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Background: The role of prophylactic high-dose gabapentin for the management of oral mucositis during radiation therapy for head and neck squamous cell carcinoma (HNSCC) remains controversial. Methods: A retrospective cohort analysis was performed on primary HNSCC patients treated at our institution. Kruskal–Wallis and Fisher’s exact tests were used to compare the patients’ baseline characteristics. Multivariate competing risk and logistic regressions were performed to evaluate time to first opioid use and feeding tube placement. Results: In total, 480 consecutive HNSCC patients were included. Within this cohort, 186 patients received 3600 mg gabapentin, 182 received 300 to 3200 mg gabapentin, and 112 received no gabapentin. The time to first opioid use was greater in the 3600 mg group compared with the no gabapentin group (34.3 vs. 23.9 days, p < 0.001) and to the 300 to 3200 mg group (28.0 days, p < 0.001). The proportion of patients requiring opioids at any point during RT was lower in the 3600 mg gabapentin group compared with the no gabapentin group (31.8% vs. 60.1%, p < 0.001) and with the 300 to 3200 mg group (63.8%, p < 0.001). Conclusions: Prophylactic use of 3600 mg gabapentin was well tolerated, halved overall opioid use, and delayed the time to first opioid use during radiation therapy.

ImportanceAfter 10 pack-years of smoking was initially established as a threshold for risk stratification, subsequent clinical trials incorporated it to identify candidates for treatment deintensification. However, several recent studies were unable to validate this threshold externally, and the threshold for smoking exposure remains unclear.ObjectiveTo estimate the threshold of pack-years of smoking associated with survival and tumor recurrence among patients with head and neck cancer.Design, Setting, and ParticipantsThis single-institution, cohort study included patients with nonmetastatic head and neck cancer receiving chemoradiation from January 2005 to April 2021. Data were analyzed from January to April 2022.ExposuresHeavy vs light smoking using 22 pack-years as a threshold based on maximizing log-rank test statistic.Main Outcomes and MeasuresOverall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF).ResultsA total of 518 patients (427 male [82.4%]; median [IQR] age, 61 [55-66] years) were included. Median (IQR) follow-up was 44.1 (22.3-72.8) months. A nonlinear Cox regression model using restricted cubic splines showed continuous worsening of OS and PFS outcomes as pack-years of smoking increased. The threshold of pack-years to estimate OS and PFS was 22. Cox multivariable analysis (MVA) showed that more than 22 pack-years was associated with worse OS (adjusted hazard ratio [aHR] 1.57; 95% CI, 1.11-2.22; P = .01) and PFS (aHR, 1.38; 95% CI, 1.00-1.89; P = .048). On Fine-Gray MVA, heavy smokers were associated with DF (aHR, 1.71; 95% CI, 1.02-2.88; P = .04), but not LRF (aHR, 1.07; 95% CI, 0.61-1.87; P = .82). When 10 pack-years of smoking were used as a threshold, there was no association for OS (aHR, 1.23; 95% CI, 0.83-1.81; P = .30), PFS (aHR, 1.11; 95% CI, 0.78-1.57; P = .56), LRF (aHR, 1.19; 95% CI, 0.64-2.21; P = .58), and DF (aHR, 1.45; 95% CI, 0.82-2.56; P = .20). Current smoking was associated with worse OS and PFS only among human papillomavirus (HPV)-positive tumors (OS: aHR, 2.81; 95% CI, 1.26-6.29; P = .01; PFS: aHR, 2.51; 95% CI, 1.22-5.14; P = .01).Conclusions and RelevanceIn this cohort study of patients treated with definitive chemoradiation, 22 pack-years of smoking was associated with survival and distant metastasis outcomes. Current smoking status was associated with adverse outcomes only among patients with HPV-associated head and neck cancer.

We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker.A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes.A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53-3.80, p 0.001) and PFS (aHR 2.01, 95 % CI 1.30-3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23-4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02-3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66-41.44, p 0.001) and PFS (aHR 5.24, 95 % CI 2.09-13.18, p 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60-5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41-3.14, p = 0.82).Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.

