bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and rationale of a first-in-human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible (irrev), pan-FGFR inhibitor (FGFRi), in adult patients with solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822).
Authors: Goyal Lipika , Perez Cesar Augusto , Kato Shumei , Sharma Manish , Garmezy Benjamin , Kobayashi Ken , Franovic Aleksandra , Tam Betty , Voong Cynthia
Published: June 2022

TPS9601

Background: FGFR1-4 gene alterations are observed in approximately 7% of all human cancers. There are currently 3 FDA-approved, reversible FGFRi for treatment of patients w/previously treated, locally advanced or metastatic (met) cholangiocarcinoma (CCA) harboring FGFR2 gene fusions/rearrangements (pemigatinib and infigratinib) or met urothelial carcinoma (UC) w/susceptible FGFR2 or FGFR3 genetic alterations (erdafitinib). A major limitation of approved and clinical-stage FGFRi is emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response. Up to 67% of CCA patients treated with either reversible or irrev FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irrev, small molecule pan-FGFRi, structurally designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated w/disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in 28d GLP toxicology studies in rats and beagle dogs and is efficacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (e.g., gatekeeper and molecular brake) in human cancer cell and PDX models in vitro and in vivo. Methods: This is a FIH, multicenter, non-randomized Ph1 study of KIN-3248 in adult pts with advanced & metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given po qd continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approx. 120 pts: Part A is a dose-escalation to MTD for pts w/AMST having either FGFR2 and/or FGFR3 alterations. Part A assesses single agent KIN-3248; Part B will evaluate a selected dose of KIN-3248 in 3 cohorts of pts (ICC, UC, or other AMST), each driven by specified FGFR alterations. Standard Ph1 enrollment criteria are required (ECOG PS 0-1, normal organ function, prior receipt of standard treatment or medical judgment that such is not appropriate). Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases and active/uncontrolled HBV/HCV. FGFRi-naïve & -pretreated patients are both eligible. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, & duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. Enrollment is expected to commence in April 2022. Clinical trial information: NCT05242822.
A first-in-human, phase 1b study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of neoadjuvant use of ph-762 administered intratumorally in subjects with advanced melanoma.
Authors: Robert Caroline , Roy Severine , Cuiffo Benjamin , Cardia James , Fricker Simon Paul
Published: June 2022

TPS9608

Background: Antibodies targeting immune checkpoints such as PD-1 and CTLA-4 has shown significant benefit in late-stage melanoma. But further improvements in therapeutic options are still required. Two approaches for improving the outcome of immunotherapy with checkpoint inhibitors are neoadjuvant treatment and local intratumoral (IT) injection. IT immunotherapy uses the tumor as its own vaccine to activate the immune system, priming an anti-tumor immune response and generating systemic tumor responses, whilst minimizing systemic exposure and off-target toxicities. Neoadjuvant therapy provides the opportunity for preoperative disease shrinkage with the potential to improve surgical morbidity. There is currently no neoadjuvant standard of care for resectable, advanced melanoma patients. PH-762 is a potent RNAi molecule targeting PD-1 with structural and chemical modifications conferring properties suitable for IT administration, including an optimized cell and tissue uptake profile. Pharmacology studies show potent in vitro silencing of PD-1 associated with T cell activation, and robust, dose-dependent in vivo inhibition of tumor growth in syngeneic tumor models. Methods: The purpose of this study is to evaluate the safety of neoadjuvant use of PH-762 administered by IT injection in subjects with resectable stage IIIB/IIIC/IIID or IV melanoma, to determine the recommended Phase 2 dose, PK after IT injection, and potential immunologic and pathologic tumor responses. Study treatment constitutes of once weekly injections with PH-762 into one designated tumor lesion for 4 weeks prior to surgical excision at 5-6 weeks after the initial injection, with up to 5 dose levels tested in a serial fashion in cohorts of 3 or more subjects. Eligible subjects will have at least one resectable melanoma deposit that is large enough to allow IT injection, and that can undergo repeated biopsy. Subjects with active brain metastases, leptomeningeal disease, uveal melanoma, and auto-immune disease are excluded. The dose of PH-762 will be normalized to tumor volume to ensure an equivalent local dose (tumor tissue concentration). Post tumor excision, subjects will be followed-up for 6 weeks. Primary endpoint is to determine a safe dose of PH-762 assessed by incidence of Dose Limiting Toxicities (DLT) prior to tumor resection. Bayesian optimal interval (BOIN) design will be employed to evaluate escalating doses of PH-762 to determine the Maximum Tolerated Dose based on occurrence of DLT. Tumor changes will be evaluated per RECIST criteria (version 1.1 and iRECIST version adapted for use with IT therapy) and pathological response. Immunological response in tumor tissue and blood samples will be assessed as secondary endpoints. Enrollment commenced in February 2022. Clinical trial information: 2021-002859-10.
High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma
Authors: Bertamini Luca , Oliva Stefania , Rota-Scalabrini Delia , Paris Laura , Morè Sonia , Corradini Paolo , Ledda Antonio , Gentile Massimo , De Sabbata Giovanni , Pietrantuono Giuseppe , Pascarella Anna , Tosi Patrizia , Curci Paola , Gilestro Milena , Capra Andrea , Galieni Piero , Pisani Francesco , Annibali Ombretta , Monaco Federico , Liberati Anna Marina , Palmieri Salvatore , Luppi Mario , Zambello Renato , Fazio Francesca , Belotti Angelo , Tacchetti Paola , Musto Pellegrino , Boccadoro Mario , Gay Francesca
Published: June 2022

