Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis

Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis

DNA unzipped under a constant force exhibits multiple metastable intermediates

Single molecule studies, at constant force, of the separation of double-stranded DNA into two separated single strands may provide information relevant to the dynamics of DNA replication. At constant applied force, theory predicts that the unzipped length as a function of time is characterized by jumps during which the strands separate rapidly, followed by long pauses where the number of separated base pairs remains constant. Here, we report previously uncharacterized observations of this striking behavior carried out on a number of identical single molecules simultaneously. When several single lphage molecules are subject to the same applied force, the pause positions are reproducible in each. This reproducibility shows that the positions and durations of the pauses in unzipping provide a sequence-dependent molecular fingerprint. For small forces, the DNA remains in a partially unzipped state for at least several hours. For larger forces, the separation is still characterized by jumps and pauses, but the double-stranded DNA will completely unzip in less than 30 min

A quadrature filter approach for registration accuracy assessment of fundus images

This paper presents a method to automatically assess the accuracy of image registration. It is applicable to images in which vessels are the main landmarks such as fundus images and angiography. The method simultaneously exploits not only the position, but also the intensity profile across the vasculatures. The accuracy measure is defined as the energy of the odd component of the 1D vessel profile in the difference image divided by the total energy of the corresponding vessels in the constituting images. Scale and orientation-selective quadrature filter banks have been employed to analyze the 1D signal profiles. Subsequently, the relative energy measure has been calibrated such that the measure translates to a spatial misalignment in pixels. The method was validated on a fundus image dataset from a diabetic retinopathy screening program at the Rotterdam Eye Hospital. An evaluation showed that the proposed measure assesses the registration accuracy with a bias of -0.1 pixels and a precision (standard deviation) of 0.9 pixels. The small Fourier footprint of the orientation selective quadrature filters makes the method robust against noise

The anisotropy of granular materials

The effect of the anisotropy on the elastoplastic response of two dimensional packed samples of polygons is investigated here, using molecular dynamics simulation. We show a correlation between fabric coefficients, characterizing the anisotropy of the granular skeleton, and the anisotropy of the elastic response. We also study the anisotropy induced by shearing on the subnetwork of the sliding contacts. This anisotropy provides an explanation to some features of the plastic deformation of granular media.Comment: Submitted to PR

Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) versus Virtual Reality Relaxation (VRelax) for People With a Psychotic Disorder:A Single-Blind Multicenter Randomized Controlled Trial

BACKGROUND AND HYPOTHESIS: Social cognition training (SCT), an intervention for social cognition and social functioning, might be improved by using virtual reality (VR), because VR may offer better opportunities to practice in a potentially more realistic environment. To date, no controlled studies have investigated VR-SCT. This study investigated a VR-SCT, "DiSCoVR". We hypothesized that DiSCoVR would improve social cognition and social functioning. STUDY DESIGN: Participants were randomized to DiSCoVR (n = 41) or VR relaxation ('VRelax', n = 40), an active control condition, and completed 16 twice-weekly sessions. Three assessments (baseline, posttreatment, and 3-month follow-up) were performed by blinded assessors. The primary outcome was social cognition (emotion perception and theory of mind). Secondary outcomes included social functioning (measured with an interview and experience sampling), psychiatric symptoms, information processing, and self-esteem. Data were analyzed using mixed-models regression analysis. Treatment effects were evaluated by the time by condition interaction terms. STUDY RESULTS: No significant time by condition interactions were found for any of the outcome variables, indicating an absence of treatment effects. Between-group effect sizes ranged from negligible to moderate (Cohen's d < |0.53|). Main effects of time were found for several outcomes. CONCLUSIONS: These results suggest that DiSCoVR was not effective, possibly because of inadequate simulation of emotional expressions in VR. This lack of efficacy may indicate that current SCT protocols are relatively unsuitable for improving social functioning. Previous studies showed small to moderate effects on higher order social cognition, but the SCT approach may need critical reevaluation, as it may not sufficiently lead to functional improvement

El Mañana: Año II Número 9 - (09/01/29)

