Miracle-dz/UniFAR-FTUs huggingface dataset:
TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL

ABSTRACT The therapeutic potential of targeting CD19 in B cell malignancies has garnered attention in the past decade, resulting in the introduction of novel immunotherapy agents. Encouraging clinical data have been reported for T cell-based targeting agents, such as anti-CD19/CD3 bispecific T-cell engager blinatumomab and chimeric antigen receptor (CAR)-T therapies, for acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma (B-NHL). However, clinical use of both blinatumomab and CAR-T therapies has been limited due to unfavorable pharmacokinetics (PK), significant toxicity associated with cytokine release syndrome and neurotoxicity, and manufacturing challenges. We present here a fully human CD19xCD3 bispecific antibody (TNB-486) for the treatment of B-NHL that could address the limitations of the current approved treatments. In the presence of CD19+ target cells and T cells, TNB-486 induces tumor cell lysis with minimal cytokine release, when compared to a positive control. In vivo, TNB-486 clears CD19+ tumor cells in immunocompromised mice in the presence of human peripheral blood mononuclear cells in multiple models. Additionally, the PK of TNB-486 in mice or cynomolgus monkeys is similar to conventional antibodies. This new T cell engaging bispecific antibody targeting CD19 represents a novel therapeutic that induces potent T cell-mediated tumor-cell cytotoxicity uncoupled from high levels of cytokine release, making it an attractive candidate for B-NHL therapy.
Russian Political Discourse on Illegal Drugs: A Thematic Analysis of Parliamentary Debates

Abstract Background: Since the beginning of the twenty first century, there has been an intensified political debate about drugs in Russia. The drug problem is now regarded as one of the country’s most serious problems and as an issue of top priority for the Russian government. Objectives: The aim of this qualitative study is to explore how illegal drugs are discussed in Russian political discourse. Methods: The material includes an analysis of 177 speeches made in the lower house of the Russian parliament, the Russian State Duma, between 2014 and 2018. The data were analyzed using qualitative content analysis (CDA). Results: In general, the study found that the debate about the drug problem was characterized by consensus, and there were small differences between the Deputy members in their understanding of the problem. Three main understandings of the drug problem were identified: (1) Illegal drugs as an increasing problem in Russia, (2) Drugs as an external threat, and (3) A need for a more repressive drug policy. Conclusion: There was a general consensus about how the drug problem should be regarded among the politicians, with a focus on a war on drugs and an absence of harm reduction ideas.
The 2017 ACC/AHA stage 1 hypertension is associated with arterial stiffness: a prospective analysis

Objective: To examine the association between stage 1 hypertension defined by the 2017 American College of Cardiology and American Heart Association (ACC/AHA) guideline and risk of developing arterial stiffness. Methods: During 2010-2015, 4595 adults aged ≥40 years without cardiovascular disease were followed up for a median of 4.3 years. BP levels at baseline were categorized into normal, elevated, stage 1 hypertension, and stage 2 hypertension. The development of arterial stiffness was defined as a normal brachial-ankle pulse wave velocity (ba-PWV) at baseline and an increased ba-PWV at follow-up. Results: Compared with participants with normal BP, participants with stage 1 hypertension had a 1.48-fold increased risk of developing arterial stiffness [odds ratio (OR) =2.48; 95% confidence interval (CI) =1.59-3.85] after adjustment for cardiovascular risk factors. The association was more evident in adults aged 40-59 years (OR =4.08; 95% CI =2.06-8.08) than that in those aged ≥60 years (OR =1.47; 95% CI =0.81-2.67). A systolic BP 130~139 mmHg was significantly associated with arterial stiffness independent of diastolic BP (OR =2.90; 95% CI =1.86-4.52). Stage 1 hypertension either at baseline or at follow-up was associated with increased risks compared with normal BP at both baseline and follow-up. Conclusions: The 2017 ACC/AHA stage 1 hypertension was significantly associated with higher risks of arterial stiffness.
Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer’s Disease

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.
Gleason Grade Group Concordance between Preoperative Targeted Biopsy and Radical Prostatectomy Histopathologic Analysis: A Comparison Between In-Bore MRI-guided and MRI-Transrectal US Fusion Prostate Biopsies.

