Interim 18F-FDG-PET based response-adaptive dose escalation of proton therapy for head and neck cancer: a treatment planning feasibility study.

BACKGROUND: Image-driven dose escalation to tumor subvolumes has been proposed to improve treatment outcome in head and neck cancer (HNC). We used 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) acquired at baseline and into treatment (interim) to identify biologic target volumes (BTVs). We assessed the feasibility of interim dose escalation to the BTV with proton therapy by simulating the effects to organs at risk (OARs). METHODS: We used the semiautomated just-enough-interaction (JEI) method to identify BTVs in 18F-FDG-PET images from nine HNC patients. Between baseline and interim FDG-PET, patients received photon radiotherapy. BTV was identified assuming that high standardized uptake value (SUV) at interim reflected tumor radioresistance. Using Eclipse (Varian Medical Systems), we simulated a 10% (6.8 Gy(RBE1.1)) and 20% (13.6 Gy(RBE1.1)) dose escalation to the BTV with protons and compared results with proton plans without dose escalation. RESULTS: At interim 18F-FDG-PET, radiotherapy resulted in reduced SUV compared to baseline. However, spatial overlap between high-SUV regions at baseline and interim allowed for BTV identification. Proton therapy planning demonstrated that dose escalation to the BTV was feasible, and except for some 20% dose escalation plans, OAR doses did not significantly increase. CONCLUSION: Our in silico analysis demonstrated the potential for interim 18F-FDG-PET response-adaptive dose escalation to the BTV with proton therapy. This approach may give more efficient treatment to HNC with radioresistant tumor subvolumes without increasing normal tissue toxicity. Studies in larger cohorts are required to determine the full potential for interim 18F-FDG-PET-guided dose escalation of proton therapy in HNC.

Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor.

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by promoting guanine nucleotide exchange. Here, we investigate the coupling of G proteins with GPCRs and describe the events that ultimately lead to the ejection of GDP from its binding pocket in the Gα subunit, the rate-limiting step during G-protein activation. Using molecular dynamics simulations, we investigate the temporal progression of structural rearrangements of GDP-bound Gs protein (Gs·GDP; hereafter GsGDP) upon coupling to the ß2-adrenergic receptor (ß2AR) in atomic detail. The binding of GsGDP to the ß2AR is followed by long-range allosteric effects that significantly reduce the energy needed for GDP release: the opening of α1-αF helices, the displacement of the αG helix and the opening of the α-helical domain. Signal propagation to the Gs occurs through an extended receptor interface, including a lysine-rich motif at the intracellular end of a kinked transmembrane helix 6, which was confirmed by site-directed mutagenesis and functional assays. From this ß2AR-GsGDP intermediate, Gs undergoes an in-plane rotation along the receptor axis to approach the ß2AR-Gsempty state. The simulations shed light on how the structural elements at the receptor-G-protein interface may interact to transmit the signal over 30 Å to the nucleotide-binding site. Our analysis extends the current limited view of nucleotide-free snapshots to include additional states and structural features responsible for signaling and G-protein coupling specificity.

Thermal Reactivation of Hydrated Cement Paste: Properties and Impact on Cement Hydration.

In this research, the properties and cementitious performance of thermally activated cement pastes (referred to as DCPs) are investigated. Hydrated pastes prepared from Portland cement and slag blended cement were subjected to different thermal treatments: 350 °C for 2 h, 550 °C for 2 h, 550 °C for 24 h and 750 °C for 2 h. The properties and the reactivity as SCM of the DCPs were characterised as well as their effect on the mechanical performance and hydration of new blended cements incorporating the DCPs as supplementary cementitious materials (SCMs). It was observed that the temperature and duration of the thermal treatment increased the grindability and BET specific surface area of the DCP, as well as the formation of C2S phases and the reactivity as SCM. In contrast, the mechanical strength results for the blended cements indicated that thermal treatment at 350 °C for 2 h provided better performance. The hydration study results showed that highly reactive DCP interfered with the early hydration of the main clinker phases in Portland cement, leading to early setting and slow strength gain. The effect on blended cement hydration was most marked for binary Portland cement-DCP blends. In contrast, in the case of ternary slag cement-DCP blends the use of reactive DCP as SCM enabled to significantly increase early age strength.

