julilili42/papers huggingface dataset:
Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426.
2020-05-20

5001 Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here. Methods: Treatment-naive patients (pts) with clear cell aRCC, KPS ≥70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world). Primary end points were OS and PFS. Secondary end points were ORR, DOR, and safety. All P values are nominal. A post-hoc exploratory analysis was done to evaluate association of depth of response (maximum reduction from baseline in sum of diameters of target lesions) and OS using landmark analysis up to 6 mo after randomization. Results: 861 pts were randomly assigned (pembro + axi, n = 432; sunitinib, n = 429). Median (range) duration of follow-up for all pts was 27.0 mo (0.1-38.4). Pembro + axi improved OS (HR, 0.68 [95% CI, 0.55-0.85]; P &lt; 0.001; 24-mo OS rate, 74% vs 66%) vs sunitinib. Median (95% CI) OS was not reached with pembro + axi and was 35.7 mo (33.3-NR) with sunitinib. Pembro + axi improved PFS (HR, 0.71 [95% CI, 0.60-0.84]; P &lt; 0.001; 24-mo PFS rate, 38% vs 27%) vs sunitinib. For pembro +axi vs sunitinib respectively, median (95% CI) PFS was 15.4 (12.7-18.9) vs 11.1 mo (9.1-12.5); ORR was 60% vs 40% ( P &lt; 0.0001); CR rate was 9% vs 3%; and median DOR was 23.5 mo (range 1.4+ to 34.5+) vs 15.9 mo (range 2.3-31.8+). In general, the pembro + axi benefit was observed in all subgroups tested, including IMDC risk and PD-L1 expression subgroups. Post-hoc landmark analysis at 6-mo showed that pts on pembro + axi with ≥80% target lesion reduction had OS similar to that of pts with CR per RECIST v1.1 based on Kaplan-Meier curves and HR [95% CI] estimates (0.20 [0.05-0.84] vs. 0.10 [0.01-0.76], respectively) vs pts with 0-30% target lesion reduction. No new safety signals were observed. Conclusions: Pembro + axi continued to demonstrate superior and durable antitumor activity vs sunitinib in pts with first-line aRCC with a 27-mo median follow up; no new safety signals were observed. Clinical trial information: NCT02853331 .
Desynchronization of temporal lobe theta-band activity during effective anterior thalamus deep brain stimulation in epilepsy
2020-05-20

This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation.
Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600-mutant melanoma.
2020-05-20

10012 Background: Treatment of patients with BRAF V600–mutant melanoma includes BRAF/MEK-inhibitor combinations based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). To better understand the proportion of patients who derive long-lived benefit and their characteristics, we performed an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), and safety was conducted after an additional 24 months’ follow-up from the initial analysis. The study is ongoing. Results: At data cutoff (November 2019, as-is data), events had occurred in 65%, 59%, and 75% of patients in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 60.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 38% (HR, 0.62 [95% CI, 0.49–0.79]). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67]). A landmark analysis showed a higher rate of OS for COMBO450 at each year analyzed, with OS rates at 4 years of 39%, 37%, and 26% COMBO450, ENCO300, and VEM, respectively. Updated safety analysis confirmed the beneficial long-term tolerability of COMBO450. Conclusions: In the COLUMBUS trial, results for updated PFS and OS with COMBO450 continue to demonstrate long-term benefits in patients with BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.
Guilt-by-Association – Functional Insights Gained From Studying the LRRK2 Interactome
2020-05-20

The Parkinson's disease-associated Leucine-rich repeat kinase 2 (LRRK2) is a complex multi-domain protein belonging to the Roco protein family, a unique group of G-proteins. Variants of this gene are associated with an increased risk of Parkinson's disease. Besides its well-characterized enzymatic activities, conferred by its GTPase and kinase domains, and a central dimerization domain, it contains four predicted repeat domains, which are, based on their structure, commonly involved in protein-protein interactions (PPIs). In the past decades, tremendous progress has been made in determining comprehensive interactome maps for the human proteome. Knowledge of PPIs has been instrumental in assigning functions to proteins involved in human disease and helped to understand the connectivity between different disease pathways and also significantly contributed to the functional understanding of LRRK2. In addition to an increased kinase activity observed for proteins containing PD-associated variants, various studies helped to establish LRRK2 as a large scaffold protein in the interface between cytoskeletal dynamics and the vesicular transport. This review first discusses a number of specific LRRK2-associated PPIs for which a functional consequence can at least be speculated upon, and then considers the representation of LRRK2 protein interactions in public repositories, providing an outlook on open research questions and challenges in this field.
Remaining Cervical Spine Movement Under Different Immobilization Techniques
2020-05-20

