Miracle-dz/UniFAR-FTUs huggingface dataset:
Quantifying Risk Pathway Crosstalk Mediated by miRNA to Screen Precision drugs for Breast Cancer Patients

Breast cancer has become the most common cancer that leads to women’s death. Breast cancer is a complex, highly heterogeneous disease classified into various subtypes based on histological features, which determines the therapeutic options. System identification of effective drugs for each subtype remains challenging. In this work, we present a computational network biology approach to screen precision drugs for different breast cancer subtypes by considering the impact intensity of candidate drugs on the pathway crosstalk mediated by miRNAs. Firstly, we constructed and analyzed the subtype-specific risk pathway crosstalk networks mediated by miRNAs. Then, we evaluated 36 Food and Drug Administration (FDA)-approved anticancer drugs by quantifying their effects on these subtype-specific pathway crosstalk networks and combining with survival analysis. Finally, some first-line treatments of breast cancer, such as Paclitaxel and Vincristine, were optimized for each subtype. In particular, we performed precision screening of subtype-specific therapeutic drugs and also confirmed some novel drugs suitable for breast cancer treatment. For example, Sorafenib was applicable for the basal subtype treatment, Irinotecan was optimum for Her2 subtype treatment, Vemurafenib was suitable for the LumA subtype treatment, and Vorinostat could apply to LumB subtype treatment. In addition, the mechanism of these optimal therapeutic drugs in each subtype of breast cancer was further dissected. In summary, our study offers an effective way to screen precision drugs for various breast cancer subtype treatments. We also dissected the mechanism of optimal therapeutic drugs, which may provide novel insight into the precise treatment of cancer and promote researches on the mechanisms of action of drugs.
Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome—Strategies for In Vivo Administration: Part-II

Diabetes is a complex disease characterized by hyperglycemia, together with polyuria, polydipsia, and polyphagia. While Type 1 diabetes mellitus (T1DM) results from genetic, environmental, or immune dysfunction factors leading to pancreatic β-cell destruction depriving the organism from endogenous insulin, Type 2 diabetes mellitus (T2DM) is characterized by peripheral insulin resistance. Depending on the type of diabetes mellitus and drug mechanism to study, the animal model should be carefully selected among the wide variety of the currently available ones. This review discusses the most common animal models currently employed to study T1DM and T2DM. Moreover, an overview on the administration routes that could be used is also discussed.
Identification of Novel Fusion Transcripts in Undifferentiated Pleomorphic Sarcomas by Transcriptome Sequencing

Background/Aim: Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal neoplasm characterized by chromosomal instability. The aim of this study was to identify fusion events involved in UPS. Materials and Methods: Transcriptome sequencing was performed to search for new fusion genes in 19 UPS samples, including two paired recurrent (R) and re-recurrent (RR) samples. Results: A total of 66 fusion genes were detected. Among them, 10 novel fusion genes were further confirmed by reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing. Retinoblastoma (RB1) fusions (2 cases) were the most recurrent fusion genes. The gene fusions RB1-RNASEH2B, RB1-FGF14-AS1, and E2F6-FKBP4 were correlated with the Rb/E2F pathway. Pseudogenes were involved in the formation of the gene fusions CIC-DUX4L8 and EIF2AK4-ANXA2P2. Importantly, targetable gene fusions (PDGFRA-MACROD2 and NCOR1-MAP2K1) were detected in UPS. Conclusion: Screening for the presence of fusion transcripts will provide vital clues to the understanding of genetic alterations and the finding of new targeted therapies for UPS.
Contrast‐enhanced ultrasound for quantification of tissue perfusion in humans

Contrast‐enhanced ultrasound is an imaging technique that can be used to quantify microvascular blood volume and blood flow of vital organs in humans. It relies on the use of microbubble contrast agents and ultrasound‐based imaging of microbubbles. Over the past decades, both ultrasound contrast agents and experimental techniques to image them have rapidly improved, as did experience among investigators and clinicians. However, these improvements have not yet resulted in uniform guidelines for CEUS when it comes to quantification of tissue perfusion in humans, preventing its uniform and widespread use in research settings. The objective of this review is to provide a methodological overview of CEUS and its development, the influences of hardware and software settings, type and dosage of ultrasound contrast agent, and method of analysis on CEUS‐derived perfusion data. Furthermore, we will discuss organ‐specific imaging challenges, advantages, and limitations of CEUS.
Leveraging plant hydraulics to yield predictive and dynamic plant leaf allocation in vegetation models with climate change