PURPOSE

High levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement.

METHODS

CTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10–5) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643 ). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10–5). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity.

RESULTS

CTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells ( r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039).

CONCLUSION

In multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.
A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)
Authors: Monk Bradley J. , Parkinson Christine , Lim Myong Cheol , O'Malley David M. , Oaknin Ana , Wilson Michelle K. , Coleman Robert L. , Lorusso Domenica , Bessette Paul , Ghamande Sharad , Christopoulou Athina , Provencher Diane , Prendergast Emily , Demirkiran Fuat , Mikheeva Olga , Yeku Oladapo , Chudecka-Glaz Anita , Schenker Michael , Littell Ramey D. , Safra Tamar , Chou Hung-Hsueh , Morgan Mark A. , Drochýtek Vít , Barlin Joyce N. , Van Gorp Toon , Ueland Fred , Lindahl Gabriel , Anderson Charles , Collins Dearbhaile C. , Moore Kathleen , Marme Frederik , Westin Shannon N. , McNeish Iain A. , Shih Danny , Lin Kevin K. , Goble Sandra , Hume Stephanie , Fujiwara Keiichi , Kristeleit Rebecca S.
Published: June 2022

PURPOSE

ATHENA (ClinicalTrials.gov identifier: NCT03522246 ) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo.

METHODS

Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population.

RESULTS

As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%).

CONCLUSION

Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.
Financial Toxicity, Symptom Burden, Illness Perceptions, and Communication Confidence in Cancer Clinical Trial Participants
Authors: Perni Subha , Azoba Chukwuma , Gorton Emily , Park Elyse R. , Chabner Bruce A. , Moy Beverly , Nipp Ryan D.
Published: June 2022

PURPOSE:

Cancer clinical trial (CCT) participants are at risk for experiencing adverse associations from financial toxicity, but these remain understudied.

METHODS:

From July 2015 to July 2017, we prospectively enrolled CCT participants referred for financial assistance and a group of patients matched by age, sex, cancer type, trial, and trial phase. We assessed financial burden of cancer care, cost concerns about CCTs, physical (Edmonton Symptom Assessment Scale [ESAS]) and psychologic (Patient Health Questionnaire-4 [PHQ-4]) symptoms, illness perceptions (Brief Illness Perception Questionnaire), and communication confidence (Perceived Efficacy in Patient-Physician Interactions). Adjusting for age, sex, race, performance status, marital status, income, insurance, and disease status, we examined associations of financial burden and cost concerns with patients' symptoms, illness perceptions, and communication confidence.

RESULTS:

Of 198 patients, 112 (56.6%) reported financial burden and 82 (41.4%) reported cost concerns. Higher ESAS-total (odds ratio [OR] = 1.03; 95% CI, 1.01 to 1.06; P = .001), PHQ-4 depression (OR = 1.58; 95% CI, 1.20 to 2.08; P < .001), PHQ-4 anxiety (OR = 1.26; 95% CI, 1.02 to 1.55; P = .025), and more negative illness perceptions (OR = 1.04; 95% CI, 1.00 to 1.07; P = .029) were associated with financial burden, but not communication confidence (OR = 0.98; 95% CI, 0.02 to 1.05; P = .587). Higher ESAS-total (OR = 1.03; 95% CI, 1.01 to 1.05; P = .004), PHQ-4 depression (OR = 1.36; 95% CI, 1.08 to 1.71; P = .03), PHQ-4 anxiety (OR = 1.26; 95% CI, 1.03 to 1.53; P = .018), more negative illness perceptions (OR = 1.06; 95% CI, 1.02 to 1.10; P = .001), and decreased communication confidence (OR = 0.93; 95% CI, 0.86 to 1.00; P = .029) were associated with cost concerns.

