Miracle-dz/UniFAR-FTUs huggingface dataset:
LIM domain only 1: an oncogenic transcription cofactor contributing to the tumorigenesis of multiple cancer types

Abstract The LIM domain only 1 (LMO1) gene belongs to the LMO family of genes that encodes a group of transcriptional cofactors. This group of transcriptional cofactors regulates gene transcription by acting as a key “connector” or “scaffold” in transcription complexes. All LMOs, including LMO1, are important players in the process of tumorigenesis. Unique biological features of LMO1 distinct from other LMO members, such as its tissue-specific expression patterns, interacting proteins, and transcriptional targets, have been increasingly recognized. Studies indicated that LMO1 plays a critical oncogenic role in various types of cancers, including T-cell acute lymphoblastic leukemia, neuroblastoma, gastric cancer, lung cancer, and prostate cancer. The molecular mechanisms underlying such functions of LMO1 have also been investigated, but they are currently far from being fully elucidated. Here, we focus on reviewing the current findings on the role of LMO1 in tumorigenesis, the mechanisms of its oncogenic action, and the mechanisms that drive its aberrant activation in cancers. We also briefly review its roles in the development process and non-cancer diseases. Finally, we discuss the remaining questions and future investigations required for promoting the translation of laboratory findings to clinical applications, including cancer diagnosis and treatment.
Outcomes after simultaneous pancreas–kidney transplantation from donation after circulatory death donors: A UK registry analysis

There are concerns that simultaneous pancreas–kidney (SPK) transplants from donation after circulatory death (DCD) donors have a higher risk of graft failure than those from donation after brain death (DBD) donors. A UK registry analysis of SPK transplants between 2005 and 2018 was performed. Pancreas survivals of those receiving organs from DCD or DBD donors were compared. Multivariable analyses were used to adjust for baseline differences between the two groups and to identify factors associated with pancreas graft loss. A total of 2228 SPK transplants were implanted; 403 (18.1%) were from DCD donors. DCD donors were generally younger, slimmer, less likely to have stroke as a cause of death, with lower terminal creatinines and shorter pancreas cold ischemic times than DBD donors. Median (IQR) follow‐up was 4.2 (1.6–8.1) years. On univariable analysis, there were no statistically significant differences in 5‐year death‐censored pancreas graft survival between the two donor types (79.5% versus 80.4%; p = .86). Multivariable analysis showed no statistically significant differences in 5‐year pancreas graft loss between transplants from DCD (n = 343) and DBD (n = 1492) donors (hazard ratio 1.26, 95% CI 0.76–1.23; p = .12). The findings from this study support the increased use of SPK transplants from DCD donors.
Can we safely use systemic treatment in atopic dermatitis during the COVID-19 pandemic? Overview of selected conventional and biologic systemic therapies

ABSTRACT Introduction: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the medical community has faced major challenges that affect disease management in all areas. Dermatologists and immunologists have to choose appropriate treatment strategy taking into consideration the risk of infection and possible exacerbation of the course of the disease in patients with confirmed infection. Management of atopic dermatitis (AD) in moderate to severe cases is based on systemic therapy such as cyclosporine, azathioprine, methotrexate and dupilumab. Areas covered: A literature search in PubMed database was performed until 6 March 2021. In this review, the authors discuss non-biologic and biologic systemic medications for AD and provide an overview of therapeutic recommendations during COVID-19 pandemic. Expert opinion: In case of an active COVID-19 infection, conventional systemic treatment and biological treatment needs to be stopped until clinical recovery. Noninfected patients with systemic treatment of AD should continue their therapy via self-application. The authors can conclude that understanding of dupilumab therapy is better recognized in context AD treatment during COVID-19 pandemic in comparison to cyclosporine, azathioprine and methotrexate. However, this systemic immunosuppressants still require further investigation and literature complementation.
Cost-effectiveness of nivolumab in squamous and non-squamous non-small cell lung cancer in Canada and Sweden: an update with 5-year data

