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Objetivo: O gene de fusão BCR::ABL1 (Ph+) ocorre em cerca de 25% dos casos de leucemia linfoblástica aguda (LLA) em adultos. Esse subtipo molecular estava associado a desfechos clínicos ruins antes dos inibidores de tirosina quinase (TKIs). Os TKIs melhoraram significativamente a sobrevida global (SG), a sobrevida livre de eventos (SLE) e as taxas de remissão completa (RC). Adicionar o TKI dasatinibe à quimioterapia aumentou as taxas de resposta molecular completa (RMC) e reduziu as taxas de recaída comparado à quimioterapia isolada. Em 2016, a OMS reconheceu uma nova entidade diagnóstica provisória chamada LLA “semelhante ao Filadélfia” (Ph-like) ou “BCR::ABL1-like”. Esse subtipo de LLA-B, embora com uma assinatura gênica semelhante à LLA Ph+, não possui a proteína de fusão BCR::ABL1. Pacientes com esse subtipo têm desfechos clínicos ruins e mostram rearranjos, mutações e variações no número de cópias de genes relacionados a quinases ou receptores de citocinas, ativando vias JAK2/STAT, ABL1 e RAS. Ensaios clínicos testaram TKIs direcionados a JAK ou ABL na LLA Ph-like, mas um tratamento padrão ainda não foi estabelecido. Identificar pacientes com LLA Ph-like é desafiador e requer metodologias que avaliem a expressão gênica de forma abrangente. Chiaretti et al. (J Haematol. 2018;181(5):642-652) propuseram uma ferramenta de triagem baseada na expressão de 10 genes e um modelo estatístico para identificar pacientes com LLA Ph-like. Material e métodos: Investigamos a expressão de genes relacionados ao Ph-like em amostras de doadores sadios (n = 12) e pacientes adultos com LLA-B (n = 83; Ph+ n = 33 e Ph- n = 50) por PCR quantitativo e sua associação com características clínicas, laboratoriais e desfechos de sobrevivência. Utilizamos o modelo estatístico de Chiaretti et al. para calcular as pontuações. A dicotomização foi feita usando curva ROC, com métricas como área sob a curva (AUC) e índice de Youden, e comparações entre grupos foram realizadas com o teste de Mann-Whitney, teste exato de Fisher ou qui-quadrado, conforme apropriado. As análises de sobrevivência foram conduzidas pelo método Kaplan-Meier e análise de regressão de Cox, com p < 0,05 considerado significativo. Resultados: A expressão gênica de CD97, CD99, CRLF2, IFITM1, IFITM2, NUDT4, SEMA6A, SOCS2 e TP53INP1 foi maior em pacientes com LLA-B comparado a doadores sadios (p < 0,05). A pontuação de 10 genes foi maior em pacientes com LLA-B Ph+ do que em LLA-B Ph- (p < 0,0001). O status Ph+ ou Ph- não previu o prognóstico dos pacientes com LLA-B, mas pontuações de 10 genes mais altas foram associadas a uma sobrevida global reduzida. Em pacientes com LLA-B Ph-, pontuações altas também foram associadas a taxas de sobrevida global mais baixas (p = 0,04). Entre os genes relacionados ao Ph-like, apenas a alta expressão de IGJ foi associada a piores desfechos clínicos. Pontuações mais altas foram associadas a níveis mais baixos de LDH (p < 0,05). No subgrupo LLA-B Ph-, pontuações mais altas correlacionaram-se com menos blastos na medula óssea e níveis mais baixos de LDH (p < 0,05). A pontuação de 10 genes foi um fator prognóstico independente na análise multivariada de regressão de Cox. Discussão e conclusão: A expressão diferencial dos genes avaliados merece investigação adicional devido a suas possíveis implicações para a biologia da doença e alvos terapêuticos. A pontuação baseada em genes Ph-like pode ser uma ferramenta valiosa para a estratificação de risco em cenários de recursos limitados. Apoiado por FAPESP, CAPES, CNPq.

Introdução: A leucemia mieloide aguda (LMA) é uma doença clínica e molecularmente heterogênea que requer uma estratificação de risco precisa para alcançar resultados ótimos de tratamento para os pacientes. A classificação de risco do grupo European LeukemiaNet (ELN) tem melhorado significativamente a sobrevida de adultos com LMA, permitindo tratamentos adaptados às mutações específicas dos pacientes. No entanto, uma parcela considerável desses pacientes não responde conforme o esperado, destacando que a classificação do ELN nem sempre reflete adequadamente a heterogeneidade da resposta clínica. Em 2024, Ortiz et al., avaliaram o transcriptoma de pacientes de cinco coortes de pacientes tratados com quimioterapia intensiva, desenvolvendo um índice de prognóstico, chamado de 4-PI, baseado na expressão de 4 genes (CYP2E1, DHCR7, IL2RA e SQLE). Objetivo: Neste estudo, buscamos validar esse índice em uma coorte brasileira de pacientes adultos com LMA tratados uniformemente com o regime 3+7. Métodos: Em total, 111 pacientes com LMA de novo foram considerados neste estudo. Todos os pacientes foram diagnosticados e tratados em centros de referência em Recife, PE, Brasil (CAAE #47769821.7.0000.5208). O diagnóstico de LMA foi determinado por citomorfologia e estudos genéticos, de acordo com os critérios da OMS. Pacientes com leucemia promielocítica aguda, LMA relacionada à terapia ou com histórico prévio de síndrome mielodisplásica foram excluídos. Os níveis de transcrição dos 4 genes foram quantificados usando RT-qPCR e normalizados com dois genes endógenos (ACTB e HPRT1). Resultados: Como primeira análise, os pacientes foram dicotomizados em grupos de baixo e alto 4-PI. A mediana de sobrevivência global de pacientes com alto 4-PI foi inferior ao grupo com baixo 4-PI (4,8 vs. 11 meses, Log-rank p = 0,042). Em seguida, dividimos os pacientes em três grupos (baixo, intermediário e alto) de acordo com a proposta original de Ortiz et al. As medianas de sobrevivência global foram de 22,3, 10,7 e 4,8 meses, respectivamente. Embora a comparação global dos três grupos não indicou diferenças (Log-rank p = 0,077), a análise de regressão de Cox mostrou que os pacientes com alto 4-PI têm um risco de morte superior ao grupo de baixo 4-PI (HR = 2,32, IC95% 1,04 – 5,23, p = 0,043). Adicionalmente, depois de considerar possíveis variáveis de confusão, como idade, sexo, número de leucócitos e a mutação FLT3-ITD, se mantiveram as diferenças entre os grupos de alto e baixo 4-PI (HR = 3,71, IC95% 1,39 – 5,70, p = 0,008). Posteriormente, observamos que os pacientes com alto índice tiveram uma taxa de remissão hematológica completa inferior comparada com os casos com 4-PI intermediário ou baixo, sendo de 52,1%, 70% e 76,6%, respectivamente (p = 0,042). Por fim, não observamos nenhum impacto na sobrevida livre de doença. Discussão e conclusões: Estes resultados demonstram que o índice prognóstico 4-PI é uma ferramenta simples e efetiva para aprimorar a predição de sobrevivência global em pacientes com LMA, apresentando potencial para refinar a estratificação de risco e o manejo clínico desta doença. A validação do índice em uma coorte de vida real, diferente do trabalho original que trabalhou com pacientes dentro de estudos clínicos controlados, reforça a aplicabilidade e a utilidade clínica do 4-PI em contextos mais amplos e variados.