CONCLUSION:

In this study of CCT participants, greater symptom burden, more negative illness perceptions, and lower communication confidence were associated with financial toxicity, underscoring the importance of addressing these issues when seeking to alleviate adverse associations of financial toxicity.
Longitudinal Shifts of Solid Tumor and Liquid Biopsy Sequencing Concordance in Metastatic Breast Cancer
Authors: Liu Minetta C. , MacKay Matthew , Kase Matthew , Piwowarczyk Aneta , Lo Christine , Schaeffer Jeff , Finkle Justin D. , Mason Christopher E. , Beaubier Nike , Blackwell Kimberly L. , Park Ben Ho
Published: June 2022

PURPOSE

Tissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tissue and cfDNA NGS relative to cfDNA sampling frequency in a large, clinically annotated mBC data set.

METHODS

Tempus LENS was used to analyze deidentified records of mBC cases with Tempus xT (tissue) and xF (cfDNA) sequencing results. Then, various metrics of concordance were assessed within overlapping probe regions of the tissue and cfDNA assays (104 genes), focusing on pathogenic variants. Variant allele frequencies of discordant and concordant pathogenic variants were also compared. Analyses were stratified by mBC subtype and time between tests.

RESULTS

Records from 300 paired tissue and liquid biopsies were analyzed. Median time between tissue and blood collection was 78.5 days (standard deviation = 642.99). The median number of pathogenic variants/patient was one for cfDNA and two for tissue. Across the cohort, 77.8% of pathogenic tissue variants were found in cfDNA and 75.7% of pathogenic cfDNA variants were found in tissue when tests were ≤ 7 days apart, which decreased to 50.3% and 51.8%, respectively, for > 365 days. Furthermore, the median patient-level variant concordance was 67% when tests were ≤7 days apart and 30%-37% when > 30 days. The median variant allele frequencies of discordant variants were generally lower than those of concordant variants within the same time frame.

CONCLUSION

We observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests. Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC.
Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2
Authors: Nowak Christoph , Lind Marcus , Sumnik Zdenek , Pelikanova Terezie , Nattero-Chavez Lía , Lundberg Elena , Rica Itxaso , Martínez-Brocca Maria A , Ruiz de Adana MariSol , Wahlberg Jeanette , Hanas Ragnar , Hernandez Cristina , Clemente-León Maria , Gómez-Gila Ana , Ferrer Lozano Marta , Sas Theo , Pruhova Stepanka , Dietrich Fabricia , Puente-Marin Sara , Hannelius Ulf , Casas Rosaura , Ludvigsson Johnny
Published: June 2022

Aims

Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM).

Methods

DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values.

Results

We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR.

Conclusions

Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.
Generation of a homozygous mutant drug transporter (ABCB1) knockout line in the sea urchinLytechinus pictus
Authors: Vyas Himanshu , Schrankel Catherine S. , Espinoza Jose A. , Mitchell Kasey L. , Nesbit Katherine T. , Jackson Elliot , Chang Nathan , Lee Yoon , Warner Jacob , Reitzel Adam , Lyons Deirdre C. , Hamdoun Amro
Published: June 2022

Sea urchins are premier model organisms for the study of early development. However, the lengthy generation times of commonly used species have precluded application of stable genetic approaches. Here, we use the painted sea urchin Lytechinus pictus to address this limitation and to generate a homozygous mutant sea urchin line. L. pictus has one of the shortest generation times of any currently used sea urchin. We leveraged this advantage to generate a knockout mutant of the sea urchin homolog of the drug transporter ABCB1, a major player in xenobiotic disposition for all animals. Using CRISPR/Cas9, we generated large fragment deletions of ABCB1 and used these readily detected deletions to rapidly genotype and breed mutant animals to homozygosity in the F2 generation. The knockout larvae are produced according to expected Mendelian distribution, exhibit reduced xenobiotic efflux activity and can be grown to maturity. This study represents a major step towards more sophisticated genetic manipulation of the sea urchin and the establishment of reproducible sea urchin animal resources.
Humanized yeast to model human biology, disease and evolution
Authors: Kachroo Aashiq H. , Vandeloo Michelle , Greco Brittany M. , Abdullah Mudabir
Published: June 2022