Abstract Aims Nivolumab has been approved for advanced squamous and non-squamous non-small cell lung cancer (NSCLC) following platinum-based chemotherapy in both Canada and Sweden. We aimed to determine the value-for-money of nivolumab versus docetaxel in a Canadian and Swedish setting based on 5-year data. Methods These cost effectiveness analyses used partitioned survival models with three mutually exclusive health states: progression-free, progressed disease, and death. All clinical parameters were derived from two registration phase 3 randomized trials, CheckMate 017 and CheckMate 057, with a minimum follow-up of 5 years. Treatment duration was based on time-on-treatment data from the clinical trials. Costs were derived from published sources. The primary outcomes of the analyses were quality-adjusted life-years (QALYs), life-years gained, and incremental cost-effectiveness ratios (ICERs). The model input parameters for each analysis were chosen in line with guidance from the respective HTA authorities. Results From a Canadian payer perspective, the ICERs were CAN$140,753 per QALY in the squamous population, and CAN$173,804 per QALY in the non-squamous population, assuming a 10-year time horizon and a 5% discount rate for both costs and outcomes. Sensitivity analyses demonstrated that changes to the discount rates for outcomes had the highest impact on the ICERs. In the Swedish analysis, the ICERs were SEK568,895 per QALY in the squamous population and SEK662,991 per QALY in the non-squamous population, assuming a 15-year time horizon, a 3% discount rate, and a 2-year maximum treatment duration for nivolumab. Sensitivity analyses demonstrated that the ICERs were most sensitive to changes in the discount rate for outcomes. Conclusion These updated analyses, based on more mature trial data with a minimum follow-up of 5 years, generate more favorable ICERs versus the previously submitted HTA assessments that resulted in approval of nivolumab for patients with previously treated NSCLC in Canada and Sweden.
Impact of COVID-19 On Breast Cancer Management: A Radiological Prespective from A Tertiary Centre.

Objective The coronavirus-2019 (COVID-19) pandemic caused delaying breast cancer management, increasing time interval in chemotherapy cycles and surgery. This has implications on radiological manifestation of cancer. Further, we evaluated changes observed in mammography. Materials and Methods This case control study was conducted from March 25th, 2020 to August 15th, 2020 at the Integrated Breast Care Centre, All India Institute of Medical Science Rishikesh (AIIMS), Rishikesh. Sonomammography was performed on follow-up patients who were on chemotherapy and were scheduled for surgery. Moreover, duration of delay from the last neoadjuvant chemotherapy (NACT) cycle was recorded. Similar data in the pre-COVID-19 period from November 4th, 2019 to March 24th, 2020 was compared with post-COVID-19 data and was analyzed by SPSS Version 23. Results The study included 54 patients who presented between March 25th, 2020 and August 15th, 2020. Furthermore, the delay in NACT cycles has been shown to be associated with disease progression (p = 0.045). Subgroup analysis of treatment duration with various parameters revealed significant correlation between size, appearance of ulceration, and response evaluation (p<0.05). However, no significant association was found between duration of delay and the histological subtype of lesion (p>0.05). A substantial difference was seen in the evaluation of NACT response in pre- and post-COVID-19 time, with partial response (n = 39, 58.24%) seen as the most common response in pre-COVID-19 time and progressive disease (n = 28, 51.9%) as the most common response in post-COVID-19 time (p<0.001). Conclusion The coronavirus pandemic has severe impact on breast cancer management. A delay in NACT causes progression in cancer. This can be seen in ultrasound and mammogram.
Cleavage of the vaspin N-terminus releases cell-penetrating peptides that affect early stages of adipogenesis and inhibit lipolysis in mature adipocytes