Purpose To determine and compare rates of grade group (GG) discrepancies between different targeted biopsy techniques (in-bore vs fusion) after propensity score weighting using whole-mount radical prostatectomy (RP) histopathologic analysis as the reference standard. Materials and Methods This retrospective study evaluated men who underwent targeted (fusion or in-bore) biopsy between April 2017 and January 2019 followed by prostatectomy. The primary endpoint of the study was a change in GG from biopsy to RP at a patient level. For downgrade and upgrade analysis, men with biopsy GG1 (downgrade not possible) and GG5 (upgrade not possible) were excluded, respectively. GG upgrade, downgrade, and concordance rates of each targeting approach were compared using propensity score weighting and logistic regression with inverse probability of treatment weighting. Significance level was set at . 05. Index lesion GG on RP specimen served as the reference standard. Results A total of 191 men (90 in the in-bore [mean age, 63 years ± 7 (standard deviation)] and 101 in the fusion biopsy group [mean age, 65 years ± 7]) were eligible and included. Fewer GG upgrades were noted in the in-bore biopsy group (14%; 12 of 85) compared with the fusion plus systematic biopsy group (30%; 28 of 93) (P = .012). The incidence of GG downgrade in the in-bore group (25%; 21 of 84) was higher than in the fusion group (17%; 16 of 93); however, the difference was not statistically significant (P = .2). Of the 77 men misclassified by both biopsy techniques, the majority (56%, n = 43) had a change in GG of 2 to 3 or 3 to 2. Conclusion Superior sampling accuracy with MRI-guided in-bore biopsies offers a lower incidence of GG upgrades compared with MRI-transrectal US fusion biopsies upon RP.Keywords: Biopsy/Needle Aspiration, MR-Imaging, Oncology, Pathology, Prostate Supplemental material is available for this article. © RSNA, 2021.
Diagnostic criteria for temporomandibular disorders (DC/TMD) for children and adolescents: An international Delphi study—Part 1‐Development of Axis I

Abstract Background Since in children and adolescence prevalence is assessed mainly on self‐reported or proxy‐reported signs and symptoms; there is a need to develop a more comprehensive standardised process for the collection of clinical information and the diagnosis of TMD in these populations. Objective To develop new instruments and to adapt the diagnostic criteria for temporomandibular disorders (DC/TMD) for the evaluation of TMD in children and adolescents. Method A modified Delphi method was used to seek international consensus among TMD experts. Fourteen clinicians and researchers in the field of oro‐facial pain and TMD worldwide were invited to participate in a workshop initiated by the International Network for Orofacial Pain and Related Disorders Methodology (INfORM scientific network) at the General Session of the International Association for Dental Research (IADR, London 2018), as the first step in the Delphi process. Participants discussed the protocols required to make physical diagnoses included in the Axis I of the DC/TMD. Thereafter, nine experts in the field were added, and the first Delphi round was created. This survey included 60 statements for Axis I, and the experts were asked to respond to each statement on a five‐item Likert scale ranging from ‘Strongly disagree’ to ‘Strongly agree’. Consensus level was set at 80% agreement for the first round, and at 70% for the next. Results After three rounds of the Delphi process, a consensus among TMD experts was achieved and two adapted DC/TMD protocols for Axis I physical diagnoses for children and adolescents were developed. Conclusion Through international consensus among TMD experts, this study adapted the Axis I of the DC/TMD for use in evaluating TMD in children and adolescents.
Is the Postsurgical Quality of Life of Patients With Esophageal or Gastric Cancer Influenced by Emotional Competence and Neoadjuvant Treatments?

Background Emotional competence (EC) via anxiety and depressive symptoms impacts the postoperative health-related quality of life (HRQoL) of esophageal and gastric cancer patients after surgery. Objective The aim of this study was to confirm the involvement of emotional processes in postsurgery HRQoL according to the presence or absence of neoadjuvant treatments. Methods After diagnosis (T1) and after surgery (T2), 271 patients completed 3 questionnaires, assessing their intrapersonal and interpersonal EC, HRQoL, and anxiety and depressive symptoms. Patients were categorized into 2 groups: patients with only surgery (group 1) and patients who received neoadjuvant treatment in addition to surgery (group 2). Analyses were based on hierarchical regression analyses and the SPSS PROCESS Macro to test the indirect effect of EC on HRQoL through anxiety and depression. Results Results showed an increase in depressive symptoms and a decrease in both anxiety symptoms and HRQoL between diagnosis and surgery, regardless of neoadjuvant treatment. At T1 and T2, EC predicted fewer anxiety and depressive symptoms and a less impaired HRQoL in the surgery-only group (group 1). Emotional competence, particularly intrapersonal EC, showed a significant indirect effect on HRQoL after surgery via fewer depressive symptoms. Conclusion Emotional competence promotes fewer anxiety and depressive symptoms and less impaired HRQoL after diagnosis and after surgery, especially for patients without neoadjuvant treatments. Implications for Practice It is important for oncology nurses and other clinicians to consider the role of emotional processes in postsurgical HRQoL in relation to the type of received treatments and to reinforce the use of EC by cancer patients to improve their adjustment.
PahT regulates carbon fluxes in Novosphingobium sp. HR1a and influences its survival in soil and rhizospheres