There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). Radiotherapy (RT) and methotrexate (MTX) are the current treatment options, but their efficacy is unknown. Recently, targeted therapies showed promising results in C-ALCL, and may therefore be an attractive first choice of treatment. To assess the efficacy of conventional treatment strategies for patients with multifocal C-ALCL, and to define which patients may require novel targeted therapies. In this multicenter study, treatment was evaluated in patients initially presenting (n=24) or relapsing with multifocal C-ALCL (n=17; 23 relapses). Distinction was made between cases with ≤ 5 (n=36) and >5 lesions (n=11). Treatments most commonly used were radiotherapy (n=21), systemic chemotherapy (n=9) and low-dose methotrexate (MTX; n=7) with complete response rates of 100%, 78% and 43%, respectively, and an overall response rate of 100%, 100%, and 57%, respectively. Four patients showed a complete spontaneous regression. Sixteen of 24 patients (67%) first presenting with multifocal C-ALCL relapsed, including all five patients initially treated with CHOP. Compared with patients presenting with 2-5 skin lesions, patients presenting with >5 lesions had a higher chance of developing extracutaneous relapse (56 vs 20%) and more often died of lymphoma (44% vs 7%). Patients with ≤5 lesions should be treated with low-dose RT (2x4 Gy). Maintenance low-dose MTX (20 mg/week) is a suitable option in patients with >5 lesions. Targeted therapies may be considered in rare patients refractory to MTX or patients developing extracutaneous disease. This article is protected by copyright. All rights reserve

A retrospective analysis of noise-induced hearing loss in the Dutch construction industry

Purpose Noise exposure is an important and highly prevalent occupational hazard in the construction industry. This study examines hearing threshold levels of a large population of Dutch construction workers and compares their hearing thresholds to those predicted by ISO-1999. Methods In this retrospective study, medical records of periodic occupational health examinations of 29,644 construction workers are analysed. Pure-tone audiometric thresholds of noise-exposed workers are compared to a non-exposed control group and to ISO-1999 predictions. Regression analyses are conducted to explore the relationship between hearing loss and noise intensity, noise exposure time and the use of hearing protection. Results Noise-exposed workers had greater hearing losses compared to their non-noise-exposed colleagues and to the reference population reported in ISO-1999. Noise exposure explained only a small proportion of hearing loss. When the daily noise exposure level rose from 80 dB(A) towards 96 dB(A), only a minor increase in hearing loss is shown. The relation of exposure time and hearing loss found was similar to ISO-1999 predictions when looking at durations of 10 years or more. For the first decade, the population medians show poorer hearing than predicted by ISO-1999. Discussion Duration of noise exposure was a better predictor than noise exposure levels, probably because of the limitations in noise exposure estimations. In this population, noise-induced hearing loss was already present at the beginning of employment and increased at the same rate as is predicted for longer exposure duration

Clinical, Histologic, and Molecular Characteristics of Anaplastic Lymphoma Kinase-positive Primary Cutaneous Anaplastic Large Cell Lymphoma

Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemical ALK expression. Clinical and histopathologic characteristics, immunophenotype and disease course were evaluated. Underlying ALK translocations were analyzed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Median age at diagnosis was 39 years (range: 16 to 53 y). All patients presented with a solitary lesion. Treatment with radiotherapy (n=5) or anthracycline-based chemotherapy (n=1) resulted in complete responses in all 6 patients. Three patients developed a relapse, of whom 2 extracutaneous. After a median follow-up of 41 months, 5 patients were alive without disease and 1 patient died of lymphoma. Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment

Frequency and prognosis of associated malignancies in 504 patients with lymphomatoid papulosis

Contains fulltext : 218179.pdf (Publisher’s version ) (Open Access)BACKGROUND: Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. OBJECTIVE: To evaluate the frequency and prognostic significance of associated HM and non-HM in LyP patients. METHODS: In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. RESULTS: After a median follow-up of 120 months (range, 6-585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large-cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B-cell (n = 14) or myeloid origin (n = 5). Even after a 25-year follow-up period, percentages of associated HM did not exceed 20%. Thirty-nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow-up, after a median of 68 months (range of 3-286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin-limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4-3.3) for non-HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. CONCLUSIONS: An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring