Machine Learning-Based Survival Prediction Models for Progression-Free and Overall Survival in Advanced-Stage Hodgkin Lymphoma.

PURPOSE: Patients diagnosed with advanced-stage Hodgkin lymphoma (aHL) have historically been risk-stratified using the International Prognostic Score (IPS). This study investigated if a machine learning (ML) approach could outperform existing models when it comes to predicting overall survival (OS) and progression-free survival (PFS). PATIENTS AND METHODS: This study used patient data from the Danish National Lymphoma Register for model development (development cohort). The ML model was developed using stacking, which combines several predictive survival models (Cox proportional hazard, flexible parametric model, IPS, principal component, penalized regression) into a single model, and was compared with two versions of IPS (IPS-3 and IPS-7) and the newly developed aHL international prognostic index (A-HIPI). Internal model validation was performed using nested cross-validation, and external validation was performed using patient data from the Swedish Lymphoma Register and Cancer Registry of Norway (validation cohort). RESULTS: In total, 707 and 760 patients with aHL were included in the development and validation cohorts, respectively. Examining model performance for OS in the development cohort, the concordance index (C-index) for the ML model, IPS-7, IPS-3, and A-HIPI was found to be 0.789, 0.608, 0.650, and 0.768, respectively. The corresponding estimates in the validation cohort were 0.749, 0.700, 0.663, and 0.741. For PFS, the ML model achieved the highest C-index in both cohorts (0.665 in the development cohort and 0.691 in the validation cohort). The time-varying AUCs for both the ML model and the A-HIPI were consistently higher in both cohorts compared with the IPS models within the first 5 years after diagnosis. CONCLUSION: The new prognostic model for aHL on the basis of ML techniques demonstrated a substantial improvement compared with the IPS models, but yielded a limited improvement in predictive performance compared with the A-HIPI.

Pulmonary diseases in patients with classical Hodgkin lymphoma relative to a matched background population: A Danish national cohort study.

Late toxicities can impact survivorship in patients with classical Hodgkin lymphoma (cHL) with pulmonary toxicity after bleomycin-containing chemotherapy being a concern. The incidence of pulmonary diseases was examined in this Danish population-based study. A total of 1474 adult patients with cHL treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, vincristine, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone) between 2000 and 2018 were included along with 7370 age- and sex-matched comparators from the background population. Median follow-up was 8.6 years for the patients. Patients with cHL had increased risk of incident pulmonary diseases (HR 2.91 [95% CI 2.30-3.68]), with a 10-year cumulative risk of 7.4% versus 2.9% for comparators. Excess risks were observed for interstitial lung diseases (HR 15.84 [95% CI 9.35-26.84]) and chronic obstructive pulmonary disease (HR 1.99 [95% CI 1.43-2.76]), with a 10-year cumulative risk of 4.1% and 3.5% respectively for patients. No excess risk was observed for asthma (HR 0.82 [95% CI 0.43-1.56]). Risk factors for interstitial lung diseases were age ≥60 years, the presence of B-symptoms and low albumin. These findings document a significant burden of pulmonary diseases among patients with cHL and emphasize the importance of diagnostic work-up of pulmonary symptoms.

Deconvoluting the Effect of Cell-Penetrating Peptides for Enhanced and Controlled Insertion of Large-Scale DNA Nanopores.

DNA nanopores have emerged as powerful tools for molecular sensing, but the efficient insertion of large DNA nanopores into lipid membranes remains challenging. In this study, we investigate the potential of cell-penetrating peptides (CPPs), specifically SynB1 and GALA, to enhance the insertion efficiency of large DNA nanopores. We constructed SynB1- or GALA-functionalized DNA nanopores with an 11 nm inner diameter and visualized and quantified their membrane insertion using a TIRF microscopy-based single-liposome assay. The results demonstrated that incorporating an increasing number of SynB1 or GALA peptides into the DNA nanopore significantly enhanced the membrane perforation. Kinetic analysis revealed that the DNA nanopore scaffold played a role in prearranging the CPPs, which facilitated membrane interaction and pore formation. Notably, the use of pH-responsive GALA peptides allowed highly efficient and pH-controlled insertion of large DNA pores. Furthermore, single-channel recording elucidated that the insertion process of single GALA-modified nanopores into planar lipid bilayers was dynamic, likely forming transient large toroidal pores. Overall, our study highlights the potential of CPPs as insertion enhancers for DNA nanopores, which opens avenues for improved molecule sensing and the controlled release of cargo molecules.

