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Healthcare systems have made rapid progress towards combining data science with precision medicine, particularly in pharmacogenomics. With the lack of predictability in medication effectiveness from patient to patient, acquiring the specifics of their genotype would be highly advantageous for patient treatment. Genotype-guided dosing adjustment improves clinical decision-making and helps optimize doses to deliver medications with greater efficacy and within safe margins. Current databases demand extensive effort to locate relevant genetic dosing information. To address this problem, Patient Optimization Pharmacogenomics (POPGx) was constructed. The objective of this paper is to describe the development of POPGx, a tool to simplify the approach for healthcare providers to determine pharmacogenomic dosing recommendations for patients taking multiple medications. Additionally, this tool educates patients on how their allele variations may impact gene function in case they need further healthcare consultations. POPGx was created on Konstanz Information Miner (KNIME). KNIME is a modular environment that allows users to conduct code-free data analysis. The POPGx workflow can access Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines and subsequently be able to present relevant dosing and counseling information. A KNIME representational state transfer (REST) application program interface (API) node was established to retrieve information from CPIC and drugs that are exclusively metabolized through CYP450, and these drugs were processed simultaneously to demonstrate competency of the workflow. The POPGx program provides a time-efficient method for users to retrieve relevant, patient-specific medication selection and dosing recommendations. Users input metabolizer gene, genetic allele data, and medication list to retrieve clear dosing information. The program is automated to display current guideline recommendations from CPIC. The integration of this program into healthcare systems has the potential to revolutionize patient care by giving healthcare practitioners an easy way to prescribe medications with greater efficacy and safety by utilizing the latest advancements in the field of pharmacogenomics.

Summary: Background: Developing strategies to prevent breast cancer-related arm lymphoedema (BCRAL) is a critical unmet need because there are no effective interventions to eradicate it once it reaches a chronic state. Certain strategies such as prospective surveillance programs and prophylactic lymphatic reconstruction have been reported to be effective in clinical trials. However, a large variation exists in practice based on clinician preference, organizational standards, and local resources. Methods: A two-round international Delphi consensus process was performed from February 27, 2023 to May 25, 2023 to compile opinions of 55 experts involved in the care and research of breast cancer and lymphoedema on such interventions. Findings: Axillary lymph node dissection, use of post-operative radiotherapy, relative within-arm volume increase one month after surgery, greater number of lymph nodes dissected, and high body mass index were recommended as the most important risk factors to guide selection of patients for interventions to prevent BCRAL. The panel recommended that prospective surveillance programs should be implemented to screen for and reduce risks of BCRAL where feasible and resources allow. Prophylactic compression sleeves, axillary reverse mapping and prophylactic lymphatic reconstruction should be offered for patients who are at risk for developing BCRAL as options where expertise is available and resources allow. Recommendations on axillary management in clinical T1–2, node negative breast cancer patients with 1–2 positive sentinel lymph nodes were also provided by the expert panel. Routine axillary lymph node dissection should not be offered in these patients who receive breast conservation therapy. Axillary radiation instead of axillary lymph node dissection should be considered in the same group of patients undergoing mastectomy. Interpretation: An individualised approach based on patients' preferences, risk factors for BCRAL, availability of treatment options and expertise of the healthcare team is paramount to ensure patients at risk receive preventive interventions for BCRAL, regardless of where they are receiving care. Funding: This study was not supported by any funding. RJC received investigator grant support from the Australian National Health and Medical Research Council (APP1194051).

Introduction Arteriovenous fistulas (AVFs) are considered the best and safest modality for providing haemodialysis in patients with end-stage renal disease. Only 20% of UK centres achieve the recommended 80% target for achieving dialysis of the prevalent dialysis population via permanent access (as opposed to a central venous catheter). This is partly due to the relatively poor maturation rate of newly created fistulas, with as many as 50% of fistulas failing to mature.The Surveillance Of arterioveNous fistulAe using ultRasound study will examine whether a protocolised programme of Doppler ultrasound (US) surveillance can identify, early after creation, potentially correctable problems in those AVFs that subsequently fail to mature.Methods and analysis This is a multicentre observational study that will assess newly created AVFs by Doppler US performed at 2, 4, 6 and 10 weeks after creation. The primary outcome measure will be primary fistula patency at week 10. Secondary outcome measures include: successful use of the fistula; clinical suitability for dialysis; creation of new fistula or radiological salvage; fistula thrombosis; secondary fistula patency rate and patient acceptability.Ethics and dissemination The study has been approved by the Cambridgeshire and Hertfordshire Research Ethics Committee and by the Health Research Authority (REC 18/EE/0234). The results generated from this work will be published as open access, within 3 years of trial commencement. We will also present our findings at key national/international renal meetings, as well as support volunteers at renal patient groups to disseminate the trial outcome.Trial registration number ISRCTN36033877

