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BackgroundASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.ObjectivesThe objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily).ResultsASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE.ConclusionsIn patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

BackgroundThe phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms.MethodsConsecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment-certified laboratory using comprehensive genomic profiling performed by next-generation sequencing (315 genes). The co-alterations evaluated included the Erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto-oncogene tyrosine kinase (MET), and mitogen-activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).ResultsAlterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P

Small molecules that target RNA Polymerase I inhibit ribosome biogenesis to activate p53 through the nucleolar surveillance response pathway. Here, the authors show that p53 induction by ribosome stress is dependent on extracellular glutamine availability.

Relevance Traumatic spinal cord injury is a complex, urgent and multidisciplinary problem with a high percentage of disability and subsequent social exclusion. Treatment of neuroorthopedic pathologies is often associated with the need to use technical means of rehabilitation. The objective was to develop a successful orthosis for a patient with severe spinal cord injury. Material and methods The article describes a clinical case of a 16-year-old female patient with the outcome of a severe concomitant injury: lower paraplegia, sensory disturbances in the lower extremities and pelvic organ function. MRI of the spinal cord revealed cystic-glial changes and atrophy of the spinal cord at the Th10-12 level. Results and discussion With clinical signs of paraplegia and a complete spinal cord injury according to the instrumentation findings, the patient had poor prognosis for the recovery of motor functions in the lower limbs. One of the main tasks of medical rehabilitation of patients with spinal cord injury is the activation of movements and restoration of locomotion. The Hip-Knee-Ankle-Foot Orthosis (HKAFO) manufactured at the Center was intended for unloading, replacement and fixation. The device was light and strong due to greater use of carbon layers, equipped with functional hinges to prevent development of contractures, had a high corset for external stabilization of the body and double knee splint for safe standing. Conclusion For the paraplegic patient, the opportunity to stand and walk with the support using successful orthosis was important from both physical and psychosocial perspectives and allowed correction of contractures in the catamnesis.

Immunotherapies are becoming increasingly important in the treatment armamentarium of a variety of malignancies. Immune checkpoint inhibitors are the most representative drugs receiving regulatory approval over the past few years. In a recent study published in Clinical Cancer Research, we demonstrated that these agents are being developed faster than other prior anticancer therapies. All checkpoint inhibitors received priority review, being granted with at least one Food and Drug Administration expedited program. Hence, some of them are getting marketing approval after preliminary trials. The model continues to rely on phase I trials, designed with traditional models for dose definition, although a substantial number of patients are treated during the dose expansion cohorts. We demonstrated that efficacy and safety are reasonably predicted from the dose-finding portion of phase I trials with these agents, assuring a low treatment-related mortality for patients throughout the development process. In this article, we further discuss and summarize these findings and update some recent approval information for immune checkpoint inhibitors.

The results of observations of selected stars orbiting the central body of our Galaxy, which, according to the latest data, has a mass of about 4 million of solar mass, are considered. Using the methods of observation and processing of binary stars used at the Pulkovo Observatory and the published exact relative positions of the star-central body obtained with the Keck and VLT telescopes, we checked the possibility of determining the preliminary orbits of the above objects in some cases from observations covering sufficient short arc in relation to the turnover period. Examples are the stars S02 and S102 with published positions and the graphical data for S27 and S4711. We attempted to calculate the assumed relativistic effects in accordance with the orbital elements obtained by Pulkovo methods. In this case, the estimates of the O–C errors for these orbits turned out to be comparable with the O–C errors for the orbits published by the Keck and VLT observers, in some cases about several milliarcseconds. The theoretical relativistic parameters also turned out to be of the same order of value with the results of these authors.

In southern and southeastern Brazil, the TP53 founder variant c.1010G>A (R337H) has been previously documented with a prevalence of 0.3% within the general population and linked to a heightened incidence of lung adenocarcinomas (LUADs). In the present investigation, we cover clinical and molecular characterizations of lung cancer patients from the Brazilian Li-Fraumeni Syndrome Study (BLISS) database. Among the 175 diagnosed malignant neoplasms, 28 (16%) were classified as LUADs, predominantly occurring in females (68%), aged above 50 years, and never-smokers (78.6%). Significantly, LUADs manifested as the initial clinical presentation of Li-Fraumeni Syndrome in 78.6% of cases. Molecular profiling was available for 20 patients, with 14 (70%) revealing EGFR family alterations. In total, 23 alterations in cancer driver genes were identified, comprising 7 actionable mutations and 4 linked to resistance against systemic treatments. In conclusion, the carriers of TP53 R337H demonstrate a predisposition to LUAD development. Furthermore, our results indicate that environmental pollution potentially impacts the carcinogenesis of lung tumors in the carriers of TP53 R337H.

