PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the ...effects of AKT inhibitors on glucose uptake and cell viability.
Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233*) were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206) with or without the glucose analogue 2-deoxyglucose (2-DG). Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG). Cell migration was assessed by scratch assay.
Activating PIK3CA (E545K, E542K) and inactivating PTEN (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) and MK-2206 (30 µM-49%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment.
The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.
Managing the nonlethal effects of disturbance on wildlife populations has been a long‐term goal for decision makers, managers, and ecologists, and assessment of these effects is currently required by ...European Union and United States legislation. However, robust assessment of these effects is challenging. The management of human activities that have nonlethal effects on wildlife is a specific example of a fundamental ecological problem: how to understand the population‐level consequences of changes in the behavior or physiology of individual animals that are caused by external stressors. In this study, we review recent applications of a conceptual framework for assessing and predicting these consequences for marine mammal populations. We explore the range of models that can be used to formalize the approach and we identify critical research gaps. We also provide a decision tree that can be used to select the most appropriate model structure given the available data. Synthesis and applications: The implementation of this framework has moved the focus of discussion of the management of nonlethal disturbances on marine mammal populations away from a rhetorical debate about defining negligible impact and toward a quantitative understanding of long‐term population‐level effects. Here we demonstrate the framework's general applicability to other marine and terrestrial systems and show how it can support integrated modeling of the proximate and ultimate mechanisms that regulate trait‐mediated, indirect interactions in ecological communities, that is, the nonconsumptive effects of a predator or stressor on a species' behavior, physiology, or life history.
Managing nonlethal effects of disturbance on wildlife is a major objective for modern conservation. We review applications of a conceptual framework for predicting the population consequences of physiological and behavioral changes, and demonstrate its general applicability. We identify critical research gaps and provide guidance to select an appropriate model structure.
To compare FIGO 2009 and FIGO 2018 cervical cancer staging criteria with a focus on stage migration and treatment outcomes.
This study is based on a database cohort of 1282 patients newly diagnosed ...with cervical cancer from 1997 to 2019. All underwent standard clinical examination and whole-body FDG-PET. Tumor stage was recorded using the FIGO 2009 system, which excluded surgical pathologic, FDG-PET and other advanced imaging findings, and then re-classified to the FIGO 2018 system, including surgical pathologic and imaging findings. Patient management was based on clinical, surgical, and imaging findings. Stage migration and prognosis were evaluated.
The distribution per the 2009 staging system was stage I in 593 (46%), stage II in 342 (27%), stage III in 263 (21%), and stage IV in 84 (7%) and the 2018 staging system was stage I in 354 (28%), stage II in 156 (12%), stage III in 601 (47%), and stage IV in 171 (13%). No patients were down-staged. Stage migration occurred in 53% (676/1282) and was attributable to detection of occult lymph node metastasis in 520 (41%), occult distant metastasis in 90 (7%), and tumor size and extent in 66 (5%). The 5-year progression-free survivals (PFS) by FIGO 2009 versus FIGO 2018 were as follows: stage I, 80% vs. 87% (p = 0.02); stage II, 59% vs. 71% (p = 0.002); stage III, 35% vs. 55% (p < 0.001), and stage IV, 20% vs. 16% (p = 0.41).
Inclusion of surgical pathologic and imaging findings resulted in upward stage migration in the majority, mostly related to nodal and distant metastasis. While FIGO 2018 improves survival discriminatory ability for stages I and IV patients, survival remains heterogeneous among stage III substages.
•Most patients are upstaged with the 2018 staging system.•Upstaging is due primarily to nodal and distant metastases.•Survival discriminatory ability is improved.•There is heterogeneous survival among the stage III substages.
In studies of the electronic structure of solids, the augmented plane wave (APW) method is the basis for the solution of the Kohn–Sham equations of density functional theory (DFT). The different ...versions and developing steps are discussed in terms of linearization, full potential, local orbitals, mixed basis sets, relativistic effects and computational aspects, as employed in the WIEN2k code.
The aim of this study was to systematically investigate the impact of chemical stabilisation on the autoxidation of microencapsulated oils rich in long-chain polyunsaturated fatty acids. During the ...microencapsulation process, the fish oil undergoes multiple changes of its physical properties: bulk oil, dispersed oil in aqueous phase, and dispersed oil in dry matrix. Autoxidation already occurred in the first stages of the microencapsulation process itself during emulsification and spray-drying. An efficient stabilisation was achieved using a ternary combination of lipophilic antioxidants, synergistic compounds and a trace metal chelator, e.g. a combination of tocopherols, rich in the δ-derivative and low in the α-derivative, with ascorbyl palmitate and lecithin. Trace metal chelation by, e.g. Citrem or lecithin in combination with ascorbyl palmitate proved to be of particular importance in the emulsion, but not during the storage of the microencapsulated oil. In the microencapsulated oil, the addition of rosemary extract rich in carnosic acid to ternary blends of tocopherols, ascorbyl palmitate and lecithin or Citrem significantly retarded autoxidation.
