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Acute myeloid leukaemia (AML) is a hematopoietic stem cell disorder in which neoplastic myeloblasts are arrested in an immature stage of differentiation. Recent publications have underlined the involvement of non-coding RNAs in cancer and particularly in AML development, with several studies regarding their possible contribution to the evolution of the disease. MicroRNAs (miRs) are a class of single-stranded non-coding RNAs that bind to the 3'-untranslated region of target mRNAs and thus negatively regulate gene expression, by translation repression or mRNA degradation. Abnormal expression of miRs in AML has been described and we here review the current data from miR expression profiles. Additionally, we review the current knowledge on the biological function of individual miRs in the development of AML. [ABSTRACT FROM AUTHOR]

Humanization in oncology patient care represents a significant innovation in health care practice, shifting the traditional focus solely on treating physical conditions to encompass the emotional and psychosocial dimensions of patient experience. This study aimed to explore the importance of humanization in oncology and the application of practices that promote a patient-centered approach. Through a narrative review of the past 2 decades, the objective was to analyze the practices, benefits, and challenges of humanization in the oncology context. The methodology involved reviewing the relevant literature on empathetic communication, psychological support, and the integration of these aspects into oncology care. The results indicated that humanization significantly contributes to improving patients' quality of life, increasing treatment adherence, and fostering a more satisfying work environment for health care teams. However, effective implementation faces challenges, such as the need for ongoing training, resource limitations, and resistance to change. Despite these obstacles, humanization is essential to provide more comprehensive and patient-centered care. The adoption of humanized practices transforms the oncology care experience, making it more empathetic and holistic., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Caregiver health literacy (HL) in patients' transition from hospital to home care is an important factor for good results., Methods: This cross-sectional study included 89 patient-informal caregiver dyads in Brazil. Data were collected using a sociodemographic questionnaire and the European Health Literacy Survey Questionnaire short-short form. Data were analyzed using descriptive statistics, univariate analyses, and a binary logistic regression model., Results: The caregivers' average age was 48 ± 13.48 years, and 73.0% of them were female. It was found that 6.7% of the caregivers had inadequate HL, 61.8% had problematic HL, and 31.4% had sufficient HL. Being a healthcare professional was significantly associated with sufficient HL (P = 0.016). Furthermore, healthcare workers had more years of schooling than other caregivers (15.3 ± 4.6 vs. 11.2 ± 4.6; P = 0.013). For every 1-year increase in caregiver age, there was a decrease of 0.041 points on the European Health Literacy Survey Questionnaire short-short form. Being a healthcare professional, increased HL scores by 11.4%., Conclusions: Key findings showed that caregivers with higher HL were typically younger, male, better educated, and more likely to be healthcare professionals. These caregivers managed patients with lower dependence on daily activities, while those with lower HL, mainly females, cared for patients with higher dependence. The study highlights the need for targeted interventions and public policies to enhance HL among caregivers, particularly to improve outcomes for patients with complex needs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Soil mineralogy and texture are directly related to soil carbon due to the physical properties of the clay surface. Traditional techniques for quantifying carbon in soil are time-consuming and expensive, making large-scale quantification for mapping unfeasible. The alternative is the use of soil sensors, such as diffuse reflectance spectroscopy (DRS), an economical, fast, and accurate technique for predicting carbon stocks. In this sense, this study aimed to (a) investigate the relationship of C with different soil mineralogical, chemical, and physical attributes for different geological and geomorphological compartments; (b) understand which spectral bands are most important for estimating C content; (c) estimate C content from diffuse reflectance spectroscopy using different mathematical techniques and indicate which one is the best for tropical soil conditions; and (d) map C contents in detail. The study area was the Western Plateau of São Paulo (WPSP), which covers approximately 13 million hectares (~ 48% of the State of São Paulo, Brazil). A total of 265 samples were collected in this area. The attributes clay, silt, sand, crystalline and non-crystalline iron, base saturation, soil density, total pore volume, total C, C stock, kaolinite/(kaolinite + gibbsite) and hematite/(hematite + goethite), hematite and goethite contents, and spectral curves were evaluated. The spectra were recorded at 0.5-nm intervals, with an integration time of 2.43 nm s -1 over the 350 to 2500-nm range (350-800 nm-visible-VIS and 801-2500 nm-near-infrared-NIR). The data were subjected to descriptive statistics, Spearman correlation, stepwise analysis, and cluster grouping for characterization purposes; partial least squares regression (PLSR) and random forest (RF) for estimation purposes; and geostatistics analysis for creation of spatial maps. Our results indicate that the highest C contents are associated with more clayey soils, oxidic mineralogy, higher total pore volume, and lower soil density in highly dissected basalt compartments. The random forest algorithm associated with the Vis-NIR spectral range is more efficient for estimating and mapping C contents. This suggests that integrating diffuse reflectance spectroscopy with machine learning techniques holds promise for shaping public policies related to land use, mitigating CO 2 emissions, and facilitating the implementation of carbon credit policies in a rapid and economically efficient manner., (© 2024. The Author(s).)

Raphanus sativus L. is a potential source of raw material for biodiesel fuel due to the high oil content in its grains. In Brazil, this species is cultivated in the low rainfall off-season, which limits the productivity of the crop. The present study investigated the effects of water restriction on the physiological and biochemical responses, production components, and oil quality of R. sativus at different development stages. The treatments consisted of 100% water replacement (control), 66%, and 33% of field capacity during the phenological stages of vegetative growth, flowering, and grain filling. We evaluated characteristics of water relations, gas exchange, chlorophyll a fluorescence, chloroplast pigment, proline, and sugar content. The production components and chemical properties of the oil were also determined at the end of the harvest cycle. Drought tolerance of R. sativus was found to be mediated primarily during the vegetative growth stage by changes in photosynthetic metabolism, stability of photochemical efficiency, increased proline concentrations, and maintenance of tissue hydration. Grain filling was most sensitive to water limitation and showed a reduction in yield and oil content. However, the chemical composition of the oil was not altered by the water deficit. Our data suggest that R. sativus is a drought-tolerant species.