Plant functional traits provide a link in process‐based vegetation models between plant‐level physiology and ecosystem‐level responses. Recent advances in physiological understanding and computational efficiency have allowed for the incorporation of plant hydraulic processes in large‐scale vegetation models. However, a more mechanistic representation of water limitation that determines ecosystem responses to plant water stress necessitates a re‐evaluation of trait‐based constraints for plant carbon allocation, particularly allocation to leaf area. In this review, we examine model representations of plant allocation to leaves, which is often empirically set by plant functional type‐specific allometric relationships. We analyze the evolution of the representation of leaf allocation in models of different scales and complexities. We show the impacts of leaf allocation strategy on plant carbon uptake in the context of recent advancements in modeling hydraulic processes. Finally, we posit that deriving allometry from first principles using mechanistic hydraulic processes is possible and should become standard practice, rather than using prescribed allometries. The representation of allocation as an emergent property of scarce resource constraints is likely to be critical to representing how global change processes impact future ecosystem dynamics and carbon fluxes and may reduce the number of poorly constrained parameters in vegetation models.
Unique genetic basis of the distinct antibiotic potency of high acetic acid production in the probiotic yeast Saccharomyces cerevisiae var. boulardii

The yeast Saccharomyces boulardii has been used worldwide as a popular, commercial probiotic, but the basis of its probiotic action remains obscure. It is considered conspecific with budding yeast Saccharomyces cerevisiae, which is generally used in classical food applications. They have an almost identical genome sequence, making the genetic basis of probiotic potency in S. boulardii puzzling. We now show that S. boulardii produces at 37°C unusually high levels of acetic acid, which is strongly inhibitory to bacterial growth in agar-well diffusion assays and could be vital for its unique application as a probiotic among yeasts. Using pooled-segregant whole-genome sequence analysis with S. boulardii and S. cerevisiae parent strains, we succeeded in mapping the underlying QTLs and identified mutant alleles of SDH1 and WHI2 as the causative alleles. Both genes contain a SNP unique to S. boulardii (sdh1F317Y and whi2S287*) and are fully responsible for its high acetic acid production. S. boulardii strains show different levels of acetic acid production, depending on the copy number of the whi2S287* allele. Our results offer the first molecular explanation as to why S. boulardii could exert probiotic action as opposed to S. cerevisiae. They reveal for the first time the molecular-genetic basis of a probiotic action-related trait in S. boulardii and show that antibacterial potency of a probiotic microorganism can be due to strain-specific mutations within the same species. We suggest that acquisition of antibacterial activity through medium acidification offered a selective advantage to S. boulardii in its ecological niche and for its application as a probiotic.
Management Strategies and Patient Selection After a Hospital Funding Reform for Prostate Cancer Surgery in Canada

Key Points Question Was a change in hospital funding policy for radical prostatectomy associated with changes in management of localized prostate cancer in the province of Ontario, Canada? Findings In this population-based interrupted time series study, which included 33 128 patients with incident localized prostate cancer and 17 159 patients treated with radical prostatectomy, no statistically significant association of the change in hospital funding policy with most outcomes was found. However, potential improvement in appropriate patient selection for prostate cancer surgery was observed. Meaning The implementation of a hospital funding policy change aimed at improving health care quality and value was not associated with management of localized prostate cancer.
Tunable holmium-doped fiber laser with multiwatt operation from 2025  nm to 2200  nm.

The emission band of holmium-doped silica fibers extends beyond 2200 nm, which means these lasers have the potential of covering considerable parts of the atmospheric transmission window between ∼2100 nm and 2250 nm. However, efficient operation toward 2200 nm is challenging due to absorption in fused silica at the laser wavelength. Here we present a holmium-doped fiber laser specifically targeting long-wavelength operation. The laser is implemented as a high-feedback wavelength selective ring cavity and is tunable from 2025 nm to 2200 nm. A maximum slope efficiency of 58% is obtained at 2050 nm and a slope of 27% is obtained at 2200 nm. A power of 5.5 W from a single aperture (8.9 W total) is demonstrated at 2200 nm. Our results represent extended coverage of the 2 μm spectral band with multiwatt-level silica fiber lasers.
Mixed Fibrinolytic Phenotypes in Decompensated Cirrhosis and Acute‐on‐Chronic Liver Failure with Hypofibrinolysis in Those With Complications and Poor Survival

Patients with liver disease acquire complex changes in their hemostatic system, which results in a fragile rebalanced status. The status of the fibrinolytic system is controversial, as is the role of fibrinolytic dysfunction in bleeding and thrombosis in patients with cirrhosis. Here, we aimed to determine fibrinolytic status and its relationship with outcome in acutely ill patients with cirrhosis.
The effects of lycopene supplement on the spermatogram and seminal oxidative stress in infertile men: A randomized, double‐blind, placebo‐controlled clinical trial