The Hera mission contributes to the international effort towards the validation of the kinetic impactor asteroid deflection technique by retrieving all the physical and dynamical properties of Dimorphos in order to validate numerical impact codes. In particular, Hera’s core objectives from the point of view of the deflection demonstration are the following: (i) Measuring the mass of Dimorphos to determine the momentum transfer efficiency from DART to the asteroid; (ii) Investigating the crater in detail to improve our understanding of the cratering process and the mechanisms by which the crater formation drives the momentum transfer efficiency; (iii) Observing subtle dynamic effects (e.g. libration imposed by the impact, orbital and spin excitation of the secondary) that are difficult to detect for remote observers; (iv) Characterising the physical properties of Dimorphos (including size, shape, volume, density, porosity, size distribution of surface material) to allow scaling of the momentum transfer efficiency to different asteroids. In addition, the Hera mission will allow the demonstration of two key technologies for future deep-space missions: (v) The use of CubeSats for multipoint investigations operated via an inter-satellite network link via Hera; (vi) Autonomous visual-based navigation for very low altitude flybys over the surface of Dimorphos. The Hera spacecraft will launch in October 2024 onboard an Ariane 6 launcher with an 18-days launch window. The trajectory foresees a Mars swing-by in mid-March 2025 and the rendezvous phase with Didymos starting end-December 2026. Following the operationally safe capture sequence, the asteroid close-proximity operation phase will start from a gate position of about 30 km. Operations will continue for about 6 months and allow for detailed investigations of the Didymos surface down to few kilometres or less from the surface of Dimorphos depending on the performance of the onboard feature-tracking navigation system. The mission is currently in phase B2 with OHB System as prime contractor together with GMV, QinetiQ, Spacebel and OHB-I as core team members. The preliminary design review is schedules in October 2020. The paper will provide an overview of the mission together with its latest system and payload configuration.

The Hera mission is the planetary defence mission approved under the ESA Space Safety Programme. Together with the NASA DART mission, it is the first Asteroid Deflection Demonstration. DART will impact Dimorphos, the natural satellite of Near Earth Asteroid Didymos, in 2022. Using the kinetic impactor technology, it will demonstrate the ability to change the trajectory of a small asteroid. Hera will launch in 2024 and arrive in the Didymos system at the end of 2026. Its primary goals are to accurately measure the mass of Dimorphos and to characterise the crater and effect of the DART impact on this small asteroid. Hera will spend over 2 years matching orbits with Didymos, travelling through near-Earth space and the inner main-belt. This potentially allows Hera to perform an additional asteroid flyby enroute to Didymos. For such a flyby, a number of factors need to be considered for target selection. Primary factors are the accuracy of the orbit of the asteroid, and distance from the nominal trajectory. Resolution of geomorphology requires a minimum number of spatial resolution elements at the desired flyby distance. Previous observations on the form of lightcurves, colours or spectra are important for flyby science planning. Finally, a dynamical class of asteroid may be targeted for specific science priorities. Analysis of the nominal trajectory shows approximately 100 asteroids passing the nominal position of Hera within 0.02 au. Ten of these potential targets are Near-Earth Asteroids, the rest being Mars-crossers and main-belt asteroids. We will present our current knowledge on these targets, and highlight the highest priority targets for further observation in the next 2-3 years. Although ground-based reconnaissance has started on some targets, further observations are required to support the flyby planning process. Figure 1. Osculating orbital elements of asteroids passing close to Hera on its nominal trajectory to the Didymos system, without any additional trajectory adjustment. Red dots indicate a current flyby distance d < 0.01 au, blue circles indicate a current flyby distance 0.01 au < d < 0.02 au. The solid line indicates a perihelion distance of 1.3 au, asteroids to the left of this line are Near-Earth Asteroids.

Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer’s disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-β (Aβ) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by balance between Aβ production and its clearance. We present evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Hence the liver could be targeted to decrease Aβ production or increase peripheral clearance.

Toponome imaging systems (TIS) can yield high-resolution subcellular colocalization images of multiple proteins within single cells and intact tissue sections, giving this technology significant potential for identifying multiplex biomarkers that simultaneously measure several aspects of a cell. The integral role of the microenvironment in malignant progression and the recently appreciated heterogeneity of cancer cells underscore the importance of characterizing complex molecular phenotypes and the large protein network structures of single cells within their preserved anatomical context. Here, we discuss the TIS technique and the potential for developing new sensitive and specific multiplex biomarkers for risk stratification and diagnosis, in addition to its utility for anticancer drug discovery by identifying 'hub' proteins that are essential regulators of protein networks.