Holding and restraining children during non-urgent clinical procedures continues to be surrounded by uncertainty and mired in controversy. This review aimed to locate, appraise and map the evidence related to health professionals reported and observed practice of holding and restraining children, from birth to 16 years, for clinical procedures. This scoping review, conducted in April 2022, was based on the Joanna Briggs Institute protocol. Screening and full text review resulted in the inclusion of 30 papers. In total, 14 different terms were used to refer to the act of holding or restraining a child for a procedure, in many papers the action of holding was not defined. Professionals report the main factors influencing their decisions to use restraint and/or holding were the age of a child, with younger children being restrained or held most frequently; a child's behaviour; and concerns around a child's safety. Professionals also report that they can perceive pressure from parent/carers to hold or restrain their child and describe how holding practices can be influenced by service and organisational pressures. Health professionals, mainly nurses, continue to report ethical and moral tensions linked to their involvement in the restraint or holding of a child against their will for a clinical procedure. Evidence indicates a need to move practice forward as the issues identified in paediatric practice are long-standing and historical., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain., (© 2024 International Society for Neurochemistry.)

This paper reviews the key information and communication technologies that are necessary to build an effective industrial energy management system considering the intermittence of renewable sources like wind and solar † . In particular, we first introduce the concept of software-defined energy networks in the context of industrial cyber-physical systems aiming at the optimal energy resource allocation in terms of its environmental impact. The task is formulated as a dynamic scheduling problem where supply and demand must match at minute-level timescale, also considering energy storage units. The use of (explainable and trustworthy) artificial intelligence (AI), (informative) networked data, demand-side management, machine-type (wireless) communications, and energy-aware scheduling in industrial plants are explored in detail. The paper also provides a framework for understanding the complexities of managing renewable energy sources in industrial plants while maintaining efficiency and environmental sustainability., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

In the present study, we show that SARS-CoV-2 can infect palatine tonsils, adenoids, and secretions in children without symptoms of COVID-19, with no history of recent upper airway infection. We studied 48 children undergoing tonsillectomy due to snoring/OSA or recurrent tonsillitis between October 2020 and September 2021. Nasal cytobrushes, nasal washes, and tonsillar tissue fragments obtained at surgery were tested by RT-qPCR, immunohistochemistry (IHC), flow cytometry, and neutralization assay. We detected the presence of SARS-CoV-2 in at least one specimen tested in 27% of patients. IHC revealed the presence of the viral nucleoprotein in epithelial surface and in lymphoid cells in both extrafollicular and follicular regions, in adenoids and palatine tonsils. Also, IHC for the SARS-CoV-2 non-structural protein NSP-16 indicated the presence of viral replication in 53.8% of the SARS-CoV-2-infected tissues. Flow cytometry showed that CD20 + B lymphocytes were the most infected phenotypes, followed by CD4+ lymphocytes and CD123 dendritic cells, CD8+ T lymphocytes, and CD14+ macrophages. Additionally, IF indicated that infected tonsillar tissues had increased expression of ACE2 and TMPRSS2. NGS sequencing demonstrated the presence of different SARS-CoV-2 variants in tonsils from different tissues. SARS-CoV-2 antigen detection was not restricted to tonsils but was also detected in nasal cells from the olfactory region. Palatine tonsils and adenoids are sites of prolonged RNA presence by SARS-CoV-2 in children, even without COVID-19 symptoms. IMPORTANCE This study shows that SRS-CoV-2 of different lineages can infect tonsils and adenoids in one quarter of children undergoing tonsillectomy. These findings bring advancement to the area of SARS-CoV-2 pathogenesis, by showing that tonsils may be sites of prolonged infection, even without evidence of recent COVID-19 symptoms. SARS-CoV-2 infection of B and T lymphocytes, macrophages, and dendritic cells may interfere with the mounting of immune responses in these secondary lymphoid organs. Moreover, the shedding of SARS-CoV-2 RNA in respiratory secretions from silently infected children raises concern about possible diagnostic confusion in the presence of symptoms of acute respiratory infections caused by other etiologies.

Several factors may increase the risk of development of ovarian cancer. In this study, we investigated the relationship between social, genetic, and histopathologic factors in women with ovarian serous cystadenocarcinoma and titin ( TTN ) mutations, whether the TTN gene mutation may be a predictor, and its impact on mortality and survival in these patients. A total of 585 samples from patients with ovarian serous cystadenocarcinoma were collected from The Cancer Genome Atlas and PanCancer Atlas through the cBioPortal for analysis of social, genetic, and histopathological factors. Logistic regression was used to investigate whether TTN mutation could be a predictor, and the Kaplan-Meier method was applied to analyze survival time. TTN mutation frequency did not differ between age at diagnosis, tumor stage, and race, and was related to increased Buffa hypoxia score ( p = 0.004), mutation count ( p < 0.0001), Winter hypoxia Score ( p = 0.030), nonsynonymous tumor mutation burden (TMB) ( p < 0.0001), and reduced microsatellite instability sensor score ( p = 0.010). The number of mutations ( p < 0.0001) and winter hypoxia score ( p = 0.008) were positively associated with TTN mutations, and nonsynonymous TMB ( p < 0.0001) proved to be a predictor. Mutated TTN affects the score of genetic variables involved in cancer cell metabolism in ovarian cystadenocarcinoma.