O monitoramento da Leucemia Mieloide Aguda (LMA) é uma estratégia de avaliação prognóstica para identificar Doença Residual Mensurável (DRM). Indica-se o estudo de DRM por métodos moleculares em casos com mutações NPM1 /translocações tipo core-binding fator; mas a citometria de fluxo multiparamétrica (CFMP) é aplicável a mais de 90% das LMAs e preditora do sucesso terapêutico. Diante da escassez no acesso a métodos moleculares em países em desenvolvimento, um protocolo de determinação de DRM na rotina laboratorial é uma necessidade não atendida. Objetivamos implantar um protocolo de DRM por CFMP para LMA e avaliá-lo quanto à sua eficiência e como fator prognóstico adicional à estratificação de risco clássica. Foram incluídos 191 pacientes com LMA de novo ou secundária à síndrome mielodisplásica, entre 18 e 65 anos (09/2015 a 02/2023), com remissão morfológica completa após tratamento com 1 ou 2 ciclos de indução (ciclo 1:3 dias de daunorrubicina 60 mg/m2 e 7 dias de citarabina 200 mg/m2; ciclo 2:3 dias de daunorrubicina 60 mg/m2 e 6 dias de citarabina 1 g/m2 2x/dia). Na Consolidação foi administrada no ciclo1:citarabina 1 g/m2 2x/dia, 6 dias e no ciclo2: idem 1 ou transplante de Medula Óssea (MO) autólogo com condicionamento BuCy. Os pacientes foram estratificados (ELN2017*-exceto mutações TP53 ou ASXL1) de acordo com cariótipo, testes moleculares e coleta de dados clínicos. As DRMs 1, 2 (Pós-indução) e 4 (Pós consolidação), foram avaliadas com: CD45, CD34, CD117, CD33, CD38, CD19, CD123, CD7, CD56, CD13, CD11b, CD14, CD64, CD300e, CD15, CD133 e HLA-DR. Utilizamos a abordagem de LAIPs e DfN, comparando dados de MO saudável e diagnóstico e sendo DRM+ a frequência de células em CD45+ ≥ 0,1% (mínimo 1 fenótipo anormal). Analisamos Sobrevida Global e Livre de Recaída (SG e SLR) e Incidência Cumulativa de Recaída (ICR) - software R (α = 5%). Não foram encontradas associações entre DRM+ e idade, leucócitos, % de blastos, subtipo morfológico e alterações citogenéticas. Observou-se 21% de DRM+ na DRM1,13% na DRM2 e 12,5 % na DRM4. Na DRM1, a frequência de DRM+ para pacientes de risco baixo, intermediário e alto foi: 46,5%, 33,4%, 20,1% e nas DRMs 2 e 4, 33,4%/ 38,9%/ 27,7% e 48,8%/ 48,8%/ 14,4%, respectivamente. Globalmente as DRMs foram definidas como LAIPs ou DfN em 72,3% e 27,7% das amostras. A expressão de CD56 foi a mais frequente (22%), seguida por alterações em CD34/CD13 (21%) e CD33 (17%). DRMsnegativas foram mais frequentes em pacientes com NPM1mut (DRM1, 69,7%) do que em FLT3-ITD (15,2%). A DRM+ após o 2ºciclo de Indução implicou em maior risco de óbito (HR = 1329 (IC;75,16-235022), p = 0,002), maior ICR (44,5% em 30 meses, p = 0,033) e menor SG (4,4 meses, p = 0,018) no risco intermediário. A detecção de DRM+ não se associou aos riscos favorável e alto. Nossos achados demonstram a padronização da DRM por CFMP em uma população brasileira com tratamento único reprodutível usando painel racional com número limitado de marcadores. A detecção de fenótipos ao diagnóstico (LAIP) é mais útil do que os fenótipos semelhantes a DfN, embora sua combinação tenha validado o tubo proposto como “consenso”, aplicável a todos os casos a despeito do fenótipo inicial. Em pacientes de risco intermediário, o resultado da DRM por CFMP se mostrou fator de risco independente para SG. Sendo este grupo correspondente à cerca 1/3 dos casos, comumente com cariótipo normal e desfechos variáveis, a identificação de fatores prognósticos adicionais e dinâmicos tem grande utilidade e pode guiar as decisões terapêuticas. Por fim, a identificação dos fenótipos de DRM definidos neste protocolo pode contribuir na busca por alvos terapêuticos para erradicação das células leucêmicas resistentes.

