Miracle-dz/UniFAR-FTUs huggingface dataset:
Trends in male breast cancer mortality: a global overview

Supplemental Digital Content is available in the text. Objectives Recent trends in male breast cancer have been inadequately studied. We updated mortality trends in selected countries and regions worldwide using most recent available data and we predicted figures for 2020. Methods We extracted official death certification data for male breast cancer and population estimates from the WHO and the Pan American Health Organization databases, from 2000 to 2017. We computed age-standardized (world population) death rates for selected countries and regions worldwide. We used joinpoint regression analysis to identify significant changes in trends and to predict death numbers and rates for 2020. Results In 2015–2017, Central-Eastern Europe had a rate of 2.85/1 000 000, and Russia of 2.22, ranking among the highest. North-Western and Southern Europe, the European Union as a whole and the USA showed rates ranging between 1.5 and 2.0. Lower rates were observed in most Latin American countries, with values below 1.35/1 000 000, in Australia, 1.22, and Japan, 0.58. Between 2000–2004 and 2015–2017, age-adjusted death rates decreased between 10 and 40% in North-Western Europe, Russia, and the USA, and between 1.5 and 25% in the other areas under study, except Latin America (+0.8%). Except for Central-Eastern Europe, predicted rates for 2020 were favourable. Conclusion Advancements in management are likely the main drivers of the favourable trends in male breast cancer death rates over the last decades. Delayed diagnosis and limited access to effective care explain the higher mortality in some areas.
Alteration of Postural Balance in Patients with Fibromyalgia Syndrome—A Systematic Review and Meta-Analysis

Balance problems are one of the most frequent symptoms in patients with Fibromyalgia Syndrome (FMS). However, the extent and nature of this balance disorder are not known. The objective of this work was to determine the best evidence for the alteration of postural balance in patients with FMS and analyze differences with healthy controls. To meet this objective, a systematic review with meta-analysis was performed. A bibliographical search was carried out in PubMed Medline, Scopus, Web of Science, CINAHL and SciELO. Observational studies that assessed postural balance in patients with FMS compared to healthy subjects in baseline conditions, were selected. In a random-effect model, the pooled effect was calculated with the Standardized Mean Difference (SMD) and its 95% confidence interval (CI). Nineteen studies reporting data of 2347 participants (95% female) were included. FMS patients showed poor balance with a large effect on static (SMD = 1.578; 95% CI = 1.164, 1.992), dynamic (SMD = 0.946; 95% CI = 0.598, 1.294), functional balance (SMD = 1.138; 95% CI = 0.689, 1.588) and on balance confidence (SMD = 1.194; 95% CI = 0.914, 1.473). Analysis of the Sensory Organization Test showed large alteration of vestibular (SMD = 1.631; 95% CI = 0.467, 2.795) and visual scores (SMD = 1.317; 95% CI = 0.153, 2.481) compared to healthy controls. Patients with FMS showed worse scores for different measures of postural balance compared to healthy controls. Concretely, FMS patients appear to have poor vestibular and visual scores with a possible somatosensory dependence.
Stomach Region Stimulated Determines Effects on Duodenal Motility in Rats.

Gastric electrical stimulation (GES) is used clinically to promote proximal GI emptying and motility. In acute experiments, we measured duodenal motor responses elicited by GES applied at 141 randomly chosen electrode sites on the stomach serosal surface. Overnight-fasted (H2O available) anesthetized male rats (n = 81) received intermittent biphasic GES for 5 min (20s-on/40s-off cycles; I = 0.3mA; pw = 0.2ms; 10 Hz). A strain gauge on the serosal surface of the proximal duodenum of each animal was used to evaluate baseline motor activity and the effect of GES. Using ratios of time blocks compared to a 15-min pre-stimulation baseline, we evaluated the effects of the 5-min stimulation on concurrent activity; on the 10-min immediately after the stimulation, and on the 15-min period beginning with the onset of stimulation. We mapped the magnitude of the duodenal response (3 different motility indices) elicited from the 141 stomach sites. Post hoc electrode site maps associated with duodenal responses suggested three zones similar to the classic regions of forestomach, corpus and antrum. Maximal excitatory duodenal motor responses were elicited from forestomach sites, whereas inhibitory responses occurred with stimulation of the corpus. Moderate excitatory duodenal responses occurred with stimulation of the antrum. Complex, weak inhibitory/excitatory responses were produced by stimulation at boundaries between stomach regions. Patterns of GES efficacies coincided with distributions of previously mapped vagal afferents, suggesting that excitation of the duodenum is strongest when GES electrodes are situated over stomach concentrations of vagal intramuscular arrays, putative stretch receptors in the muscle wall.
HN1L promotes invasion and metastasis of the esophagogastric junction adenocarcinoma