Infertility is a major, worldwide problem that is affected, and mediated, by several factors, in particular, oxidative stress. Thus, the aim of this study was to evaluate the effect of lycopene supplementation on spermatogram and seminal oxidative stress. In this randomized, double‐blind, placebo‐controlled trial study, 44 infertile men with oligozoospermia were randomly divided into two groups: The experimental group was supplemented with 25 mg of lycopene, and the control group received placebo for 12 weeks. Anthropometric, physical activity and dietary assessment, semen analysis, total antioxidant capacity (TAC), malondialdehyde, and glutathione peroxidase were measured pre‐ and post‐intervention. At the end of the study, there was a significant increase in total sperm count and concentration in the lycopene group, and the latter total count remained significant after adjustment (p < .05). Intragroup analysis showed a significant increase in ejaculate volume, total sperm count, concentration total motility, nonprogressive, and nonmotility in lycopene group (p < .05). The TAC changes, in both groups, remained significant after adjustment (p < .05). Also, within‐group analysis showed a significant increase in TAC levels (p < .05). Lycopene supplement can improve sperm parameters and oxidative stress biomarkers in oligozoospermia infertile men; however, further studies with larger sample size and duration are required.
Invariant Kalman Filtering

The Kalman filter—or, more precisely, the extended Kalman filter (EKF)—is a fundamental engineering tool that is pervasively used in control and robotics and for various estimation tasks in autonomous systems. The recently developed field of invariant extended Kalman filtering uses the geometric structure of the state space and the dynamics to improve the EKF, notably in terms of mathematical guarantees. The methodology essentially applies in the fields of localization, navigation, and simultaneous localization and mapping (SLAM). Although it was created only recently, its remarkable robustness properties have already motivated a real industrial implementation in the aerospace field. This review aims to provide an accessible introduction to the methodology of invariant Kalman filtering and to allow readers to gain insight into the relevance of the method as well as its important differences with the conventional EKF. This should be of interest to readers intrigued by the practical application of mathematical theories and those interested in finding robust, simple-to-implement filters for localization, navigation, and SLAM, notably for autonomous vehicle guidance.
Telomere length determinants in childhood

Abstract Telomere length (TL) is a dynamic marker that reflects genetic predispositions together with the environmental conditions of an individual. It is closely related to longevity and a number of pathological conditions. Even though the extent of telomere research in children is limited compared to that of adults, there have been a substantial number of studies providing first insights into child telomere biology and determinants. Recent discoveries revealed evidence that TL is, to a great extent, determined already in childhood and that environmental conditions in adulthood have less impact than first believed. Studies have demonstrated that large inter-individual differences in TL are present among newborns and are determined by diverse factors that influence intrauterine development. The first years of child growth are associated with high cellular turnover, which results in fast shortening of telomeres. The rate of telomere loss becomes stable in early adulthood. In this review article we summarise the existing knowledge on telomere dynamics during the first years of childhood, highlighting the conditions that affect newborn TL. We also warn about the knowledge gaps that should be filled to fully understand the regulation of telomeres, in order to implement them as biomarkers for use in diagnostics or treatment.
Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAFV600E (98%, 95% confidence interval [CI 96–99%]), PAX8/PPARG (55% [CI 34–78%]), HRASQ61R (45% [CI 22–72%]), BRAFK601E (42% [CI 19–68%]), and NRASQ61R (38% [CI 23–55%]). Excluding BRAFV600E, the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in ∼1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAFV600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.
Is fecal calprotectin always normal in children with irritable bowel syndrome?

Background/Aims Fecal calprotectin (FC) is a marker of intraluminal intestinal inflammation. Intestinal inflammation may contribute to the pathophysiology of irritable bowel syndrome (IBS). This study evaluated FC levels in children with IBS and differences in FC levels in children stratified by IBS subtype and healthy controls (HCs). Methods A total of 157 children with IBS and 56 HCs aged 4–16 years (119 boys, 94 girls, mean age of 9.48 years) were included in this prospective study. Children with IBS were diagnosed using the Rome III criteria and classified into 4 subtypes: IBS with constipation (IBS-C, n=37), IBS with diarrhea (IBS-D, n=54), IBS with alternating constipation and diarrhea (IBS-M, n=49), and IBS unsubtyped (IBS-U, n=17); postinfectious IBS (PI-IBS) was also considered. The FC concentration in stool samples was analyzed using an enzyme-linked immunosorbent assay. All participants answered a questionnaire regarding several demographic and clinical characteristics. Results Children with IBS had significantly higher levels of FC than the HCs (88.71 μg/g vs. 17.77 μg/g). Among the 4 IBS subtypes, the FC concentration was highest in children with IBS-D, followed by those with IBS-M, IBS-C, and IBS-U (169.94 μg/g vs. 45.04, 31.22, and 33.52 μg/g, respectively), and these differences were statistically significant. For PI-IBS, 90% of cases were in the IBS-D group. Conclusions The FC level was significantly higher in children with IBS than in HCs and differed depending on the IBS subtype, supporting the notion that IBS is a type of low-grade bowel inflammation.
Storage stability of solutions of DNA standards.