Vertical transmission of Chikungunya virus (CHIKV) has been reported in humans, but the transmission routes have not been completely understood, and experimental animal models are needed to enable detailed investigation of the transmission and pathogenesis of congenital infections. The intertwining of immune response and virus components at the gestation/breastfeeding interfaces between mother and fetus/newborn may have effects during the offspring development. An experimental model of CHIKV was established by infecting pregnant BALB/c female mice that enabled confirmation that dams inoculated up to the 10 th gestational day transmit CHIKV transplacentally to approximately 8.4% of the fetuses, resulting in severe teratogenic effects. CHIKV neutralizing antibodies were detected in sera from adult mice born to healthy females and breastfed by CHIKV-infected dams, while no neutralization was detected in sera from animals born to CHIKV-infected dams. Moreover, adult mice born to healthy dams and cross-fostered for breastfeeding by CHIKV-infected dams were resistant to challenge with CHIKV on the 90 th day after birth. The animals also had reduced viral loads in brain and spleen as compared to controls. There was expression of fluorescent CHIKV non-structural protein, and detection of viral RNA by RT-PCR in breast tissue from infected dams. CHIKV RNA and proteins were also detected in breast milk retrieved from the stomachs of recently fed newborns. The experimental results were also complemented by the finding of CHIKV RNA in 6% of colostrum samples from healthy lactating women in a CHIKV-endemic area. Breastfeeding induces immune protection to challenge with CHIKV in mice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In certain clinical situations, root canal treatment in teeth with apical periodontitis is performed in multiple visits, with the use of intracanal dressing between visits, aiming to reduce microorganisms and their by-products of the root canal system prior to filling. However, in recent years, discussions have been growing about the real need for the use of intracanal dressing in these cases. The use of ultrasonic activation of the auxiliary chemical substance has increased the potential for decontamination promoted during the chemomechanical preparation of the root canal. Thus, this study is designed to explore whether the use of intracanal dressing between visits during endodontic treatment favors periradicular repair in teeth with apical periodontitis., Methods: This is a randomized, prospective, double-blinded, controlled clinical trial designed to evaluate 3 distinct clinical approaches used during endodontic therapy: group 1-root canal treatment in a single visit (RCT-SV); group 2-root canal treatment in two visits with intracanal dressing (RCT-TVWD); and group 3-root canal treatment in two visits without intracanal dressing (RCT-TVWOD). A total of 150 adult patients aged 18 to 60, with at least one tooth diagnosed with asymptomatic apical periodontitis and periradicular lesion (confirmed with a cone beam computed tomography (CBCT)), will be randomized and will undergo one of the types of clinical approaches during endodontic therapy. Patients' postoperative pain levels will also be recorded in periods of 24, 48, and 72 h and 7 days. Subsequently, clinical findings and long-term follow-up evaluations, with periradicular repair, will be performed at 6 and 12 months by intraoral periapical radiograph (IOPAR) and CBCT at the 24-month follow-up., Discussion: This study will evaluate the periradicular repair of mandibular molar teeth with apical periodontitis, providing information about the efficacy, benefits, and safety of performing the endodontic treatment in a single and two visits, with and without the use of calcium hydroxide dressing. All endodontic therapy procedures will be performed under a dental operating microscope and using ultrasonic activation of auxiliary chemical substances. These results may contribute to changes in the clinical approaches adopted during endodontic therapy of teeth with apical periodontitis and reveal the potential of complementary approaches that aim to enhance the decontamination of the root canal system during the preparation stage., Trial Registration: ClinicalTrials.gov NCT05256667. Registered on 24 February 2022., (© 2023. The Author(s).)

MDM4 is an important p53-negative regulator, consequently, it is involved in cell proliferation, DNA repair, and apoptosis regulation. MDM4 overexpression and amplification are described to lead to cancer formation, metastasis, and poor disease prognosis. Several MDM4 SNPs are in non-coding regions, and some affect the MDM4 regulation by disrupting the micro RNA binding site in 3'UTR (untranslated region). Here, we gathered several association studies with different MDM4 SNPs and populations to understand the relationship between its SNPs and solid tumor risk. Many studies failed to replicate their results regarding different populations, cancer types, and risk genotypes, leading to conflicting conclusions. We suggested that distinct haplotype patterns in different populations might affect the association between MDM4 SNPs and cancer risk. Thus, we propose to investigate some linkage SNPs in specific haplotypes to provide informative MDM4 markers for association studies with cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Globally, depression affects more than 322 million people. Studies exploring the relationship between diet and depression have revealed the benefits of certain dietary patterns and micronutrients in attenuating the symptoms of this disorder. Among these micronutrients, selenium stands out because of its multifaceted role in the brain., Objective: To assess the impact of selenium intake and status on symptoms of depression., Data Sources: A systematic search was performed in databases, including PubMed, Web of Science, EMBASE, PsycINFO, Scopus, and gray literature (on April 6, 2021, updated on January 28, 2022), without restrictions of date, language, or study type., Data Extraction: Studies of adults (18-60 y of age) with depression or depressive symptoms were included. Data on selenium biomarkers and/or intake were included. The risk of bias was assessed using the Joanna Briggs Institute checklists., Data Analysis: Of the 10 studies included, 2 were cohorts (n = 13 983 and 3735), 3 were cross-sectional (n = 736, 7725, and 200), 1 was case-control (n = 495), and 4 were randomized controlled trials (n = 30, 11, 38, and 63). Several studies have indicated that low selenium intake or concentration may be associated with symptoms of depression. However, this association was inconsistent across the studies included in this systematic review; due to the high heterogeneity, it was not possible to perform meta-analyses. The main contributing factors to the high heterogeneity include the different methodological designs, methods for diagnosing depression, selenium assessment, and clinical conditions., Conclusion: Overall, there is insufficient evidence to support a positive role of selenium status in depression. Studies with more accurate methods and adequate assessment of selenium status are needed to better understand the role of this nutrient in depression., Systematic Review Registration: PROSPERO registration no. CRD42021220683., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