Adenocarcinoma of the esophagogastric junction (AEG) refers to cancer that crosses the line of the gastroesophageal junction and includes distal esophageal cancer and proximal gastric cancer. It is characterized by early metastasis and a poor prognosis and has few treatment options. Here, we report a novel potential therapeutic target, hematological and neurological expressed 1‐like (HN1L), in AEG.
Research Article: A phylogenetic analysis of haloarchaea found in a solar saltern

Abstract In this study, the diversity of the haloarchaea found within a crystallizer pond of a solar saltern located in San Diego, California, USA was examined. Both cultured-based and culture-independent polymerase chain reaction (PCR) 16S ribosomal DNA (rDNA) molecular phylogenetic methodology was employed. Of the eighteen defined genera in the family Halobacteriaceae, three different genera were found to be represented in this study, along with two apparent novel lineages containing only uncultivated representatives. These two novel lineages are most closely related to the genera Halogeometricum and Haloferax. Of the three defined genera represented, Haloarcula, Halobacterium, and Halorubrum, we were able to identify both cultured isolates and DNA from uncultivated members from within these groups. Based on culturing and culture-independent sampling, the predominant members of the haloarchaeal crystallizer community in this particular saltern belonged to the genus Halobacterium. It is also noteworthy that no halophilic bacteria were detected as part of the community in these studies.
Oncolytic adenovirus ORCA-010 activates pro-inflammatory myeloid cells and facilitates T cell recruitment and activation by PD-1 blockade in melanoma.

Immune checkpoint inhibitors have advanced the treatment of melanoma. Nevertheless, a majority of patients are resistant, or develop resistance, to immune checkpoint blockade, which may be related to prevailing immune suppression by myeloid regulatory cells in the tumor microenvironment. ORCA-010 is a novel oncolytic adenovirus that selectively replicates in, and lyses, cancer cells. We previously showed that ORCA-010 can activate melanoma-exposed conventional dendritic cells (cDC). To study the effect of ORCA-010 on melanoma-conditioned macrophage development, we used an in vitro co-culture model of human monocytes with melanoma cell lines. We observed a selective survival and polarization of monocytes into M2-like macrophages (CD14+CD80-CD163+) in co-cultures with cell lines that expressed macrophage colony-stimulating factor. Oncolysis of these melanoma cell lines, effected by ORCA-010, activated the resulting macrophages and converted them to a more pro-inflammatory state, evidenced by higher levels of PD-L1, CD80, and CD86 and an enhanced capacity to prime allogenic T cells and induce a type-1 T cell response. To assess the effect of ORCA-010 on myeloid subset distribution and activation in vivo, ORCA-010 was intratumorally injected and tested for T cell activation and recruitment in the human adenovirus non-permissive B16-OVA mouse melanoma model. While systemic PD-1 blockade in this model in itself did not modulate myeloid or T cell subset distribution and activation, when it was preceded by i.t. injection of ORCA-010, this induced an increased rate and activation state of CD8α+ cDC1, both in the tumor microenvironment and in the spleen. Observed increased rates of activated CD8+ T cells, expressing CD69 and PD-1, were related to both increased CD8α+ cDC rates and M1/M2 shifts in tumor and spleen. In conclusion, the myeloid modulatory properties of ORCA-010 in melanoma, resulting in recruitment and activation of T cells, could enhance the antitumor efficacy of PD-1 blockade.
Spatio-Temporal Mitosis Detection in Time-Lapse Phase-Contrast Microscopy Image Sequences: A Benchmark