The ocean is filled with mesoscale eddies that account for most of the oceanic kinetic energy. The importance of eddies in transporting properties and energy across the ocean basins has led to numerous efforts to track their motion. Here, we implement a computer vision technique—the optical flow—to map the pathways of mesoscale eddies in the South Atlantic Ocean. The optical flow is applied to the pairs of consecutive sea surface height maps produced from a nearly 30-year-long satellite altimetry record. In contrast to other methods to estimate the eddy propagation velocity, the optical flow can reveal the temporal evolution of eddy motion, which is particularly useful in the regions of strong currents. We present the time-dependent estimates of the speed and direction of eddy propagation in the Eulerian frame of reference. In an excellent agreement with earlier studies, the obtained pattern of eddy propagation reveals the interaction of eddies with the background flow and the bottom topography. We show that in the Antarctic Circumpolar Current, the variability of the eddy propagation velocity is correlated with the variability of the surface geostrophic velocity, demonstrating the robustness of the optical flow to detect the time-variable part of eddy motion.

BackgroundWe analyzed clinical associations of MET alterations in the plasma of patients with diverse malignancies.MethodsDigital sequencing of circulating tumor DNA (ctDNA) (54-70 genes) was performed in 438 patients; 263 patients also had tissue sequencing (182-315 genes). The most represented tumor types were gastrointestinal (28.1%), brain (24.9%), and lung (23.2%). Most patients (71.2%) had recurrent/metastatic disease.ResultsMET alterations were observed in 31 patients (7.1%) and correlated with bone metastasis (P = 0.007), with TP53 (P = 0.001) and PTEN (P = 0.003) abnormalities, and with an increased number of alterations (median, 4 vs 1, P = 0.001) (all multivariable analyses). Patients with MET alterations demonstrated a significantly shorter median time to metastasis/recurrence (1.0 vs 10.4 months, P = 0.044, multivariable) and a poorer survival (30.6 vs 58.4 months, P = 0.013, univariate only). Of the 31 patients with MET alterations, 18 also had tissue testing; only two also had tissue MET alterations (11.1%); MET alterations were detected at a lower frequency in tissue (1.14%) compared to ctDNA (7.1%), with P = 0.0002.ConclusionsIn conclusion, the detection of MET alterations by liquid biopsy is feasible. MET ctDNA alterations were associated with a poorer prognosis, higher numbers of genomic abnormalities, and bone metastases. The correlation with bone metastases may explain the higher frequency of MET alterations in blood ctDNA than in tissue (since bones are rarely biopsied) and the previous observations of bone-predominant responses to MET inhibitors. The high number of co-altered genes suggests that MET inhibitors may need to be combined with other agents to induce/optimize responses.

Abstract Transcriptional and cellular-stress surveillance deficits are hallmarks of Huntington’s disease (HD), a fatal autosomal-dominant neurodegenerative disorder caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD are still unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo remains elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its prominent nucleolar localization. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases the distribution of mHTT in a disperse state in the nucleus, exacerbating motor deficits. We confirmed NPM1 delocalization in the gradually progressing zQ175 knock-in HD mouse model: in the striatum at a presymptomatic stage and in the skeletal muscle at an early symptomatic stage. In Huntington’s patient skeletal muscle biopsies, we found a selective redistribution of NPM1, similar to that in the zQ175 model. Taken together, our study demonstrates that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identifies NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

PURPOSECOVID-19 has affected cancer care worldwide. Clinical trials are an important alternative for the treatment of oncologic patients, especially in Latin America, where trials can be the only opportunity for some of them to access novel and, sometimes, standard treatments.METHODSThis was a cross-sectional study, in which a 22-question survey regarding the impact of the COVID-19 pandemic on oncology clinical trials was sent to 350 representatives of research programs in selected Latin American institutions, members of the Latin American Cooperative Oncology Group.RESULTSThere were 90 research centers participating in the survey, with 70 of them from Brazil. The majority were partly private or fully private (n = 77; 85.6%) and had confirmed COVID-19 cases at the institution (n = 57; 63.3%). Accruals were suspended at least for some studies in 80% (n = 72) of the responses, mostly because of sponsors' decision. Clinical trials' routine was affected by medical visits cancelation, reduction of patients' attendance, reduction of other specialties' availability, and/or alterations on follow-up processes. Formal COVID-19 mitigation policies were adopted in 96.7% of the centers, including remote monitoring and remote site initiation visits, telemedicine visits, reduction of research team workdays or home office, special consent procedures, shipment of oral drugs directly to patients' home, and increase in outpatient diagnostic studies. Importantly, some of these changes were suggested to be part of future oncology clinical trials' routine, particularly the ones regarding remote methods, such as telemedicine.CONCLUSIONTo our knowledge, this was the first survey to evaluate the impact of COVID-19 on Latin American oncology clinical trials. The results are consistent with surveys from other world regions. These findings may endorse improvements in clinical trials' processes and management in the postpandemic period.