Positional nystagmus is observed in the vast majority of healthy individuals.

INTRODUCTION: Benign paroxysmal positional vertigo (BPPV) is a vestibular disease characterized by brief  positional vertigo. When examined, characteristic patterns of positional nystagmus (PN) are found with specific head position changes. Previous studies have shown a high prevalence of PN among vestibular healthy subjects. Considering the current diagnostic criteria of BPPV and the potentially high prevalence of PN in healthy individuals, this raises the question of potential over diagnosing BPPV, if diagnostics are based exclusively upon objective findings. This study aims to determine the prevalence of PN within a healthy, adult population and furthermore include a characterization of the PN observed. METHODS: This is a prospective cross-sectional study. 78 subjects were included. The subjects underwent four standardized positional tests for BPPV in a mechanical rotational chair while using a VNG-goggle to monitor and record eye movements. RESULTS: Positional nystagmus was recorded in 70.5% (55/78) of the subjects. Of the 55 subjects, who presented with PN, 81.8% (45/55) had upbeating PN. The 95th percentile of the maximum a-SPV was found to be 10.4 degrees per second, with a median of 4. Five subjects (6.4%) in total presented with PN mimicking BPPV. CONCLUSION: This study found PN to be a common finding within a healthy, adult population based on the high prevalence of PN in the study population. Upbeating PN mimicking posterior canalolithiasis was found in numerous subjects. The authors recommend a cautious approach when diagnosing BPPV, especially in cases of purely vertical PN (without a torsional component) and if no vertiginous symptoms are present during Dix-Hallpike and Supine Roll Test examinations.

Parallel Functionalization of DNA Origami.

DNA origami enables the creation of large supramolecular structures, with precisely defined features at the nanoscale. The concept thus naturally lends itself to the concept of molecular patterning, i.e., the positioning of molecular moieties and functional features. Creation of nanoscale patterns was already disseminated by Rothemund in 2006, in which DNA hairpins were used to produce nanoscale patterns on the flat origami canvases (Rothemund PWK, Nature 440(7082):297-302, 2006). For this type of application, it is often desired to produce multiple different patterns using the same origami canvas by reusing existing origami staple strands, rather than ordering new, custom oligonucleotides for each unique pattern. This chapter presents a method where the enzyme terminal deoxynucleotidyl transferase (TdT) is used in a parallelized reaction to add functional moieties to the end of a selected pool of unmodified staple strand oligonucleotides, which are then incorporated at precisely defined positions in the DNA origami canvas. Introducing arrays of functional features using this enzymatic functionalization of origami staple strands offers a very high degree of flexibility, versatility, and ease of use and can often be obtained faster than custom synthesis. For small synthesis scales, typically employed during initial functional screening of many different molecular patterns, the method also offers a significant advantage in terms of cost. During the past years, we have utilized this to incorporate a large variety of molecules including bulky proteins (Sørensen RS, Okholm AH, Schaffert D, Kodal ALB, Gothelf KV, Kjems J, ACS Nano 7:8098-8104, 2013) in designed patterns from modified nucleotide triphosphate (NTP) building blocks (Jahn K, Tørring T, Voigt NV, Sørensen RS, Kodal ALB, Andersen ES, Bioconjug Chem 22:819-823, 2011). The near-quantitative yields obtained by enzymatic functionalization allow synthesis of a large set of oligonucleotides in a one-pot reaction from commercial starting materials without the need for individual post-purification. Based on the chosen subset of staple strand, it is possible to create any designed functionality, array, or pattern. Here we describe the process going from an idea/design of a DNA origami-specific molecular pattern to nucleotide synthesis and subsequent parallel functionalization of the DNA origami, assembly, and the final characterization.

The Role of Nanoscale Distribution of Fibronectin in the Adhesion of Staphylococcus aureus Studied by Protein Patterning and DNA-PAINT.