Apesar dos recentes progressos no tratamento da leucemia mieloide aguda (LMA), a sobrevida global de pacientes idosos permanece desanimadora. Preocupações em relação à adaptação de indivíduos idosos para tolerar regimes de quimioterapia intensiva motivaram o desenvolvimento de terapias não intensivas. O gene Slit Guidance Ligand 2 (SLIT2) codifica uma glicoproteína que demonstrou desempenhar papéis-chave em diferentes processos fisiológicos. No contexto da leucemia, demonstramos anteriormente que SLIT2 apresenta funções supressoras de tumor com baixa citotoxicidade em LPA, destacando seu potencial terapêutico. Assim, decidimos investigar o papel de SLIT2 em LMA. A análise de componentes principais usando análise transcriptômica comparando pacientes de TCGA com níveis mais altos versus níveis mais baixos de SLIT2, revelou que pacientes com SLIT2 low estavam associados a aumento da expressão de genes relacionados à leucemogênese, como HOXA10/HOXA7, enquanto LMAs com SLIT2 high foram correlacionado com os termos “CELL_CYCLE_CONTROL” e “POSITIVE_REGULATION_OF_APOPTOSIS”. Adicionalmente, análise de deconvolução em pacientes com SLIT2 alto e baixo mostrou um acúmulo de compartimento quiescente de células-tronco progenitoras de leucemia (LSPC) no SLIT2 low. Na distribuição dos subtipos de LMA (Zheng et al., 2022), SLIT2 low parece estar associado a uma maior percentagem do subtipo de LMA primitivo, que é enriquecido para LSPC (40%), enquanto os pacientes com SLIT2 high apresentaram perfil GMP-like (37%), que está associado a um bom prognóstico na LMA. Como o SLIT2 é um fator solúvel, medimos o nível de SLIT2 em amostras de plasma isoladas de aspirados de MO no momento do diagnóstico de pacientes adultos com LMA do Instituto do Câncer do Estado de São Paulo, e de doadores saudáveis (DS). Cerca de 83% (n = 43 de 52) dos pacientes com LMA apresentaram concentração diminuída de SLIT2 em comparação com DS. Além disso, a análise dos resultados indicou que pacientes com alta concentração de SLIT2 foram associados à melhor sobrevida global em comparação com pacientes com baixa concentração de SLIT2. Em seguida, nos perguntamos se a administração exógena do peptídeo SLIT2 apresentaria efeitos anti leucêmicos em modelos de LMA. O tratamento ex vivo de amostras primárias de LMA com peptídeo SLIT2 recombinante (50 ng/mL) reduziu significativamente a contagem de células e a detecção de Ki67 em células de LMA em comparação com o controle do veículo, com alterações não significativas na viabilidade celular, apoiando o papel de SLIT2 como um agente citostático na LMA. O modelo de camundongo de xenotransplante usando células MV4-11 transplantadas por via intravenosa em camundongos NSGS mostrou que o tratamento com SLIT2 (dosagem diária única; 7 dias) atrasou significativamente a leucemogênese e reduziu a carga tumoral in vivo. Camundongos tratados com SLIT2 exibiram aumento de sobrevida global e redução da infiltração de órgãos secundários em comparação com o grupo veículo. Juntos, nossos dados demonstram o papel da SLIT2 como uma proteína supressora de tumor na LMA, de modo que sua maior concentração no plasma da MO está associada a maior sobrevida. Demonstramos ainda, que a proteína SLIT2 apresenta efeitos citostáticos nas células da LMA, retardando a progressão da leucemia in vivo. Em conjunto, nossos dados destacam o potencial terapêutico da SLIT2 na LMA, especialmente em situações em que esquemas quimioterápicos intensivos não são uma opção.

Evidências recentes sugerem que a via SLIT-ROBO não possui papel apenas em processos fisiológicos, mas também na progressão do câncer, de modo que dependendo do tipo de neoplasia, o eixo SLIT -ROBO pode apresentar perfil de genes supressores de tumor, em que quando isso ocorre a região promotora de SLIT2 encontra-se frequentemente hipermetilada ou como oncogenes, no qual sua alta expressão está frequentemente associada a um pior prognóstico. No contexto da leucemia mieloide aguda (LMA), a baixa expressão de SLIT2 foi associada à uma menor sobrevida global (OS) (Golos et al., 2019), no entanto o papel funcional de SLIT2 em doenças hematológicas malignas permanece desconhecido. Recentemente, nosso grupo mostrou que o knockdown de SLIT2 foi capaz de aumentar a proliferação celular de células de leucemia promielocítica aguda (APL), resultando em doença mais agressiva no modelo de APL in vivo. Objetivo: Estudar o papel funcional da SLIT2 em uma doença heterogênea, como a LMA. Resultados: Usando conjuntos de dados disponíveis publicamente. (GSE58477, blastos de cariótipo normal: 62, CD34+ saudável: 10; GSE63409, LSC: 14, HSC: 5) detectamos níveis de aumentados de metilação no sítio promotor de SLIT2 em células de LMA em comparação com células CD34+ saudáveis, sugerindo funções supressoras de tumor de SLIT2 (p < 0,05). Em seguida, analisamos a concentração de SLIT2 no plasma da medula óssa (MO) de pacientes de LMA por ELISA, e observamos que o nível plasmáticos de SLIT2 foi significativamente menor em pacientes com LMA em comparação com doadores saudáveis (p < 0,05). Para avaliar o papel biológico de SLIT2, tratamos diferentes linhagens de células de LMA (KASUMI1, MV4-11 e MOLM13, as últimas duas não apresentam a expressão dos receptores canônicos de SLIT2) com SLIT2 recombinante (50 ng/mL) in vitro. A administração de SLIT2 reduziu a proliferação celular e a capacidade de formação de colônias dessas células, com retenção do ciclo celular na fase G1 (p < 0,0001). Por outro lado, o knockdown SLIT2 em células THP-1 e OCI-AML3 aumentou as taxas de proliferação dessas linhagens. Em seguida, determinamos se o tratamento com SLIT2 poderia atrasar a leucemogênese in vivo. Para isso, células de LMA MV4-11 expressando luciferase foram transplantadas em camundongos NSG-SGM3, de modo que os animais foram, em seguida, tratados por sete dias com 25 ng/g de SLIT2 recombinante ou com o veículo (grupo de controle). A progressão da doença foi monitorada pelo sistema de imagem in vivo IVIS. Observamos então que a terapia com SLIT2 resultou em menor carga tumoral da doença, levou à diminuição da infiltração leucêmica na MO e no baço, resultando assim no aumento da sobrevida global dos animais tratados em comparação com o grupo controle (p < 0,05). Conclusão: Em conclusão, mostramos que a metilação de SLIT2 é recorrente em pacientes com LMA e que o nível de SLIT2 no plasma de pacientes com LMA é reduzido. Além disso, o tratamento com SLIT2 parece ter um efeito citostático em diferentes linhas de células de LMA e atrasa a leucemogênese in vivo, mesmo em linhagens de LMA que não apresentam a expressão de seus receptores canônicos, propondo assim uma via alternativa à qual os efeitos desse peptídeo podem estar sendo mediados. Nosso estudo revela o potencial terapêutico do SLIT2 em neoplasias hematológicas, podendo ser utilizado como coadjuvante na clínica.