Machine Learning-Based Prediction of Cattle Activity Using Sensor-Based Data.

Livestock monitoring is a task traditionally carried out through direct observation by experienced caretakers. By analyzing its behavior, it is possible to predict to a certain degree events that require human action, such as calving. However, this continuous monitoring is in many cases not feasible. In this work, we propose, develop and evaluate the accuracy of intelligent algorithms that operate on data obtained by low-cost sensors to determine the state of the animal in the terms used by the caregivers (grazing, ruminating, walking, etc.). The best results have been obtained using aggregations and averages of the time series with support vector classifiers and tree-based ensembles, reaching accuracies of 57% for the general behavior problem (4 classes) and 85% for the standing behavior problem (2 classes). This is a preliminary step to the realization of event-specific predictions.

Time-resolved cryo-EM of G-protein activation by a GPCR.

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Gα subunit1. To visualize this mechanism, we developed a time-resolved cryo-EM approach that examines the progression of ensembles of pre-steady-state intermediates of a GPCR-G-protein complex. By monitoring the transitions of the stimulatory Gs protein in complex with the ß2-adrenergic receptor at short sequential time points after GTP addition, we identified the conformational trajectory underlying G-protein activation and functional dissociation from the receptor. Twenty structures generated from sequential overlapping particle subsets along this trajectory, compared to control structures, provide a high-resolution description of the order of main events driving G-protein activation in response to GTP binding. Structural changes propagate from the nucleotide-binding pocket and extend through the GTPase domain, enacting alterations to Gα switch regions and the α5 helix that weaken the G-protein-receptor interface. Molecular dynamics simulations with late structures in the cryo-EM trajectory support that enhanced ordering of GTP on closure of the α-helical domain against the nucleotide-bound Ras-homology domain correlates with α5 helix destabilization and eventual dissociation of the G protein from the GPCR. These findings also highlight the potential of time-resolved cryo-EM as a tool for mechanistic dissection of GPCR signalling events.

Discrimination/Classification of Edible Vegetable Oils from Raman Spatially Solved Fingerprints Obtained on Portable Instrumentation.

Currently, the combination of fingerprinting methodology and environmentally friendly and economical analytical instrumentation is becoming increasingly relevant in the food sector. In this study, a highly versatile portable analyser based on Spatially Offset Raman Spectroscopy (SORS) obtained fingerprints of edible vegetable oils (sunflower and olive oils), and the capability of such fingerprints (obtained quickly, reliably and without any sample treatment) to discriminate/classify the analysed samples was evaluated. After data treatment, not only unsupervised pattern recognition techniques (as HCA and PCA), but also supervised pattern recognition techniques (such as SVM, kNN and SIMCA), showed that the main effect on discrimination/classification was associated with those regions of the Raman fingerprint related to free fatty acid content, especially oleic and linoleic acid. These facts allowed the discernment of the original raw material used in the oil's production. In all the models established, reliable qualimetric parameters were obtained.

Mucinous adenocarcinoma arising from complex perianal fistula: a diagnostic and therapeutic challenge.

We present a case of a 64-year-old male with a history of perianal abscesses that have been surgically treated on 10 occasions. Eight months after the last drainage procedure, he presented with a new abscess. Drainage was performed, revealing a cavity with smooth walls, a chronic appearance, filled with mucoid material. An internal fistulous opening was identified at the 6 o'clock position above the anorectal line, which communicated with the described cavity, forming a trans-sphincteric fistula to the mid-anal canal. Biopsy with pathological anatomy showed a mucinous adenocarcinoma with possible intestinal origin (CK20+, CDX2+, TTF1-, CK7+). After completing the evaluation, he was diagnosed with T4N1M0 rectal neoplasia. A diverting colostomy was performed, followed by neoadjuvant therapy, and subsequently, a laparoscopic abdominoperineal amputation. Pathological anatomy revealed residual adenocarcinoma ypT2N0 N0V0L0, R0. This case is notable for both the rarity of a mucinous adenocarcinoma originating in a perianal fistula and the nonspecific clinical presentation of such tumors. Clinical suspicion is crucial, especially in cases of recurrent abscesses with the discharge of mucoid material through fistulous openings, prompting the need for biopsies to ensure proper diagnosis and subsequent optimal treatment.

