ...(COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4-6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St George's Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohen's effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1-20.1 m), 24.2 m (95% CI 23.4-25.4 m), 24.6 m (95% CI 23.4-25.7 m) and 26.4 m (95% CI 25.4-27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0-2.4 W), 3.2 W (95% CI 3.0-3.4 W), 3.2 W (95% CI 3.0-3.4 W) and 3.3 W (95% CI 3.0-3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26 ± 2 m for 6MWD and 4 ± 1 W for MCEC for patients with severe COPD.
Genetic elimination of dengue vector mosquitoes Wise de Valdez, Megan R; Nimmo, Derric; Betz, John ...
Proceedings of the National Academy of Sciences,
03/2011, Letnik:
108, Številka:
12
Journal Article
Recenzirano
Odprti dostop
An approach based on mosquitoes carrying a conditional dominant lethal gene (release of insects carrying a dominant lethal, RIDL) is being developed to control the transmission of dengue viruses by ...vector population suppression. A transgenic strain, designated OX3604C, of the major dengue vector, Aedes aegypti, was engineered to have a repressible female-specific flightless phenotype. This strain circumvents the need for radiation-induced sterilization, allows genetic sexing resulting in male-only releases, and permits the release of eggs instead of adult mosquitoes. OX3604C males introduced weekly into large laboratory cages containing stable target mosquito populations at initial ratios of 8.5-10:1 OX3604C:target eliminated the populations within 10-20 weeks. These data support the further testing of this strain in contained or confined field trials to evaluate mating competitiveness and environmental and other effects. Successful completion of the field trials should facilitate incorporation of this approach into area-wide dengue control or elimination efforts as a component of an integrated vector management strategy.
Poly (ADP-ribose) polymerases (PARPs) catalyze the transfer of multiple poly(ADP-ribose) units onto target proteins. Poly(ADP-ribosyl)ation plays a crucial role in a variety of cellular processes ...including, most prominently, auto-activation of PARP at sites of DNA breaks to activate DNA repair processes. In humans, PARP1 (the founding and most characterized member of the PARP family) accounts for more than 90% of overall cellular PARP activity in response to DNA damage. We have found that, in contrast with animals, in Arabidopsis thaliana PARP2 (At4g02390), rather than PARP1 (At2g31320), makes the greatest contribution to PARP activity and organismal viability in response to genotoxic stresses caused by bleomycin, mitomycin C or gamma-radiation. Plant PARP2 proteins carry SAP DNA binding motifs rather than the zinc finger domains common in plant and animal PARP1 proteins. PARP2 also makes stronger contributions than PARP1 to plant immune responses including restriction of pathogenic Pseudomonas syringae pv. tomato growth and reduction of infection-associated DNA double-strand break abundance. For poly(ADP-ribose) glycohydrolase (PARG) enzymes, we find that Arabidopsis PARG1 and not PARG2 is the major contributor to poly(ADP-ribose) removal from acceptor proteins. The activity or abundance of PARP2 is influenced by PARP1 and PARG1. PARP2 and PARP1 physically interact with each other, and with PARG1 and PARG2, suggesting relatively direct regulatory interactions among these mediators of the balance of poly(ADP-ribosyl)ation. As with plant PARP2, plant PARG proteins are also structurally distinct from their animal counterparts. Hence core aspects of plant poly(ADP-ribosyl)ation are mediated by substantially different enzymes than in animals, suggesting the likelihood of substantial differences in regulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Functional magnetic resonance imaging (fMRI) is an essential workhorse of modern neuroscience, providing valuable insight into the functional organisation of the brain. The physiological mechanisms ...underlying the blood oxygenation level dependent (BOLD) effect are complex and preclude a straightforward interpretation of the signal. However, by employing appropriate calibration of the BOLD signal, quantitative measurements can be made of important physiological parameters including the absolute rate of cerebral metabolic oxygen consumption or oxygen metabolism (CMRO2) and oxygen extraction (OEF). The ability to map such fundamental parameters has the potential to greatly expand the utility of fMRI and to broaden its scope of application in clinical research and clinical practice. In this review article we discuss some of the practical issues related to the calibrated-fMRI approach to the measurement of CMRO2. We give an overview of the necessary precautions to ensure high quality data acquisition, and explore some of the pitfalls and challenges that must be considered as it is applied and interpreted in a widening array of diseases and research questions.
•Dual calibrated fMRI can map the rate of cerebral metabolic oxygen consumption (CMRO2) and oxygen extraction fraction (OEF).•The techniques have recently been demonstrated in clinical research of dementia, ageing and pharmacological interventions.•We review the experimental and analysis methods used to estimate these physiological parameters.•We discuss the prospects for future clinical research use and the potential limitations of the methods.
Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the ...acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.
Animal studies have established a role for the brainstem reticular formation, in particular the rostral ventromedial medulla (RVM), in the development and maintenance of central sensitisation and its ...clinical manifestation, secondary hyperalgesia. Similar evidence in humans is lacking, as neuroimaging studies have mainly focused on cortical changes. To fully characterise the supraspinal contributions to central sensitisation in humans, we used whole-brain functional magnetic resonance imaging at 3
T, to record brain responses to punctate mechanical stimulation in an area of secondary hyperalgesia. We used the heat/capsaicin sensitisation model to induce secondary hyperalgesia on the right lower leg in 12 healthy volunteers. A paired
t-test was used to compare activation maps obtained during punctate stimulation of the secondary hyperalgesia area and those recorded during control punctate stimulation (same body site, untreated skin, separate session). The following areas showed significantly increased activation (
Z>2.3, corrected
P<0.01) during hyperalgesia: contralateral brainstem, cerebellum, bilateral thalamus, contralateral primary and secondary somatosensory cortices, bilateral posterior insula, anterior and posterior cingulate cortices, right middle frontal gyrus and right parietal association cortex. Brainstem activation was localised to two distinct areas of the midbrain reticular formation, in regions consistent with the location of nucleus cuneiformis (NCF) and rostral superior colliculi/periaqueductal gray (SC/PAG). The PAG and the NCF are the major sources of input to the RVM, and therefore in an ideal position to modulate its output. These results suggest that structures in the mesencephalic reticular formation, possibly the NCF and PAG, are involved in central sensitisation in humans.
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