Background: Locoregionally advanced, stage IV head and neck cancer has traditionally carried a poor prognosis. We sought to assess changes in patterns of failure, prognostic factors for recurrence, ...and overall outcome, using two different strategies of chemoradiotherapy conducted in prospective, multi-institutional phase II trials. Patients and methods: Three hundred and thirty-seven stage IV patients were treated from 1989 to 1998. We compared locoregional and distant recurrence rates, overall survival and progression-free survival from two different treatment strategies: intensive induction chemotherapy followed by split-course chemoradiotherapy (type 1, n=127), or intensified, split-course, hyperfractionated multiagent chemoradiotherapy alone (type 2, n=210). Univariate and multivariate analyses of 12 chosen covariates were assessed separately for the two study types. Results: The pattern of failure varied greatly between study types 1 and 2 (5-year locoregional failure of 31% and 17% for study types 1 and 2, respectively, P=0.01; 5-year distant failure rate of 13% and 22% for study types 1 and 2, P=0.03). Combined 5-year overall survival was 47% 95% confidence interval (CI) 41% to 53%) and progression-free survival was 60% (95% CI 55% to 66%). Both treatment strategies yielded similar survival rates. Poor overall survival and distant recurrence were best predicted by advanced nodal stage. Locoregional recurrence was extremely rare for patients with T0–T3 tumor stage, regardless of lymph-node stage. Conclusions: This analysis suggests that pattern of failure in primary head and neck cancer may be dependent upon treatment strategy. Randomized clinical trials of induction chemotherapy are warranted as a means to determine if a decrease in distant metastases can lead to an increase in survival rates in the setting of effective chemoradiotherapy for locoregional control. Additionally, this analysis provides impetus for randomized clinical trials of organ preservation chemoradiotherapy in sites outside the larynx and hypopharynx.
Abstract
To advance our understanding of the fuelling and feedback processes which power the Universe’s most massive black holes, we require a significant increase in our knowledge of the molecular ...gas which exists in their immediate surroundings. However, the behaviour of this gas is poorly understood due to the difficulties associated with observing it directly. We report on a survey of 18 brightest cluster galaxies lying in cool cores, from which we detect molecular gas in the core regions of eight via carbon monoxide (CO), cyanide (CN) and silicon monoxide (SiO) absorption lines. These absorption lines are produced by cold molecular gas clouds which lie along the line of sight to the bright continuum sources at the galaxy centres. As such, they can be used to determine many properties of the molecular gas which may go on to fuel supermassive black hole accretion and AGN feedback mechanisms. The absorption regions detected have velocities ranging from −45 to 283 km s−1 relative to the systemic velocity of the galaxy, and have a bias for motion towards the host supermassive black hole. We find that the CN N = 0 − 1 absorption lines are typically 10 times stronger than those of CO J = 0 − 1. This is due to the higher electric dipole moment of the CN molecule, which enhances its absorption strength. In terms of molecular number density CO remains the more prevalent molecule with a ratio of CO/CN ∼10, similar to that of nearby galaxies. Comparison of CO, CN, and H i observations for these systems shows many different combinations of these absorption lines being detected.
Biological phase separation is known to be important for cellular organization, which has recently been extended to a new class of biomolecules that form liquid-like droplets coexisting with the ...surrounding cellular or extracellular environment. These droplets are termed membraneless organelles, as they lack a dividing lipid membrane, and are formed through liquid-liquid phase separation (LLPS). Elucidating the molecular determinants of phase separation is a critical challenge for the field, as we are still at the early stages of understanding how cells may promote and regulate functions that are driven by LLPS. In this review, we discuss the role that disorder, perturbations to molecular interactions resulting from sequence, posttranslational modifications, and various regulatory stimuli play on protein LLPS, with a particular focus on insights that may be obtained from simulation and theory. We finally discuss how these molecular driving forces alter multicomponent phase separation and selectivity.
Some frequently encountered deficiencies in all-atom molecular simulations, such as nonspecific protein–protein interactions being too strong, and unfolded or disordered states being too collapsed, ...suggest that proteins are insufficiently well solvated in simulations using current state-of-the-art force fields. To address these issues, we make the simplest possible change, by modifying the short-range protein–water pair interactions, and leaving all the water–water and protein–protein parameters unchanged. We find that a modest strengthening of protein–water interactions is sufficient to recover the correct dimensions of intrinsically disordered or unfolded proteins, as determined by direct comparison with small-angle X-ray scattering (SAXS) and Förster resonance energy transfer (FRET) data. The modification also results in more realistic protein-protein affinities, and average solvation free energies of model compounds which are more consistent with experiment. Most importantly, we show that this scaling is small enough not to affect adversely the stability of the folded state, with only a modest effect on the stability of model peptides forming α-helix and β-sheet structures. The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, protein–protein association, and crowded cellular environments.