Michela Gatta1, Elisabetta Ramaglioni3, Jessica Lai3, Lorenza Svanellini3, Irene Toldo1, Lara Del Col3, Cinzia Salviato3, Andrea Spoto2, Battistella Pier Antonio31Paediatrics Department, 2Department of General Psychology, University of Padua, Padua, Italy; 3Neuropsychiatric Unit for Children and Adolescents, Azienda ULSS 16, Padua, ItalyAbstract: The aim of the study is to analyze the clinician’s alliance with parents during the diagnostic process in relation to therapeutic compliance and clinical evolution of individuals aged 0–11 years. The sample was formed by 84 individuals aged 0 to 11 years (18 < 6 years, 66 aged 6 to 11 years; 62 males and 22 females) who came to the Neuropsychiatric Unit for Children and Adolescents for a consultation regarding psychorelational and behavioral problems. Neuropsychiatric consultation took place in five diagnostic interviews with child and parents, separately. The last session was devoted to communication of psychiatric diagnosis (according to ICD 10) and therapeutic suggestions, if any. The clinician’s relationship with parents and patients’ participation were evaluated in terms of collaboration and quality of interaction, on the basis of pre-established criteria. Data about patients’ therapeutic compliance and clinical outcome were collected during a follow-up visit eight months after the last session. Results suggest that the better the alliance between parents and clinician, the higher the therapeutic compliance and the likelihood of a positive outcome for patients. Our data suggest that good communication with parents benefits child patients, both in terms of response to the parents’ need to report their children’s worrying behavior and as a response to the discomfort expressed by children when they come in for consultation.Keywords: psychopathology, developmental age, psychotherapy, alliance relationship, parental function

No final de abril de 1518, Lutero é convocado à cidade de Heidelberg. Lutero vai direto ao ponto e fala sobre a natureza de Deus e a natureza da criatura humana presa no pecado. Tais afirmações constituíram uma mudança no debate teológico ocidental, bem como a maneira de Deus lidar com o mal e o que significa ser “humano”. A Disputa de Heidelberg é considerada especial tanto histórica quanto teologicamente. Lutero buscou apresentar uma nova estrutura conceitual para pensar sobre Deus e a criatura humana. Ele forneceu uma nova base ou conjunto de pressupostos para proclamar a mensagem do Evangelho. Este artigo aborda o aspecto profundo da teologia da cruz (Theologia Crucis) de Lutero, trazendo à tona sua necessidade de buscar um equilíbrio entre o racional e o existencial na vida cristã.

Abstract Macrotermes termite mounds in the Kruger National Park occupy a significant part of the savanna landscapes, occurring at densities of up to 70 km−2 and often exceeding 10 m in width and 4 m in height. The mounds are usually devoid of trees, but have dense grass cover in wet years. As a result, these mounds form large patches of grassland amongst the wooded savanna. To our knowledge, it is not known why trees are largely excluded from the mounds. We analysed soil surface nutrient concentrations on and off mounds (0–2 cm deep, n = 80) to ascertain whether the availability of nutrients could be influencing competition between grasses and tree seedlings. The results showed that potential deficiencies in P, Ca, Cu, Zn and B in soils off the mounds are likely to be constraining plant growth. Notably, only B, with an average concentration of 0.19 mg kg−1, was likely to be limiting plant growth on the mounds. Notwithstanding likely interactions with herbivory and fire, we hypothesise that because grasses are far less susceptible to deficiencies of B than dicotyledonous trees, it is likely that grass competition with tree seedlings is considerably greater on mounds than off mounds.