Background: Despite numerous studies assessing bundled interventions to enhance hand hygiene compliance (HHC), compliance rates persist at suboptimal levels. Our objective was to employ Kotter's Change Model (KCM) to enhance HHC and conduct a comprehensive process evaluation among medical staff within the intensive care unit (ICU)., Methods: KCM was implemented at the ICU of Zhongnan Hospital of Wuhan University from March 2018 to August 2021, with a 41-month longitudinal monitoring of HHC. The primary outcome focused on the absolute monthly change in HHC. Secondary outcomes encompassed the HHC characteristics across different phases, varying trends in HHC concerning different hand hygiene opportunities and occupations, quarterly incidences of central line-associated bloodstream infections (CLABSI) and catheter-associated urinary tract infections (CAUTI)., Results: This study included 20,222 hand hygiene actions and 24,195 opportunities. The overall HHC was 83.58 % (95 %CI, 83.11 %-84.04 %). Following the KCM implementation, HHC surged from 35.71 % (95 % CI, 22.99 %-50.83 %) to 87.75 % (95 % CI, 85.53 %-89.67 %), reflecting a notable increase of 145.73 %. The most rapid growth in HHC occurred post-patient contact, elevating from 35.29 % to 89.8 %. Despite escalating patient numbers and treatment complexities annually, the quarterly rates of CLABSI (0 ‰-3.53 ‰) and CAUTI (0.96 ‰-4.26 ‰) remained consistently low., Conclusion: Utilizing KCM systematically alters healthcare providers' perception of hand hygiene, fostering an environment that advocates for and sustains improved HHC among ICU personnel., Implications for Clinical Practice: The Kotter's change model can be an effective framework for healthcare organizations to systematically improve and maintain hand hygiene compliance among healthcare providers, which can in turn help reduce healthcare-associated infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The therapeutic use of synthetic message RNA (mRNA) has been validated in COVID-19 vaccines and shows enormous potential in developing infectious and oncological vaccines. However, double-stranded RNA (dsRNA) byproducts generated during the in vitro transcription (IVT) process can diminish the efficacy of mRNA-based therapeutics and provoke innate immune responses. Existing methods to eliminate dsRNA byproducts are often cumbersome and labor-intensive. In this study, we revealed that a loose mRNA secondary structure and more unpaired U bases in the sequence generally lead to the formation of more dsRNA byproducts during the IVT process. We further developed a predictive model for dsRNA byproducts formation based on sequence characteristics to guide the optimization of mRNA sequences, helping to minimize unwanted immune response and improve the protein expression of mRNA products. Collectively, our study provides novel clues and methodologies for developing effective mRNA therapeutics with minimized dsRNA byproducts and increased protein expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Limited organic carbon in drinking water constrains the removal of nitrate‑nitrogen (NO 3 - -N) via aerobic denitrification. This paper reports the use of silica-coated nano zero-valent iron (nZVI@SiO 2 ) as a stable and sustainable electron donor to enhance aerobic denitrification. The nZVI@SiO 2 , synthesized via a one-step method, was resistant to oxidation and exhibited excellent stability. In conjunction with aerobic denitrifying bacteria, nZVI@SiO 2 achieved NO 3 - -N and total nitrogen TN removal efficiencies of 90.64 % and 80.94 %, respectively. This represents an increase of 24.15 % in the efficiency of TN removal compared with that of the nZVI system. The activity of the nZVI system diminished gradually after just three cycles, whereas nZVI@SiO 2 maintained NO 3 - -N and TN removal efficiencies of 89.33 % and 78.08 %, respectively, after four cycles, respectively, indicating its sustainable ability to enhance aerobic denitrification. Cyclic voltammetry and electrochemical impedance spectroscopy demonstrated enhanced electron transfer efficiency of nZVI@SiO 2 . Furthermore, nZVI@SiO 2 significantly promoted the activity of the electron transfer system, ATP levels, nitrate/nitrite reductase activity, contents of complexes I and III, and extracellular polymeric substances. nZVI@SiO 2 significantly enhanced electron generation, transfer, and consumption during biological denitrification by functioning as both an electron donor and mediator. The findings implicate nZVI@SiO 2 as a means to enhance nitrogen removal by aerobic denitrifying microorganisms in oligotrophic water via sustained donation of electrons., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer poses a significant threat to human health, and there is an urgent need for more effective treatments. Combining chemotherapy and immunotherapy is an effective strategy to enhance curative outcomes and holds great potential for widespread application. The natural phytochemical genistein (GEN) exhibits cytotoxicity against tumors and is a potential chemotherapeutic agent. Lentinan (LTN) is a natural polysaccharide with immune-enhancing properties that has been utilized in tumor treatment. This study constructed a pH-responsive nanoparticle GEN@LTN-BDBA with chemotherapy and immunotherapy functions using GEN and LTN. After characterizing the nanoparticles, the molecular mechanism of GEN@LTN-BDBA formation was explored using in silico simulation. GEN@LTN-BDBA can significantly inhibit the proliferation of A549 and HepG2 cells in vitro. The in vivo experiment results demonstrated that treatment with GEN@LTN-BDBA can significantly reduce tumor cell mass and prevent metastasis. In this nanoparticle, GEN induced oxidative stress and apoptosis of tumor cells. Meanwhile, the released LTN initiated an anti-tumor immune response by promoting dendritic cell (DC) maturation and upregulating the expression of costimulatory molecules and major histocompatibility complex. The construction method of GEN@LTN-BDBA can be extended to the preparation of other polysaccharides and hydrophobic chemotherapy molecules, offering a novel strategy to enhance the efficacy of monotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Reservoirs are important drinking water sources. The metalimnetic oxygen minimum (MOM) usually occurs periodically in summer and autumn in deep-water reservoirs due to algae blooms and thermal stratification. This study aimed to explore the physiological and molecular responses of Microcystis aeruginosa (M. aeruginosa) under MOM conditions (darkness coupled with low dissolved oxygen (DO) concentration, hydrostatic pressure, and nutrient starvation). The comprehensive response of M. aeruginosa