Background
Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard‐of‐care pelvic chemoradiation (CRT). However, the safety of the ...combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements.
Methods
Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB‐IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol‐defined dose‐limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion.
Results
As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment‐related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab.
Conclusions
Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially.
Lay Summary
Pembrolizumab is a humanized antibody against programmed cell death protein 1 that is used in cancer immunotherapy.
Preliminary data suggest that pembrolizumab can be safely combined with chemotherapy and pelvic radiation in the treatment of locally advanced cervical cancer.
Future studies of the addition of immunotherapy to traditional chemoradiation are planned to determine the best way to deliver the treatment and whether any improvement is seen with the addition of immunotherapy to traditional therapy.
With complete safety data for 52 patients, this study provides preliminary support regarding the safety and feasibility of the combination of immune checkpoint inhibitors and pelvic chemoradiotherapy in locally advanced cervical cancer.
Key points
Thalamic activity is regulated by corticothalamic feedback from layers 5B and 6.
To selectively study the importance of the layer 6 corticothalamic (L6 CT) projection, a transgenic mouse ...line was used in which layer 6 cells projecting to posterior medial thalamus (POm) were targeted for expression of channelrhodopsin‐2.
Repetitive optogenetic stimulation of this sub‐type of L6 cells caused a rapid adaptation in POm spiking output, but had little effect on the spiking activity in the other cortical layers.
L6 photoactivation increased POm spiking to the first, but not to subsequent whisker deflections in a 4 Hz train.
A sub‐population of L6 CT cells that can cause an initial increase in POm activity, that is not sustained with repetitive stimulation, could indicate that this L6 projection does not modulate ongoing sensory processing, but rather serves to briefly increase POm activity in specific behavioural contexts.
Thalamic activity is regulated by corticothalamic feedback from layers 5B and 6. The nature of these feedback systems differs, one difference being that whereas layer 5 provides ‘driver’ input, the layer 6 input is thought to be ‘modulatory’. To selectively study the importance of the layer 6 corticothalamic (L6 CT) projection, a transgenic mouse line was used in which layer 6 cells projecting to posterior medial thalamus (POm) were targeted for expression of channelrhodopsin‐2 and in vivo electrophysiology recordings were done in urethane‐anaesthetized mice. Pre‐ and postsynaptic targets were identified using tracing techniques and light‐sheet microscopy in cleared intact brains. We find that optogenetic activation of this subtype of L6 CT cells (L6‐Drd1) has little effect on cortical activity, but activates POm. Repetitive photoactivation of L6‐Drd1 cells evoked a reliable response following every photoactivation, whereas in the connected POm area spiking was only initially increased. The response to repetitive whisker stimulation showed a similar pattern with only an initial increase in whisker‐evoked spiking. Furthermore, the increase in whisker‐evoked spiking with optogenetic activation of L6‐Drd1 cells is additive, rather than multiplicative, causing even cells that in the absence of L6 activation produce relatively few spikes to increase their spiking substantially. We show that layer 6 corticothalamic cells can provide a strong, albeit rapidly depressing, input to POm. This type of cortical L6 activity could be important for rapid gain control in POm, rather than providing a modulation in phase with the whisking cycle.
Key points
Thalamic activity is regulated by corticothalamic feedback from layers 5B and 6.
To selectively study the importance of the layer 6 corticothalamic (L6 CT) projection, a transgenic mouse line was used in which layer 6 cells projecting to posterior medial thalamus (POm) were targeted for expression of channelrhodopsin‐2.
Repetitive optogenetic stimulation of this sub‐type of L6 cells caused a rapid adaptation in POm spiking output, but had little effect on the spiking activity in the other cortical layers.
L6 photoactivation increased POm spiking to the first, but not to subsequent whisker deflections in a 4 Hz train.
A sub‐population of L6 CT cells that can cause an initial increase in POm activity, that is not sustained with repetitive stimulation, could indicate that this L6 projection does not modulate ongoing sensory processing, but rather serves to briefly increase POm activity in specific behavioural contexts.
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