For decades, budding yeast, a single-cellular eukaryote, has provided remarkable insights into human biology. Yeast and humans share several thousand genes despite morphological and cellular differences and over a billion years of separate evolution. These genes encode critical cellular processes, the failure of which in humans results in disease. Although recent developments in genome engineering of mammalian cells permit genetic assays in human cell lines, there is still a need to develop biological reagents to study human disease variants in a high-throughput manner. Many protein-coding human genes can successfully substitute for their yeast equivalents and sustain yeast growth, thus opening up doors for developing direct assays of human gene function in a tractable system referred to as ‘humanized yeast’. Humanized yeast permits the discovery of new human biology by measuring human protein activity in a simplified organismal context. This Review summarizes recent developments showing how humanized yeast can directly assay human gene function and explore variant effects at scale. Thus, by extending the ‘awesome power of yeast genetics’ to study human biology, humanizing yeast reinforces the high relevance of evolutionarily distant model organisms to explore human gene evolution, function and disease.
How inclusive are cell lines in preclinical engineered cancer models?
Authors: Raghavan Shreya
Published: June 2022

Diverse factors contribute to significant and dire disparities in cancer risk and treatment outcomes. To address this, there was a call for inclusion of sex as a biological variable, which resulted in more instances of careful inclusion of sex in preclinical studies of cancer. Another variable in cancer treatment is genetic ancestry. Although this is considered explicitly in clinical research, it is considerably neglected in preclinical studies. Preclinical research can use several 3D in vitro model systems, such as spheroids/organoids, xenografts, or other bioengineered systems that combine biomaterials and cellular material. Ultimately, the cellular base for all of these in vitro model systems is derived from human cell lines or patient samples, to investigate mechanisms of cancer and screen novel therapeutics, all of which aim to maximize successful outcomes in clinical trials. This in itself offers an opportunity to potentiate effective treatments for many groups of people, when diverse variables like genetic ancestry are consciously included into study design. This Perspective highlights the need for conscious inclusion of genetic ancestry in preclinical cancer tissue engineering, especially when it pertains to determining therapeutic outcomes.
Analysis of monocyte cell tractions in 2.5D reveals mesoscale mechanics of podosomes during substrate-indenting cell protrusion
Authors: Schürmann Hendrik , Abbasi Fatemeh , Russo Antonella , Hofemeier Arne D. , Brandt Matthias , Roth Johannes , Vogl Thomas , Betz Timo
Published: June 2022

Podosomes are mechanosensitive protrusive actin structures that are prominent in myeloid cells, and they have been linked to vascular extravasation. Recent studies have suggested that podosomes are hierarchically organized and have coordinated dynamics on the cell scale, which implies that the local force generation by single podosomes can be different from their global combined action. Complementary to previous studies focusing on individual podosomes, here we investigated the cell-wide force generation of podosome-bearing ER-Hoxb8 monocytes. We found that the occurrence of focal tractions accompanied by a cell-wide substrate indentation cannot be explained by summing the forces of single podosomes. Instead, our findings suggest that superimposed contraction on the cell scale gives rise to a buckling mechanism that can explain the measured cell-scale indentation. Specifically, the actomyosin network contraction causes peripheral in-plane substrate tractions, while the accumulated internal stress results in out-of-plane deformation in the central cell region via a buckling instability, producing the cell-scale indentation. Hence, we propose that contraction of the actomyosin network, which connects the podosomes, leads to a substrate indentation that acts in addition to the protrusion forces of individual podosomes.

This article has an associated First Person interview with the first author of the paper.
Fluorescence exclusion – a rapid, accurate and powerful method for measuring yeast cell volume
Authors: García-Ruano Daniel , Venkova Larisa , Jain Akanksha , Ryan Joseph C. , Radhakrishnan Balasubramaniam Vasanthakrishnan , Piel Matthieu , Coudreuse Damien
Published: June 2022

Cells exist in an astonishing range of volumes across and within species. However, our understanding of cell size control remains limited, owing in large part to the challenges associated with accurate determination of cell volume. Much of our comprehension of size regulation derives from yeast models, but even for these morphologically stereotypical cells, assessment of cell volume has mostly relied on proxies and extrapolations from two-dimensional measurements. Recently, the fluorescence exclusion method (FXm) was developed to evaluate the size of mammalian cells, but whether it could be applied to smaller cells remained unknown. Using specifically designed microfluidic chips and an improved data analysis pipeline, we show here that FXm reliably detects subtle differences in the volume of fission yeast cells, even for those with altered shapes. Moreover, it allows for the monitoring of dynamic volume changes at the single-cell level with high time resolution. Collectively, our work highlights how the coupling of FXm with yeast genetics will bring new insights into the complex biology of cell growth.
An interpretable and versatile machine learning approach for oocyte phenotyping
Authors: Letort Gaelle , Eichmuller Adrien , Da Silva Christelle , Nikalayevich Elvira , Crozet Flora , Salle Jeremy , Minc Nicolas , Labrune Elsa , Wolf Jean-Philippe , Terret Marie-Emilie , Verlhac Marie-Hélène
Published: June 2022