suggested that MOM conditions led to an immediate collapse of gas vesicles. This was followed by a gradual inhibition of photosynthesis by disturbing the electron transport chain and a significant downregulation of energy metabolism and carbohydrate metabolism. The active cells were approximately 5 % and > 45 % under MOM aerobic (3.0-7.0 mg/L DO) and anaerobic conditions (< 0.5 mg/L DO), respectively, for 20 days. In addition, a single exposure to darkness or pressure accelerated the decay of M. aeruginosa cells; however, MOM conditions with a low DO concentration had the opposite effect. The survival of M. aeruginosa cells under MOM conditions could be attributed to stringent response and the activation of HIF-1 signal when DO concentration decreased to < 2.0 mg/L by promoting the formation of cellular quiescence and resource redistribution. This study sheds light on the molecular response and adaptation mechanism of M. aeruginosa under MOM conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The risk of fungal pollution in drinking water has been paid attention. Solar/chlorine dioxide (ClO 2 ) combined system is an environment-friendly, economical and efficient disinfection method, especially for countries and regions that are economically backward and still exposed to unsafe drinking water. In this paper, the kinetics, influencing factors, mechanism and regrowth potential of inactivated Aspergillus niger (A. niger) spores by solar/ClO 2 were reported for the first time. The inactivation curve can be divided into three stages: instant inactivation within 1-2 min, slow linear inactivation and finally a tail. The synergistic factors produced by solar/ClO 2 in terms of log reduction and maximum inactivation rate were 1.194 and 1.112, respectively. The inhibitory effect on the regrowth of A. niger spores inactivated by solar/ClO 2 was also stronger than that by ClO 2 alone. Strongly oxidizing reactive species produced by solar/ClO 2 accelerated the accumulation of endogenic reactive oxygen species (ROS) caused by oxidation stress of A. niger spores, improving the inactivation ability of the system. The inactivation order of A. niger spores was: loss of culturability, accumulation of intracellular ROS, loss of membrane integrity, leakage of intracellular species and change of morphology. The inactivation performance of solar/ClO 2 was better than solar/chlor(am)ine according to the comparison of inactivation efficiency and regrowth potential. Results also suggested that solar/ClO 2 process was more suitable for the treatment of ground water sources., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Maternal exposure to nanoparticles during gestation poses potential risks to fetal development. The placenta, serving as a vital interface for maternal-fetal interaction, plays a pivotal role in shielding the fetus from direct nanoparticle exposure. However, the impact of nanoparticles on placental function is still poorly understood, primarily due to the absence of proper human placental models. In this study, we established a placenta-on-a-chip model capable of recapitulating nanoparticle exposure to assess potential nanotoxicity. The model was assembled by coculturing human trophoblast stem cells (hTSCs) and endothelial cells within a dynamic microsystem. hTSCs exhibited progressive differentiation into syncytiotrophoblasts under continuous fluid flow, forming a bilayered trophoblastic epithelium that mimicking both structural and functional aspects of human placental villi. Copper oxide nanoparticles (CuO NPs) were introduced into the trophoblastic side to simulate maternal blood exposure. Our findings revealed that CuO NPs hindered hTSCs differentiation, leading to diminished hormone secretion and impaired glucose transport. Subsequent analysis indicated that CuO NPs disrupted the autophagic flux in trophoblasts and induced apoptosis. Furthermore, the placenta-on-a-chip model exhibited inflammatory responses to CuO NP exposure, including maternal macrophage activation, inflammatory cytokine secretion, and endothelial barrier disruption. Dysfunction of the placental barrier and the ensuing inflammatory cascades may contribute to aberrant fetal development. Overall, our placenta-on-a-chip model offers a promising platform for assessing nanoparticle exposure-related risks and conducting toxicology studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Helicobacter pylori (H. pylori) infection may be associated with colorectal polyps/adenomas, but the current evidence remains controversial., Methods: We retrospectively screened the medical records of 655 participants who underwent both colonoscopy and H. pylori test from June 15, 2020 to April 30, 2023. The number, size, location, and pathological type of colorectal polyps/adenomas were compared between H. pylori positive and negative groups. Adjusting for age, gender, smoking, drinking, hypertension, diabetes, fatty liver, body mass index, and inflammatory and metabolic indicators, multivariate logistic regression analyses were performed to evaluate the association of H. pylori infection with the number, size, location, and pathological type of colorectal polyps/adenomas, where no polyp/adenoma was used as reference., Results: Overall, 508 participants were included, of whom 154 and 354 were divided into H. pylori positive and negative groups, respectively. H. pylori positive group had significantly higher colorectal polyps/adenomas (74.7 % vs. 65.8 %, P=0.048), low-grade adenomas (55.7 % vs. 47.6 %, P=0.026), advanced adenomas (22.6 % vs. 13.3 %, P=0.008), and colorectal polyps/adenomas with sizes of ≥6 mm (61.7 % vs. 48.5 %, P=0.002) and ≥10 mm (25.2 % vs. 14.6 %, P=0.004) than H. pylori negative group. In multivariate logistic regression analyses, H. pylori infection was independently associated with low-grade adenomas (OR=2.677, 95 %CI=1.283-5.587, P=0.009), advanced adenomas (OR=3.017, 95 %CI=1.007-9.036, P=0.049), right-side colon polyps/adenomas (OR=5.553, 95 %CI=1.679-18.360, P=0.005), and colorectal polyps/adenomas with sizes of ≥10 mm (OR=4.436, 95 %CI=1.478-13.310, P=0.008), but not number of colorectal polyps/adenomas., Conclusion: H. pylori infection is associated with increased risk of colorectal polyps/adenomas, especially low-grade adenomas, advanced adenomas, right-side colon polyps/adenomas, and large colorectal polyps/adenomas., Competing Interests: Declaration of competing interest 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 © 2024 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is a significant global health concern, with high rates of morbidity and mortality. Bucidarasin A, a natural diterpenoid, has been shown to exert notable cytotoxic effects across a range of tumor