Miracle-dz/UniFAR-FTUs huggingface dataset:
Follicular Lymphoma Diagnostic Caveats and Updates.

CONTEXT. — Follicular lymphoma is a common small B-cell lymphoma, likely to be encountered by any practicing pathologist, regardless of specialty. Although the features of typical follicular lymphoma are well known and in most instances easily identifiable, there are lesser-appreciated morphologic appearances that can raise alternative diagnostic possibilities. The limited tissue available in core needle biopsies can make it additionally challenging to thoroughly evaluate those features in the context of architecture. Furthermore, ancillary testing including immunohistochemistry and molecular/genetic analysis do not always show classic findings and may pose additional challenges to interpretation. OBJECTIVES. — To review the morphologic features of follicular lymphoma with a discussion of morphologic variants and mimics; to discuss pitfalls of ancillary testing and provide the practicing pathologist with an appropriate context for interpretation of immunohistochemical and molecular/genetic studies when follicular lymphoma is part of the differential diagnosis; and to propose diagnostic strategies when there is limited tissue for evaluation. DATA SOURCES. — We used examples of follicular lymphoma from our institution as well as a review of the literature, with a focus on the diagnostic aspects that are broadly relevant to a general pathology practice. CONCLUSIONS. — Follicular lymphoma can occasionally present with atypical morphologic, immunohistochemical, or molecular/genetic features. In particular, those findings can be difficult to interpret in the setting of a limited tissue sample. Awareness of those possibilities will help guide the pathologist to a more accurate and precise diagnosis.
CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection

Interrupting T cell costimulatory signals as a strategy to control undesired immune responses, such as occur in autoimmunity or transplantation, has the potential to alleviate many of the unwanted side effects associated with current immunosuppressive therapies. Belatacept, a high-affinity version of CTLA4-Ig that blocks ligand ligation to CD28, has been approved for use in kidney transplant recipients. Despite the long-term benefits associated with its use, such as improved renal function and lower cardiovascular risk, a subset of patients treated with belatacept experience elevated rates of acute T cell–mediated rejection, tempering enthusiasm for its use. Here we demonstrate that costimulation-independent T cell alloreactivity relies on signaling through CD122, the shared IL-2 and IL-15 receptor &bgr;-chain. Combined costimulatory and CD122 blockade improved survival of transplanted tissue in mice and nonhuman primates by controlling proliferation and effector function of CD8+ T cells. The high-affinity IL-2 receptor was dispensable for memory CD8+ T cell responses, whereas signaling through CD122 as a component of the high-affinity IL-15 receptor was critical for costimulation-independent memory CD8+ T cell recall, distinguishing specific roles for IL-2 and IL-15 in T cell activation. These studies outline a novel approach for clinical optimization of costimulatory blockade strategies in transplantation by targeting CD122.
Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

ABSTRACT The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.
Relationship between nutritional status and the systemic inflammatory response: micronutrients

Micronutrients such as trace elements and vitamins are important as enzyme cofactors in the metabolism of all cells in the body and therefore key to determining nutritional status. The present systematic review examined the evidence of the impact of the systemic inflammatory response on plasma micronutrient status in acute (surgical) and chronic tissue injury. A literature review using targeted subject headings was carried out. Plasma C-reactive protein was used to classify minor (<10 mg/l), moderate (11–80 mg/l) and major (>80 mg/l) inflammation. The literature search produced 2344 publications and plasma vitamin D, zinc and carotenoids were most commonly studied and plasma vitamins K, B2 and B6 were least studied. In acute injury thirteen studies (all prospective) and in chronic injury twenty-four studies (largely retrospective) were included in the review. There was consistent evidence that most common measured micronutrients in the plasma (zinc, selenium, vitamins A, D, E, K, B2, B6, B12, C, lutein, lycopene, α- and β-carotene) were significantly lowered from minor to moderate to major inflammation. The results of the present systematic review indicate that most plasma micronutrients fall as part of the systemic inflammatory response irrespective of acute or chronic injury. Therefore, in the presence of a systemic inflammation, plasma micronutrient concentrations should be interpreted with caution. There are a number of methods applied to adjust plasma micronutrient concentrations to avoid misdiagnosis of deficiency. Alternatively, intracellular measurements appear to obviate the need for such plasma adjustment to assess micronutrient status.
Low Persistence Rates in Patients With Rheumatoid Arthritis Treated With Triple Therapy and Adverse Drug Events Associated With Sulfasalazine

Combination treatments for patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX) alone include the addition of a tumor necrosis factor inhibitor (TNFi) or the addition of sulfasalazine (SSZ) and hydroxychloroquine to MTX (triple therapy). We compared persistence and adherence rates between these 2 combination therapies in US veterans and report the reasons for discontinuation of combination treatment in these groups.
Neutron reflectometry with the Multi-Blade 10B-based detector