Abstract Background: Immobilization of the cervical spine by Emergency Medical Services (EMS) personnel is a standard procedure. In most EMS, multiple immobilization tools are available. The aim of this study is the analysis of residual spine motion under different types of cervical spine immobilization. Methods: In this explorative biomechanical study, different immobilization techniques were performed on three healthy subjects. The test subjects’ heads were then passively moved to cause standardized spinal motion. The primary endpoints were the remaining range of motion for flexion, extension, bending, and rotation measured with a wireless human motion detector. Results: In the case of immobilization of the test person (TP) on a straight (0°) vacuum mattress, the remaining rotation of the cervical spine could be reduced from 7° to 3° by additional headblocks. Also, the remaining flexion and extension were reduced from 14° to 3° and from 15° to 6°, respectively. The subjects’ immobilization was best on a spine board using a headlock system and the Spider Strap belt system (MIH-Medical; Georgsmarienhütte, Germany). However, the remaining cervical spine extension increased from 1° to 9° if a Speedclip belt system was used (Laerdal; Stavanger, Norway). The additional use of a cervical collar was not advantageous in reducing cervical spine movement with a spine board or vacuum mattress. Conclusions: The remaining movement of the cervical spine is minimal when the patient is immobilized on a spine board with a headlock system and a Spider Strap harness system or on a vacuum mattress with additional headblocks. The remaining movement of the cervical spine could not be reduced by the additional use of a cervical collar.
When Can Elimination of SARS-CoV-2 Infection be Assumed? Simulation Modelling in a Case Study Island Nation
2020-05-20

Aims: We aimed to determine the length of time from the last detected case of SARS-CoV-2 infection before elimination can be assumed at a country level in an island nation. Methods: A stochastic version of the SEIR model CovidSIM v1.1 designed specifically for COVID-19 was utilised. It was populated with data for the case study island nation of New Zealand (NZ) along with relevant parameters sourced from the NZ and international literature. This included a testing level for symptomatic cases of 7,800 tests per million people per week. Results: It was estimated to take between 27 and 33 days of no new detected cases for there to be a 95% probability of epidemic extinction. This was for effective reproduction numbers (Re) in the range of 0.50 to 1.0, which encompass such controls as case isolation (the shorter durations relate to low Re values). For a 99% probability of epidemic extinction, the equivalent time period was 37 to 44 days. In scenarios with lower levels of symptomatic cases seeking medical attention and lower levels of testing, the time period was up to 53 to 91 days (95% level). Conclusions: In the context of a high level of testing, a period of around one month of no new notified cases of COVID-19 would give 95% certainty that elimination of SARS-CoV-2 transmission had been achieved.
Point-of-care testing of coagulation in patients treated with edoxaban
2020-05-20

Abstract Edoxaban, alongside other direct oral anticoagulants (DOAC), is increasingly used for prevention of thromboembolism, including stroke. Despite DOAC therapy, however, annual stroke rate in patients with atrial fibrillation remains 1–2%. Rapid exclusion of relevant anticoagulation is necessary to guide thrombolysis or reversal therapy but, so far, no data exists on the effect of edoxaban on available point-of-care test systems (POCT). To complete our previous investigation on global coagulation-POCT for the detection of DOAC, we evaluated whether CoaguChek®-INR (CC-INR) is capable of safely ruling out edoxaban concentrations above the current treatment thresholds of 30/50 ng/mL in a blood sample. We studied patients receiving a first dose of edoxaban; excluding subjects receiving other anticoagulants. Six blood samples were collected from each patient: before drug intake, 0.5, 1, 2 and 8 h after intake, and at trough (24 h). CC-INR and mass spectrometry for edoxaban concentrations were performed for each time-point. One hundred and twenty blood samples from 20 patients contained 0–302 ng/mL of edoxaban. CC-INR ranged from 0.9 to 2.3. Pearson’s correlation coefficient showed strong correlation between CC-INR and edoxaban concentrations (r = 0.73, p &lt; 0.001). Edoxaban concentrations &gt; 30 and &gt; 50 ng/mL were ruled out by CC-INR ≤ 1.0 and ≤ 1.1, respectively, with high specificity (&gt; 95%), and a sensitivity of 44% (95%-confidence interval: 30–59%) and 86% (74–93%), respectively. Our study represents the first evaluation of coagulation-POCT in edoxaban-treated patients. CC-POCT is suitable to safely exclude clinically relevant edoxaban concentrations prior to thrombolysis, or guide reversal therapy in stroke patients.
Hepatitis E Virus Seroprevalence and Associated Risk Factors in Apparently Healthy Individuals from Osun State, Nigeria
2020-05-20