Meiotic maturation is a crucial step of oocyte formation allowing its potential fertilization and embryo development. Elucidating this process is important both for fundamental research and assisted reproductive technology. Few computational tools based on non-invasive measurements are however available to characterize oocyte meiotic maturation. Here, we develop a computational framework to phenotype oocytes based on images acquired in transmitted light. We trained neural networks to segment the contour of oocytes and their zona pellucida using oocytes from diverse species. We defined a comprehensive set of morphological features to describe an oocyte. These steps are implemented in an open-source Fiji plugin. We present a feature based machine learning pipeline to recognize oocyte populations and determine their morphological differences. We first demonstrate its potential to screen oocyte from different strains and automatically identify their morphological characteristics. Its second application is to predict and characterize the maturation potential of oocytes. We identify the texture of the zona pellucida and the cytoplasmic particles size as features to assess mouse oocyte maturation potential and tested whether these features were applicable to human oocyte's developmental potential.
Association of Cardiovascular Risk Markers and Fitness with Task-Related Neural Activity during Animacy Perception
Authors: ISHIHARA TORU , MIYAZAKI ATSUSHI , TANAKA HIROKI , MATSUDA TETSUYA
Published: June 2022

Purpose

Numerous studies have demonstrated the association between cardiovascular risk markers and fitness, and broad aspects of cognition; however, the possible association of cardiovascular risk markers and fitness with social cognition, which plays a significant role in the development and maintenance of social relationships, has largely been ignored. Herein, we investigated the relationship of cardiovascular risk markers and fitness with task-related neural activity during animacy perception.

Methods

We analyzed data from the Human Connectome Project derived from 1027 adults age 22–37 yr. Canonical correlation analysis (CCA) was conducted to evaluate the association between participants’ body mass index, systolic and diastolic blood pressure, submaximal endurance, gait speed, hand dexterity, and muscular strength with task-related neural activity during animacy perception.

Results

We observed a single significant CCA mode. Body mass index and blood pressure demonstrated negative cross-loadings with task-related neural activity in the temporoparietal, superior and anterior temporal, posterior cingulate, and inferior frontal regions, whereas submaximal endurance, hand dexterity, and muscular strength demonstrated positive cross-loadings. The observed CCA variates did not seem highly heritable, as the absolute differences in CCA variates in monozygotic twins, dizygotic twins, and nontwin siblings were not statistically different. Furthermore, the cardiovascular risk markers and fitness CCA variates were positively associated with animacy perception and emotion recognition accuracy, which was mediated by the task-related neural activity.

Conclusions

The present findings can provide new insights into the role of markers for cardiovascular health and fitness, specifically their association with social cognition and the underlying neural basis. The intervention for cardiovascular risk and fitness could be a potentially cost-effective method of targeting social cognition.
Ameliorative effects of L-carnitine on florfenicol-induced hepatotoxicity in broilers
Authors: Haggag Nourhan A. , Aziz Mustafa A. , Zahra Abu Elnasr A. , Belih Soad S. , Khalifa Hazim Omar
Published: June 2022

L-carnitine is a non-essential amino acid derivative naturally occurring and widely distributed in nature. It received a growing interest in its potential uses as a medicinal agent possess protective effects that postulated to be related to its antioxidant action. This study was aimed to evaluate the ameliorative role of L-carnitine on florfenicol induced hepatic toxicity in broilers. A total of 150 broiler chicks were grouped into 6 groups each of 25 chicks. Group one was kept as a control group, while group two and three were treated with florfenicol and L-carnitine, respectively. Group 4 was pre-treated with L-carnitine for three days before florfenicol administration. Groups five and sex were cotreated with L-carnitine and florfenicol and post-treated with L-carnitine for three days after florfenicol administration, respectively. The biochemical analysis, liver indices, antioxidant profile, and histopathological examination were performed to evaluate its ameliorative effects. Results emphasized that florfenicol induced hepatic toxicity in broilers and L-carnitine can ameliorate its action when its usage preceded the florfenicol or when they were used together which reflected by an enhancement in liver indices, antioxidant profile, and histopathological findings. As far as we know this the first study confirming the ameliorative potency of L-carnitine on florfenicol-induced hepatotoxicity.
Determination of Nutritional Value of Alfalfa Varieties and Lines by Using the In Vitro Method and Gas Production Technique
Authors: BOGA Mustafa , Ayasan Tugay
Published: June 2022