cell lines. However, the underlying mechanisms responsible for this cytotoxicity remain unclear. In this study, we sought to elucidate the antitumor mechanisms of bucidarasin A, a natural diterpenoid derived from Casearia graveolens, with a particular focus on its effects on HCC. Furthermore, we employed surface plasmon resonance (SPR), molecular docking, and cellular thermal shift assay (CETSA) to gain further insight into the target protein of bucidarasin A. Our findings revealed that bucidarasin A exhibited pronounced cytotoxicity towards HepG2 cells. In vitro analysis indicated that bucidarasin A interrupted the cell cycle at the S phase and inhibited the proliferation and metastasis of HepG2 cells by modulating the FAK and STAT3 signaling pathways. Moreover, in vivo studies demonstrated that bucidarasin A not only exhibited antitumor effects but also impeded neovascularization, a finding that was corroborated by SPR interactions between vascular endothelial growth factor (VEGF) and bucidarasin A. This research substantiated that bucidarasin A, a clerodane diterpenoid, held promise as a therapeutic candidate against HCC, showcasing substantial antitumor efficacy both in vitro and in vivo through direct targeting of the STAT3 and FAK signaling pathways., Competing Interests: Declaration of competing interest Each author has completed the corresponding work, and there is no conflict of interest between the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chlorinated paraffins (CPs) are chlorinated alkane mixtures widely used as flame retardants and plasticizers in multiple industrial products. Systematic research on how homolog-specific properties affect their atmospheric behaviors is limited. Herein, we investigated the levels of short-chain CPs (SCCPs) and medium-chain CPs (MCCPs) in long-timescale, seasonal, and size-fractioned particles in the urban area of Dalian, a coastal city in northern China. The average SCCP and MCCP concentrations in particles with diameters ≤ 10 µm were 3.36 and 4.89 ng/m 3 , respectively, and a general increase in the SCCP concentration was observed from 2.59 ng/m 3 in 2018 - 2019 to 7.84 ng/m 3 in 2021 - 2023. CP levels and patterns showed significant seasonal variation, with a higher abundance of C 11-13 Cl 7-9 in winter and C 10-12 Cl 5 in summer. Elevated particle levels in winter and high temperatures in summer contributed to the seasonal variations. SCCPs and MCCPs were concentrated on particles with diameters of < 1 µm and their geometric mean diameter increased with the increasing carbon and chlorine numbers. Total Daily intake of SCCP and MCCP was calculated to be 0.15 and 0.22 ng/kg bw/day for adults. 53.1 %, 8.5 %, and 38.4 % of inhaled SCCPs, and 60.6 %, 7.6 %, and 31.8 % of inhaled MCCPs deposited into the head airway, tracheobronchial region, and alveolar region, respectively. This study reports on how homolog-specific physicochemical properties alter the temporal variations, size distributions, and inhaled fractions of CPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The extensive utilization of rubber-related products can lead to a substantial release of p-phenylenediamine (PPD) antioxidants into the environment. In recent years, studies mainly focus on the pollution characteristics and health risks of PM 2.5 -bound PPDs. This study presents long-time scale data of PPDs and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) in PM 2.5 and proposes the innovative use of PPDs as new markers for vehicular emissions in the Positive Matrix Factorization (PMF) source apportionment. The results indicate that PPDs and 6PPD-Q were detectable in 100 % of the winter PM 2.5 samples, and the concentration ranges of PPDs and 6PPD-Q are 15.6-2.92 × 10 3 pg·m -3 and 3.90-27.4 pg·m -3 , respectively, in which 6PPD and DNPD are the main compounds. Moreover, a competitive formation mechanism between sulfate, nitrate, ammonium (SNA) and 6PPD-Q was observed. The source apportionment results show that the incorporation of PPDs in PMF reduced the contribution of traffic source to PM 2.5 from 13.5 % to 9.5 %. In the traffic source factor profiles, the load of IPPD, CPPD, DPPD, DNPD and 6PPD reaches 91.8 %, 91.6 %, 92.9 %, 80.6 % and 87.2 %, respectively. It`s amazing that traditional markers of traffic source, which often overlap with coal burning and industrial sources, over-estimated the contribution of vehicles by one third or more. The discovery of PPDs as specific markers for vehicular emissions holds significant utility, particularly considering the growing proportion of new energy vehicles in the future. The results may prove more accurate policy implications for pollution control. SYNOPSIS: PPDs are excellent indicators of vehicle emissions, and PMF without PPDs over-estimated the contribution of traffic source to PM 2.5 ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Artificial intelligence (AI) has been extensively used in the field of stomatology over the past several years. This study aimed to evaluate the effectiveness of AI-based models in the procedure, assessment, and treatment planning of surgical extraction., Study Design: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a comprehensive search was conducted on the Web of Science, PubMed/MEDLINE, Embase, and Scopus databases, covering English publications up to September 2023. Two reviewers performed the study selection and data extraction independently. Only original research studies utilizing AI in surgical extraction of stomatology were included. The Cochrane risk of bias tool for randomized trials (RoB 2) was selected to perform the quality assessment of the selected literature., Results: From 2,336 retrieved references, 35 studies were deemed eligible. Among them, 28 researchers reported the pioneering role of AI in segmentation, classification, and detection, aligning with clinical needs. In addition, another 7 studies suggested promising results in tooth extraction decision-making, but further model refinement and validation were required., Conclusions: Integration of AI in stomatology surgical extraction has significantly progressed, enhancing decision-making accuracy. Combining and comparing algorithmic outcomes across studies is essential for determining optimal clinical applications in the future., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Reducing nitrate contamination in drinking water has become a critical issue in urban water resource management. Here a novel oligotrophic aerobic denitrifying bacterium, Pelomonas puraquae WJ1, was isolated and purified from artificial lake sediments. For the first time, excellent aerobic denitrification capabilities were demonstrated. At a carbon-to‑nitrogen ratio of 5.0, strain WJ1 achieved 