Hepatitis E virus (HEV) infection is a major public health concern in low-income countries, yet incidence and prevalence estimates are often lacking. Serum (n = 653) and faecal (n = 150) samples were collected from apparently healthy individuals using convenience sampling technique in six communities (Ore, Oke-Osun, Osogbo, Ede, Esa-Odo, and Iperindo) from Osun State, Nigeria. Serum samples were analysed for total anti-HEV IgG/IgM and anti-HEV IgM using commercially available HEV ELISA kits. Total anti-HEV positive serum and all stool samples were analysed for HEV RNA by RT-PCR. Overall, 15.0% (n = 98/653) and 3.8% (n = 25/653) of the serum samples were positive for anti-HEV total and IgM antibodies, respectively. Total anti-HEV and IgM in Ore, Oke-Osun, Osogbo, Ede, Esa-Odo, and Iperindo was 21.0% (n = 13/62) and 3.2% (n = 2/62), 19.4% (n = 20/103) and 6.8% (n = 7/103), 11.4% (n = 12/105) and 2.9% (n = 3/105), 8.0% (n = 16/199) and 1.5% (n = 3/199), 22.0% (n = 22/100) and 10.0% (n = 10/100), and 17.9% (n = 15/84) and 0.0% (n = 0/84), respectively. All samples (stool and serum) were HEV RNA negative. Anti-HEV seroprevalence was associated with rural location, increasing age, alcohol consumption, and rearing of animals. This study demonstrated a high anti-HEV seroprevalence in Osun State, indicating the need to implement surveillance and asses the hepatitis E burden in Nigeria.
Autoantibodies as predictors for survival and immune-related adverse events in checkpoint inhibition therapy of metastasized melanoma.
2020-05-20

10011 Background: Increasing evidence suggests that the B cell response in cancer patients is an important component of anti-tumour immunity. Autoantibodies targeting tumour and self-antigens may serve as biomarkers of anti-tumour and auto-immunity. As they can be measured in patient' sera, they have great potential as clinical routine biomarkers. The objective of this study was to explore if autoantibodies are associated with survival and immune related adverse events (irAE) in patients with metastatic melanoma under checkpoint inhitibor (CPI) therapy. Methods: Pre-treatment serum samples from 333 metastatic melanoma patients receiving CPI therapy at 5 European centers were retrospectively used to identify autoantibody signatures for survival and irAE. We designed a cancer immunotherapy antigen array comprising 832 autoimmune and tumour antigens as well as immune and cancer pathway proteins. Statistical tests were separately performed for patients treated with anti-CTLA4 (alone or in combination) and with anti-PD1 antibody monotherapy. Cox-regression analysis and univariate statistical tests were applied for biomarker discovery. Progression free and overall survival was measured from treatment initiation to tumor progression or death date. irAE were recorded including onset date and grade (CTC-AE). Results: For each therapy group we identified a set of autoantibody reactivities in untreated melanoma patients that were associated with the development of irAEs and/or survival. The identified autoantibodies target a diverse set of antigens comprising neoantigens (p53), cancer testis antigens (MAGEB4), paraneoplastic antigens (gephyrin), autoantigens (ribosomal proteins, Nor-90) and FGFR1. Autoantigens that correlated with irAE and survival were e.g. anti-MAGEB4 and anti-FGFR1. Elevated anti-MAGEB4 pre-treatment levels were associated with longer overall survival (p = 0.002, HR = 0.77) and the development of irAEs (p = 0.002, HR = 1.27) in ipilimumab +/- nivolumab treated patients. Higher pre-treatment anti-FGFR1 antibodies were associated with shorter survival (p = 0.008, HR = 1.27) and a lower a lower frequency of irAEs (p = 0.04, HR = 0.69) in these patients. Conclusions: We identified autoantibody targets suggesting a diverse B cell response to antigens expressed in tumours and those associated with autoimmunity. Depending on the specific antigen, the immune response towards those antigens may be associated with anti-tumour or pro-tumour responses.
Use-wear analysis of bone and antler tools from Farneto (Bologna, Italy) and Sa Osa (Oristano, Italy) archaeological sites
2020-05-20