This study was organized to determine the nutritional value of different alfalfa varieties and lines selected within the scope of the “Cukurova Region Alfalfa Breeding Project”, conducted at the Eastern Mediterranean Agricultural Research Institute, by using the in vitro gas production technique. In the project, Nimet was certified as a new variety. The used alfalfa lines were YSH 26-12, YSH 23-9, YSH 21-1, YSH 27-9, YSH 37-12, YSH 35-11, YSH 28-6, YSH 16-11, YSH 14-3, and YSH 11-4. The certified Nimet variety was used as a control. Alfalfas have been harvested in April, at the beginning of blooming. Chemical composition, metabolic energy (ME), net energy lactation (NEL), and organic matter digestibility (OMD) of the certified Nimet variety with 10 different alfalfa lines used in the experiment were determined by Hohenheim in vitro gas production technique. The incubation times in the Hohenheim gas production technique are 3, 6, 9, 12, 24, 48, 72 and 96th hours. Crude protein (CP), crude cellulose (CC), NDF, and ADF contents of the alfalfa varieties and lines ranged between 19.06-22.40%, 24.90-33.30%, 33.16-45.73%, and 30.77-39.75%, respectively. After 96-hour incubation, the highest total gas production (GP) was found at the YSH 11-4 line (45.32 ml) (P < 0.05). While ME, OMD and NEL contents were found to be high at the YSH 11-4 line, ME and OMD values were statistically different from the YSH 28-6, YSH 16-11, YSH 14-3, and YSH 21-1 lines. On the other hand, NEL values were determined different from YSH 23-9, YSH 21-1, YSH 28-6, YSH 16-11, YSH 14-3 lines.
The comparison between AgB-ELISA and a new method of Nano-ELISA for diagnosis of hydatidosis in sheep
Authors: Shirazi Shahrokh , Hoghooghi-Rad Nasser , Madani Rasoul
Published: June 2022

Hydatidosis is one of the most important zoonotic diseases, and it is transmitted via dogs to intermediate hosts such as humans and domestic animals including sheep and cattle. Epidemiological studies and genetic investigations indicate that the sheep strain is the most common species causing hydatid cysts in humans. The prevalence and incidence of this disease are increasing. According to surveys, economic losses due to this parasite in intermediate hosts are significant. In this survey, 25 serum samples were obtained from newborn lambs as negative control and obtained 25 serum samples from infected sheep to hydatidosis as the positive control. Antigen B isolated from hydatid cysts fluid was used for designing ELISA methods. Using Antigen B in ELISA design for hydatidosis diagnosis has attracted researchers in recent years. During this study, an Iranian native B antigen was used to design the specific detection of hydatidosis in sheep using a specific ELISA technique. The first method used the anti-Sheep conjugate (SIGMA, at 1:3000 dilution), and the second method used gold nanoparticles in combination with anti-sheep conjugate. According to the results, sensitivity and specificity in sheep of the AgB-ELISA method were both 92% and for the Nano-ELISA with Gold Nanoparticles 100% and 96%, respectively. Moreover, results indicated that using Antigen B in ELISA design is valuable but specificity and sensitivity will increase significantly, especially in lower titer, when gold nanoparticles with anti-sheep conjugate are used.
Age-and sex-related changes in selected hematological parameters, lipid peroxidation and erythrocytes osmotic fragility of Turkish Angora cats
Authors: Kabakci Ruhi
Published: June 2022

This study was conducted to investigate the changes in selected hematological parameters, lipid peroxidation and osmotic fragility of erythrocytes in Angora cats depending on the age and gender. For this purpose, the blood samples were collected from 9 young and 14 adult cats which also classified as male (n=12) and female (n=11). Following hematological analysis, samples were washed with PBS by centrifugation and 10% hematocrit suspension was prepared from the erythrocytes pellet for osmotic fragility test. The concentration of malondialdehyde (MDA) was also measured from lysed erythrocyte to determine lipid peroxidation level. Red blood cells (RBCs), hemoglobin, and hematocrit were high in adults while mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were high in young cats. Erythrocyte MDA level was also higher in adult cats than in young cats. There was no significance in these parameters between male and female cats. Findings of fragility tests were showed that erythrocytes of young and male cats were more susceptible to hypotonic NaCl solutions than those of adult and female cats, respectively. It was concluded that erythrocytes related parameters in Angora cats changed depending on the age rather than gender except stability of RBCs.
The effect of the challenge with Newcastle disease virus on the gastrointestinal bacterial population in Japanese quail (Coturnix japonica)
Authors: Talazadeh Forough
Published: June 2022