Staphylococcus aureus is a widespread and highly virulent pathogen that can cause superficial and invasive infections. Interactions between S. aureus surface receptors and the extracellular matrix protein fibronectin mediate the bacterial invasion of host cells and is implicated in the colonization of medical implant surfaces. In this study, we investigate the role of distribution of both fibronectin and cellular receptors on the adhesion of S. aureus to interfaces as a model for primary adhesion at tissue interfaces or biomaterials. We present fibronectin in patches of systematically varied size (100-1000 nm) in a background of protein and bacteria rejecting chemistry based on PLL-g-PEG and studied S. aureus adhesion under flow. We developed a single molecule imaging assay for localizing fibronectin binding receptors on the surface of S. aureus via the super-resolution DNA points accumulation for imaging in nanoscale topography (DNA-PAINT) technique. Our results indicate that S. aureus adhesion to fibronectin biointerfaces is regulated by the size of available ligand patterns, with an adhesion threshold of 300 nm and larger. DNA-PAINT was used to visualize fibronectin binding receptor organization in situ at ∼7 nm localization precision and with a surface density of 38-46 µm-2, revealing that the engagement of two or more receptors is required for strong S. aureus adhesion to fibronectin biointerfaces.

Late recurrence of lymphoid malignancies after initial treatment for Hodgkin lymphoma - A study from the Danish Lymphoma Registry.

We analysed a large cohort of Hodgkin lymphoma (HL) patients in order to characterize: (1) the pattern of late recurrence of lymphoid malignancies (LR) after initial treatment for HL over a 35-year period; (2) the clinicopathological parameters influencing the risk of LR; and (3) the outcome of patients experiencing LR. We reviewed data of 3350 HL patients diagnosed in Denmark between 1982 and 2018 and registered in the Danish National Lymphoma Registry (LYFO). LR was defined as a recurrence of lymphoid malignancy at least five years after initial diagnosis. LR occurred in 58 patients, with a cumulative incidence at 10, 15 and 20 years of 2.7%, 4.0% and 5.4% respectively. LR was more frequently observed in patients with nodular lymphocyte-predominant HL (NLPHL) [hazard ratio (HR) 4.5; 95% confidence interval (CI): 2.4-8.4, p < 0.001]. In classical HL (cHL) patients, older age and lymphocytopenia were risk factors for LR with HRs of 1.04 per additional year (95% CI: 1.02-1.06) and 5.6 (95% CI: 2.7-11.5) respectively. Mixed cellularity histological subtype was a risk factor for LR, but only in females, with a HR of 5.4 (95% CI: 1.4-20.4, p = 0.014). In contrast to what was observed in NLPHL, LR in cHL was associated with an almost threefold increased risk of death compared with patients in continuous complete remission. Approximately one fifth (22.4%) of patients with LR experienced a second relapse.

Mental health among patients with non-Hodgkin lymphoma: A Danish nationwide study of psychotropic drug use in 8750 patients and 43 750 matched comparators.

Psychological distress following cancer diagnosis may lead to mental health complications including depression and anxiety. Non-Hodgkin lymphomas (NHLs) include indolent and aggressive subtypes for which treatment and prognosis differ widely. Incident use of psychotropic drugs (PDs-antidepressants, antipsychotics, and anxiolytics) and its correlation to lymphoma types can give insights into the psychological distress these patients endure. In this prospective matched cohort study, we used nationwide population-based registries to investigate the cumulative risk of PD use in NHL patients compared to a sex- and age-matched cohort from the Danish background population. In addition, contact patterns to psychiatric departments and incident intentional self-harm or completed suicide were explored. In total, 8750 NHL patients and 43 750 matched comparators were included (median age 68; male:female ratio 1.6). Median follow-up was 7.1 years. Two-year cumulative risk of PD use was higher in NHL patients (16.4%) as compared to the matched comparators (5.1%, p < .01); patients with aggressive NHL subtypes had the highest incidence. Prescription rates were higher in the first years after diagnosis but approached the rate of the matched population 5 years into survivorship in aggressive NHLs, whereas patients with indolent subtypes continued to be at higher risk. NHL patients had a slightly higher two-year risk of suicide/intentional self-harm (0.3%) as compared to the matched comparators (0.2%, p = .01). These results demonstrate that mental health complications among NHL patients are frequent. Routine assessment for symptoms of depression and anxiety should be consider as part of standard follow-up of NHL patients.

Parenthood Rates and Use of Assisted Reproductive Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study.