COVID-19 causes more than million deaths worldwide. Although much is understood about the immunopathogenesis of the lung disease, a lot remains to be known on the neurological impact of COVID-19. Here, we evaluated immunometabolic changes using astrocytes in vitro and dissected brain areas of SARS-CoV-2 infected Syrian hamsters. We show that SARS-CoV-2 alters proteins of carbon metabolism, glycolysis, and synaptic transmission, many of which are altered in neurological diseases. Real-time respirometry evidenced hyperactivation of glycolysis, further confirmed by metabolomics, with intense consumption of glucose, pyruvate, glutamine, and alpha ketoglutarate. Consistent with glutamine reduction, the blockade of glutaminolysis impaired viral replication and inflammatory response in vitro. SARS-CoV-2 was detected in vivo in hippocampus, cortex, and olfactory bulb of intranasally infected animals. Our data evidence an imbalance in important metabolic molecules and neurotransmitters in infected astrocytes. We suggest this may correlate with the neurological impairment observed during COVID-19, as memory loss, confusion, and cognitive impairment., (© 2022 International Society for Neurochemistry.)

Pathogenic bacteria are attracted toward mucosa, as it is their way of entry into the body. However, we know surprisingly little about the phage-bacterium interactions in the mucosal environment. Here, we explored the effect of the mucosal environment on growth characteristics and phage-bacterium interactions in Streptococcus mutans , a causative agent of dental caries. We found that although mucin supplementation increased bacterial growth and survival, it decreased S. mutans biofilm formation. More importantly, the presence of mucin had a significant effect on S. mutans phage susceptibility. In two experiments done in Brain Heart Infusion Broth, phage M102 replication was detected only with 0.2% mucin supplementation. In 0.1 × Tryptic Soy Broth, 0.5% mucin supplementation led to a 4-log increase in phage titers compared with the control. These results suggest that the mucosal environment can have a major role in the growth, phage sensitivity, and phage resistance of S. mutans , and underline the importance of understanding the effect of mucosal environment on phage-bacterium interactions., Competing Interests: G.M.d.F.A., L.-R.S. and University of Jyväskylä have patented the commercial use of mucin in a patent titled “Improved methods and culture media for production, quantification and isolation of bacteriophages” (FI20185086, PCT/FI2019/050073)., (Copyright 2022, Mary Ann Liebert, Inc., publishers.)

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Parasitism by bacteriophages has led to the evolution of a variety of defense mechanisms in their host bacteria. However, it is unclear what factors lead to specific defenses being deployed upon phage infection. To explore this question, we co-evolved the bacterial fish pathogen Flavobacterium columnare and its virulent phage V156 in presence and absence of a eukaryotic host signal (mucin) for sixteen weeks. The presence of mucin leads to a dramatic increase in CRISPR spacer acquisition, especially in low nutrient conditions where over 60% of colonies obtain at least one new spacer. Additionally, we show that the presence of a competitor bacterium further increases CRISPR spacer acquisition in F. columnare. These results suggest that ecological factors are important in determining defense strategies against phages, and that the phage-bacterium interactions on mucosal surfaces may select for the diversification of bacterial immune systems., (© 2022. The Author(s).)

Serine tRNAs (tRNA Ser ) are frequently overexpressed in tumors and associated with poor prognosis and increased risk of recurrence in breast cancer. Impairment of tRNA biogenesis and abundance also impacts proteome homeostasis, and activates protein quality control systems. Herein, we aimed at testing whether increasing tRNA Ser abundance could foster tumor establishment through activation of the UPR. In order to do so, firstly we confirmed that the expression of tRNA-Ser-AGA-2-1 [hereafter tRNA Ser (AGA)] was upregulated by 1.79-fold in Stage I NSCLC tumors when compared to normal adjacent tissue. To study the impact of tRNA Ser (AGA) in early stage tumorigenesis, we induced its upregulation in a non-tumoral bronchial cell line, BEAS-2B. Upregulation of this tRNA increased cellular proliferation and protein synthesis rate, driven by eIF2 α dephosphorylation and ATF4 activation downstream of PERK signaling. Futhermore, tRNA Ser (AGA) enhanced transformation potential in vitro , and promoted the establishment of slow growing tumors with aggressive features in nude mice. Our work highlights the importance of studying tRNA deregulation on early stage tumorigenesis, as they may be potential malignancy and aggressiveness biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Santos, Fidalgo, Varanda, Soares, Almeida, Martins, Mendes, Oliveira and Santos.)