Motivation: Bioimaging techniques rapidly develop toward higher resolution and dimension. The increase in dimension is achieved by different techniques such as multitag fluorescence imaging, Matrix Assisted Laser Desorption / Ionization (MALDI) imaging or Raman imaging, which record for each pixel an N-dimensional intensity array, representing local abundances of molecules, residues or interaction patterns. The analysis of such multivariate bioimages (MBIs) calls for new approaches to support users in the analysis of both feature domains: space (i.e. sample morphology) and molecular colocation or interaction. In this article, we present our approach WHIDE (Web-based Hyperbolic Image Data Explorer) that combines principles from computational learning, dimension reduction and visualization in a free web application. Results: We applied WHIDE to a set of MBI recorded using the multitag fluorescence imaging Toponome Imaging System. The MBI show field of view in tissue sections from a colon cancer study and we compare tissue from normal/healthy colon with tissue classified as tumor. Our results show, that WHIDE efficiently reduces the complexity of the data by mapping each of the pixels to a cluster, referred to as Molecular Co-Expression Phenotypes and provides a structural basis for a sophisticated multimodal visualization, which combines topology preserving pseudocoloring with information visualization. The wide range of WHIDE's applicability is demonstrated with examples from toponome imaging, high content screens and MALDI imaging (shown in the Supplementary Material). Availability and implementation: The WHIDE tool can be accessed via the BioIMAX website http://ani.cebitec.uni-bielefeld.de/BioIMAX/; Login: whidetestuser; Password: whidetest. Supplementary information: Supplementary data are available at Bioinformatics online. Contact: tim.nattkemper@uni-bielefeld.de

In a proof of principle study, we have applied an automated fluorescence toponome imaging system (TIS) to examine whether TIS can find protein network structures, distinguishing cancerous from normal colon tissue present in a surgical sample from the same patient. By using a three symbol code and a power of combinatorial molecular discrimination (PCMD) of 2(21) per subcellular data point in one single tissue section, we demonstrate an in situ protein network structure, visualized as a mosaic of 6813 protein clusters (combinatorial molecular phenotype or CMPs), in the cancerous part of the colon. By contrast, in the histologically normal colon, TIS identifies nearly 5 times the number of protein clusters as compared to the cancerous part (32 009). By subcellular visualization procedures, we found that many cell surface membrane molecules were closely associated with the cell cytoskeleton as unique CMPs in the normal part of the colon, while the same molecules were disassembled in the cancerous part, suggesting the presence of dysfunctional cytoskeleton-membrane complexes. As expected, glandular and stromal cell signatures were found, but interestingly also found were potentially TIS signatures identifying a very restricted subset of cells expressing several putative stem cell markers, all restricted to the cancerous tissue. The detection of these signatures is based on the extreme searching depth, high degree of dimensionality, and subcellular resolution capacity of TIS. These findings provide the technological rationale for the feasibility of a complete colon cancer toponome to be established by massive parallel high throughput/high content TIS mapping.

Eines der grosen Ziele der Marsforschung besteht darin, mit einer unbemannten Sonde Proben von unserem Nachbarplaneten zur Erde zu holen. Eine solche Mars Sample Return-Mission (MSR) ist jedoch erheblich aufwendiger als ein vergleichbares Unternehmen beim Mond. Fur eine MSR werden zwei Raketen notig sein. Eine bringt einen Orbiter, die andere eine Landeeinheit auf den Weg zum Mars. Der Ruckflug ist mit einem schwierigen Rendezvous-Manover der Landeeinheit und des Orbiters in der Marsumlaufbahn verbunden, wie es in ahnlicher Form bei den – allerdings bemannten – Apollo-Missionen am Mond stattgefunden hat. Auserdem muss man bei einer MSR sowohl beim Hin- als auch beim Ruckflug das Startfenster beachten, weswegen die ganze Mission etwa funf Jahre dauern wird.