In this paper, we report the results of the first international contest on mitosis detection in phase-contrast microscopy image sequences (https://www.iti-tju.org/mitosisdetection), which was held at the workshop of computer vision for microscopy image analysis (CVMI) in CVPR 2019. This contest aims to promote research on spatiotemporal mitosis detection under microscopy images. In this contest, we released a large-scale time-lapse phase-contrast microscopy image dataset (C2C12-16) for the mitosis detection task. Compared with the previous popular datasets (e.g., C2C12, C3H10), C2C12-16 contains more annotated mitotic events and more diverse cell culture environments. A total of ten different mitosis detection methods were submitted in the contest and evaluated on the test sets of four different cell culture environments in C2C12-16. In this benchmark, we describe all methods and conduct a thorough analysis based on their performances and discuss a feasible direction for mitosis detection. To the best of our knowledge, this is the first benchmark for the mitosis detection problem using a time-lapse phase-contrast microscopy spatiotemporal image sequence model.
Therapeutic targeting of transcriptional elongation in diffuse intrinsic pontine glioma.

BACKGROUND DIPG is associated with transcriptional dysregulation driven by H3K27 mutation. The super elongation complex (SEC) is required for transcriptional elongation through release of RNA polymerase II (Pol II). Inhibition of transcription elongation by SEC disruption can be an effective therapeutic strategy of H3K27M-mutant diffuse intrinsic pontine glioma (DIPG). Here, we tested the effect of pharmacological disruption of the SEC in H3K27M-mutant DIPG to advance understanding of the molecular mechanism and as a new therapeutic strategy for DIPG. METHODS Short hairpin RNAs (shRNAs) were used to suppress the expression of AF4/FMR2 4 (AFF4), a central SEC component, in H3K27M-mutant DIPG cells. A peptidomimetic lead compound KL-1 was used to disrupt a functional component of SEC. Cell viability assay, colony formation assay, and apoptosis assay were utilized to analyze the effects of KL-1 treatment. RNA- and ChIP-sequencing were used to determine the effects of KL-1 on gene expression and chromatin occupancy. We treated mice bearing human H3K27M-mutant DIPG xenografts with KL-1. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival. RESULTS Depletion of AFF4 significantly reduced the cell growth of H3K27M-mutant DIPG. KL-1 increased genome-wide Pol II occupancy and suppressed transcription involving multiple cellular processes that promote cell proliferation and differentiation of DIPG. KL-1 treatment suppressed DIPG cell growth, increased apoptosis, and prolonged animal survival with human H3K27M-mutant DIPG xenografts. CONCLUSIONS SEC disruption by KL-1 increased therapeutic benefit in vitro and in vivo, supporting a potential therapeutic activity of KL-1 in H3K27M-mutant DIPG.
Spectral model of depth‐integrated water column photosynthesis and its inhibition by ultraviolet radiation

Depth‐integrated models of primary production (DIMs) are used to estimate water column photosynthesis as a function of chlorophyll concentration, irradiance at the surface, the penetration of photosynthetically available radiation (PAR), and parameters of the relationship between photosynthesis and PAR. These models are inherently unable to account for variability in the ratio of photosynthetically utilizable radiation (PUR) to PAR with depth and water type, and they cannot account for the inhibition of photosynthesis by ultraviolet radiation, UVR. These important spectral effects — all sensitive to climate change — are readily described with numerical models that require many computations and are unsuitable for some important applications, including the estimation of aquatic productivity from remote sensing. We present a simple DIM that accounts for the spectral effects of irradiance on photosynthesis, including inhibition by UVR. Water column photosynthesis, normalized to surface chlorophyll and scaled to the maximum rate per unit chlorophyll, is described as a function of four dimensionless derived variables:E*PUR, PUR at the surface scaled to the saturation irradiance for photosynthesis; T*PUR, water transparency, normalized to a depth scale and weighted spectrally for photosynthetic absorption; E*PIR, surface irradiance weighted spectrally for inhibition of photosynthesis; and T*PIR, scaled transparency weighted for photosynthesis‐inhibiting radiation. Simple functions of these variables closely approximate (within 6%) the results of a full‐spectral numerical model of instantaneous and daily integrated water column photosynthesis with and without UVR for a broad range of water types, solar angles, stratospheric ozone concentrations and biological properties of phytoplankton. The spectral DIM is suitable for examining patterns in global ocean productivity and can be used to assess the biological effects of variations in solar radiation (e.g., ozone depletion) and water clarity in climate‐change scenarios for lakes and oceans.
The Antibiotic Negamycin Crosses the Bacterial Cytoplasmic Membrane by Multiple Routes