PURPOSE: The majority of young adults with Hodgkin lymphoma (HL) are cured, but chemotherapy-induced infertility can have profound psychosocial consequences. Providing data on parenthood rates and use of assisted reproductive techniques (ARTs) after contemporary HL treatment is important for patient counseling and survivorship care. MATERIALS AND METHODS: All Danish patients with HL diagnosed during 2000-2015 at the ages 18-40 years who achieved remission after first-line therapy were included and matched on age, sex, and parenthood status to five random persons from the general population. Parenthood rates were defined as the rate of first live birth per 1,000 person years, starting 9 months after HL diagnosis. Nationwide birth and patient registers were used to capture parenthood outcomes and ARTs use. RESULTS: A total of 793 HL survivors and 3,965 comparators were included (median follow-up 8.7 years). Similar parenthood rates were observed for male and female HL survivors when compared with matched comparators (56.2 v 57.1; P = .871 for males and 63.8 v 61.2; P = .672 for females). For male HL survivors, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) therapy was associated with lower parenthood rates as compared to the matched comparators (28.1 v 60.8; P = .020). Live birth after ARTs were more common for HL survivors than for comparators (males 21.6% v 6.3%; P < .001; females 13.6% v 5.5%; P = .001). There were no differences in gestational age, Apgar score, or newborn measurements between HL survivors and matched comparators. CONCLUSION: The parenthood rates for HL survivors who have not experienced relapse were generally similar to the general population. However, ARTs were used more often before the first live birth in HL survivors, which is relevant information when discussing possible long-term side effects and fertility-preserving treatment options.

The learning curve of robot-assisted vitreoretinal surgery - A randomized trial in a simulated setting.

PURPOSE: To investigate the learning curve of robot-assisted vitreoretinal surgery compared to manual surgery in a simulated setting. METHODS: The study was designed as a randomized controlled longitudinal study. Eight ophthalmic trainees in the 1st or 2nd year of their specialization were included. The participants were randomized to either manual or robot-assisted surgery. Participants completed repetitions of a test consisting of three vitreoretinal modules on the Eyesi virtual reality simulator. The primary outcome measure was time to learning curve plateau (minutes) for total test score. The secondary outcome measures were instrument movement (mm), tissue treatment (mm2 ) and time with instruments inserted (seconds). RESULTS: There was no significant difference in time to learning curve plateau for robot-assisted vitreoretinal surgery compared to manual. Robot-assisted vitreoretinal surgery was associated with less instrument movements (i.e. improved precision), -0.91 standard deviation (SD) units (p < 0.001). Furthermore, robot-assisted vitreoretinal surgery was associated with less tissue damage when compared to manual surgery, -0.94 SD units (p = 0.002). Lastly, robot-assisted vitreoretinal surgery was slower than manual surgery, 0.93 SD units (p < 0.001). CONCLUSIONS: There was no significant difference between the lengths of the learning curves for robot-assisted vitreoretinal surgery compared to manual surgery. Robot-assisted vitreoretinal surgery was more precise, associated with less tissue damage, and slower.

Depression and anxiety in Hodgkin lymphoma patients: A Danish nationwide cohort study of 945 patients.

Cancer-related psychological distress may lead to depression and anxiety among survivors. The vast majority of patients with Hodgkin lymphoma (HL) become long-term survivors, but the risk of mental health problems after HL is not well-characterized. Using national population-based registries, we investigated the cumulative incidence of psychotropic drug (antidepressants, antipsychotics, and anxiolytics) use (proxies for depression and anxiety) in HL patients as well as if an increased risk would normalize over time for patients in remission. The study included 945 HL patients aged 18-92 years and 4725 matched persons. In total, 215 HL patients (22.8%) received a prescription of any psychotropic drug (PD) at some point after date of diagnosis compared to 545 persons (11.5%) in the matched cohort. Cumulative incidences with death/relapse as competing risk confirmed that HL patients were at higher risk of receiving psychotropic drug prescriptions, but the increased risk was transient and normalized to the matched population 5 years into survivorship. Increased age, Eastern Cooperative Oncology Group performance status, and disease stage were associated with higher risk of psychotropic drug prescriptions. Given the increased rate of psychotropic drug prescriptions after HL diagnosis, screening for symptoms of depression and anxiety is warranted after HL diagnosis and first years into survivorship.

Extrusion of RNA from a DNA-Origami-Based Nanofactory.

Cells often spatially organize biomolecules to regulate biological interactions. Synthetic mimicry of complex spatial organization may provide a route to similar levels of control for artificial systems. As a proof-of-principle, we constructed an RNA-extruding nanofactory using a DNA-origami barrel with an outer diameter of 60 nm as a chassis for integrated rolling-circle transcription and processing of RNA through spatial organization of DNA templates, RNA polymerases, and RNA endonucleases. The incorporation efficiency of molecular components was quantified to be roughly 50% on designed sites within the DNA-origami chassis. Each integrated nanofactory with RNA-producing units, composed of DNA templates and RNA polymerases, produced 100 copies of target RNA in 30 min on average. Further integration of RNA endonucleases that cleave rolling-circle transcripts from concatemers into monomers resulted in 30% processing efficiency. Disabling spatial organization of molecular components on DNA origami resulted in suppression of RNA production as well as processing.