The Influence of the Thermal Treatment of Copper Slag on the Microstructure and Performance of Phosphate Cements.

In general, phosphate cements have a very rapid setting reaction at room temperature. The same holds for copper slag-based phosphate cements. This means that using them as a binder, for instance as mortar, is always possible on a small scale, but very difficult on a large scale. In this paper, the heat treatment of the copper slag was shown to be an effective way to increase the setting time and keep the mix workable for an adequate period. The main objective of this research was to examine the changes in the phase composition of quenched copper slag after exposure to 500 °C and to evaluate the impact of these changes on the reactivity of the material in an acidic environment, as well as on the mechanical properties, microstructure, and structure of the produced phosphate cement materials. Various experimental methods were utilized to characterize the raw materials and the obtained phosphate cementitious materials, including isothermal microcalorimetry (TAM Air), thermogravimetric analysis (TGA), infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), as well as the determination of the chemical composition using X-ray fluorescence (XRF) and the particle size distribution. Furthermore, compressive strength tests were conducted to gauge the mechanical resistance of the materials. The main findings of this work revealed that subjecting the copper slag to a thermal treatment of 500 °C induced a partial transformation in its structure. The high temperature caused the oxidation of some of the divalent iron oxide in the slag, leading to the formation of hematite. This treatment increased the setting time and reduced the reactivity of the copper slag with phosphoric acid, ultimately enabling the production of a dense phosphate-based cementitious material with outstanding mechanical properties. The compressive strength of the newly developed cement was recorded to be greater than 78.9 MPa after 7 days, and this strength continued to increase, reaching 82.5 MPa after 28 days.

Eating-induced seizures: A semiological sign of the right temporal pole.

OBJECTIVE: Eating-induced seizures (EIS) are a rare form of reflex seizures. The objective of this study was to report a series of cases of EIS involving patients admitted to our epilepsy unit, and to analyze the clinical characteristics, etiology, and treatment response of this type of infrequent seizure. METHODS: We performed a single-center retrospective analysis of all consecutive patients diagnosed with epilepsy with eating-induced seizures between 2008 and 2020. RESULTS: We included eight patients (six women) with mean age 54.75 years (range: 40-79), and mean age at epilepsy onset 30.75 years (range: 9-58 years). EIS were triggered during a meal in 5/8 (at dinner 1/8, at breakfast in 1/8, and without time preference in 3/8), by a certain flavor in 1/8, by eating different textures or drinking soft drinks in 1/8, and by slicing food in 1/8. All patients suffered nonreflex seizures and 3/8 other types of reflex seizures. In 6/8 of patients, EIS originated in the right hemisphere. In 5/8, the EIS progressed to impaired awareness with oromandibular automatisms. In 6/8, the epilepsy was drug-resistant. Temporopolar encephalocele was the most frequent etiology, in 4/8. Three of the eight underwent surgical treatment, with Engel IA 1 year in 3/3. Three of the eight were treated with vagal stimulation therapy, with McHugh A 1 year in 2/3. SIGNIFICANCE: In our series, eating-induced seizures were observed in patients with focal epilepsy. It was frequently drug-resistant and started predominantly in the right hemisphere, due to temporal pole involvement in half of the patients.

Function and dynamics of the intrinsically disordered carboxyl terminus of ß2 adrenergic receptor.

Advances in structural biology have provided important mechanistic insights into signaling by the transmembrane core of G-protein coupled receptors (GPCRs); however, much less is known about intrinsically disordered regions such as the carboxyl terminus (CT), which is highly flexible and not visible in GPCR structures. The ß2 adrenergic receptor's (ß2AR) 71 amino acid CT is a substrate for GPCR kinases and binds ß-arrestins to regulate signaling. Here we show that the ß2AR CT directly inhibits basal and agonist-stimulated signaling in cell lines lacking ß-arrestins. Combining single-molecule fluorescence resonance energy transfer (FRET), NMR spectroscopy, and molecular dynamics simulations, we reveal that the negatively charged ß2AR-CT serves as an autoinhibitory factor via interacting with the positively charged cytoplasmic surface of the receptor to limit access to G-proteins. The stability of this interaction is influenced by agonists and allosteric modulators, emphasizing that the CT plays important role in allosterically regulating GPCR activation.

