Background Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. ...However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN. Methods We performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only. Results At baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group. Conclusion The results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas. Trial registration Registered in the Netherlands Trial Register ( Keywords: Anorexia nervosa, Deep brain stimulation, Treatment-refractory, Body Mass Index, Neurosurgery, Clinical trial, Functional neuroimaging, Brain networks, Reward
The soil sorption coefficient Kd and the soil organic carbon sorption coefficient KOC of pesticides are basic parameters used by environmental scientists and regulatory agencies worldwide in ...describing the environmental fate and behavior of pesticides. They are a measure of the strength of sorption of pesticides to soils and other geosorbent surfaces at the water/solid interface, and are thus directly related to both environmental mobility and persistence. KOC is regarded as a universal parameter related to the hydrophobicity of the pesticide molecule, which applies to a given pesticide in all soils. This assumption is known to be inexact, but it is used in this way in modeling and estimating risk for pesticide leaching and runoff. In this report we examine the theory, uses, measurement or estimation, limitations and reliability of these parameters and provide some rules of thumb for the use of these parameters in describing the behavior and fate of pesticides in the environment, especially in analysis by modeling.
Background: Tumor-positive surgical margins during primary breast cancer (BCa) surgery are associated with a two-fold increase in the risk of local recurrence when compared with tumor-negative ...margins. Pathological microscopic evaluation of the samples only assesses about 1/10 of 1% of the entire volume of the removed BCa specimens, leading to margin under-sampling and potential local recurrence in patients with pathologically clean margins, i.e., false negative margins. In the case of tumor-positive margins, patients need to undergo re-excision and/or radiation therapy, resulting in increases in complications, morbidity, and healthcare costs. Development of a simple real-time imaging technique to identify residual BCa in the surgical cavity rapidly and precisely could significantly improve the quality of care. Methods: A small-molecule, fluorescently quenched protease-substrate probe, AKRO-QC-ICG, was tested as part of a thermosensitive imaging gel formulated for topical application and imaging of the BCa surgical cavity. Results: More than forty formulations of gel mixtures were investigated to enable easy fluid application and subsequent solidification once applied, preventing dripping and pooling in the surgical cavity. The final formulation was tested using human BCa orthotopic implants in nude and NSG patient-derived xenografts (PDX) mice. This formulation of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel was found to be a good solvent for the probe, with a desirable thermo-reversible solid–gel transition and mechanical strength for distribution of AKRO-QC-ICG on the surfaces of tissue. It demonstrated excellent ability to detect BCa tissue after 10 min exposure, with a high signal-to-noise ratio both in mouse xenografts and freshly excised human lumpectomy tissue. The in vivo efficacy of the AKRO-QC-ICG imaging gel to detect BCa revealed the levels of sensitivity/specificity = 0.92/1 in 12 nude mice, which was corroborated with the sensitivity/specificity = 0.94/1 in 10 PDX mice. Conclusions: Utilization of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel for topical application to detect BCa in the surgical cavity during surgery has the potential to reduce re-excisions, with consequent savings in healthcare costs and enhancement in patient quality of life.
Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including ...HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of −48% and −90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was −79% and −94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. Conclusions: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer.
The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, ...which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate
in vivo
breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients.
Hydrogels from phospholipid vesicles Gräbner, D.; Hoffmann, H.; Förster, S. ...
Advances in colloid and interface science,
06/2014, Volume:
208
Journal Article
Peer reviewed
It is shown that phospholipid dispersions with a few percent of diacylphosphocholine PC in water can be swollen to single-phase lyotropic liquid crystalline Lα-phases by the addition of co-solvents ...like glycerol, 1,3-butyleneglycol BG or 1,2-propyleneglycol PG. The birefringent Lα-phases contain small unilamellar and multilamellar vesicles if the temperature of the samples is above the Krafft-Temperature Tm of the phospholipid. When such transparent birefringent viscous samples are cooled down below Tm the samples are transformed into birefringent gels. Cryo-TEM and FF-TEM measurements show that the bilayers of the vesicles are transformed from the liquid to the crystalline state during the transformation while the vesicle structure remains. The bilayers of the crystalline vesicles form adhesive contacts in the gel. Pulsed-field gradient NMR measurements show that two different kinds of water or co-solvent can be distinguished in the gels. One type of solvent molecules can diffuse like normal solvent in a continuous bulk phase. A second type of water diffuses much more slowly. This type of solvent is obviously trapped in the vesicles. The permeability of the crystalline vesicles for water and solvent molecules is much lower in the crystalline state than in the fluid state.