Surgical resection with lymphadenectomy and perioperative chemotherapy is the universal mainstay for curative treatment of gastric cancer (GC) patients with locoregional disease. However, GC survival remains asymmetric in West- and East-world regions. We hypothesize that this asymmetry derives from differential clinical management. Therefore, we collected chemo-naïve GC patients from Portugal and South Korea to explore specific immunophenotypic profiles related to disease aggressiveness and clinicopathological factors potentially explaining associated overall survival (OS) differences. Clinicopathological and survival data were collected from chemo-naïve surgical cohorts from Portugal (West-Europe cohort [WE-C]; n = 170) and South Korea (East-Asia cohort [EA-C]; n = 367) and correlated with immunohistochemical expression profiles of E-cadherin and CD44v6 obtained from consecutive tissue microarrays sections. Survival analysis revealed a subset of 12.4% of WE-C patients, whose tumors concomitantly express E-cadherin&#95;abnormal and CD44v6&#95;very high, displaying extremely poor OS, even at TNM stages I and II. These WE-C stage-I and -II patients tumors were particularly aggressive compared to all others, invading deeper into the gastric wall (P = .032) and more often permeating the vasculature (P = .018) and nerves (P = .009). A similar immunophenotypic profile was found in 11.9% of EA-C patients, but unrelated to survival. Tumours, from stage-I and -II EA-C patients, that display both biomarkers, also permeated more lymphatic vessels (P = .003), promoting lymph node (LN) metastasis (P = .019), being diagnosed on average 8 years earlier and submitted to more extensive LN dissection than WE-C. Concomitant E-cadherin&#95;abnormal/CD44v6&#95;very-high expression predicts aggressiveness and poor survival of stage-I and -II GC submitted to conservative lymphadenectomy., (© 2021 UICC.)

Biodiversity in the Brazilian Cerrado biome has been declining sharply with the continued expansion of agriculture and the excessive use of herbicides. Thus, the aim of this study was to evaluate the morphophysiological and biochemical responses in Dipteryx alata plants to various doses of the herbicide 2,4-D. Specific biomarkers that characterize the phytoindicator potential of this species were determined. Gas exchange, chlorophyll a fluorescence, photosynthetic pigments, and the activities of antioxidant enzymes and cellulase were performed after 24, 96 and/or 396 hours after 2,4-D application (HAA). The herbicide caused higher antioxidant enzymatic activity 24 HAA and damage to the photosynthetic machinery after 96 HAA. Reduction in gas exchange, chlorophyll content, and photochemical traits were observed. Increased respiratory rates, non-photochemical quenching, and carotenoid concentrations in 2,4-D-treated plants were important mechanisms in the defense against the excess energy absorbed. Furthermore, the absence of leaf symptoms suggested tolerance of D. alata to 2,4-D. Nevertheless, changes in the photosynthetic and biochemical metabolism of D. alata are useful as early indicators of herbicide contamination, especially in the absence of visual symptoms. These results are important for early monitoring of plants in conserved areas and for preventing damage to sensitive species.

Oropouche virus (OROV) is an emerging arbovirus in South and Central Americas with high spreading potential. OROV infection has been associated with neurological complications and OROV genomic RNA has been detected in cerebrospinal fluid from patients, suggesting its neuroinvasive potential. Motivated by these findings, neurotropism and neuropathogenesis of OROV have been investigated in vivo in murine models, which do not fully recapitulate the complexity of the human brain. Here we have used slice cultures from adult human brains to investigate whether OROV is capable of infecting mature human neural cells in a context of preserved neural connections and brain cytoarchitecture. Our results demonstrate that human neural cells can be infected ex vivo by OROV and support the production of infectious viral particles. Moreover, OROV infection led to the release of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and diminished cell viability 48 h post-infection, indicating that OROV triggers an inflammatory response and tissue damage. Although OROV-positive neurons were observed, microglia were the most abundant central nervous system (CNS) cell type infected by OROV, suggesting that they play an important role in the response to CNS infection by OROV in the adult human brain. Importantly, we found no OROV-infected astrocytes. To the best of our knowledge, this is the first direct demonstration of OROV infection in human brain cells. Combined with previous data from murine models and case reports of OROV genome detection in cerebrospinal fluid from patients, our data shed light on OROV neuropathogenesis and help raising awareness about acute and possibly chronic consequences of OROV infection in the human brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Almeida, Souza, Mendes, Pontelli, Pinheiro, Nogueira, Cardoso, Paiva, Ferrari, Veras, Cunha, Horta-Junior, Alberici, Cunha, Podolsky-Gondim, Neder, Arruda and Sebollela.)

Debulking surgery followed by chemotherapy are the standard of care for high-grade serous carcinoma. After an initial good response to treatment, the majority of patients relapse with a chemoresistant profile, leading to a poor overall survival. Chemotherapy regimens used in high-grade serous carcinomas are based in a combination of classical chemotherapeutic drugs, namely, Carboplatin and Paclitaxel. The mechanisms underlying drug resistance and new drug discovery are crucial to improve patients' survival. To uncover the molecular mechanisms of chemoresistance and test drugs capable of overcoming this resistant profile, it is fundamental to use good cellular models capable of mimicking the chemoresistant disease. Herein, we established two high-grade serous carcinoma cell lines with intrinsic resistance to Carboplatin and induced Paclitaxel resistance (OVCAR8 PTX R C and OVCAR8 PTX R P) derived from the OVCAR8 cell line. These two chemoresistant cell line variants acquired an enhanced resistance to Paclitaxel-induced cell death by increasing the drug efflux capacity, and this resistance was stable in long-term culture and following freeze/thaw cycles. The mechanism underlying Paclitaxel resistance resides in a significant increase in P-glycoprotein expression and, when this drug efflux pump was blocked with Verapamil, cells re-acquired Paclitaxel sensitivity. We generated two high-grade serous carcinoma cell lines, with a double-chemoresistant (Carboplatin and Paclitaxel) phenotype that mimics the majority of tumor recurrences in ovarian cancer context. This robust tool is suitable for preliminary drug testing towards the development of therapeutic strategies to overcome chemoresistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nunes, Silva, Coelho, Pinto, Resende, Bousbaa, Almeida and Ricardo.)

