Miracle-dz/UniFAR-FTUs huggingface dataset:
First-Line Immune-Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Current Landscape and Future Progress

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide. Most of these patients with non-small cell lung cancer (NSCLC) present with the advanced stage of the disease at the time of diagnosis, and thus decrease the 5-year survival rate to about 5%. Immune checkpoint inhibitors (ICIs) can act on the inhibitory pathway of cancer immune response, thereby restoring and maintaining anti-tumor immunity. There are already ICIs targeting different pathways, including the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) pathway. Since March 2015, the US Food and Drug Administration (FDA) approved nivolumab (anti-PD-1 antibody) as the second-line option for treatment of patients with advanced squamous NSCLC. Additionally, a series of inhibitors related to PD-1/PD-L1 immune-checkpoints have helped in the immunotherapy of NSCLC patients, and modified the original treatment model. However, controversies remain regarding the use of ICIs in a subgroup with targeted oncogene mutations is a problem that we need to solve. On the other hand, there are continuous efforts to find biomarkers that effectively predict the response of ICIs to screen suitable populations. In this review, we have reviewed the history of the continuous developments in cancer immunotherapy, summarized the mechanism of action of the immune-checkpoint pathways. Finally, based on the results of the first-line recent trials, we propose a potential first-line immunotherapeutic strategy for the treatment of the patients with NSCLC.
Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.
Rational design of balanced dual-targeting antibiotics with limited resistance

Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] ≤1 μg/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections.
Genotoxic effect of simultaneous therapeutic exposure to polycyclic aromatic hydrocarbons and UV radiation

Polycyclic aromatic hydrocarbons (PAHs) and ultraviolet radiation (UV) represent genotoxic factors that commonly occur in the living and working environment. The dermal form of exposure represents a significant part of the total load of dangerous chemical and physical environmental factors to which an organism is subjected. However, simultaneous dermal exposures to PAHs (pharmaceutical crude coal tar [CCT]) and UV (UVA and UVB) also have therapeutic uses. A typical example is Goeckerman therapy (GT) for psoriasis. The question of the therapeutic efficacy of GT and the related level of genotoxic danger is still under discussion. The aim of the present study was to compare four GT variants (G1–G4) in terms of efficacy and acceptable genotoxic hazard. Efficacy was expressed by the psoriasis area of severity index (PASI) score, genotoxic hazard by chromosomal aberration in peripheral lymphocytes. The lowest risk of genotoxic hazard and the lowest efficiency was observed in G1 variant (3% of the CCT and UVA + UVB). The efficacy of G2 (4% CCT and UVA + UVB), G3 (4% CCT and UVB), and G4 variants (5% CCT and UVA + UVB) was comparable. The highest risk of genotoxic hazard was found in the G3 variant. In the terms of sufficient efficacy and acceptable genotoxic hazard, a combination of 4% or 5% of CCT and UVA and UVB seems to be acceptable (variants G2 and G4).
Towards the Metropolitan City: adaptation strategies to climate change using new technologies and integrated approaches for e-governance and spatial planning decision-making

1 School of Doctorate Studies in Regional Planning and Public Policy, Università IUAV di Venezia, S. Polo 2468, I-30125, Venice, Italy 2 School of Doctorate Studies in Innovation and ICT for the city, the land and the environment, Università IUAV di Venezia, S. Polo 2468, I-30125, Venice, 3 Department of Design and Planning in Complex Environments, Università IUAV di Venezia, S. Croce 1957 30135 Venezia Italy
Detection of an unusual G8P[8] rotavirus in a Rotarix-vaccinated child with acute gastroenteritis using Nanopore MinION sequencing