Maximum swelling of the diacylphosphocholin dispersions occurs when the refractive index of the solvent is matched to the refractive index of the bilayers. The attraction between the bilayers is at a minimum in this state and the liquid crystalline Lα-phase's undulation forces between the bilayers push the bilayers apart. On transformation to the gel state the crystalline bilayers assume a high elastic bending rigidity. Undulations of the bilayers are now suppressed, and the bilayers can form adhesive contacts.
Oscillating rheological measurements show that the gels with only 1% of phospholipids can have a storage modulus of 1000Pa. The gels are very brittle. They break when they are deformed by a few percent.
Cryo-TEM micrograph of multilamellar vesicles with crystalline bilayers. Display omitted
•Dispersions of diacylphosphocholin (PC) can be swollen to Lα-phases by addition of glycerol and other solvents.•Swelling occurs when the refractive index of the solvent is matched to the refractive index of the bilayers.•Vesicle phases with a few % of PC can be transformed to stiff gels by cooling samples below the Krafft-temperature.•The gels contain vesicles with the PC-molecules in the crystalline state.•2 types of water molecules can be distinguished in the gels by PFG-NMR.
Amino acid salt based solvents can be used for CO2 removal from flue gas in a conventional absorption–thermal desorption process. Recently, new process concepts have been developed based on the ...precipitation of the amino acid zwitterion species during the absorption of CO2. In this work, a new concept is introduced which requires the precipitation of the pure amino acid species and the partial recycle of the remaining supernatant to the absorption column. This induces a shift in the pH of the rich solution treated in the stripper column that has substantial energy benefits during CO2 desorption. To describe and evaluate this concept, this work provides the conceptual design of a new process (DECAB Plus) based on a 4 M aqueous solution of potassium taurate. The design is supported by experimental data such as amino acid speciation, vapor–liquid equilibria of CO2 on potassium taurate solutions, and solid–liquid partition. The same conceptual design method has been used to evaluate a baseline case based on 5 M MEA. After thorough evaluation of the significant variables, the new DECAB Plus process can lower the specific reboiler energy for solvent regeneration by 35% compared to the MEA baseline. The specific reboiler energy is reduced from 3.7 GJ/tCO2, which corresponds to the MEA baseline, to 2.4 GJ/tCO2, which corresponds to the DECAB Plus process described in this work, excluding the low-grade energy required to redissolve the precipitates formed during absorption. Although this low-grade energy will eventually reduce the overall energy savings, the evaluation of DECAB Plus has indicated the potential of this concept for postcombustion CO2 capture.
Precipitating amino acid solvents are an alternative to conventional amine scrubbing for CO2 capture from flue gas. Process operation with these solvents leads to the formation of precipitates during ...absorption that need to be re-dissolved prior to desorption of CO2. The process configuration is crucial for the successful application of these solvents. Different process configurations have been analyzed in this work, including a full analysis of the baseline operating conditions (based on potassium taurate), the addition of lean vapor compression, multiple absorber feeds, and the use of different amino acids as alternative solvents to the baseline based on potassium taurate. The analysis is carried out with an equilibrium model of the process that approximates the thermodynamics of the solvents considered. The results show that the precipitating amino acid solvents can reduce the reboiler duty needed to regenerate the solvent with respect to a conventional MEA process. However, this reduction is accompanied by an expenditure in lower grade energy needed to dissolve the precipitates. To successfully implement these processes into power plants, an internal recycle of the rich stream is necessary. This configuration, known as DECAB Plus, can lower the overall energy use of the capture process, which includes the energy needed to regenerate the solvent, the energy needed to dissolve the precipitates, and the energy needed to compress the CO2 to 110 bar. With respect to the energy efficiency, the DECAB Plus with lean vapor compression configuration is the best configuration based on potassium taurate, which reduces the reboiler duty for regeneration by 45% with respect to conventional MEA. Retrofitting this process into a coal fired power plant will result in overall energy savings of 15% with respect to the conventional MEA process, including compression of the CO2 stream to 110 bar. Potassium alanate was found to reduce the energy use with respect to potassium taurate under similar process configurations. Therefore, the investigation of potassium alanate in a DECAB Plus configuration is highly recommended, since it can reduce the energy requirements of the best process configuration based on potassium taurate.
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