Newcastle disease (ND), caused by virulent strains of Newcastle disease virus (NDV), is a devastating disease of poultry worldwide. The effect of a challenge with Newcastle disease virus on bacterial population in quail is poorly documented, so for this purpose, a total of 100 day-old Japanese quail were purchased and divided into 2 equal groups randomly. Each group was divided into 2 subgroups of 25 quails. The birds in group A challenged with a velogenic chicken isolate of Newcastle disease virus. The birds in group B did not challenge with Newcastle disease virus as the control group. For the determination of lactobacillus counts in the intestine and crop of Japanese quail, at the end of the period, 10 birds of each subgroup (20 birds of each treatment) were chosen randomly. One gram of the crop and ileocecal content were taken and cultured on MRS for determination of lactobacillus counts. The colony-forming units of Escherichia coli in digesta of ileocecal on Mac Conkey agar were investigated. Also, crop and ileocecal content of dead birds were taken and cultured on MRS and Mac Conkey agar. The results of this study showed that challenge with a velogenic chicken isolate of Newcastle disease virus could increase colony-forming units of Escherichia coli in group A compared to the control group. Also, it reduced lactobacillus counts of intestine and crop compared to the control group. So it concluded that velogenic chicken isolate of Newcastle disease virus influences microflora of intestine and crop of Japanese quail.
Use of Multivariate Adaptive Regression Splines, Classification Tree and Roc Curve in Diagnosis of Subclinical Mastitis in Dairy Cattle
Authors: ALTAY Yasin , AYTEKİN İbrahim , EYDURAN Ecevit
Published: June 2022

Subclinical mastitis is one of the most significant diseases that cause economic losses in dairy cattle farming. This investigation was conducted on 112 head Holstein Friesian cows in order to reveal relationship between subclinical mastitis and electrical conductivity milk composition and milk quality. In the study, CMT (California Mastitis Test) and CSCC (Classified Somatic Cell Count) used in diagnosis of subclinical mastitis were used as a binary response variable i.e. healthy and unhealthy. Potential predictors included here were lactation number, days in milk (DIM), L, a, b, H, C, milk fat, milk protein, lactose, milk freezing point, SNF, density, solids, pH and electrical conductivity. CART, CHAID, Exhaustive CHAID, QUEST and multivariate adaptive regression splines (MARS) were used as data mining algorithms that help to make an accurate decision about detecting influential factors increasing risk of subclinical mastitis.In conclusion, better classification performances of CART and MARS data mining algorithms were determined compared with those of remaining algorithms in order to correctly discriminate healthy and unhealthy cows.
Aggressive behavior in cats exposed to trauma
Authors: YAYLA Sadık , ALTAN Semih , Ersöz kanay Berna , çatalkaya Emine , Saylak Nahit
Published: June 2022

Aggression is an important behavioral problem in cats. This issue can occur as a reaction when there is disease or pain in a normal cat. The aim of this study is to evaluate the behavior changes of cats exposed to trauma using behavior scoring system and demeanour scoring system. In this study consisted of 135 cats of different breeds, ages and genders with high rise syndrome and traffic accidents. These cats were given a detailed clinical and radiological examination. Demeanour scoring system, behavior tests, and visual analog scale were used to identify behavior changes and pain in cats. The findings from this study showed that cats exposed to trauma may experience behavioral changes or agression, and this may result from pain or stress from trauma. As a result, stress from trauma in cats can also lead to a change in behavior, a temporary aggressiveness.
Prevalence of oral manifestations in patients with lupus erythematosus in a sample of the Egyptian population: a hospital based cross-sectional study
Authors: Saeed Hager Moustafa , Mohammad Amr Eman , Rezk Lotfy Rezk Alshaimaa , Abd Elmoneim Wesam
Published: June 2022

Background: Several systemic diseases manifest themselves in the oral cavity. Dentists who are unaware of these lesions will possibly miss them. This cross-sectional study aimed to assess the prevalence of oral manifestations in patients with LE in a sample of the Egyptian population.

Methods: The present cross-sectional study was performed on 189 patients attending the Internal Medicine Department, Rheumatology Clinic in EL Qasr El Ainy Hospital, Cairo University. Every patient was examined clinically after completing a questionnaire. Patients’ medical records were evaluated.  

The oral manifestations were assessed according to the WHO guide to physical examination of the oral cavity and classified according to their morphologic aspects and localization.

Results: Out of 189 patients, there were 182 females (96.3%) and seven males (3.7%). The prevalence of oral lesions in SLE patients was 55.6%. The most affected site was the tongue 25.7%. The most common clinical aspect was patches, 53%. About 77.1% of the lesions were asymptomatic. 