Abstract Rationale: Rotavirus is routinely diagnosed by the detection of antigens or the viral genome. However, these tests have limitations, in that they do not detect all rotavirus strains. Patient concerns: We present a case of a 27-month-old girl who was hospitalized for 4 days with severe gastroenteritis, including high fever, vomiting, diarrhea, mild dehydration, and periumbilical pain. Notably, the patient previously received the Rotarix vaccine. Diagnoses: The laboratory tests were negative for rotavirus, astrovirus, adenovirus, and norovirus as well as common diarrhea-causing bacteria. Human-bovine recombinant rotavirus was detected by MinION sequencing. Interventions: To investigate the cause agents from the unexplained severe gastroenteritis infant, the stool sample was prepared by random amplification for Nanopore MinION sequencing. Outcomes: Treatment through the administration of ORS solution and galtase powder with probiotics was successful after the diagnosis of unusual rotavirus infection. Lessons: This case report is the first detection of an unusual human-bovine recombinant rotavirus in an idiopathic gastroenteritis using Nanopore MinION sequencing.
A Wargame-Augmented Knowledge Elicitation Method for the Agile Development of Novel Systems

There are inherent difficulties in designing an effective Human–Machine Interface (HMI) for a first-of-its-kind system. Many leading cognitive research methods rely upon experts with prior experiences using the system and/or some type of existing mockups or working prototype of the HMI, and neither of these resources are available for such a new system. Further, these methods are time consuming and incompatible with more rapid and iterative systems development models (e.g., Agile/Scrum). To address these challenges, we developed a Wargame-Augmented Knowledge Elicitation (WAKE) method to identify information requirements and underlying assumptions in operator decision making concurrently with operational concepts. The developed WAKE method incorporates naturalistic observations of operator decision making in a wargaming scenario with freeze-probe queries and structured analytic techniques to identify and prioritize information requirements for a novel HMI. An overview of the method, required apparatus, and associated analytical techniques is provided. Outcomes, lessons learned, and topics for future research resulting from two different applications of the WAKE method are also discussed.
The distribution of bird species in the New World: Patterns in species turnover

Spatial patterns of species richness are most often analysed at large scales by covering the area in question with a grid and comparing the richness of different squares. This method ignores species turnover across squares, or beta diversity, which has the potential either to reduce or to exaggerate richness patterns demonstrated using grid methodologies, and may itself show interesting spatial patterns. A consideration of spatial patterns of turnover should accompany any analysis of spatial patterns in species richness. Here, we analyse latitudinal patterns in turnover for the avifauna of the New World, using a variety of different turnover measures. Depending on the measure used, turnover either decreases with latitude, mirroring the pattern in species richness, or shows no significant latitudinal variation. Thus, the latitudinal pattern in richness previously shown for New World birds is not caused by turnover. Turnover is negatively related to the mean geographic range size of species at a given latitude, although this is again method-dependent. We discuss the relationship between the different measures of turnover, and assess how appropriate each is as a measure of this quantity. We conclude that more studies are required before we can make any generalisations about patterns in turnover, and that close attention to methodology will be required in all future considerations.
BeyondSilos, a Telehealth-Enhanced Integrated Care Model in the Domiciliary Setting for Older Patients: Observational Prospective Cohort Study for Effectiveness and Cost-Effectiveness Assessments

Background Information and communication technology may provide domiciliary care programs with continuity of care. However, evidence about the effectiveness and cost-effectiveness of information and communication technology in the context of integrated care models is relatively scarce. Objective The objective of our study was to provide evidence on the clinical effectiveness and cost-effectiveness of the BeyondSilos project for patients enrolled in the Badalona city pilot site in Spain. Methods A quasi-experimental study was used to assess the cost-effectiveness of information and communication technology–enhanced integration of health and social care, including the third sector (intervention), compared to basic health and social care coordination (comparator). The study was conducted in Badalona between 2015 and 2016. Participants were followed for 8 months. Results The study included 198 patients: 98 in the intervention group and 100 in the comparator group. The mean Barthel index remained unchanged in the intervention group (mean change 0.14, 95% CI –4.51 to 4.78; P=.95) but decreased in the comparator group (mean change –3.23, 95% CI –5.34 to –1.11; P=.003). Instrumental Activities of Daily Living significantly decreased in both groups: mean changes of –0.23 (95% CI –0.44 to –0.02; P=.03) and –0.33 (95% CI –0.46 to –0.20; P<.001) in the intervention and comparator groups, respectively. No differences were found in the Geriatric Depression Scale (intervention: mean change 0.28, 95% CI –0.44 to 1.01, P=.44; comparator: mean change –0.29, 95% CI –0.59 to 0.01, P=.06). The intervention showed cost-effectiveness (incremental cost-effectiveness ratio €6505.52, approximately US $7582). Conclusions The information and communication technology–enhanced integrated domiciliary care program was cost-effective. The beneficial effects of this approach strongly rely upon the commitment of the professional staff involved. Trial Registration ClinicalTrials.gov NCT03111004; http://clinicaltrials.gov/ct2/show/ NCT03111004
THE EFFECTS OF SYNCHRONIZATION OF CARBOHYDRATE AND PROTEIN SUPPLY IN SUGARCANE BAGASSE BASED RATION ON BODY COMPOSITION OF SHEEP