In gastric cancer (GC), biomarkers that define prognosis and predict treatment response remain scarce. We hypothesized that the extent of CD44v6 membranous tumor expression could predict prognosis and therapy response in GC patients. Two GC surgical cohorts, from Portugal and South Korea ( n = 964), were characterized for the extension of CD44v6 membranous immuno-expression, clinicopathological features, patient survival, and therapy response. The value of CD44v6 expression in predicting response to treatment and its impact on prognosis was determined. High CD44v6 expression was associated with invasive features (perineural invasion and depth of invasion) in both cohorts and with worse survival in the Portuguese GC cohort (HR 1.461; 95% confidence interval 1.002-2.131). Patients with high CD44v6 tumor expression benefited from conventional chemotherapy in addition to surgery ( p < 0.05), particularly those with heterogeneous CD44v6-positive and -negative populations (CD44v6&#95;3+) ( p < 0.007 and p < 0.009). Our study is the first to identify CD44v6 high membranous expression as a potential predictive marker of response to conventional treatment, but it does not clarify CD44v6 prognostic value in GC. Importantly, our data support selection of GC patients with high CD44v6-expressing tumors for conventional chemotherapy in addition to surgery. These findings will allow better stratification of GC patients for treatment, potentially improving their overall survival.

The aim of this study is to evaluate the effect of different thermal pretreatments of the inoculum on the diversity of the microbial community producing hydrogen from sugarcane vinasse. High-throughput sequencing of the 16S and 18S rRNA genes was performed. The reactor samples were also selected for the isolation of strict anaerobes. Decreased microbial diversity was observed with increasing pretreatment temperatures, with Firmicutes predominating: 90% to 97%. The highest abundance of Staphylococcus (7.9%) was found in pretreatment at 120 °C / 20 min at pH 6. The fungal analysis revealed a high prevalence of Candida (47%), Agaricomycetes, Pezizomycotina and Aspergillus in assays with higher H 2 production (90° C / 10 min at pH 6). Three species of Clostridium were isolated: C. bifermentans, C. saccharoperbutylacetonicum and C. saccharobutylicum. The isolates were tested separately and in co-cultures for the production of hydrogen. Hydrogen-producing capacity by co-culture of Clostridium species was increased by 18%. Knowing microorganisms and understanding the interaction between eukaryotes and prokaryotes is essential to obtain strategies for biotransformation of vinasse for the production of bioenergy.

Little is known about the role of light intensity in modulating plant responses to stress due to water deficit (WD). Thus, the objective of this study was to determine the WD and contrasting irradiance effects on the physiology, anatomy, and grain yield of soybean plants. The experimental design was a randomized block in a growth chamber and a 2 × 2 factorial treatment arrangement: 90% (well-watered, WW) and 40% (WD) of soil field capacities (FC); and 750 (medium irradiance, MI) and 1500 (higher irradiance, HI) μmol (photons) m -2  s -1 irradiance. The WD caused a lower photosynthetic rate - as well as observed in the light curve and in the relative parameters, such as apparent quantum efficiency -, less investment in shoot biomass and pollen grain germination, resulting in lower grain yield. However, there was an increase in non-photochemical energy dissipation, a higher concentration of total soluble sugars, proline, and malondialdehyde. The WD + MI-soybean plants developed thicker spongy parenchyma (related to higher mesophilic conductance of CO 2 ). In the WW + HI condition the palisade parenchyma was thicker, conferring maintenance of photosynthetic efficiency. In addition, there was an increase in the activity of superoxide dismutase, catalase, peroxidase, and ascorbate peroxidase antioxidant enzymes in leaves due to HI, regardless of FC. This induced higher energy expenditure, reflected in the reduction of the number of leaf and branches, leaf area, dry mass of leaves and stem in the WW + HI. Interestingly, these strategies of osmotic adjustment, photoprotection, and antioxidant defenses act together in the WD + HI., (© 2021 Scandinavian Plant Physiology Society.)

Imidazo[1,2-a]pyridines (IP) and organoselenium compounds have been widely exploited in medicinal chemistry due to their pharmacological activities. Hepatocellular carcinoma (HCC) has few treatment options, and unfortunately, the prognosis is poor. Thus, the development of novel therapeutic drugs is urgent. The present study aimed at evaluating the antitumor mechanism of selenylated IP against HepG2 cells and in vivo. The selenylated IP named IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-a]pyridine) showed high cytotoxicity against HepG2 cells (half-maximal inhibitory concentration [IC 50 ] = 0.03 µM) and selectivity for this tumor cell line. At nontoxic concentration, IP-Se-06 decreased the protein levels of Bcl-xL and increased the levels of p53, leading to inhibition of cell proliferation and apoptosis. This compound decreased the level of extracellular signal-regulated kinase 1/2 protein and changed the levels of proteins involved in the drive of the cell cycle, tumor growth, and survival (cyclin B1, cyclin-dependent kinase 2). In addition, IP-Se-06 decreased the number of cells in the S phase. In addition, IP-Se-06 led to increased generation of reactive oxygen species, changed antioxidant defenses, and caused DNA fragmentation. Finally, IP-Se-06 significantly inhibited the growth of Ehrlich ascites tumors in mice, increased survival time, and inhibited angiogenesis. Therefore, IP-Se-06 may be an important compound regarding the development of a therapeutic drug for HCC treatment., (© 2020 Wiley Periodicals LLC.)