Summary: Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2 variants. We aimed to investigate clinical characteristics and outcomes of MIS-C across SARS-CoV-2 eras. Methods: We performed a multicentre observational retrospective study including seven paediatric hospitals in four countries (France, Spain, U.K., and U.S.). All consecutive confirmed patients with MIS-C hospitalised between February 1st, 2020, and May 31st, 2022, were included. Electronic Health Records (EHR) data were used to calculate pooled risk differences (RD) and effect sizes (ES) at site level, using Alpha as reference. Meta-analysis was used to pool data across sites. Findings: Of 598 patients with MIS-C (61% male, 39% female; mean age 9.7 years [SD 4.5]), 383 (64%) were admitted in the Alpha era, 111 (19%) in the Delta era, and 104 (17%) in the Omicron era. Compared with patients admitted in the Alpha era, those admitted in the Delta era were younger (ES −1.18 years [95% CI −2.05, −0.32]), had fewer respiratory symptoms (RD −0.15 [95% CI −0.33, −0.04]), less frequent non-cardiogenic shock or systemic inflammatory response syndrome (SIRS) (RD −0.35 [95% CI −0.64, −0.07]), lower lymphocyte count (ES −0.16 × 109/uL [95% CI −0.30, −0.01]), lower C-reactive protein (ES −28.5 mg/L [95% CI −46.3, −10.7]), and lower troponin (ES −0.14 ng/mL [95% CI −0.26, −0.03]). Patients admitted in the Omicron versus Alpha eras were younger (ES −1.6 years [95% CI −2.5, −0.8]), had less frequent SIRS (RD −0.18 [95% CI −0.30, −0.05]), lower lymphocyte count (ES −0.39 × 109/uL [95% CI −0.52, −0.25]), lower troponin (ES −0.16 ng/mL [95% CI −0.30, −0.01]) and less frequently received anticoagulation therapy (RD −0.19 [95% CI −0.37, −0.04]). Length of hospitalization was shorter in the Delta versus Alpha eras (−1.3 days [95% CI −2.3, −0.4]). Interpretation: Our study suggested that MIS-C clinical phenotypes varied across SARS-CoV-2 eras, with patients in Delta and Omicron eras being younger and less sick. EHR data can be effectively leveraged to identify rare complications of pandemic diseases and their variation over time. Funding: None.

Pressure to send sexually explicit messages, or ‘sexting coercion’ is associated with adverse mental health outcomes and sexual risk behaviors. This study explores Differentiation of Self (DoS) as a potential protective factor to reduce susceptibility to sexting coercion. A convenience sample of 399 Australian participants, aged 18 to 21 years (Mage = 19.63; SD = 1.14, 68.2% women) completed an online survey measuring sexting behaviors and DoS. Women were four times more likely to send willing unwanted sexts, and seven times more likely to engage in coerced unwanted sexting than men. Participants with low DoS were four times more likely to engage in coerced unwanted sexting. DoS significantly mediated the relationship between gender and coerced unwanted sexting. Results support the proposal of a sexting coercion typology encompassing discrete sub-types of sexting coercion. Results also indicate DoS may operate as a protective factor for young people in Australia, reducing compliance with sexting when coerced.

A compostagem apresenta-se como uma maneira ambientalmente adequada de tratamento dos resíduos orgânicos, uma vez que por meio dos mecanismos naturais de degradação biológica, converte os resíduos em dois subprodutos que podem ser utilizados como fertilizante natural, na recuperação de áreas degradadas, contribuindo com a redução da emissão de gases de efeito estufa e ainda, como material alternativo para cobertura de aterros sanitários. Somado a isso, uma vez realizada a compostagem, há uma diminuição do volume de resíduos que chega aos aterros, aumentando a vida útil desses locais, consequentemente reduzindo a necessidade de busca por novas áreas, evitando assim, outros impactos, como a contaminação de solos e águas subterrâneas, emissão de gases de efeito estufa e ainda o alto custo de tratamento de seus efluentes. Isso posto, o presente trabalho objetivou analisar a qualidade do composto orgânico proveniente de duas composteiras caseiras, e comparou a viabilidade de sua comercialização com base na legislação brasileira vigente. Apesar de parte dos requisitos mínimos exigidos por lei não terem sido atendidos, o material produzido possui boa qualidade para uso próprio, pois não apresenta microrganismos patogênicos, e contém diversos macronutrientes em quantidade satisfatória.

Renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) have a different site of interaction and modulate vascular tone and inflammatory response as well on exercise adaptation, which is modulated by exercise-induced cytokines. The aim of the study was to evaluate the role of ACE I/D and BDKRB2 +9/−9 polymorphism on exercise-induced cytokine response. Seventy-four male marathon finishers, aged 30 to 55 years, participated in this study. Plasma levels of exercise-induced cytokines were determined 24 h before, immediately after, and 24 h and 72 h after the São Paulo International Marathon. Plasma concentrations of MCP-1, IL-6 and FGF-21 increased after marathon in all genotypes of BDKRB2. IL-10, FSTL and BDNF increased significantly after marathon in the genotypes with the presence of the −9 allele. FSTL and BDNF concentrations were higher in the −9/−9 genotype compared to the +9/+9 genotype before (p = 0.006) and after the race (p = 0.023), respectively. Apelin, IL-15, musclin and myostatin concentrations were significantly reduced after the race only in the presence of −9 allele. Marathon increased plasma concentrations of MCP1, IL-6, BDNF and FGF-21 in all genotypes of ACE I/D polymorphism. Plasma concentrations of IL-8 and MIP-1alpha before the race (p = 0.015 and p = 0.031, respectively), of MIP-1alpha and IL-10 after the race (p = 0.033 and p = 0.047, respectively) and VEGF 72 h after the race (p = 0.018) were lower in II homozygotes compared to runners with the presence of D allele. One day after the race we also observed lower levels of MIP-1alpha in runners with II homozygotes compared to DD homozygotes (p = 0.026). Before the marathon race myostatin concentrations were higher in DD compared to II genotypes (p = 0.009). Myostatin, musclin, IL-15, IL-6 and apelin levels decreased after race in genotypes with the presence of D allele. After the race ACE activity was negatively correlated with MCP1 (r = −56, p < 0.016) and positively correlated with IL-8, IL-10 and MIP1-alpha (r = 0.72, p < 0.0007, r = 0.72, p < 0.0007, r = 0.47, p < 0.048, respectively). The runners with the −9/−9 genotype have greater response in exercise-induced cytokines related to muscle repair and cardioprotection indicating that BDKRB2 participate on exercise adaptations and runners with DD genotype have greater inflammatory response as well as ACE activity was positively correlated with inflammatory mediators. DD homozygotes also had higher myostatin levels which modulates protein homeostasis.

An 85-year-old women with transthyretin cardiac amyloidosis presented with generalized weakness, elevated liver function test levels, and creatinine kinase consistent with rhabdomyolysis 1 week after starting tafamidis. She was already taking atorvastatin and amiodarone, raising the possibility of a drug–drug interaction inhibiting the breakdown and excretion of atorvastatin, causing drug-induced rhabdomyolysis. (Level of Difficulty: Intermediate.)

RT-PCR testing data provides opportunities to explore regional and individual determinants of test positivity and surveillance infrastructure. Using Generalized Additive Models, we explored 222,515 tests of a random sample of individuals with COVID-19 compatible symptoms in the Brazilian state of Bahia during 2020. We found that age and male gender were the most significant determinants of test positivity. There was evidence of an unequal impact among socio-demographic strata, with higher positivity among those living in areas with low education levels during the first epidemic wave, followed by those living in areas with higher education levels in the second wave. Our estimated probability of testing positive after symptom onset corroborates previous reports that the probability decreases with time, more than halving by about two weeks and converging to zero by three weeks. Test positivity rates generally followed state-level reported cases, and while a single laboratory performed ~90% of tests covering ~99% of the state’s area, test turn-around time generally remained below four days. This testing effort is a testimony to the Bahian surveillance capacity during public health emergencies, as previously witnessed during the recent Zika and Yellow Fever outbreaks.

This research aimed to evaluate the impact of atmospheric cold plasma (ACP) treatment on the fungal spores naturally present in sundried tomatoes, as well as their influence on the physico-chemical properties and antioxidant activity. ACP was performed with a Surface Dielectric Barrier Discharge (SDBD), applying 6 kV at 23 kHz and exposure times up to 30 min. The results showed a significant reduction of mesophilic aerobic bacteria population and of filamentous fungi after the longer ACP exposure. In particular, the effect of the treatment was assessed on Aspergillus rugulovalvus (as sensible strain) and Aspergillus niger (as resistant strain). The germination of the spores was observed to be reliant on the species, with nearly 88% and 32% of non-germinated spores for A. rugulovalvus and A. niger, respectively. Fluorescence probes revealed that ACP affects spore viability promoting strong damage to the wall and cellular membrane. For the first time, the sporicidal effect of ACP against A. rugulovalvus is reported. Physicochemical parameters of sundried tomatoes such as pH and water activity (aw) were not affected by the ACP treatment; on the contrary, the antioxidant activity was not affected while the lycopene content was significantly increased with the increase in ACP exposure time (p ≤ 0.05) probably due to increased extractability.