100.0 % nitrate removal and 84.92 % total nitrogen removal within 24 h, with no nitrite accumulation. PCR amplification and sequencing confirmed the presence of the denitrification genes napA, nirS, and nosZ in the strain. The nitrogen balance demonstrated that approximately 74.95 % of the initial nitrogen was eliminated as gaseous products under aerobic conditions. Furthermore, carbon balance analysis showed that most electron donors from strain WJ1 were directed towards oxygen, with limited availability for nitrate reduction. A combination of bio-ECO analysis and network modeling indicated that strain WJ1 has robust metabolic capabilities for diverse carbon sources and exhibits high adaptability to complex carbon environments. Overall, Pelomonas puraquae WJ1 removed approximately 45.89 % of the nitrates in raw water, demonstrating significant potential for practical applications in oligotrophic denitrification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The primary driver of increasing atmospheric concentrations of nitrous oxide (N 2 O) is the use of organic and synthetic fertilizer to increase agricultural crop production. Current global estimates are based on IPCC N 2 O emission factor (EF) calculations, although there are shortcomings as many of the N 2 O EFs are derived from measurements during the cropping season. These neglect the fallow season, and do not adequately account for double or even triple cropping systems or legacy effects on soil N 2 O emissions in the following year. In this study, we assessed the legacy effect of fertilization on soil N 2 O fluxes using data from a long-term double-cropping field experiment with summer maize and winter wheat in rotation, in which no nitrogen (N; NN) and balanced manure with synthetic N (MN) fertilized treatments were switched to allow an assessment of legacy effects. Based on high-frequency measurements of N 2 O and previous data, we calculated that the historical N fertilization, or legacy effect, explained 23 % of the annual flux of 0.81 kg N ha -1  yr -1 in the first season of observation. In the following three seasons, the legacy effect of the previous N fertilization regime decreased to a negligible level, with N 2 O emissions mainly driven by in-season fertilization. Our data show that, on average, the seasonal EF for N 2 O was about 0.11 % higher in response to the previous N fertilization. Our study indicates that the current N 2 O EF may severely underestimate emissions because studies ignore legacy effects on N 2 O emissions from zero N plots and only compare zero N with N fertilization treatments for a given season or year to derive seasonal or annual N 2 O EF., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chlorinated paraffins (CPs) are intricate industrial compounds synthesized through alkane chlorination. Researches on the size distribution of short-chain (SCCPs) and medium-chain chlorinated paraffins (MCCPs) in atmospheric particulate matter (PM) are limited. Here, we conducted a thorough investigation on the size-dependent distribution characteristics, deposition behavior in respiratory tract, and health risks associated with CPs in atmospheric PM. The concentration of SCCPs in atmospheric particulate matter (PM 10 ) was much higher than MCCPs, with concentration ranges of 2.53-31.8 and 1.07-4.62 ng m -3 , respectively. Concentrations of CPs increase with decreasing PM size, peaking at aerodynamic diameters (Dp) < 0.49 μm. Physicochemical properties influence the distribution of CP homologs in PM. Those with lower vapor pressure, higher octanol-air and octanol-water partition coefficients tended to accumulate in PM with larger geometric mean diameters. Most of the inhaled CPs in PM deposited in the upper airways, with a small amount in the trachea and alveolar regions. The estimated daily intakes values were highest when Dp < 0.49 μm. Particle size is an essential determinant for the deposition of inhaled CPs in PM and should be considered in health risk assessments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aim: Observational studies have suggested a potential association between hypertension and Iron deficiency anemia (IDA). However, it is unclear whether there is a genetic and causal link between hypertension and IDA., Methods and Results: Genome-Wide Association Studies (GWAS) data for hypertension were sourced from the UK Biobank and FinnGen. Genetic variants data for IDA were extracted from FinnGen and the IEU Open GWAS project, all derived from European populations. The genetic association between hypertension and IDA was assessed using Linkage Disequilibrium Score Regression (LDSC), with MR employed to determine causality. Inverse variance weighted (IVW) as a major analytical method for MR. Sensitivity and heterogeneity analyses were conducted to ensure result reliability. Furthermore, validation analysis was performed to further strengthen the robustness of the findings. A genetic association between hypertension and IDA was observed (r g  = 0.121, P = 0.002). Our findings suggest that hypertension increases the risk of developing IDA (OR = 2.493,P = 0.038), and IDA maybe serve as a risk factor for hypertension (OR = 1.006,P < 0.001). Validation analysis yielded consistent results. Importantly, our findings demonstrated no heterogeneity or horizontal pleiotropy., Conclusion: Additional insights into the connection between hypertension and IDA were gained. Regular testing of iron ions and anemia-related markers in hypertensive patients is crucial for early identification of IDA. Furthermore, it is imperative to closely monitor the blood pressure of patients with IDA to promptly identify and diagnose hypertension. The implementation of these integrated health strategies is vital for global efforts to tackle the dual challenges of hypertension and IDA., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: MicroRNA (miRNA)-processing machinery may modify the risk of primary Sjögren's syndrome (pSS) by altering miRNA expression profiles. Inflammatory cytokines and reactive oxygen species (ROS) are also involved in pSS; however, the role of altered miRNAs expression in its pathogenesis is still unclear. We aimed to evaluate the relationship between single-nucleotide polymorphisms (SNPs) in miRNA processing machinery genes, including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348), and the risk of pSS in female patients. The potential associations of cytokines and ROS with pSS-susceptible SNPs were also evaluated., Materials and Methods: The SNPs confirmed by polymerase chain reaction ligase detection reaction were genotyped in 74 female patients with pSS and 77 controls. The relationship was analyzed by Student's t-test, Wilcoxon rank-sum test, chi-square test, Pearson's correlation test, and binary logistic regression analysis., Results: For rs197412 of the GEMIN3 gene, the genotype TT carrier was associated with a 2.172-fold increased risk for pSS when compared with that of CT+CC carrier (odds ratio: 2.172, 95% CI, 1.133-4.166, p=0.019). Simultaneously, the pSS-susceptible TT carriers were associated with increased interferon-γ (IFN-γ) (P < 0.001) and tumor necrosis factor-α (TNF-α) (P = 0.003) levels when compared with that of CT+CC genotype carriers in female patients with pSS. The subsequent analysis also showed a weak positive correlation between IFN-γ and TNF-α levels (r=0.271, P = 0.019)., Conclusion: The predictors of GEMIN3 SNPs might modify pSS development in females by mediating the expression of miRNAs and therefore regulate the levels of IFN-γ and TNF-α., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests related to this study., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