Immunohistochemical (IHC) analysis of tissue biopsies is currently used for clinical screening of solid cancers to assess protein expression. The large amount of image data produced from these tissue samples requires specialized computational pathology methods to perform integrative analysis. Even though proteins are traditionally studied independently, the study of protein co-expression may offer new insights towards patients' clinical and therapeutic decisions. To explore protein co-expression, we constructed a modular image analysis pipeline to spatially align tissue microarray (TMA) image slides, evaluate alignment quality, define tumor regions, and ultimately quantify protein expression, before and after tumor segmentation. The pipeline was built with open-source tools that can manage gigapixel slides. To evaluate the consensus between pathologist and computer, we characterized a cohort of 142 gastric cancer (GC) cases regarding the extent of E-cadherin and CD44v6 expression. We performed IHC analysis in consecutive TMA slides and compared the automated quantification with the pathologists' manual assessment. Our results show that automated quantification within tumor regions improves agreement with the pathologists' classification. A co-expression map was created to identify the cores co-expressing both proteins. The proposed pipeline provides not only computational tools forwarding current pathology practices to explore co-expression, but also a framework for merging data and transferring information in learning-based approaches to pathology.

Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context.

Background: Intravenous (IV) use of proton pump inhibitors (PPIs) is advised only in cases of suspected upper gastrointestinal bleeding (UGIB) or impossibility of receiving oral medication, although there has been a persistent practice of their inappropriate use in health institutions., Objective: The purpose of our study was to measure the inappropriate use of IV PPIs in a high complexity hospital in Brazil and to estimate its costs., Methods: Retrospective study of 333 patients who received IV omeprazole between July and December of 2018 in a high complexity hospital in Brazil., Results: IV omeprazole was found to be appropriately prescribed in only 23.4% patient reports. This medication was administered mainly in cases of suspected UGIB (19.1%) and stress ulcer prophylaxis in patients with high risk of UGIB unable to receive medication orally (18.7%). It was observed a statistically significant association between adequate prescription and stress ulcer prophylaxis in patients with high risk of UGIB unable to receive medication orally; patient nil per os with valid indication for PPIs usage; prescription by intensive care unit doctors; prescription by emergency room doctors; intensive care unit admission; evolution to death; sepsis; and traumatic brain injury (P<0.05). On the other hand, inadequate prescription had a statistically significant association with surgical ward prescription and non-evolution to death (P<0.05). The estimated cost of the vials prescribed inadequately was US$1696., Conclusion: There was a high number of inappropriate IV omeprazole prescriptions in the studied hospital, entailing greater costs to the institution and unnecessary risks.

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Veras et al.)

Background: Because MS-related fatigue could be associated with enhanced proinflammatory cytokine production, drugs with immunomodulatories properties, such as salbutamol, may represent an alternative treatment. We aimed to evaluate the effect of salbutamol on MS-related fatigue., Methods: Thirty patients with relapsing-remitting MS who were between 18 and 69 years old, and suffering from fatigue, were evaluated with the Fatigue Severity Scale (FSS) and the Brazilian version of the neurological fatigue index for multiple sclerosis (NFI/MS-BR). They received salbutamol 2 mg twice a day or a placebo in a pilot randomized, double-masked placebo-controlled trial. The primary outcome was the change in the FSS score at the end of 90 days. The secondary outcome was the efficacy, represented by changes in their scores on the NFI/MS-BR subdomains (in the same period) and the Expanded Disability Status Scale (EDSS) at the end of 90 days., Results: Thirty subjects were allocated to receive either salbutamol (14) or a placebo (16). There was no superiority of salbutamol over the placebo in the FSS outcome at 30 (p ==0.498), 60 (p = 0.854) and 90 (p = 0.240) days. There was no a significant decrease in the proportion of patients with severe or moderate fatigue in the salbutamol group at the end of the follow-up. The scores on the NFI/MS-BR and its subscales did not improve significantly with treatment. No significant difference was observed in the EDSS outcome (p = 0.313). No serious adverse events were found. An increase in heart rate was evident in the salbutamol group only in the first 30 days, but without statistical significance in relation to placebo (p = 0.077)., Conclusion: Treatment with salbutamol does not improve fatigue in patients with relapsing-remitting MS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

De novo expressed CD44 isoforms containing exon-v6 are frequently associated with gastric cancer (GC) aggressiveness, and may predict chemotherapy response in vitro. Whether exon-v6 itself is responsible for conferring these properties to CD44v6-containing isoforms remains to be elucidated. CRISPR/Cas9 and Phosphorodiamidate Morpholino oligomers (PMOs) were used to induce specific exon-v6 skipping, maintaining the CD44 reading frame, in two GC cell lines endogenously expressing CD44v6. Cisplatin and 5-fluorouracil treatment response, and self-renewal ability was compared between CRISPR/Cas9-edited, CD44v6 knockdown and mock cells. We obtained homozygous genome-edited cell lines with exon-v6 deletion. Edited cells transcribed CD44v isoforms presenting in frame v5-v7 splicing, mimicking exon-v6 skipping. Results showed that removing specifically exon-v6 sensitizes cells to cisplatin and impairs cells' self-renewal ability, similarly to CD44v6 knockdown. In parallel, we also tested a clinically feasible approach for transient exon-v6 skipping with a PMO-based strategy. We demonstrate that exon-v6 specific removal from CD44v isoforms increases cell sensitivity to cisplatin and impairs GC cells self-renewal. We trust that a PMO approach designed towards CD44v6 overexpressing GC cells may be a suitable approach to sensitize tumor cells for conventional therapy.