Carcinosarcoma uterino presentándose como masa cervical ­ reporte de un caso

El carcinosarcoma es un tumor poco frecuente que se presenta principalmente en el tracto genital femenino. Su característica más importante es la presencia sincrónica de un componente epitelial maligno (carcinoma) y un componente mesenquimal maligno (sarcoma). Estudios recientes demuestran que la mayoría de las veces el componente sarcomatoso se origina de una diferenciación metaplásica del componente epitelial. Debido a su poca frecuencia, no se conoce con certeza la relación entre las distintas presentaciones histológicas con los posibles factores de riesgo asociados, el pronóstico y la respuesta terapéutica. En este trabajo se reportaron las características histopatológicas y la expresión inmunohistoquímica de un caso de carcinosarcoma uterino en una paciente de 73 años que se presentó inicialmente como una masa cervical. El patrón microscópico documentado fue el de un tumor epitelial de bajo grado asociado a un componente mesenquimal con diferenciación rabdomiosarcomatosa (inmunohistoquímica positiva para desmina y miogenina). La documentación fenotípica es importante para en un futuro desarrollar posibles opciones terapéuticas dirigidas a los distintos patrones histológicos y determinar su posible asociación con factores de riesgo. (provisto por Infomedic International)

Carcinosarcoma is a rare tumor occurring mainly in the female genital tract. Its most important characteristic is the synchronous presence of a malignant epithelial component (carcinoma) and a malignant mesenchymal component (sarcoma). Recent studies show that most of the time the sarcomatous component originates from a metaplastic differentiation of the epithelial component. Due to its infrequency, the relationship between the different histologic presentations with possible associated risk factors, prognosis and therapeutic response is not known with certainty. In this paper we report the histopathologic features and immunohistochemical expression of a case of uterine carcinosarcoma in a 73-year-old female patient who initially presented as a cervical mass. The microscopic pattern documented was that of a low-grade epithelial tumor associated with a mesenchymal component with rhabdomyosarcomatous differentiation (positive immunohistochemistry for desmin and myogenin). Phenotypic documentation is important for future development of possible therapeutic options targeting the different histologic patterns and determining their possible association with risk factors. (provided by Infomedic International)

Time-resolved cryo-EM of G protein activation by a GPCR.

G protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating the exchange of guanine nucleotide in the Gα subunit. To visualize this mechanism, we developed a time-resolved cryo-EM approach that examines the progression of ensembles of pre-steady-state intermediates of a GPCR-G protein complex. Using variability analysis to monitor the transitions of the stimulatory Gs protein in complex with the ß 2 -adrenergic receptor (ß 2 AR) at short sequential time points after GTP addition, we identified the conformational trajectory underlying G protein activation and functional dissociation from the receptor. Twenty transition structures generated from sequential overlapping particle subsets along this trajectory, compared to control structures, provide a high-resolution description of the order of events driving G protein activation upon GTP binding. Structural changes propagate from the nucleotide-binding pocket and extend through the GTPase domain, enacting alterations to Gα Switch regions and the α5 helix that weaken the G protein-receptor interface. Molecular dynamics (MD) simulations with late structures in the cryo-EM trajectory support that enhanced ordering of GTP upon closure of the alpha-helical domain (AHD) against the nucleotide-bound Ras-homology domain (RHD) correlates with irreversible α5 helix destabilization and eventual dissociation of the G protein from the GPCR. These findings also highlight the potential of time-resolved cryo-EM as a tool for mechanistic dissection of GPCR signaling events.

InvitroSPI and a large database of proteasome-generated spliced and non-spliced peptides.