The objective of this research was to study the effects of synchronization of carbohydrate and protein supply in sugarcane bagasse based ration on the body composition of sheep. The study was consisted of two steps of experiment. The first step of experiment used two rumen cannulated adult rams to create formulation of three diets with different synchronization index, namely 0.37; 0.50 and 0.63 respectively. The experimental diets were designed to be iso-energy, iso-nitrogenous and iso-neutral detergent fibre (iso-NDF). The second step of experiment was to determine the body composition of sheep fed the experimental diets, which were created in the first experiment. The body composition of fifteen rams were determined on week 0; 4; and 8 of experimental period, these were accomplished using the technique of urea dilution. The alteration of synchronization index did not affect on feed intake, ratio of ruminal acetate to propionate and serum glucose concentration, but dry matter (DM) digestibility was affected (P<0.05) by the treatment of synchronization index in the diet. The alteration of synchronization index in the diet did not affect on the percentage of body protein, fat and water significantly, though body weight of sheep gained slightly during the experimental period.
Streamlining Quantitative Analysis of Long RNA Sequencing Reads

Transcriptome analyses allow for linking RNA expression profiles to cellular pathways and phenotypes. Despite improvements in sequencing methodology, whole transcriptome analyses are still tedious, especially for methodologies producing long reads. Currently, available data analysis software often lacks cost- and time-efficient workflows. Although kit-based workflows and benchtop platforms for RNA sequencing provide software options, e.g., cloud-based tools to analyze basecalled reads, quantitative, and easy-to-use solutions for transcriptome analysis, especially for non-human data, are missing. We therefore developed a user-friendly tool, termed Alignator, for rapid analysis of long RNA reads requiring only FASTQ files and an Ensembl cDNA database reference. After successful mapping, Alignator generates quantitative information for each transcript and provides a table in which sequenced and aligned RNA are stored for further comparative analyses.
Latent Factor Structure and Measurement Invariance of the NIH Toolbox Cognition Battery in an Alzheimer’s Disease Research Sample

Abstract Objective: This study investigated the latent factor structure of the NIH Toolbox Cognition Battery (NIHTB-CB) and its measurement invariance across clinical diagnosis and key demographic variables including sex, race/ethnicity, age, and education for a typical Alzheimer’s disease (AD) research sample. Method: The NIHTB-CB iPad English version, consisting of 7 tests, was administered to 411 participants aged 45–94 with clinical diagnosis of cognitively unimpaired, dementia, mild cognitive impairment (MCI), or impaired not MCI. The factor structure of the whole sample was first examined with exploratory factor analysis (EFA) and further refined using confirmatory factor analysis (CFA). Two groups were classified for each variable (diagnosis or demographic factors). The confirmed factor model was next tested for each group with CFA. If the factor structure was the same between the groups, measurement invariance was then tested using a hierarchical series of nested two-group CFA models. Results: A two-factor model capturing fluid cognition (executive function, processing speed, and memory) versus crystalized cognition (language) fit well for the whole sample and each group except for those with age < 65. This model generally had measurement invariance across sex, race/ethnicity, and education, and partial invariance across diagnosis. For individuals with age < 65, the language factor remained intact while the fluid cognition was separated into two factors: (1) executive function/processing speed and (2) memory. Conclusions: The findings mostly supported the utility of the battery in AD research, yet revealed challenges in measuring memory for AD participants and longitudinal change in fluid cognition.
Marginal impacts of rising temperature on Arctic benthic microalgae production based on in situ measurements and modelled estimates