Objective: Enzymes involved in the oxidative metabolism of n-6 polyunsaturated fatty acids, like lipoxygenase (LOX) and cyclooxygenase (COX), are significant in the pathogenesis of colorectal cancer. Of these enzymes, 15-LOX-1 is expressed in colon. Aim of this article is to describe the role and regulation of 15-LOX-1 in colorectal cancer and highlight its importance in cancer therapeutics. Methods: For our electronic literature research in PubMed and MEDLINE, key words related to 15-LOX-1 and colorectal cancer were used to find articles for this review. Results: From the evidences, we believe that 15-LOX-1 has anti-carcinogenic effects in colorectal cancer, dependent or independent of its metabolites, and is manifested through downstream pathways involving cGMP, PPAR, p53, p21 and NAG-1, increasing apoptosis and decreasing proliferation in cancer cells. Regulation of 15-LOX-1 expression is achieved at transcription level by global histone acetylation and may also be dependent on GATA-6, IL-4 and IL-13. Positive relationship exists between 15-LOX-1 and survival in colorectal cancer. Conclusion: Evidences strongly support that therapeutic modulation of 15-LOX-1 may be a key to the treatment of colorectal cancer. However, it is still undecided whether the up-regulation of 15-LOX-1 alone can be sufficient to treat colorectal cancer and further studies are awaited. Copyright (C) 2009 S. Karger AG, Basel

Reduced β-cell numbers and function (β-cell failure) contribute to essentially all forms of diabetes, and must be corrected if established disease is to be cured. Current therapies have been shown not to prevent β-cell failure and the availability of insulin-secreting cells for replacement-based therapies is severely restricted. Researchers have responded to this challenge by aiming to generate new β-cells (or β-like cells) in vitro or potentially in situ, by diverse strategies in- cluding manipulation of stem cells, β-cells, or even non- β-cells such as hepatocytes. Which ever approach is ultimately most successful is at present not known, what is certain is that progress will needs to be informed by a deeper under- standing of those cellular processes which determine β-cell differentiation, renewal and survival. Interest in this approach has been fuelled by the remarkable capacity for β-cell replication and renewal demonstrated in many model systems. Po- tential regulatory factors have already been identified and include various proteins required for promoting the G1/S transi- tion of the cell cycle, including c-Myc and downstream transcriptional targets such as cyclin D and E2F family members. It is likely that for these factors to be exploited therapeutically, that we will need to circumvent the inherent tumor sup- pressor activity associated with aberrant activity of these proteins, including avoidance of apoptosis and growth arrest. Much recent work has begun to unravel the complexity of growth-regula ting networks in which these proteins are in- volved and there is reason for future optimism.

During normal tissue homeostasis apoptotic cells (AC) are rapidly recognised and engulfed by neighbouring cells or macrophages (Mphi), thus preventing an inflammatory response. Conversely, in chronically inflamed tissues, including the atherosclerotic artery and rheumatoid joint, removal of AC is defective despite the co-localisation of seemingly adequate numbers of Mphi. Mechanisms preventing removal of AC in vivo remain obscure, but might include oxidised low-density lipoprotein (ox-LDL), which is abundant in chronic inflammatory lesions. Although implicated in their pathogenesis, defining the role of ox-LDL on inflammatory processes has proved complicated. In fact, seemingly contradictory results have previously been described, though these may in part reflect the heterogeneous nature of ox-LDL applied in these studies. We wished to investigate the effect of physiologically representative ox-LDL on the binding and engulfment of apoptotic vascular smooth muscle cells (VSMC) and fibroblasts, as these have previously been shown to co-localise with Mphi in chronically inflamed tissues in vivo. We show that Mphi recognition of AC in vitro is not affected at physiological levels of ox-LDL. However, engulfment of intact AC is dramatically reduced/delayed. Importantly, in the absence of ox-LDL rapid phagocytosis of intact AC suppresses Mphi inflammatory cytokine release. In striking contrast, in the presence of ox-LDL, despite binding of AC to Mphi, release of IL-6 and MCP-1 is no longer suppressed. We propose that ox-LDL could maintain an inflammatory response by inhibiting the engulfment of AC, required for Mphi de-activation. This mechanism may contribute to chronic persisting inflammation in the atherosclerotic artery and rheumatoid joint.