The Multi-Blade is a boron-10-based gaseous detector developed for neutron reflectometry instruments at the European Spallation Source in Sweden. The main challenges for neutron reflectometry detectors are the instantaneous counting rate and spatial resolution. The Multi-Blade has been tested on the CRISP reflectometer at the ISIS Neutron and Muon Source in the UK. A campaign of scientific measurements has been performed to study the Multi-Blade response in real instrumental conditions. The results of these tests are discussed in this paper.
Pharmacokinetics and safety of single and multiple doses of rasagiline in healthy Japanese and caucasian subjects

As of March 2018, rasagiline is approved for the treatment of Parkinson disease in 55 countries including Japan. The present study evaluated the pharmacokinetics (PK) and safety of rasagiline in healthy Japanese and Caucasian subjects following single and multiple administrations of three rasagiline doses. In this double‐blind, placebo‐controlled study, 64 healthy subjects (32 Japanese and 32 Caucasian) received either rasagiline (0.5, 1.0, or 2.0 mg) or placebo for 10 days with PK sampling for single‐dose administration on day 1 and for multiple administration on day 10. Regardless of administration schedule, rasagiline plasma concentrations and dose‐related increases in exposure parameters were similar between Japanese and Caucasians. Rasagiline accumulation (2‐fold for 0.5 mg and 3‐fold for 1.0 mg and 2.0 mg doses) following multiple administration was similar across the ethnic groups. Geometric mean ratios (GMR) comparing Japanese to Caucasians for AUC0‐24, Cmax and AUCinf following single administration were 1.38, 1.17 and 1.38 for 0.5 mg; 1.22, 1.20 and 1.22 at 1.0 mg; and 1.02, 1.00 and 1.02 at for 2.0 mg. GMR for AUCtau and Cmax,ss following multiple administration were 1.43 and 1.06 at 0.5 mg, 1.06 and 1.00 at 1.0 mg, and 1.09 and 1.07 at 2.0 mg. Safety measures were unremarkable and similar between Caucasian and Japanese subjects. Comparable systemic exposure and safety parameters were demonstrated for rasagiline administered to healthy Japanese and Caucasian subjects.
Metronomic Chemotherapy with Vinorelbine Produces Clinical Benefit and Low Toxicity in Frail Elderly Patients Affected by Advanced Non-Small Cell Lung Cancer

Background Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and comorbidities. In the present study, we focused on the effect of metronomic vinorelbine treatment in elderly patients with advanced unresectable non-small cell lung cancer (NSCLC). Methods From January 2016 to December 2016, 44 patients affected by non-small cell lung cancer referred to our oncology day hospital were progressively analyzed. The patients were treated with oral vinorelbine 30 mg x 3/wk or 40 mg x 3/wk meaning one day on and one day off. The patients were older than 60, stage IIIB or IV, ECOG PS ≥ 1, and have at least one important comorbidity (renal, hepatic, or cardiovascular disease). The schedule was based on ECOG-PS and comorbidities. The primary endpoint was progression-free survival (PFS). PFS was used to compare patients based on different scheduled dosage (30 or 40 mg x3/weekly) and age (more or less than 75 years old) as exploratory analysis. We also evaluated as secondary endpoint toxicity according to Common Toxicity Criteria Version 2.0. Results Vinorelbine showed a good safety profile at different doses taken orally and was effective in controlling cancer progression. The median overall survival (OS) was 12 months. The disease control rate (DCR) achieved 63%. The median PFS was 9 months. A significant difference in PFS was detected comparing patients aged below with those over 75, and the HR value was 0.72 (p<0.05). Not significant was the difference between groups with different schedules. Conclusions This study confirmed the safety profile of metronomic vinorelbine and its applicability for patients unfit for standard chemotherapies and adds the possibility of considering this type of schedule not only for very elderly patients.
Race-Related Content of Animated Cartoons

Relying upon a content analysis of 1 specific type of medium to which young people are exposed beginning at an early age, on a regular basis, and for many years (i.e., animated cartoons), the present study examines what types of messages are provided about being members of different racial groups. This research examines the following issues: (a) How prevalent are race-related content and overt acts of racism in animated cartoons? (b) Has this prevalence changed over time? (c) What “types” of characteristics tend to be associated with being Caucasian, African American, Latino, Native American, and Asian? Results indicate that the prevalence of racial minority groups has been low over the years, with gradual decreases in representation during recent years, when the American population of racial minorities has grown. As time has gone on, the presence of overt racism has decreased greatly, demonstrating particularly sharp declines in the years since the Civil Rights Movement of the 1960s. On most dimensions studied, members of different races were portrayed similarly.
High‐intensity interval training changes mitochondrial respiratory capacity differently in adipose tissue and skeletal muscle