Membrane bioreactor (MBR) has been widely employed for industrial effluent treatment, as its higher efficiency in removing pollutants makes effluent reuse more feasible. However, membrane fouling remains as a limiting factor for its greater diffusion. This work performed a sensitivity analysis study to investigate the effects of analytical and operating variables on membrane permeability. The case study is a MBR treating oil refinery effluents. After the identification and validation of a predictive neural model for permeability, sensitivity analysis methods based on both connection weights and variable disturbances were used to quantify and rank the variables influence. A comprehensive analysis showed that Suspended solids and Days between cleanings exerted greater effects on permeability, whereas sludge filterability and sludge temperature were less significant. In sequence, a specific analysis revealed distinct dynamics in MBR operation given different solids concentrations. For instance, from higher solids concentrations, among all the evaluated parameters, only COD presented low significance to the permeability. This evidence suggests that permeability is more susceptible to variations when operating with higher concentrations of Suspended solids. The global result of this study contributes to more efficient MBR operations since distinct relations with permeability imply different effects on membrane fouling.

Household food insecurity (HFI) is a powerful stressor negatively associated with early childhood development (ECD). However, no comprehensive review has examined the association of HFI and ECD. Therefore, this systematic review and meta-analysis investigated the association between HFI and ECD domains and subdomains in children under 5 years old. Peer-reviewed and grey literature were systematically searched in electronic databases with no year or language restrictions. Studies were eligible if they assessed the association between HFI and one or more ECD domains. Data were extracted using a standard predefined protocol. Meta-analysis was performed, and the heterogeneity across studies was explored. Nineteen studies were included in the systematic review and 14 in the meta-analysis. Of the studies, 15 were from high income countries (HICs) and four from low-middle income countries (LMICs). For developmental risk and the cognitive/math and cognitive/school readiness and reading subdomains, the only studies available were conducted in HICs. The meta-analysis showed that HFI was associated with developmental risk (OR 1.28; 95% CI [1.14, 1.45]), cognitive/vocabulary (OR 0.94; 95% CI [0.90, 0.98]), and cognitive/math (OR 0.84; 95% CI [0.73, 0.96]). HFI was marginally associated with cognitive/school readiness and reading (OR 0.91; 95% CI [0.82, 1.00]) and motor development (OR; 0.91, 95% CI [0.80, 1.04]). HFI was associated with poor ECD in children under 5 years old. Specifically, HFI was associated with developmental risk and poor math skills in studies conducted in HICs and with poor vocabulary skills in studies conducted in both HICs and LMICs. Prospective studies examining HFI and ECD are needed in LMICs., (© 2020 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

CD44v6-containing isoforms are frequently de novo expressed in gastric cancer (GC). Whether CD44v6 has a central role in GC transformation and/or progression, whether it conditions response to therapy or whether it is only a bystander marker is still not known. Therefore, we aimed to clarify the role of CD44v6 in GC. We generated GC isogenic cell lines stably expressing CD44s or CD44v6 and tested them for different cancer hallmarks and response to cisplatin, and we further confirmed our findings in cells that endogenously express CD44v6. No correlation between overexpression of CD44v6 and the tested cancer hallmarks was observed, suggesting CD44v6 is not a driver of GC progression. Upon cisplatin treatment, CD44v6+ cells survive better and have lower apoptosis levels than CD44v6- cells, possibly due to concomitant activation of STAT3 and P38. In co-culture experiments, we discovered that CD44v6+ cells are involved in GC cell overgrowth after cisplatin treatment. In conclusion, we show that CD44v6 expression increases cell survival in response to cisplatin treatment in GC cells and that these cells override CD44v6-negative cells after cisplatin-treatment. This suggests that tumor expression of CD44v6-containing variants may condition the outcome of GC patients treated with chemotherapy.

Objective: To identify the objectives and competencies sought by the discipline of food and nutrition education (FNE) in the training of nutritionists., Design: A qualitative study, based on the Theory of Social Representations., Setting: A total of 381 Brazilian public and private higher education institutions with undergraduate courses in nutrition were invited to complete an online questionnaire., Participants: A total of 104 professors of FNE participated in the study., Analysis: Qualitative analysis using the Discourse of the Collective Subject method and the Central Core Theory., Results: The FNE discipline aims to bring awareness to the importance of the promotion of health and food and nutrition security, to break with the biological and normative vision of food, to problematize the factors related to food, and to seek strategies of promoting healthy eating habits. In addition to preparing students for their role as educators, from planning to the evaluation of FNE actions, the intended competencies range from the development of criticality in educational practices to the application of appropriate pedagogical approaches., Conclusion: The objectives of FNE and the desired competencies are articulated and involve, among others, preparing nutritionists for their role of educators., (Copyright © 2019 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Approximately 90% of pre-clinically validated drugs fail in clinical trials owing to unanticipated clinical outcomes, costing over several hundred million US dollars per drug. Despite such critical importance, translating pre-clinical data to clinical outcomes remain a major challenge. Herein, we designed a modality-independent and unbiased approach to predict clinical outcomes of drugs. The approach exploits their multi-organ transcriptome patterns induced in mice and a unique mouse-transcriptome database "humanized" by machine learning algorithms and human clinical outcome datasets. The cross-validation with small-molecule, antibody, and peptide drugs shows effective and efficient identification of the previously known outcomes of 5,519 adverse events and 11,312 therapeutic indications. In addition, the approach is adaptable to deducing potential molecular mechanisms underlying these outcomes. Furthermore, the approach identifies previously unsuspected repositioning targets. These results, together with the fact that it requires no prior structural or mechanistic information of drugs, illustrate its versatile applications to drug development process., Competing Interests: Declaration of Interests T.N.S. is the inventor of the patents filed on hMDB-i and is the scientific founder of and holds shares of Karydo TherapeutiX, Inc., which owns the right to this patent. S.K., S.F., S.E., G.M.D.A., and Y.M. are employees of Karydo TherapeutiX, Inc. Correspondence and requests for materials should be addressed to T.N.S (island1005@gmail.com)., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)