The aim of this study is the reconstruction of past use and function of bone and antler tools, referring to two archaeological sites of Copper Age occupation: Farneto rockshelter (Bologna, Italy) and Sa Osa site (Oristano, Italy). The collections respectively result from a museum old collection, and a preventive excavation rescue. Besides, a de-contextualisation and the nearly total lack of manufacturing waste are recorded: the collections are mainly composed by finished tools, with pointed tools and bevelled tools as recurring typologies. The applied methodology take instance from the bone industry studies and functional analyses, which allow identifying the modalities of exploitation of osseous materials during Prehistory for utilitarian purposes. Observations under stereomicroscope and metallographic microscope highlight the presence of anthropic marks formed on tools surface during their use in past recurring activities. An experimental activity is also performed, in order to create a reliable reference collection to compare with the macro and micro traces recorded on the archaeological tools. The resulting data and the integration of different approaches in an interdisciplinary research, allowed reconstructing the past use for the most recurrent tools typologies identified at Farneto rockshelter and Sa Osa sites' collections.
A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).
2020-05-20

TPS5103 Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky &gt; 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non-papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423 .
Major histocompatibility complex class 1 (MHC1) loss among patients with glioblastoma (GBM).
2020-05-20

e14523 Background: Immune evasion represents a hallmark behavior of cancer and may occur through many mechanisms. Among these, intact tumor antigen presentation at the cell surface is a fundamental prerequisite to achieving successful adaptive immunotherapy. The loss of MHC1 expression due to molecular events, including mutation, deletion, or epigenetic silencing of B2M is commonly acquired during immunotherapy. On the other hand, molecular events affecting antigen presentation machinery may be present prior to immunotherapy administration. Among these, TP53 mutations causing loss of ERAP1 and TAP1 expression compromise transport of MHC1 molecules from the endoplasmic reticulum to the cell surface and mutant peptide integration into the HLA context resulting in absent antigen presentation. Thus far, clinical trials of PD-1/L1 agents have failed to demonstrate a benefit for GBM patients and responses are seen only among a minority. Hence, we set out to assess the integrity of MHC1 expression by using immunohistochemistry. Methods: Immunohistochemical (IHC) stains for HLA, B and C were developed and validated with internal controls. Staining intensity and location (membrane-bound or cytoplasmic) was evaluated semi-quantitatively. The first 10 consecutive patients with GBM who were referred for neoepitope vaccine were evaluated. Results: Absent staining was seen among 6/10, negligible, or faint staining was present in 2, and only 2 tumors demonstrated intact membrane-bound expression. Conclusions: In addition to low tumor mutation burden and an immunosuppressive tumor microenvironment, MHC1 loss is a frequent event among patients with GBM, and may be a dominant cause of immunotherapy failure for as many as 80% of patients. Thus, development of strategies to reverse this loss may be an essential component of successful adaptive immunotherapy for this disease. These data suggest that routine assessment of MHC1 should become a component of eligibility checking for GBM patients being considered for an MHC-restricted approaches. [Table: see text]
Total Synthesis of the Plant Growth Promoter Auxofuran Featuring a Gold(I) Catalyzed Furan Formation
2020-05-20

A concise synthesis of auxofuran (<b>1</b>) was developed. Starting with a Sonogashira cross-coupling reaction, enynol (<b>10</b>) was prepared. A gold(I) catalyzed cycloisomerization led to disubstituted furan <b>12</b>. Via an intramolecular Friedel-Crafts cyclization, a dihydrobenzofuranone was obtained. Functional group manipulations, including benzylic oxidation, led to the target molecule.
Draft Genome Sequence of Lipopeptide-Producing Strain Pseudomonas fluorescens DSM 11579 and Comparative Genomics with Pseudomonas sp. Strain SH-C52, a Closely Related Lipopeptide-Producing Strain
2020-05-20

Pseudomonas fluorescens DSM 11579 is known to be a producer of the lipopeptides brabantamide and thanamycin. Its draft genome gives insight into the complete secondary metabolite production capacity of the strain and builds the basis for a comparative study with Pseudomonas sp. strain SH-C52, a lipopeptide-producing strain involved in natural disease-suppressive soils.