Summary Novosphingobium sp. HR1a is a good biodegrader of PAHs and aromatic compounds, and also a good colonizer of rhizospheric environments. It was previously demonstrated that this microbe is able to co‐metabolize nutrients existing in root exudates together with the PAHs. We have revealed here that PahT, a regulator of the IclR‐family, regulates the central carbon fluxes favouring the degradation of PAHs and mono‐aromatic compounds, the ethanol and acetate metabolism and the uptake, phosphorylation and further degradation of mono‐ and oligo‐saccharides through a phosphoenolpyruvate transferase system (PTS). As final products of these fluxes, pyruvate and acetyl‐CoA are obtained. The pahT gene is located within a genomic region containing two putative transposons that carry all the genes for PAH catabolism; PahT also regulates these genes. Furthermore, encoded in this genomic region, there are genes that are involved in the recycling of phosphoenolpyruvate, from the obtained pyruvate, which is the motor molecule involved in the saccharide uptake by the PTS system. The co‐metabolism of PAHs with different carbon sources, together with the activation of the thiosulfate utilization and an alternative cytochrome oxidase system, also regulated by PahT, represents an advantage for Novosphingobium sp. HR1a to survive in rhizospheric environments.
SLEEP DISORDERS IN RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS.

OBJECTIVE The aim: Our study aimed at evaluating the relationships between sleep disorders (SD), cognitive impairment (CI), anxiety and depression in patients with relapsing-remitting multiple sclerosis (RRMS). PATIENTS AND METHODS Materials and methods: One hundred and five patients with RRMS (80 females and 25 males) aged from 22 to 67 years (mean age: 41,8±10,7; EDSS:3,5±1,6; disease duration (DD): 10,3±8,5 years) were enrolled into the study. All participants completed questionnaires on sleep (the Pittsburgh Sleep Quality Index /PSQI), cognitive functions (The Montreal Cognitive Assessment /MoCA), anxiety (Hamilton Anxiety Rating Scale /HAM-A), depression (Beck Depression Inventory/ BDI). RESULTS Results: According to PSQI score the patients were divided into two groups: with (n=42) and without SD (n=63). The patients with SD were older (45,36±1,66 vs 39,41±1,27, p=0.005), had higher EDSS score (3,98±0,26 vs 3,14±0,19, p=0,008), BDI (13,79±1,14 vs 8,96±0,86, p=0,0009) and HAM-A (24,52±1,42 vs 16,56±0,99, p<0,0001) scales compared with patients without SD. The frequency of anxiety (p=0,0034) and depression (p=0,038) was significantly higher in RRMS patients with compared to those without SD. No significant difference was found in gender, DD and MoCA score. In patients with SD significant negative correlation between MoCA and BDI score (r = -0,42, p<0,005) was found. In the group of patients without SD significant negative correlation between MoCA and EDSS (r = -0,27, p=0,03), MoCA and BDI (r = -0,26, p=0,043),) MoCA and HAM-A (r = -0,25, p=0,041) score was detected. CONCLUSION Conclusions: Insomnia type SD in RRMS patients were associated with older age, higher EDSS score and presence of anxiety and depression.
A machine learning approach for building an adaptive, real-time decision support system for emergency response to road traffic injuries

Abstract In this paper, historical data about road traffic accidents are utilized to build a decision support system for emergency response to road traffic injuries in real-time. A cost-sensitive artificial neural network with a novel heuristic cost matrix has been used to build a classifier capable of predicting the injury severity of occupants involved in crashes. The proposed system was designed to be used by the medical services dispatchers to better assess the severity of road traffic injuries, and therefore to better decide the most appropriate emergency response. Taking into account that the nature of accidents may change over time due to several reasons, the system enables users to build an updated version of the prediction model based on the historical and newly reported accidents. A dataset of accidents that occurred over a 6-year period (2008-2013) has been used for demonstration purposes throughout this paper. The accuracy of the prediction model was 65%. The Area Under the Curve (AUC) showed that the generated classifier can reasonably predict the severity of road traffic injuries. Importantly, using the cost-sensitive learning technique, the predictor overcame the problem of imbalanced severity distributions which are inherent in traffic accident datasets.
Serum proteins associated with periodontitis relapse post-surgery: A pilot study.