Atualmente os excipientes farmacotécnicos estão sendo vistos não só como componentes da forma farmacêutica, mas também como substâncias capazes de influenciar na biodisponibilidade e, consequentemente, no efeito terapêutico dos fármacos, considerando que a utilização adequada destes é um ponto crucial para o sucesso de uma formulação. Baseado neste fato, o objetivo do estudo foi avaliar o uso de excipientes em cápsulas de fármacos previamente elencados e, com isso, verificar a qualidade destas formulações, bem como a perícia dos profissionais responsáveis por estas manipulações. A coleta de dados se deu por meio de um formulário a ser preenchido pelo farmacêutico de cada estabelecimento pesquisado, selecionando os excipientes utilizados pela farmácia para o preparo de cada fármaco. Para avaliação e consolidação dos resultados foram definidas pontuações para cada formulação, considerando se o uso dos excipientes estava adequado, aceitável ou inadequado. Os dados foram expostos percentualmente em gráficos. A média geral de acerto das farmácias voluntárias foi de 40,1%. Dentre os medicamentos, a Bupropiona aparece em destaque por apresentar 100% de erro na utilização de excipientes. A Ranitidina apresentou menor índice de erro 31,3%. O excipiente mais utilizado com 72,2% foi o amido. Concluiu-se que se faz necessário um melhor preparo das farmácias magistrais bem como de seus profissionais, pois apresentaram de forma geral, e também, na avaliação individual de cada fármaco, um baixo índice de acerto na escolha dos excipientes, comprometendo a qualidade, eficácia e segurança do medicamento.

The effect of two kinds of casings on the production and characteristics of a dry fermented sausage was investigated. In detail, an Italian product, naturally fermented at low temperatures and normally wrapped in beef casing instead of the most diffused hog one, was selected. Two different productions (one traditionally in beef casing (MCB) and another in hog casing (MCH)) were investigated over time to determine the differences particularly regarding proteolytic changes during fermentation and ripening. First of all, the product in hog casing required a longer ripening time, up to 120 days, instead of 45–50 days, because of the lower drying rate, while the microbial dynamics were not significantly modified. Conversely, the proteolysis showed a different evolution, being more pronounced, together with the biogenic amines content up to 341 mg/Kg instead of 265 mg/Kg for the traditional products. The latter products were instead characterized by higher quantities of total free amino acids, 3-methyl butanoic acid, 3-Methyl-1-butanal, and 2-Methylpropanal, enriching the final taste and aroma. The traditional product MCB also showed lower hardness and chewiness than MCH. The results highlight how the choice of casing has a relevant impact on the development of the final characteristics of fermented sausages.

O presente artigo teve como objetivo analisar um pequeno corpus compilado a partir da seção de compreensão oral do TOEFL - Test of English as a Foreign Language, e, posteriormente, comparar a frequência e chavicidade das palavras com o corpus MICASE – Michigan Corpus of Academic Spoken English, e o BASE – British Academic Spoken English. Dessa maneira, o artigo visou elencar uma lista das palavras-chave que poderão servir de base para criação de material didático preparatório para o teste. O estudo tem como referencial teórico as discussões sobre inglês para fins acadêmicos – IFA (ROBINSON, 1991; JORDAN, 1997 e GOH, 2012); testagem (MCNAMARA, 2009, 2000; FULCHER, 1999 e DOUGLAS, 2005, 2000) e uso de corpora no ensino de língua estrangeira – LE (FLOWERDEW, 2001; MCENERY; XIAO, 2011). Os resultados indicam uma lista de palavras relativamente mais frequentes em palestras acadêmicas da área de Ciências Biológicas, desta forma, as mesmas servem de possíveis recursos para o ensino de IFA.