Noncanonical epitopes presented by Human Leucocyte Antigen class I (HLA-I) complexes to CD8+ T cells attracted the spotlight in the research of novel immunotherapies against cancer, infection and autoimmunity. Proteasomes, which are the main producers of HLA-I-bound antigenic peptides, can catalyze both peptide hydrolysis and peptide splicing. The prediction of proteasome-generated spliced peptides is an objective that still requires a reliable (and large) database of non-spliced and spliced peptides produced by these proteases. Here, we present an extended database of proteasome-generated spliced and non-spliced peptides, which was obtained by analyzing in vitro digestions of 80 unique synthetic polypeptide substrates, measured by different mass spectrometers. Peptides were identified through invitroSPI method, which was validated through in silico and in vitro strategies. The peptide product database contains 16,631 unique peptide products (5,493 non-spliced, 6,453 cis-spliced and 4,685 trans-spliced peptide products), and a substrate sequence variety that is a valuable source for predictors of proteasome-catalyzed peptide hydrolysis and splicing. Potential artefacts and skewed results due to different identification and analysis strategies are discussed.

Prostate gland metastasis as a late relapse of rectal adenocarcinoma.

We present a case report of a 49 year old patient with a known history of rectal adenocarcinoma treated with extended abdominal perineal resection. After five the patient was diagnosed with metastases to the prostate gland. This case stands out not only due to the infrequency of an onset of a colorectal tumor in the prostatic gland but also the late onset of the tumor. In these cases the differential diagnosis between a metastatic tumor and a primary urologic tumor is difficult due to similar morphology and histology, making the CDX-2 immunohistochemical maker expression an important tool to define the histopathology of the tumor.

Ictericia obstructiva secundaria a un pseudoaneurisma de arteria mesentérica superior / Obstructive jaundice secondary to a pseudoaneurysm of the superior mesenteric artery

Los pseudoaneursimas de arteria mesentérica superior son una entidad rara, generalmente asintomáticos pero que pueden debutar con dolor abdominal, masa pulsátil o shock, siendo excepcional la ictericia como forma de presentación. El diagnóstico se realiza mediante pruebas de imagen (TC) y en la actualidad el abordaje endovascular es el más extendido reservándose la cirugía abierta en casos seleccionados. Describimos el caso de una paciente con un pseudoaneurisma de la AMS de 86mm con compresión de la vía biliar extrahepática. (AU)

Hypoxia adapted relative biological effectiveness models for proton therapy: a simulation study.

In proton therapy, a constant relative biological effectiveness (RBE) factor of 1.1 is applied although the RBE has been shown to depend on factors including the Linear Energy Transfer (LET). The biological effectiveness of radiotherapy has also been shown to depend on the level of oxygenation, quantified by the oxygen enhancement ratio (OER). To estimate the biological effectiveness across different levels of oxygenation the RBE-OER-weighted dose (ROWD) can be used. To investigate the consistency between different approaches to estimate ROWD, we implemented and compared OER models in a Monte Carlo (MC) simulation tool. Five OER models were explored: Wenzl and Wilkens 2011 (WEN), Tinganelliet al2015 (TIN), Strigariet al2018 (STR), Dahleet al2020 (DAH) and Meinet al2021 (MEI). OER calculations were combined with a proton RBE model and the microdosimetric kinetic model for ROWD calculations. ROWD and OER were studied for a water phantom scenario and a head and neck cancer case using hypoxia PET data for the OER calculation. The OER and ROWD estimates from the WEN, MEI and DAH showed good agreement while STR and TIN gave higher OER values and lower ROWD. The WEN, STR and DAH showed some degree of OER-LET dependency while this was negligible for the MEI and TIN models. The ROWD for all implemented models is reduced in hypoxic regions with an OER of 1.0-2.1 in the target volume. While some variations between the models were observed, all models display a large difference in the estimated dose from hypoxic and normoxic regions. This shows the potential to increase the dose or LET in hypoxic regions or reduce the dose to normoxic regions which again could lead to normal tissue sparing. With reliable hypoxia imaging, RBE-OER weighting could become a useful tool for proton therapy plan optimization.

Obstructive jaundice secondary to a pseudoaneurysm of the superior mesenteric artery.

Superior mesenteric arteries pseudoaneurysms are rare entity, usually asymptomatic but they can appear as an abdominal pain, throbbing mass or shock, being jaundice an exceptional type of presentation. Diagnosis is made by imaging tests (CT) and currently the endovascular approach is the most widespread, reserving open surgery in selected cases. We describe the case of a patient with an 86mm SMA pseudoaneurysm with compression of the extrahepatic bile duct.