The effect of high‐intensity training (HIT) on mitochondrial ADP sensitivity and respiratory capacity was investigated in human skeletal muscle and subcutaneous adipose tissue (SAT). Twelve men and women underwent 6 weeks of HIT (7 × 1 min at app. 100% of maximal oxygen uptake (VO2max)). Mitochondrial respiration was measured in permeabilized muscle fibers and in abdominal SAT. Mitochondrial ADP sensitivity was determined using Michaelis Menten enzyme kinetics. VO2max, body composition and citrate synthase (CS) activity (skeletal muscle) and mtDNA (SAT) were measured before and after training. VO2max increased from 2.6 ± 0.2 to 2.8 ± 0.2 L O2/min (P = 0.011) accompanied by a decreased mitochondrial ADP sensitivity in skeletal muscle (Km: 0.14 ± 0.02 to 0.29 ± 0.03 mmol/L ADP (P = 0.002)), with no changes in SAT (Km: 0.12 ± 0.02 to 0.16 ± 0.05 mmol/L ADP; P = 0.186), following training. Mitochondrial respiratory capacity increased in skeletal muscle from 57 ± 4 to 67 ± 4 pmol O2·mg−1·sec−1 (P < 0.001), but decreased with training in SAT from 1.3 ± 0.1 to 1.0 ± 0.1 pmol O2·mg−1·sec−1 (P < 0.001). CS activity increased (P = 0.027) and mtDNA was unchanged following training. Intrinsic mitochondrial respiratory capacity was unchanged in skeletal muscle, but increased in SAT after HIT. In summary, our results demonstrate that mitochondrial adaptations to HIT in skeletal muscle are comparable to adaptations to endurance training, with an increased mitochondrial respiratory capacity and CS activity. However, mitochondria in SAT adapts differently compared to skeletal muscle mitochondria, where mitochondrial respiratory capacity decreased and mtDNA remained unchanged after HIT.
Cross‐scale interactions affect tree growth and intrinsic water use efficiency and highlight the importance of spatial context in managing forests under global change

We investigated the potential of cross‐scale interactions to affect the outcome of density reduction in a large‐scale silvicultural experiment to better understand options for managing forests under climate change. We measured tree growth and intrinsic water‐use efficiency (iWUE) based on stable carbon isotopes (δ13C) to investigate impacts of density reduction across a range of progressively finer spatial scales: site, stand, hillslope position and neighbourhood. In particular, we focused on the influence of treatments beyond the boundaries of treated stands to include impacts on downslope and neighbouring stands across sites varying in soil moisture. Trees at the wet site responded with increased growth when compared with trees at the dry site. Additionally, trees in treated stands at the dry site responded with increased iWUE while trees at the wet site showed no difference in iWUE compared to untreated stands. We hypothesized that water is not the primary limiting factor for growth at our sites, but that density reduction released other resources, such as growing space or nutrients to drive the growth response. At progressively finer spatial scales we found that tree responses were not driven by hillslope location (i.e. downslope of treatment) but to changes in local neighbourhood tree density. Synthesis. This study demonstrated that water can be viewed as an agent to investigate cross‐scale interactions as it links processes operating at coarse to finer spatial scales and vice versa. Consequently, management prescriptions such as density reductions to increase resistance and resilience of trees to climate change, specifically to drought, need to consider cross‐scale interactions as specific magnitude and mechanisms of growth responses can only be predicted when multiple scales are taken into account.
Awake craniotomy without sedation in treatment of patients with lesional epilepsy

Background: The use of awake craniotomy for surgical treatment of epilepsy was applied in surgery of convexital tumors, arteriovenous malformations, some superficial aneurysms, and stereotactic neurosurgery. The aim of this study was to show the advantages of awake craniotomy without sedation, accompanied by intraoperative neurophysiological monitoring in patients with symptomatic epilepsy. Methods: This article describes the results of surgical treatment in 41 patients with various pathologies; 31 among them suffered from epilepsy. Results: Most frequently, the pathological foci were located in frontal and parietal lobes nearby eloquent brain areas. Irrespective of damage location, simple partial and complex partial seizures were seen almost with the same frequency. Intraoperative mapping of eloquent cortical areas and subcortical tracts without sedation resulted in total resection of pathological area in 75% of cases with low rate of permanent neurological deficit (two patients). Minor perioperative complications, including the decrease in blood pressure in six patients and intraoperative convulsions in two patients, were handled and did not led to operation termination or anesthesia conversion. Excellent seizures control (Engel 1) was achieved in 80% of patients with available catamnesis. Conclusion: Thus, the proposed method allows eliminating the complications associated with sedation and provides radical resection of pathological epileptogenic foci with low complication rate.
A short, robust brain activation control task optimised for pharmacological fMRI studies