ABSTRACT Vaspin expression and function is related to metabolic disorders and comorbidities of obesity. In various cellular and animal models of obesity, diabetes and atherosclerosis vaspin has shown beneficial, protective and/or compensatory action. While testing proteases for inhibition by vaspin, we noticed specific cleavage within the vaspin N-terminus and sequence analysis predicted cell-penetrating activity for the released peptides. These findings raised the question whether these proteolytic peptides exhibit biological activity. We synthesized various N-terminal vaspin peptides to investigate cell-penetrating activity and analyse uptake mechanisms. Focusing on adipocytes, we performed microarray analysis and functional assays to elucidate biological activities of the vaspin–derived peptide, which is released by KLK7 cleavage (vaspin residues 21-30; VaspinN). Our study provides first evidence that proteolytic processing of the vaspin N-terminus releases cell-penetrating and bioactive peptides with effects on adipocyte biology. The VaspinN peptide increased preadipocyte proliferation, interfered with clonal expansion during the early stage of adipogenesis and blunted adrenergic cAMP-signalling, downstream lipolysis as well as insulin signalling in mature adipocytes. Protease-mediated release of functional N-terminal peptides presents an additional facet of vaspin action. Future studies will address the mechanisms underlying the biological activities and clarify, if vaspin-derived peptides may have potential as therapeutic agents for the treatment of metabolic diseases.
Utilising multi-large omics data to elucidate biological mechanisms within multiple sclerosis genetic susceptibility loci

Background: Genome-wide association studies (GWAS) have succeeded in identifying over 200 susceptibility loci for multiple sclerosis (MS). However, the potential functional variants and the mechanisms by which these loci affect MS risk remain largely unexplained. Objectives: We used summary data-based Mendelian randomisation to prioritise risk genes and infer potential biological mechanisms for MS risk loci. Methods: The data used consisted of DNA methylation (n = 1980) QTL (mQTL) and gene expression (n = 31,684) QTL (eQTL) derived from whole blood as well as MS GWAS summary statistics (14,802 cases, 26,703 controls). The findings were further evaluated using data derived from independent brain mQTL (n = 1160) and eQTL (n = 1194). Results: In whole blood, we identified two independent genomic loci (lincRNA: RP11-326C3.13 and TNFSF14) with consistent genome-wide significant pleiotropic associations across different omics layers. In brain tissue, a similar effect for the RP11-326C3.13 locus was observed but not for TNFSF14, indicating a potential tissue-specific effect for the TNFSF14 locus. Conclusion: We provide in silico evidence for the putative biological mechanisms by which the identified DNA methylation sites and target genes are functionally relevant to MS development in different tissues. Future research targeting these genes and DNA methylation sites will determine their roles in the pathophysiology of MS.
Pridopidine reduces mutant huntingtin‐induced endoplasmic reticulum stress by modulation of the Sigma‐1 receptor

The endoplasmic reticulum (ER)‐localized Sigma‐1 receptor (S1R) is neuroprotective in models of neurodegenerative diseases, among them Huntington disease (HD). Recent clinical trials in HD patients and preclinical studies in cellular and mouse HD models suggest a therapeutic potential for the high‐affinity S1R agonist pridopidine. However, the molecular mechanisms of the cytoprotective effect are unclear. We have previously reported strong induction of ER stress by toxic mutant huntingtin (mHtt) oligomers, which is reduced upon sequestration of these mHtt oligomers into large aggregates. Here, we show that pridopidine significantly ameliorates mHtt‐induced ER stress in cellular HD models, starting at low nanomolar concentrations. Pridopidine reduced the levels of markers of the three branches of the unfolded protein response (UPR), showing the strongest effects on the PKR‐like endoplasmic reticulum kinase (PERK) branch. The effect is S1R‐dependent, as it is abolished in cells expressing mHtt in which the S1R was deleted using CRISPR/Cas9 technology. mHtt increased the level of the detergent‐insoluble fraction of S1R, suggesting a compensatory cellular mechanism that responds to increased ER stress. Pridopidine further enhanced the levels of insoluble S1R, suggesting the stabilization of activated S1R oligomers. These S1R oligomeric species appeared in ER‐localized patches, and not in the mitochondria‐associated membranes nor the ER‐derived quality control compartment. The colocalization of S1R with the chaperone BiP was significantly reduced by mHtt, and pridopidine restored this colocalization to normal, unstressed levels. Pridopidine increased toxic oligomeric mHtt recruitment into less toxic large sodium dodecyl sulfate‐insoluble aggregates, suggesting that this in turn reduces ER stress and cytotoxicity.
Resistance of Antarctic moss Sanionia uncinata to photoinhibition: Chlorophyll fluorescence analysis of the samples from Western and Eastern coast of the Antarctic Peninsula.