In yeast, TFIP11 and DHX15 promote the disassembly of spliceosome complex after splicing is completed. Here the authors show that human TFIP11 functions independently of DHX15 and is required for U6 snRNA 2’-O-methylation and U4/U6.U5 tri-snRNP assembly.

The herbarium of the South-Siberian Botanical Garden of Altai State University (ALTB) is the largest collection of plants from transboundary territory of the Altai Mountain Country (AMC) including Russia, Kazakhstan, Mongolia and China. The herbarium contains more than 450,000 specimens (ranks seventh in the country in terms of herbarium specimen’s number and fourth among universities collections). Altai State University(ASU) being one of the most important center of academic education and research, and socio-cultural complex in Siberia and the Far East serves to provide a distinguished learning environment for undergraduate and graduate students in many scholarly and professional fields meeting the needs of modern knowledge-based post-industrial society, and contributing to the development of the region. It actively promotes international cooperation and strategic collaboration with neighboring countries of Asia (Kazakhstan, China, Mongolia, etc.) in the field of science, education, and culture. In particular, the goals of the South-Siberian Botanical Garden include: preparation and publication of a multi-volume work "Flora Altaica", research of flora and vegetation of the AMC, monographic study of individual plant groups,conducting laboratory classes,summer practices, special courses, development of measures to protect rare and endangered plant species.Virtual Herbarium ALTB (altb.asu.ru, GBIF) is the largest digital collection of plants from transboundary territory of the Altai Mountain Country and the main empirical material of the project "Flora Altaica" (http://altaiflora.asu.ru/en/). The dataset contains 22,466 digital specimens of vascular plants (67% of them has exact location, accessed on 30.03.2021). The most part of herbarium material was collected in the period from 1977 to nowadays (the most intensive was from 1995 to 2008). In 2019, the table of accumulated label data of Herbarium ALTB was adapted to the Darwin Core specification (http://altb.asu.ru/). The problem of storage and exchange of data on phytodiversity of Altai Krai and adjacent territory in multilingual environment of the AMC was technically solved with the help of this universal specification.

Similar to electron waves, the phonon states in semiconductors can undergo changes induced by external boundaries. However, despite strong scientific and practical importance, conclusive experimental evidence of confined acoustic phonon polarization branches in individual free-standing nanostructures is lacking. Here we report results of Brillouin-Mandelstam light scattering spectroscopy, which reveal multiple (up to ten) confined acoustic phonon polarization branches in GaAs nanowires with a diameter as large as 128 nm, at a length scale that exceeds the grey phonon mean-free path in this material by almost an order-of-magnitude. The dispersion modification and energy scaling with diameter in individual nanowires are in excellent agreement with theory. The phonon confinement effects result in a decrease in the phonon group velocity along the nanowire axis and changes in the phonon density of states. The obtained results can lead to more efficient nanoscale control of acoustic phonons, with benefits for nanoelectronic, thermoelectric and spintronic devices.

Measurement(s) DNA sequencing • temperature of water • concentration of phosphate in water • concentration of nitrogen atom in water Technology Type(s) Illumina sequencing • watercraft • continuous flow autoanalyzer Sample Characteristic - Organism marine metagenome Sample Characteristic - Environment ocean Sample Characteristic - Location global Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.13971122

Accessibility to next-generation sequencing (NGS) technologies has enabled the profiling of microbial communities living in distinct habitats. 16S ribosomal RNA (rRNA) gene sequencing is widely used for microbiota profiling with NGS technologies. Since most used NGS platforms generate short reads, sequencing the full-length 16S rRNA gene is impractical. Therefore, choosing which 16S rRNA hypervariable region to sequence is critical in microbiota profiling studies. All nine 16S rRNA hypervariable regions are taxonomically informative, but due to variability in profiling performance for specific clades, choosing the ideal 16S rRNA hypervariable region will depend on the bacterial composition of the habitat under study. Recently, NGS allowed the identification of microbes in the urinary tract, and urinary microbiota has become an active research area. However, there is no current study evaluating the performance of different 16S rRNA hypervariable regions for male urinary microbiota profiling. We collected urine samples from male volunteers and profiled their urinary microbiota by sequencing a panel of six amplicons encompassing all nine 16S rRNA hypervariable regions. Systematic comparisons of their performance indicate V1V2 hypervariable regions better assess the taxa commonly present in male urine samples, suggesting V1V2 amplicon sequencing is more suitable for male urinary microbiota profiling. We believe our results will be helpful to guide this crucial methodological choice in future male urinary microbiota studies.