High accuracy, reliability and reproducibility of genetic analyses in various applications require optimized and validated protocols and standards. Optimal procedures for storing the genetic material extracted from biological samples are equally important. In this study, we investigated the stability of dilute (4 000 cp/µL, nominal concentration, equivalent to 0.02 ng/mL) DNA solutions stored at 4°C, -20°C and -80°C in the presence or absence of nucleic acid carriers. As representative examples, we used different formulations of a linearized plasmid DNA solution considered for characterization as reference materials (RM) for specific applica-tions. Employing droplet digital PCR, a highly accurate and precise method for quantification of nucleic acid not requiring a cali-brant, we demonstrated that inclusion of a carrier nucleic acid in the formulation (at 50 ng/µL) improved the plasmid stability at -20°C and -80°C. For the case of a DNA standard used in real-time PCR assays for human erythropoietin gene, cDNA or tran-script, we found that inclusion of yeast RNA in the formulation was preferred over salmon testes DNA as it had no effect on PCR amplification and provided the lowest relative expanded uncertainty for the characterized RM. RNA background may also be preferred as it is applicable to a broader range of DNA RMs. Our findings are important in production of reliable, stable DNA standards, including DNA RMs. These results can be used when selecting protocols for stable storage of DNA either extracted from biological samples or synthesized in a laboratory.
Impact of different b-value combinations on radiomics features of apparent diffusion coefficient in cervical cancer

Background The impact of variable b-value combinations on apparent diffusion coefficient (ADC)-based radiomics features has not been fully addressed in literature. Purpose To investigate the correlation between radiomics features extracted from ADC maps and various b-value combinations in cervical cancer. Material and Methods Diffusion-weighted images (b-values: 0, 600, 800, and 1000 s/mm2) of 20 patients with cervical cancer were included. Tumors were identified with the largest transversal cross-section and manually segmented by radiologist. For each b-value combination, 92 radiomics features were extracted and coefficient of variance (CV) was used to evaluate the robustness of radiomics features with different b-value combinations. Features with CV > 5% were normalized by the mean feature variation across the group. Results Out of a total of 92 radiomics features, 18 were classified as robust features with CV ≤5%. Among the rest (CV > 5%), 11, 23, and 40 features demonstrated 5%< CV ≤10%, 10%< CV ≤20%, and CV > 20%, respectively. A subset of features in each category (CV > 5%) showed strong correlation with the b-value combination variation, including 44% (7/16) features in gray level co-occurrence matrix, 62% (8/13) features in gray level dependence matrix, 64% (9/14) features in first order, 50% (8/16) features in gray level run length matrix, 57% (8/14) features in gray level size matrix, and 20% (1/5) features in neighborhood gray-tone difference matrix. Conclusions Variations in b-value combinations demonstrated impact on radiomics features extracted from ADC maps for cervical cancer. The radiomics features with CV <5% can be considered as robust features and are recommended to be used in multicenter radiomics studies.
Generation of neuroinflammation in human African trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection due to protozoan parasites of the Trypanosoma genus and is a major fatal disease throughout sub-Saharan Africa. After an early hemolymphatic stage in which the peripheral tissues are infected, the parasites enter the CNS causing a constellation of neurologic features. Although the CNS stage of HAT has been recognized for over a century, the mechanisms generating the neuroinflammatory response are complex and not well understood. Therefore a better understanding of the mechanisms utilized by the parasites to gain access to the CNS compartment is critical to explaining the generation of neuroinflammation. Contrast-enhanced MRI in a murine model of HAT has shown an early and progressive deterioration of blood-CNS barrier function after trypanosome infection that can be reversed following curative treatment. However, further studies are required to clarify the molecules involved in this process. Another important determinant of brain inflammation is the delicate balance of proinflammatory and counterinflammatory mediators. In mouse models of HAT, proinflammatory mediators such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and CXCL10 have been shown to be crucial to parasite CNS invasion while administration of interleukin (IL)-10, a counter inflammatory molecule, reduces the CNS parasite burden as well as the severity of the neuroinflammatory response and the clinical symptoms associated with the infection. This review focuses on information, gained from both infected human samples and animal models of HAT, with an emphasis on parasite CNS invasion and the development of neuroinflammation.