Interspecific differences in the sensitivity of Antarctic moss Sanionia uncinata from the King George Island (KGI) and James Ross Island (JRI) to photoinhibititory treatment were studied in laboratory conditions by chlorophyll fluorescence techniques. Slow (Kautsky) and fast (OJIP) kinetics were used for the measurements. Samples were exposed to a short-term (60 min) photoinhibitory treatment (PIT, 2000 μmol m-2 s-1 of photosynthetically active radiation). The photoinhibitory treatment (PIT) led to photoinhibition which was indicated by the decrease in FV /FM and ΦPSII in the KGI but not JRI samples. The decrease was, however, low and full recovery was reached 90 minutes after the PIT termination. Non-photochemical quenching (NPQ) was activated during the PIT, and relaxed fast during recovery. Early stages of photoinhibition showed the drop of FV /FM and ΦPSII to minimum values within the first 10 s of the PIT with their subsequent increase apparent within fast (0-5 min PIT) and slow phase (5-50 min PIT) of adjustment. The PIT caused the decrease of performance index (Pi_Abs), photosynthetic electron transport per reaction center (ET0 /RC (RC). The PIT induced an increase in thermal dissipation per RC (DI0 /RC), effectivity of thermal dissipation (Phi_D0 ), absorption per reaction center (ABS/RC), and trapping rate per RC (TR0 /RC). In conclusion, PIT led to only slight photoinhibition followed by fast recovery in S. uncinata from KGI and JRI since FV /FM and ΦPSII returned to pre-photoinhibitory. Therefore, S. uncinata might be considered photoinhibition resistant even in wet state. The KGI samples showed higher resistance to photoinhibition than JRI ones.
Maximum Possible Doses for a Cohort of Individuals with Intakes Possibly Containing a Component of a Ceramic-type Material

Abstract Recently, a glovebox breach led to the potential exposure of 15 Los Alamos National Laboratory employees to 238Pu. Given what is known about the material involved in the incident, the possibility of an intake with a ceramic-type component must be considered. Incidents in which intakes of ceramic solubility-type material is suspected represent a challenge for internal dose assessment via urine bioassay because even relatively large doses cannot be detected in urine until many months after the intake. Ideally, in these situations fecal samples should be collected to assess the intake, but in this case fecal sampling was delayed. This paper presents a method to calculate the maximum possible doses for all individuals involved in an incident using only early time-decreasing urine bioassay measurements.
Why People Hate Congress but Love Their Own Congressperson: An Information Processing Explanation

Citizens in Western democracies often have negative attitudes toward political bodies, yet consistently re-elect their own representatives to these same political bodies. They hate Congress, but love their own congressperson. In contrast to resource-based explanations, we propose that this Paradox of Congressional Support is partly due to the wide availability of negative information about politicians in open societies combined with basic processes of information processing. Five studies found that unrelated negative political information decreases attitudes toward political categories such as U.S. governors but has no effect on attitudes of familiar, individual politicians (e.g., one’s own governor); additional studies further identify familiarity as the critical process. Importantly, we demonstrate that this effect generalizes to all U.S. regions and remains when controlling for and is not moderated by political ideology. These results place a presumed macrolevel political paradox within the domain of cognitive mechanisms of basic information processing.
Patch Testing to Carvone: North American Contact Dermatitis Group Experience, 2009 to 2018

Background/Objectives Carvone, a flavoring agent, may cause allergic contact dermatitis. This study summarizes patch test reactions to carvone in patients tested by the North American Contact Dermatitis Group, 2009 to 2018. Methods This was a retrospective analysis of patients positive to carvone (5% petrolatum). Demographics were compared with those of patients who were negative. Other analyses included reaction strength, clinical relevance, coreactivity with other fragrance/flavor allergens, and exposure sources. Results Of 24,124 patients tested to carvone, 188 (0.78%) were positive. As compared with carvone-negative patients, carvone-positive patients were significantly more likely older than 40 years (P = 0.0284). Women (76.1%) and/or facial involvement (33.0%) were common in the carvone-positive group but not statistically different from carvone-negative patients; 73.3% (n = 138) of the reactions were currently relevant. Relevant sources were personal care products (46.3%, n = 87) and food (14.3%, n = 27). Coreactivity with other fragrance/flavor markers was present in 60.6% of carvone-positive patients, most commonly fragrance mix I (34.6%), balsam of Peru (24.5%), and cinnamic aldehyde (15.4%). Conclusions Ten-year prevalence of carvone sensitivity was 0.78%. Most carvone-positive patients were female, were older than 40 years, and/or had facial dermatitis. Personal care products were the most common source. Two-fifths of carvone reactions would have been missed by relying on other fragrance/flavoring allergens.
Global projections of the soil microbiome in the Anthropocene