Strong gusts negatively affect wind turbines in many ways. They (1) harm their structural safety; (2) reduce their wind energy output; and (3) lead to a shorter wind turbine rotor blade fatigue life. Therefore, the goal of this study was to provide a global assessment of the gust climate, considering its influence on wind turbines. The gust characteristics analyzed were: (1) the gust speed return values for 30, 50 and 100 years; (2) the share of gust speed exceedances of cut-out speed; and (3) the gust factor. In order to consider the seasonal variation of gust speed, gust characteristics were evaluated on a monthly basis. The global monthly wind power density was simulated and geographical restrictions were applied to highlight gust characteristics in areas that are generally suitable for wind turbine installation. Gust characteristics were computed based on ERA-interim data on a 1° × 1° spatial resolution grid. After comprehensive goodness-of-fit evaluation of 12 theoretical distributions, Wakeby distribution was used to compute gust speed return values. Finally, the gust characteristics were integrated into the newly developed wind turbine gust index. It was found that the Northeastern United States and Southeast Canada, Newfoundland, the southern tip of South America, and Northwestern Europe are most negatively affected by the impacts of gusts. In regions where trade winds dominate, such as eastern Brazil, the Sahara, southern parts of Somalia, and southeastern parts of the Arabian Peninsula, the gust climate is well suitable for wind turbine installation.

Abstract: Seedlings for commercial growing of passion fruit are preferentially acquired through seeds. Success in germination and seedling emergence, in turn, is influenced by the genetic constitution of the progenies and the thermal conditions imposed on the growth environment. The aim of this study was to evaluate the emergence and vigor of seedlings of passion fruit cultivars exposed to different temperatures. The experiment was conducted in a germination chamber at the Unidade de Ensino, Pesquisa e Extensão / Pomar Campus of the Department of Plant Science of the Universidade Federal de Viçosa (UFV). The study was carried out in 5 × 3 factorial arrangement, with five temperature ranges (5-15, 10-20, 15-25, 20-30 and 25-35 °C) and three varieties of passion fruit (BRS Sol do Cerrado, BRS Gigante Amarelo and FB-200 Yellow Master) in a completely randomized design with six replications of 25 seeds per plot. The variables analyzed were the percentage, the speed index, and the average time of emergence, shoot length, total length, and seedling dry matter. The cultivars BRS Sol do Cerrado and BRS Gigante Amarelo exhibited seedling emergence of over 95% in the temperature ranges of 20-30 °C and 25-35 °C. Alternating temperatures from 20-30 °C stimulates seedling emergence, seedling growth, and greater accumulation of seedling dry matter.

As many societies age, primary osteoporosis (PO) is increasingly a major health problem. Current drug treatments such as alendronate and risedronate have known side effects. We took an agnostic empirical approach to find PO therapeutic compounds. We examined 13,548,960 probe data-points from mesenchymal stromal cell (hMSC) lines and found that PGF, DDIT4, and COMP to be up-regulated, and CHI3L1, down-regulated. We then identified their druggable domains. For the up-regulated differentially-expressed genes, we used protein–protein interactions to find residue clusters as binding surfaces. We then employed pharmacophore models to screen 15,407,096 conformations of 22,723,923 compounds, which identified (6R,9R)-6-(2-furyl)-9-(1H-indol-3-yl)-2-(trifluoromethyl)-5,6,7, 9-tetrahydro-4H[1,2,4]triazolo[5,1],(2S)-N1-[2-[2-(methylamino)-2-oxo-ethyl]phenyl]-N2-phenylpyrrolidine-1,2-dicarboxamide, and 2-furyl-(1H-indol-3-yl)-methyl-BLAHone as candidate compounds. For the down-regulated CH13L1, we relied on genome-wide disease signatures to identify (11alpha)-9-fluoro-11,17,21-trihydroxypregn-4-ene-3,20-dione and Genistein as candidate compounds. Our approach differs from previous research as we did not confine our drug targets to hypothesized compounds in the existing literature. Instead, we allowed the full expression profile of PO cell lines to reveal the most desirable targets. Second, our differential gene analysis revealed both up- and down-regulated genes, in contrast to the literature, which has focused on inhibiting only up-regulated genes. Third, our virtual screening universe of 22,723,923 compounds was more than 100 times larger than those in the known literature.