A large size-selective DNA nanopore with sensing applications.

Transmembrane nanostructures like ion channels and transporters perform key biological functions by controlling flow of molecules across lipid bilayers. Much work has gone into engineering artificial nanopores and applications in selective gating of molecules, label-free detection/sensing of biomolecules and DNA sequencing have shown promise. Here, we use DNA origami to create a synthetic 9 nm wide DNA nanopore, controlled by programmable, lipidated flaps and equipped with a size-selective gating system for the translocation of macromolecules. Successful assembly and insertion of the nanopore into lipid bilayers are validated by transmission electron microscopy (TEM), while selective translocation of cargo and the pore mechanosensitivity are studied using optical methods, including single-molecule, total internal reflection fluorescence (TIRF) microscopy. Size-specific cargo translocation and oligonucleotide-triggered opening of the pore are demonstrated showing that the DNA nanopore can function as a real-time detection system for external signals, offering potential for a variety of highly parallelized sensing applications.

Single molecule analysis of structural fluctuations in DNA nanostructures.

DNA origami is an excellent tool for building complex artificial nanostructures. Functionalization of these structures provides the possibility of precise organization of matter at the nanoscale. In practice, efforts in this endeavour can be impeded by electrostatic repulsion or other dynamics at the molecular scale, resulting in uncompliant local structures. Using single molecule FRET microscopy combined with coarse-grained Brownian dynamics simulations, we investigated here the local structure around the lid of a DNA origami box, which can be opened by specific DNA keys. We found that FRET signals for the closed box depend on buffer ion concentrations and small changes to the DNA structure design. Simulations provided a view of the global and local structure and showed that the distance between the box wall and lid undergoes fluctuations. These results provide methods to vizualise and improve the local structure of three-dimensional DNA origami assemblies and offer guidance for exercising control over placement of chemical groups and ligands.

The association between smoking and knee osteoarthritis in a cohort of Danish patients undergoing knee arthroscopy.

BACKGROUND: It has been suggested that smoking is associated with reduced risk of knee osteoarthritis (OA). However, supplementary studies are needed to further investigate any such potential association. Thus, our aim was to examine the relationship between smoking and early or more established knee OA in a cohort of relatively young patients with meniscal tears. METHODS: This cross-sectional study included 620 participants from the Knee Arthroscopy Cohort Southern Denmark (KACS) undergoing knee arthroscopy for a meniscal tear (mean age 49.2 (18.0-76.8) years). Recruitment of patients was performed between February 1, 2013, and January 31, 2015, at four different hospitals in Denmark. We defined early or more established knee OA as the combination of patient-reported frequent knee pain, degenerative meniscal tissue and presence of cartilage defects assessed by the operating surgeons. The relationship between smoking status and knee OA was examined by risk ratio (RR) with a 95% confidence interval (CI), estimated from logistic regression adjusted for age, sex, BMI, education, work status and level of physical activity. RESULTS: The prevalence of early or more established knee OA was 37.7% in current smokers and 45.0% in non-smokers. We found no statistically significant association between current smoking and knee OA (adjusted RR 1.09, 95% CI 0.91-1.30). CONCLUSIONS: This study found no relationship between current smoking and early or more established knee OA in a cohort of patients undergoing arthroscopic meniscal surgery. Thus, the inverse association between smoking and knee OA that has been suggested by previous studies was not confirmed.

Tungsten Iodide Clusters as Singlet Oxygen Photosensitizers: Exploring the Domain of Resonant Energy Transfer at 1 eV.

The photophysics of selected tungsten iodide clusters was examined with respect to their role as a photosensitizer for the production of singlet oxygen, O2(a1Δg). We examined all-iodo octahedral clusters, [W6I8(I6)]2-, and ligand-substituted octahedral clusters, [W6I8(L6)]2-, in which the ligand, L, occupies the outer apical positions surrounding the cluster core. We also examined a square-pyramidal cluster, [W5I8(I5)]-, in which the tungsten core was presumably more accessible to diffusional encounter with ground state oxygen, O2(X3Σg-). For the compounds examined, we find pronounced cluster-dependent changes in the yield of photosensitized O2(a1Δg) production. In particular, although the iodine-encased octahedral cluster, [W6I8(I6)]2-, is an efficient O2(a1Δg) sensitizer, the pyramidal cluster, [W5I8(I5)]-, does not make O2(a1Δg) at all. The latter provides fundamental insight into the important case where the sensitizer triplet state is nearly degenerate with the O2(X3Σg-)-O2(a1Δg) transition energy at 1 eV. Our data indicate that even with near resonance, energy transfer to form O2(a1Δg) will not occur within the 3sensitizer-O2(X3Σg-) encounter pair if other more efficient channels for energy dissipation are available.