Arctic microphytobenthic in situ net community production (NCP) was measured via the oxygen exchange rate in benthic chambers equipped with optical sensor spots at 3 representative sandy sites in Kongsfjorden (Svalbard, 79° N, 12° E) at 3 to 11 m water depth during June 2008. No significant differences were detected between stations and depths in either photoautotrophic biomass or primary production. All sites showed low but variable rates of NCP, ranging from −0.3 to +0.6 mmol O2 m−2 h−1 (−9 to +18 mg O2 m−2 h−1). The numerical model of Walsby (1997) was applied to estimate seasonal and regional rates of nearshore NCP for 2008 using in situ P/E curve parameters, solar global radiation, wind data and satellite-derived sea surface temperatures. The highest daily NCP rates of 15 to 18 mmol O2 m−2 d−1 were found throughout the Arctic spring and summer seasons (1 April until 31 August 2008) at shallow depths <15 m. The differences between modelled stratified and fully mixed water column conditions were small and in the range of 10%. Depthand time-integrated NCP of the entire Kongsfjorden coastline during June 2008 yielded 9 t of O2. A predicted increase in the sea surface temperature by 2°C would have only a marginal impact on the NCP (<3%). Our model sensitivity analysis of the uncertainties associated with P/E curve parameters and Q10 values clearly showed a crucial dependence of NCP on the Q10 values. Thus, further studies on temperature dependence are required.
Microtubule affinity–regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.
Preoperative serum circulating microRNAs as potential biomarkers for chronic postoperative pain after total knee replacement

Background Chronic postoperative pain affects approximately 20% of patients with knee osteoarthritis after total knee replacement. Circulating microRNAs can be found in serum and might act as biomarkers in a variety of diseases. The current study aimed to investigate the preoperative expression of circulating microRNAs as potential predictive biomarkers for the development of chronic postoperative pain in the year following total knee replacement. Methods Serum samples, collected preoperatively from 136 knee osteoarthritis patients, were analyzed for 21 circulatory microRNAs. Pain intensity was assessed using a visual analog scale before and one year after total knee replacement. Patients were divided into a low-pain relief group (pain relief percentage <30%) and a high-pain relief group (pain relief percentage >30%) based on their pain relief one year after total knee replacement, and differences in microRNAs expression were analyzed between the two groups. Results We found that three microRNAs were preoperatively dysregulated in serum in the low-pain relief group compared with the high-pain relief group. MicroRNAs hsa-miR-146a-5p, -145-5p, and -130 b-3p exhibited fold changes of 1.50, 1.55, and 1.61, respectively, between the groups (all P values < 0.05). Hsa-miR-146a-5p and preoperative pain intensity correlated positively with postoperative pain relief (respectively, R = 0.300, P = 0.006; R = 0.500, P < 0.001). Discussion This study showed that patients with a low postoperative pain relief present a dysregulation of circulating microRNAs. Altered circulatory microRNAs expression correlated with postoperative pain relief, indicating that microRNAs can serve as predictive biomarkers of pain outcome after surgery and hence may foster new strategies for preventing chronic postoperative pain after total knee replacement (TKR).
MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation.

Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost the CD8+ T cell-mediated cytotoxicity. However, this action is eventually dependent on the efficient recognition of tumor-specific antigens via T cell receptors. One primary mechanism by which tumor cells evade immune surveillance is to downregulate their antigen presentation. Little progress has been made towards harnessing potential therapeutic targets for enhancing antigen presentation on the tumor cell. Here, we identified MAL2 as a key player that determines the turnover of the antigen-loaded MHC-I complex and reduces the antigen presentation on tumor cells. MAL2 promotes the endocytosis of tumor antigens via direct interaction with the MHC-I complex and endosome-associated RAB proteins. In preclinical models, depletion of MAL2 in breast tumor cells profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that MAL2 is a potential therapeutic target for breast cancer immunotherapy.