•Nanocomposite of Gg-cl-P(AA-co-AAm) and Fe3O4 MNPs were successfully synthesized.•The maximum adsorption capacity was found to be 654.87mg/L.•The adsorption isotherm data fitted well with Langmuir ...isotherm model.•Adsorption kinetics followed the pseudo second order rate model.•Desorption studies confirmed the reusability of the adsorbent.
This article reports the development of a new nanocomposite using gum ghatti crosslinked with poly(acrylic acid-co-acrylamide) reinforced with iron oxide magnetic nanoparticles. The nanocomposite was characterized through BET, FT-IR, XRD, SEM-EDX, TGA and TEM and applied for the removal of RhB. Different optimized adsorption parameters were adsorbent dose (0.8g/L) and pH (7.0). The adsorption isotherm data was used to study Langmuir, Freundlich and Dubinin–Kaganer–Radushkevich isotherm models. The value of correlation coefficient confirmed the applicability of Langmuir isotherm model with maximum adsorption efficiency of 654.87mg/g. The adsorption kinetics data showed pseudo second order reaction. Thermodynamic studies showed that the adsorption process was endothermic and spontaneous. Moreover, the adsorbent was successfully utilized for successive three cycles for the adsorption–desorption of RhB.
Background. This study presents a comparative analysis of recently published guidelines to manage cutaneous squamous cell carcinoma (cSCC) and cutaneous basal cell carcinoma (cBCC) within the United ...States (US). Methods. A PubMed database search was performed for the time period between June 1, 2016, and December 1, 2022. A comprehensive comparison was performed in the following clinical interest areas: staging and risk stratification, management of primary tumor and regional nodes with curative intent, and palliative treatment. Results. Guidelines from 3 organizations were analyzed: the American Academy of Dermatology (AAD), the National Comprehensive Cancer Network (NCCN), and the American Society for Radiation Oncology (ASTRO). The guidelines used different methodologies to grade evidence, making comparison difficult. There was agreement that surgery is the preferred treatment for curative cBCC and cSCC. For patients ineligible for surgery, there was a consensus to recommend definitive radiation. AAD and NCCN recommended consideration of other topical modalities in selected low-risk cBCC. Postoperative radiation therapy (PORT) was uniformly recommended in patients with positive margins that could not be cleared with surgery and in patients with nerve invasion. The definition and extent of nerve invasion varied. All guidelines recommended surgery as the primary treatment in patients with lymph node metastases in a curative setting. The criteria used for PORT varied; NCCN and ASTRO used lymph node size, number of nodes, and extracapsular extension for recommending PORT. Both NCCN and ASTRO recommend consideration of systemic treatment along with PORT in patients with extracapsular extension. Conclusion: US guidelines provide contemporary and complementary information on the management of cBCC and cSCC. There are opportunities for research, particularly in the areas of staging, indications for adjuvant treatment in curative settings, extent of nerve invasion and prognosis, and the role of systemic treatments in curative and palliative settings.
•Liquid-liquid phase separation underlies the formation of membraneless organelles within cells.•Theory and molecular simulations help to relate interactions at the molecular level to macroscopic ...properties of biomolecular condensates.•Atomistic simulation models are helpful to predict local structural motifs and atomic interaction modes.•Coarse-grained simulation models and theory can be used to predict phase equilibria from sequence properties.•Polymer field theory models can help bridge the gap between molecular simulations of single IDPs and a complete description of phase separation.
Intrinsically disordered proteins (IDPs) are an important class of proteins that do not fold to a well-defined three-dimensional shape but rather adopt an ensemble of inter-converting conformations. This feature makes their experimental characterization challenging and invites a theoretical and computational approach to complement experimental studies. In this review, we highlight the recent progress in developing new computational and theoretical approaches to study the structure and dynamics of monomeric and order higher assemblies of IDPs, with a particular emphasis on their phase separation into protein-rich condensates.
Hepatocellular carcinoma (HCC) is increasing in incidence and has a very high fatality rate. Cirrhosis due to chronic hepatitis B or hepatitis C is the leading risk factor for HCC. Global ...epidemiology of HCC is determined by the prevalence of dominant viral hepatitis and the age it is acquired in the underlying population. Upcoming risk factors include obesity, diabetes, and related nonalcoholic fatty liver disease. This review discusses the latest trends of HCC globally and in the United States. It also provides an evidence-based commentary on the risk factors and lists some of the preventive measures to reduce the incidence of HCC.
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