Stimulation history affects vasomotor responses in rat mesenteric arterioles.

Resistance vessels regulate blood flow by continuously adjusting activity of the wall smooth muscle cells. These cells integrate a variety of stimuli from blood, endothelium, autonomic nerves, and surrounding tissues. Each stimulus elicits an intracellular signaling cascade that eventually influences activation of the contractile machinery. The characteristic time scale of each cascade and the sharing of specific reactions between cascades provide for complex behavior when a vessel receives multiple stimuli. Here, we apply sequential stimulation with invariant concentrations of vasoconstrictor (norepinephrine/methoxamine) and vasodilator (SNAP/carbacol) to rat mesenteric vessels in the wire myograph to show that (1) time elapsed between addition of two vasoactive drugs and (2) the sequence of addition may significantly affect final force development. Furthermore, force oscillations (vasomotion) often appear upon norepinephrine administration. Using computational modeling in combination with nitric oxide (NO) inhibition/NO addition experiments, we show that (3) amplitude and number of oscillating vessels increase over time, (4) the ability of NO to induce vasomotion depends on whether it is applied before or after norepinephrine, and (5) emergence of vasomotion depends on the prior dynamical state of the system; in simulations, this phenomenon appears as "hysteresis." These findings underscore the time-dependent nature of vascular tone generation which must be considered when evaluating the vasomotor effects of multiple, simultaneous stimuli in vitro or in vivo.

Solvent and Heavy-Atom Effects on the O2(X3Σg-) → O2(b1Σg+) Absorption Transition.

The effect of 16 liquid solvents on both the spectrum and molar absorption coefficient of the X3Σg- → b1Σg+ transition in molecular oxygen has been examined. The ability to monitor this weak transition using air or oxygen saturated samples at atmospheric pressure was facilitated by the rapid and efficient O2(b1Σg+) → O2(a1Δg) transition, which allowed the use of O2(a1Δg) phosphorescence as a sensitive probe of O2(b1Σg+) production. The results of these O2(a1Δg) phosphorescence experiments are consistent with the results of independent experiments in which the O2(a1Δg) thus produced was "trapped" via a chemical reaction. The data recorded were used to calculate rate constants for the O2(b1Σg+) → O2(X3Σg-) radiative transition, a parameter that is otherwise difficult to directly obtain from such a wide range of solvents using O2(b1Σg+) → O2(X3Σg-) phosphorescence. The data show that the response of the O2(b1Σg+) → O2(X3Σg-) radiative transition to solvent is not the same as that of the O2(b1Σg+) → O2(a1Δg) and O2(a1Δg) → O2(X3Σg-) radiative transitions, both of which have been extensively examined over the years. However, our data are consistent with a theoretical model proposed by Minaev for the effect of solvent on radiative transitions in oxygen and, as such, arguably provide one of the final chapters in describing a system that has challenged the scientific community for years.

A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis.

Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to the World Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between them may be challenging and several studies have not been able to distinguish between them. Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH. Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of "ET" patients.

Intracellular Delivery of a Planar DNA Origami Structure by the Transferrin-Receptor Internalization Pathway.

DNA origami provides rapid access to easily functionalized, nanometer-sized structures making it an intriguing platform for the development of defined drug delivery and sensor systems. Low cellular uptake of DNA nanostructures is a major obstacle in the development of DNA-based delivery platforms. Herein, significant strong increase in cellular uptake in an established cancer cell line by modifying a planar DNA origami structure with the iron transport protein transferrin (Tf) is demonstrated. A variable number of Tf molecules are coupled to the origami structure using a DNA-directed, site-selective labeling technique to retain ligand functionality. A combination of confocal fluorescence microscopy and quantitative (qPCR) techniques shows up to 22-fold increased cytoplasmic uptake compared to unmodified structures and with an efficiency that correlates to the number of transferrin molecules on the origami surface.