Aim Soil microbes are essential for maintenance of life-supporting ecosystem services, but projections of how these microbes will be affected by global change scenarios are lacking. Therefore, our aim was to provide projections of future soil microbial distribution using several scenarios of global change. Location Global. Time period 1950-2090. Major taxa studied Bacteria and fungi. Methods We used a global database of soil microbial communities across six continents to estimate past and future trends of the soil microbiome. To do so, we used structural equation models to include the direct and indirect effects of changes in climate and land use in our predictions, using current climate (temperature and precipitation) and land-use projections between 1950 and 2090. Results Local bacterial richness will increase in all scenarios of change in climate and land use considered, although this increase will be followed by a generalized community homogenization process affecting > 85% of terrestrial ecosystems. Changes in the relative abundance of functional genes associated with the increases in bacterial richness are also expected. Based on an ecological cluster analysis, our results suggest that phylotypes such as Geodermatophilus spp. (typical desert bacteria), Mycobacterium sp. (which are known to include important human pathogens), Streptomyces mirabilis (major producers of antibiotic resistance genes) or potential fungal soil-borne plant pathogens belonging to Ascomycota fungi (Venturia spp., Devriesia spp.) will become more abundant in their communities. Main conclusions Our results provide evidence that climate change has a stronger influence on soil microbial communities than change in land use (often including deforestation and agricultural expansion), although most of the effects of climate are indirect, through other environmental variables (e.g., changes in soil pH). The same was found for microbial functions such as the prevalence of phosphate transport genes. We provide reliable predictions about the changes in the global distribution of microbial communities, showing an increase in alpha diversity and a homogenization of soil microbial communities in the Anthropocene.
Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats.

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end-stage renal failure and increases cardiovascular disease risk. Hyperglycemia promotes renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity- and age-related risk factors. This study aimed to define sexual dimorphism and renal function in a non-obese type 2 diabetes model with the spontaneous development of advanced diabetic nephropathy (T2DN rats). T2DN rats at 12- and over 48-weeks old were used to define disease progression and kidney injury development. We found impaired glucose tolerance and glomerular hyperfiltration in T2DN rats to compare with non-diabetic Wistar control. The T2DN rat displays a significant sexual dimorphism in insulin resistance, plasma cholesterol, renal and glomerular injury, urinary nephrin shedding, and albumin handling. Our results indicate that both male and female T2DN rats developed non-obese type 2 DKD phenotype, where the females had significant protection from the development of severe forms of DKD. Our findings provide further evidence for the T2DN rat strain's effectiveness for studying the multiple facets of DKD.
Six new triterpenoids from the root of Potentilla reptans and their cardioprotective effects in silico

Abstract Tormentic acid ester glucosides derivatives (1, 2 and 4), 3-oxoursane ester glycoside (3) and 11-methoxy-ursane ester glycosides (5, 6) as six new triterpenoids, along with catechin were isolated from the ethyl acetate fraction of Potentilla reptans root (Et) methanolic extract. The structures of the compounds were elucidated by 1D, 2D NMR, IR and MS spectroscopy. Additionally, isolated triterpenoid compounds (1–6) and catechin were evaluated for their cardioprotective effects via glycogen synthase kinase 3β (GSK-3β) and glucocorticoid regulated kinase-1 (SGK1) protein kinase inhibition by Molecular Docking. Compound 1 and catechin (compound 7) exhibited significant inhibitory effects against GSK-3β and SGK1 protein kinases with a binding energy value −9.1 and −8.8 kcal/mol, respectively. Hence, Et can be a suitable natural candidate to protect cardiomyocytes injury. Graphical abstract