Negamycin is a natural pseudodipeptide antibiotic with promising activity against Gram-negative and Gram-positive bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus, and good efficacy in infection models. It binds to ribosomes with a novel binding mode, stimulating miscoding and inhibiting ribosome translocation. ABSTRACT Negamycin is a natural pseudodipeptide antibiotic with promising activity against Gram-negative and Gram-positive bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus, and good efficacy in infection models. It binds to ribosomes with a novel binding mode, stimulating miscoding and inhibiting ribosome translocation. We were particularly interested in studying how the small, positively charged natural product reaches its cytoplasmic target in Escherichia coli. Negamycin crosses the cytoplasmic membrane by multiple routes depending on environmental conditions. In a peptide-free medium, negamycin uses endogenous peptide transporters for active translocation, preferentially the dipeptide permease Dpp. However, in the absence of functional Dpp or in the presence of outcompeting nutrient peptides, negamycin can still enter the cytoplasm. We observed a contribution of the DppA homologs SapA and OppA, as well as of the proton-dependent oligopeptide transporter DtpD. Calcium strongly improves the activity of negamycin against both Gram-negative and Gram-positive bacteria, especially at concentrations around 2.5 mM, reflecting human blood levels. Calcium forms a complex with negamycin and facilitates its interaction with negatively charged phospholipids in bacterial membranes. Moreover, decreased activity at acidic pH and under anaerobic conditions points to a role of the membrane potential in negamycin uptake. Accordingly, improved activity at alkaline pH could be linked to increased uptake of [3H]negamycin. The diversity of options for membrane translocation is reflected by low resistance rates. The example of negamycin demonstrates that membrane passage of antibiotics can be multifaceted and that for cytoplasmic anti-Gram-negative drugs, understanding of permeation and target interaction are equally important.
Microwave-Assisted Synthesis, Characterization and Modeling of CPO-27-Mg Metal-Organic Framework for Drug Delivery

The coordination polymer CPO-27-Mg was rapidly synthesized under microwave irradiation. This material exhibits a sufficiently high drug loading towards aspirin (~8% wt.) and paracetamol (~14% wt.). The binding of these two molecules with the inner surface of the metal-organic framework was studied employing the Gaussian and Plane Wave approach of the Density Functional Theory. The structure of CPO-27-Mg persists after the adsorption of aspirin or paracetamol and their desorption energies, being quite high, decrease under solvent conditions.
A Review of Plant Extracts and Plant-Derived Natural Compounds in the Prevention/Treatment of Neonatal Hypoxic-Ischemic Brain Injury

Neonatal hypoxic-ischemic (HI) brain injury is one of the major drawbacks of mortality and causes significant short/long-term neurological dysfunction in newborn infants worldwide. To date, due to multifunctional complex mechanisms of brain injury, there is no well-established effective strategy to completely provide neuroprotection. Although therapeutic hypothermia is the proven treatment for hypoxic-ischemic encephalopathy (HIE), it does not completely chang outcomes in severe forms of HIE. Therefore, there is a critical need for reviewing the effective therapeutic strategies to explore the protective agents and methods. In recent years, it is widely believed that there are neuroprotective possibilities of natural compounds extracted from plants against HIE. These natural agents with the anti-inflammatory, anti-oxidative, anti-apoptotic, and neurofunctional regulatory properties exhibit preventive or therapeutic effects against experimental neonatal HI brain damage. In this study, it was aimed to review the literature in scientific databases that investigate the neuroprotective effects of plant extracts/plant-derived compounds in experimental animal models of neonatal HI brain damage and their possible underlying molecular mechanisms of action.
The resting membrane potential of hSC-CM in a syncytium is more hyperpolarised than that of isolated cells