Functional magnetic resonance imaging (fMRI) is a popular method for examining pharmacological effects on the brain; however the BOLD response is an indirect measure of neural activity, and as such is vulnerable to confounding effects of pharmacological probes. Controlling for such non-specific effects in pharmacological fMRI studies is therefore an important consideration. We have developed two variants of a standardized control task that are short (5 minutes duration) simple (for both the subject and experimenter), widely applicable, and yield a number of readouts in a spatially diverse set of brain networks. The tasks consist of four functionally discreet three-second trial types (plus additional null trials) and contain visual, auditory, motor and cognitive (eye-movements, and working memory tasks in the two task variants) stimuli. Performance of the tasks was assessed in a group of 15 subjects scanned on two separate occasions, with test-retest reliability explicitly assessed using intra-class correlation coefficients. Both tasks produced robust patterns of brain activation in the expected brain regions, and reliability coefficients for the tasks were generally high, with four out of eight task conditions rated as ‘excellent’, and only one out of eight rated as ‘poor’. Voxel-wise reliability measures also showed good spatial concordances with the brain activation results. Either of the two task variants would be suitable for use as a control task in future pharmacological fMRI studies or for any situation where a short, reliable, basic task paradigm is required. Stimulus code is available online for re-use by the scientific community.
Ameliorative Influence of Ajwa Dates on Ochratoxin A-Induced Testis Toxicity

Ajwa dates (Phoenix dactylifera), cultivated particularly in Al-Madina Al-Monawarh in Saudi Arabia, and considered as a rich source of natural antioxidants such as anthocyanins, carotenoids and phenolics. It is believed that Ajwa dates have a wide range of protective effects. For this reason, this work aimed to investigate the ameliorative effect of Ajwa dates aqueous extract against ochratoxin A (OTA)-induced testicular lesions in rats. Rats were divided into four groups and treated for 28 days. Group I served as normal control, group II (OTA exposed) treated orally with 289 μg/kg/day. Group III (Ajwa dates aqueous extract) treated orally with 1 g/kg/day. The last group served as the protective group (pretreated with Ajwa dates extract, then OTA). Histological studies revealed that OTA induced lesions in the testicular structure included proliferation of sertoli cells, impairment of some spermatogenesis stages and accumulation of premeiotic germinal cells. However, pretreatment with Ajwa dates extract prevented all the testicular damage and improved spermatogenesis, as well as remarkably enhanced the testicular structure. In conclusion, Ajwa dates aqueous extract has a powerful protective effect and ameliorative influence against OTA- induced testicular damage and may be used to treat sexual impairment and male infertility.
MicroRNA-552 promotes hepatocellular carcinoma progression by downregulating WIF1

MicroRNAs (miRNAs/miRs) are involved in the metastasis of hepatocellular carcinoma (HCC). In the present study, it was demonstrated that miR-552 was upregulated in HCC tissues. High miR-552 expression was associated with malignant clinicopathological features and decreased survival rates. The in vitro results indicated that miR-552 overexpression promoted migration, invasion and epithelial-mesenchymal transition in Hep3B cells. However, the knockdown of miR-552 inhibited its oncogenic roles in Huh-7 cells. Additionally, Wnt inhibitory factor 1 (WIF1) was demonstrated to be a direct target of miR-552 in Hep3B and Huh-7 cells. Additional experiments identified that miR-552 promotes β-catenin expression by increasing the phosphorylation of GSK3β at Ser9. In conclusion, the results suggested that miR-552 may promote HCC progression by blocking WIF1-mediated GSK3β dephosphorylation. miR-552 may be a biomarker for predicting the outcomes of patients with HCC.
Nectin1 expression is frequently decreased in gastric cancers

Gastric cancer (GC) is rich in many different histological types, but how the histological pattern is defined remains to be proved. The relation between GC histological types and the expression of nectin1, which is one of the cell adhesion molecules that composes adherens junction, has not been reported. According to a publicly available database of 406 GC patients, the median overall survival of Nectin1 high expression patients was 55.4 months and that of low expression patients was 25.6 months (P = 0.0246). Using surgically or endoscopically resected GC samples, nectin1 expression was analyzed by immunohistochemistry. Nectin1 expressed at adherens junction in all the normal epithelial cells. However, nectin1 expressed not at adherens junction but at apical membrane in epithelial cells in intestinal metaplasia. The expression pattern of nectin1 in intestinal type GC resembled to intestinal metaplasia. In order to analyze the difference in nectin1 expression between GC histological types, a total of 116 intestinal type GC and 33 diffuse type GC. The expression of necitin1 in diffuse type GC (3.0%) was remarkably decreased compared to that in intestinal type GC (65.5%) (P < 0.0001). In conclusion, this is the first report showing an association between nectin1 expression and histological subtypes of GC.