BACKGROUND The knowledge of which genes and proteins that are connected to the susceptibility to gingivitis with subsequent local tissue degradation seen in periodontitis is insufficient. Changes of serum proteins associated with recurrence of bleeding on probing (BOP) and increased periodontal pocket depths (PPD) after surgical treatment of periodontitis could reveal molecules that could be early signals of tissue destruction and/or of importance for systemic effects in other tissues or organs. METHODS We performed a longitudinal pilot study and followed 96 inflammation-related proteins over time in serum from patients who underwent surgical treatment of periodontitis (n = 21). The samples were taken before (time 0), and then at 3-, 6-, and 12-months after surgery. Changes in protein levels were analysed in relation to the clinical outcome measures, i.e. proportion of surfaces affected by BOP and PPD. RESULTS Changes in treatment outcomes with early signs of relapse in periodontitis after surgical treatment, e.g. increased BOP and PPDs, were during 12-months follow up associated with increased serum levels of high-sensitivity C-reactive protein (hs-CRP) and programmed death-ligand 1 (PD-L1), and reduced serum levels of cystatin-D protein. CONCLUSION This study shows that clinical signs of recurrence of periodontitis after surgery are reflected in serum, but larger studies are needed for verification. Our novel findings of an association between increased PD-L1- and decreased cystatin D-levels and recurrence in periodontitis are interesting because PD-L1 has been shown to facilitate bacterial infections and chronic inflammation and cystatin D to inhibit tissue destruction. Our results justify mechanistic studies regarding the role of these molecules in periodontitis. This article is protected by copyright. All rights reserved.
Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair

Cell therapy for Parkinson’s disease (PD) is aimed to replace the degenerated midbrain dopamine (mDA) neurons and restore DA neurotransmission in the denervated forebrain targets. A limitation of the intrastriatal grafting approach, which is currently used in clinical trials, is that the mDA neurons are implanted into the target area, in most cases the putamen, and not in the ventral midbrain where they normally reside. This ectopic location of the cells may limit their functionality due to the lack of appropriate afferent regulation from the host. Homotopic transplantation, into the substantia nigra, is now being pursued in rodent PD models as a way to achieve more complete circuitry repair. Intranigral grafts of mDA neurons, derived from human embryonic stem cells, have the capacity to re-establish the nigrostriatal and mesolimbic pathways in their entirety and restore dense functional innervations in striatal, limbic and cortical areas. Tracing of host afferent inputs using the rabies tracing technique shows that the afferent connectivity of grafts implanted in the nigra matches closely that of the intrinsic mDA system, suggesting a degree of circuitry reconstruction that exceeds what has been achieved before. This approach holds great promise, but to match the larger size of the human brain, and the 10 times greater distance between substantia nigra and its forebrain targets, it may be necessary to find ways to improve the growth capacity of the grafted mDA neurons, pointing to a combined approach where growth promoting factors are used to enhance the performance of mDA neuron grafts.
Migraine Features in Patients with Persistent Postural-Perceptual Dizziness

Objectives: To evaluate the presence of migraine features in patients with persistent postural-perceptual dizziness (PPPD). Methods: In a retrospective survey study, consecutive patients presenting to a tertiary care neurotology clinic during an 18-month period were given questionnaires about headache and dizziness symptoms. The survey responses plus history and examination of the patient were used to diagnose patients with PPPD. The prevalence of migraine headache, vestibular migraine (VM), and migraine characteristics was evaluated. Results: In total, 36 subjects with PPPD were included in the study. The mean age of the subjects was 56 ± 16 years with a female (72%) predominance. A total of 19 (53%) patients met the International Classification of Headache Disorders criteria for migraine headache, and 6 of those (17%) met the criteria for definite VM. Of the patients who did not meet full migraine headache criteria, 6 (17%) patients met 4 of 5 criteria, and 5 (14%) patients met 3 of 5 criteria. There was no significant difference between PPPD patients who fulfilled full migraine headache criteria and those who did not in sensitivity to light, sound, smells, weather changes, feelings of mental fog/confusion, and sinus pain/facial pressure. Conclusions: This study demonstrates that a majority of patients with PPPD fulfill the criteria for migraine headache. A large proportion of PPPD patients who do not meet the full criteria for migraine headache still meet a majority of the migraine headache criteria. This suggests an association between the 2 conditions. PPPD may be a part of the spectrum of otologic migraine, where migraine manifests as otologic symptoms.