ABSTRACT Human-induced pluripotent stem cell (hiPSC) and stem cell (hSC) derived cardiomyocytes (CM) are gaining popularity as in vitro model for cardiology and pharmacology studies. A remaining flaw of these cells, as shown by single-cell electrophysiological characterization, is a more depolarized resting membrane potential (RMP) compared to native CM. Most reports attribute this to a lower expression of the Kir2.1 potassium channel that generates the IK1 current. However, most RMP recordings are obtained from isolated hSC/hiPSC-CMs whereas in a more native setting these cells are interconnected with neighboring cells by connexin-based gap junctions, forming a syncytium. Hereby, these cells are electrically connected and the total pool of IK1 increases. Therefore, the input resistance (Ri) of interconnected cells is lower than that of isolated cells. During patch clamp experiments pipettes need to be well attached or sealed to the cell, which is reflected in the seal resistance (Rs), because a nonspecific ionic current can leak through this pipette-cell contact or seal and balance out small currents within the cell such as IK1. By recording the action potential of isolated hSC-CMs and that of hSC-CMs cultured in small monolayers, we show that the RMP of hSC-CMs in monolayer is approximately −20 mV more hyperpolarized compared to isolated cells. Accordingly, adding carbenoxolone, a connexin channel blocker, isolates the cell that is patch clamped from its neighboring cells of the monolayer and depolarizes the RMP. The presented data show that the recorded RMP of hSC-CMs in a syncytium is more negative than that determined from isolated hSC/hiPSC-CMs, most likely because the active pool of Kir2.1 channels increased.
Lab-on-Microsphere—FRET-Based Multiplex Sensor Platform

Here we report on the development and investigation of a novel multiplex assay model based on polymer microspheres (PMS) encoded with ternary AIS/ZnS quantum dots (QDs). The system was prepared via layer-by-layer deposition technique. Our studies of Förster resonance energy transfer (FRET) between the QD-encoded microspheres and two different cyanine dyes have demonstrated that the QD photoluminescence (PL) quenching steadily increases with a decrease in the QD-dye distance. We have found that the sensitized dye PL intensity demonstrates a clear maximum at two double layers of polyelectrolytes between QDs and Dye molecules on the polymer microspheres. Time resolved PL measurements have shown that the PL lifetime decreases for the QDs and increases for the dyes due to FRET. The designed system makes it possible to record spectrally different bands of FRET-induced dye luminescence with different decay times and thereby allows for the multiplexing by wavelength and photoluminescence lifetimes of the dyes. We believe that PMS encoded with AIS/ZnS QDs have great potential for the development of new highly selective and sensitive sensor systems for multiplex analysis to detect cell lysates and body fluids’ representative biomarkers.
A 3-Year Observational Study of Patients with Progressive Systemic Sclerosis Treated with an Intensified B Lymphocyte Depletion Protocol: Clinical and Immunological Response

Background: B-cells have been suggested to play a role in the pathogenesis of systemic sclerosis (SSc), representing, therefore, a potential therapeutic target. Objectives: We aimed at investigating the 36-month outcomes of 20 SSc patients who underwent an intensified B-depletion therapy (IBCDT) scheme, including both Rituximab (RTX) and cyclophosphamide (CYC). Methods: Data from 20 severe patients (18 females and 2 males, mean age 66.7 ± 11.0 years) with diffuse SSc (anti-topoisomerase I antibody in 95%) patients with multiorgan involvement including interstitial lung disease (ILD) treated with an IBCDT were prospectively collected. IBCDT comprehended: RTX 375 mg/m2 administered for four weekly doses (on days 1, 8, 15, and 22), followed by two additional doses after 30 and 60 days, in addition to two administrations of 10 mg/kg of intravenous CYC plus three methylprednisolone pulses (15 mg/kg) and subsequently followed by oral prednisone rapidly tapered to low minimum dosage of 5 mg daily. In addition, 10 patients with more severe functional respiratory impairment at baseline were also treated with RTX 500 mg every 4 months during the first year and two times a year during the second and the third year. Results: After 36 months of follow-up, we recorded significant amelioration in N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels (mean 385.4 ± 517 pg/mL at baseline to 279 ± 543 after 36 months). In addition, a significant radiological improvement of ILD in 20% of patients (4/20) and a radiological stabilization with no sign of progression of interstitial involvement in 13/20 (65%) were documented. A total of 3 out of 20 (15%) patients experienced a worsening of the ILD. No patient showed further decrease in functional respiratory parameters, including forced vital capacity, forced expiratory volume in one second, and mean values of diffusing capacity for carbon monoxide Moreover, no patient showed any change in the ejection fraction and pulmonary artery pressure when comparing values at baseline and after 24 and 36 months of observation. No severe infection, renal flare, RTX-related side effects were observed. No patient died. Conclusions: Our findings support that the IBCDT was well tolerated and might be a promising therapeutic option for the management of SSc, especially in those subjects with multiorgan involvement that includes ILD.