Conclusions: The present study emphasizes the importance of early diagnosis of oral lesions to recognize patients with SLE as the WHO considers oral manifestations of SLE a widespread state. Also, the implementation of oral hygiene measures to improve patients’ nutritional state and health-related quality of life is recommended.
Development of an online pan-European Integrated Pest Management Resource Toolbox
Authors: Ramsden Mark , Furiosi Margherita , Debenedettis Paolo , Stojacic Isidora , Mendes Marta , Munier-Jolain Nicolas , Caffi Tito
Published: June 2022

The IPMWORKS IPM Resource Toolbox (Toolbox) has been developed as an interactive, online repository of integrated pest management (IPM) resources. Populated with high priority resources for farmers and their advisors during the project, its structure enables additional resources added over time. The repository is a public interactive website, available to anyone looking to access, understand, and implement IPM. Built on an open-source content management system, the toolbox is designed to require minimal post-production site maintenance and support, while being easily expanded to integrate resources from future initiatives.

To ensure an efficient but comprehensive website design, population, maintenance, a survey of target user needs was conducted. Internal and external IPM stakeholders indicated the relative importance of key requirements such as practical information about diseases and pests’ management and economic thresholds. The resources were explained in different languages, with images, divided by topics, with the possibility to find additional details and accessible by smartphone. Feedbacks and answers from the survey, carried out across Europe in multiple languages, by different stakeholders provided the key elements and foundation for the IPM Resource Toolbox website development and specification.
Design of an aircraft generator with radial force control
Authors: Brecher Christian , Neus Stephan , Gärtner Marcus , Eckel Hans-Martin , Hoppert Maik , James Barry , Gerada Chris , Degano Michele , Ilkhani Mohammad Reza , Di Nardo Mauro
Published: June 2022

With the increasing electrical energy demands in aviation propulsion systems, the increase in the onboard generators’ power density is inevitable. During the flight, forces coming from the gearbox or gyroscopic forces generated by flight manoeuvres like take-off and landing can act on the generators' bearings, which can lead to wear and fatigue in the bearings. Utilizing the radial force control concept in the electrical machine can relieve loads from the bearings that not only minimize the bearing losses but also increase bearing life. The objective of the MAGLEV project (Measurement and Analysis of Generator bearing Loads and Efficiency with Validation) is to study, demonstrate, and test a new class of high-speed generators with radial force control. In this paper, design steps of this type of generator and its test rig are presented and the measurement methodology used for radial force control is explained. The concept is developed in an electrical machine and is validated on a test rig by measuring required parameters like shaft displacement, vibrations and bearing temperature. Additionally, the friction moment of each generator’s bearings is measured and validated in a separate test rig under comparable conditions to the bearing loads in the generator. Therefore, a novel approach to determine precisely the bearing friction in a radial load unit, rotatably supported by an additional needle bearing is used, which shows a good agreement with the calculated friction. Furthermore, new calculation methods for the operating behavior of cylindrical roller bearings with clearance are presented, which are utilized in the generator test rig.
Appointment of forensic examinations
Authors: Karagodin Valeriy , Nadonenko Ol'ga , Nikolaenkova Aleksandra , Sokolova Svetlana , Smirnova Irina , Baranova Kseniya , Kokovin Andrey , Kulyukin Ivan , Shuklin Aleksandr , Kuzevanova Ol'ga , Kurinova Marina
Published: June 2022

The textbook provides information about the structure of the forensic expert system of the Russian Federation, discusses procedural and organizational issues of preparation, appointment and production of forensic examinations, features of the design of a procedural document - a resolution on the appointment of a forensic examination, including in connection with differences between categories of forensic experts. The stages of the emergence and development of certain types of forensic examinations are shown. The basic recommendations of forensic experts on the preparation of materials, comparison samples for the appointment of specific forensic examinations are systematically stated and justified, in accordance with various investigative situations, formulations of questions submitted for expert permission are proposed, recommendations on the seizure, packaging, storage and transportation of objects for specific types of forensic examinations are given. The recommendations are illustrated with examples from the authors' expert practice.
The work was prepared by an author's team of acting forensic experts with practical experience from 8 to 30 years.
Meets the requirements of the federal state educational standards of higher education of the latest generation.
For students, trainees, postgraduates, adjuncts and teachers of law schools and faculties, practitioners of investigative and investigative law enforcement agencies, judges, prosecutors, lawyers, as well as for a wide audience of persons interested in criminology and forensic examination.
Descriptive geometry
Authors: Sal'kov Nikolay
Published: June 2022

The textbook contains a complete course on descriptive geometry for architects. It covers the theoretical issues of orthogonal projections, axonometry, perspective and shadow theory in these sections.
It fully meets the requirements of the Federal State Educational Standard of Secondary Vocational Education, approved by the order of the Ministry of Education and Science of the Russian Federation No. 850 dated July 28, 2014.
It is addressed to students of secondary vocational education institutions studying in the specialty 07.02.01 "Architecture". It can be useful for students of other fields of study, as well as teachers of geometric and graphic disciplines.