The c-MYC proto-oncogene is essential for cellular proliferation but, paradoxically, may also promote cell death. Deregulated expression of c-MYC is present in most, if not all, human cancers, and is associated with a poor prognosis. However, given that human tumours at diagnosis generally carry multiple genetic lesions that have accumulated during (although they are not necessarily essential for) tumour progression, it has proved difficult to attribute a specific role to any given single factor or indeed to explore the therapeutic potential of selectively mitigating their biological functions. Regulatable transgenic mouse models of oncogenesis have shed light on these issues, influenced our thinking about cancer and provided encouragement for the future development of cancer therapies based on targeting individual oncogenes such as c-MYC. Although still in its infancy, encouraging results have been reported using antisense oligodeoxynucleotide-based methods, as well as other approaches to interfere with MYC expression both in vitro and in vivo.

The proto-oncogene c-MYC is implicated in various physiological processes-cell growth, proliferation, loss of differentiation, and cell death (apoptosis). Oncogenic c-MYC implies constitutive or deregulated expression of c-MYC and is associated with many human cancers often with poor prognosis. Recently, c-MYC has been implicated in the loss and dysfunction of insulin-producing beta cells in diabetes. Intriguingly, this raises the possibility that c-Myc may be a key contributor to disease, not only by deregulating cell proliferation, which is well established, but also by virtue of its opposing role in engendering apoptosis. However, given the fact that human diseases at diagnosis are generally advanced and pathologically complex, it is generally difficult to attribute a specific pathogenic role to c-MYC, or indeed any given single factor, or to assess the potential of therapies targeting individual such factors. Regulatable transgenic mouse models have shed light on these issues, have influenced our thinking about cancer, and have provided encouragement for the future development of cancer therapies based on targeting individual oncogenes such as c-MYC. Although still in its infancy, encouraging results have been reported for several approaches using gene targeting to interfere with c-MYC expression or activity both in vitro and in vivo.

Deregulated expression of c-MYC occurs in a broad range of human cancers and is often associated with poor prognosis, indicating a key role for this oncogene in tumour progression. However, as established human tumours often bear multiple genetic lesions, it is difficult to determine whether c-MYC is instrumental in the initiation/progression of the tumour, or indeed whether inactivating c-MYC would lead to tumour regression. Regulatable transgenic mouse models of oncogenesis have shed light on these issues and provide hope for effective cancer therapies.

Lipids and lipoproteins, particularly triglyceride rich lipoproteins, could influence the development and progression of microalbuminuria in diabetes. Lipoprotein lipase gene variants have been found to correlate with lipid/lipoprotein concentrations, especially hypertriglyceridaemia. We assessed the influence of this gene on microalbuminuria in Type II (insulin-dependent) diabetes mellitus.Microalbuminuria was determined quantitatively in 386 sequential Type II diabetic patients by measurement of the albumin-to-creatinine ratio (ACR). DNA was analysed for two common intronic LPL single nucleotide polymorphisms (Pvu II, intron 6, and Hind III, intron 8), and three common exonic mutations (Asp(9)-Asn, exon 2, Asn(291)-Ser, exon 6, and Ser(447)-Ter, exon 9).Individuals with P (2) P (2) (Pvu II) and H (2) H (2) (Hind III) genotypes had significantly greater ACRs ( P(2)P(2) vs P(1)P(1)+ P(1)P(2), 5.0+/-0.5 vs 3.4+/-0.3, p=0.0004 and H(2)H(2) vs H(1)H(1)+ H(1)H(2), 4.3+/-0.4 vs 3.4+/-0.3, p=0.04). Logistic regression analysis demonstrated that only the P(2)P(2) genotype ( p=0.0004), systolic BP ( p=0.008) and creatinine ( p=0.031) were independently associated with the presence of microalbuminuria/proteinuria. P(2) homozygotes were 170% more likely to have microalbuminuria or proteinuria, O.R. 2.7 (1.6-4.5, p=0.0001), 150% more likely to have microalbuminuria, O.R. 2.5 (1.5-4.3, p=0.001), and 330% more likely to have proteinuria, O.R. 4.3 (1.6-11.4, p=0.004). There were no associations of microalbuminuria with any of the exonic polymorphisms.Genetic variants of lipoprotein lipase correlate with presence and severity of microalbuminuria in Type II diabetes, independent of effect on serum lipids. This association is only apparent in genetic variants demonstrating greatest heterozygosity.