It is well known that Rosa roxburghii, as a homology of both medicine and food, is rich in polysaccharides. To discover bioactive macromolecules for combating cancer, the polysaccharides in R. roxburghii were investigated, leading to the purification of a polysaccharide (RRTP80-1). RRTP80-1 was measured to have an average molecular weight of 8.65 × 10 3  g/mol. Monosaccharide composition analysis revealed that RRTP80-1 was formed from three types of monosaccharides including arabinose, glucose, and galactose. Methylation and GC-MS analysis suggested that the backbone of RRTP80-1 consisted of →5)-α-l-Araf-(1→, →6)-α-d-Glcp-(1→, →2,5)-α-l-Araf-(1→, →4,6)-β-d-Galp-(1→, and →3)-α-l-Araf-(1→, with branch chains composed of α-l-Araf-(1→. In vivo studies indicated that RRTP80-1 exhibited inhibitory activity against the growth and proliferation of neoplasms in the zebrafish tumor xenograft model by suppressing angiogenesis. Additionally, RRTP80-1 was found to upregulate reactive oxygen species (ROS) and nitric oxide (NO) production levels in zebrafish models. All these studies suggest that RRTP80-1 activates the immune system to inhibit tumors. The potential role of the newly discovered homogeneous polysaccharide RRTP80-1 in cancer treatment was preliminarily clarified in this study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Guoliang Chen reports financial support was provided by Key Research Project of Department of Education of Liaoning Province. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Iruplinalkib (WX-0593) is a new-generation, potent ALK tyrosine kinase inhibitor (TKI) that has been found to have systemic and central nervous system (CNS) efficacy in ALK-positive NSCLC. We compared the efficacy and safety of iruplinalkib with crizotinib in patients with ALK TKI-naive, locally advanced or metastatic ALK-positive NSCLC., Methods: In this open-label, randomized, multicenter, phase 3 study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-d run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary end point was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival, and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of the study drugs. This study is registered with Center for Drug Evaluation of China National Medical Products Administration (CTR20191231) and Clinicaltrials.gov (NCT04632758)., Results: From September 4, 2019, to December 2, 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range: 3.7-37.7) in the iruplinalkib group and 25.9 months (range: 0.5-35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 mo [95% confidence interval (CI): 26.3-not estimable] versus 14.6 mo [95% CI: 11.1-16.5] in the crizotinib group; hazard ratio, 0.34 [98.02% CI: 0.23-0.52], p < 0.0001). The ORR assessed by IRC was 93.0% (95% CI: 87.5-96.6) in the iruplinalkib group and 89.3% (95% CI: 83.1-93.7) in the crizotinib group. The intracranial ORR was 90.9% (10 of 11, 95% CI: 58.7-99.8) in the iruplinalkib group and 60.0% (nine of 15, 95% CI: 32.3-83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group., Conclusions: Iruplinalkib was found to have significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naive NSCLC., Funding: This study was funded by Qilu Pharmaceutical Co., Ltd., Jinan, People's Republic of China, and partly supported by the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015)., Competing Interests: Disclosure Dr. Si, Ms. Mao, Dr. H. Li, Dr. L. Li, and Dr. Kang are full-time employees of Qilu Pharmaceutical Co., Ltd., Jinan, People’s Republic of China. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Etomidate (ETO) is used as an anesthetic in surgery, but it is being abused in some populations. The damage caused by long-term intake of ETO to intestinal and brain functions is not yet clear, and it remains to be determined whether the drug affects the central nervous system through the gut-brain axis. This study aimed to investigate the neurotoxic and gastrointestinal effects of ETO at doses of 1 mg/kg and 3 mg/kg in mice over 14 consecutive days. The results showed that long-term injection of ETO led to drug resistance in mice, affecting their innate preference for darkness and possibly inducing dependence on ETO. The levels of 5-hydroxytryptamine in the brain, serum, and colon decreased by 37%, 51%, and 42% respectively, while the levels of γ-aminobutyric acid reduced by 38%, 52%, and 41% respectively. H&E staining revealed that ETO reduced goblet cells in the colon and damaged the intestinal barrier. The expression of tight junction-related genes Claudin4 and ZO-1 was downregulated. The intestinal flora changed, the abundance of Akkermansia and Lactobacillus decreased by 33% and 14%, respectively, while Klebsiella increased by 18%. TUNEL results showed that high-dose ETO increased apoptotic cells in the brain. The expression of Claudin1 in the brain was downregulated. Untargeted metabolomics analysis of the colon and brain indicated that ETO caused abnormalities in glycerophospholipid metabolism. Abnormal lipid metabolism might lead to the production or accumulation of lipotoxic metabolites, causing central nervous system diseases. ETO induced changes in the intestinal flora and metabolism, further affecting the central nervous system through the gut-brain axis. The study unveiled the detrimental effects on the brain and gastrointestinal system resulting from long-term intake of ETO, which holds significant implications for comprehending the adverse impact of ETO abuse on human health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liver regeneration after liver tumor resection or liver transplantation is crucial, the remaining liver frequently fails to regenerate in some patients. Oleanolic acid (OA), a pentacyclic triterpenoid compound which has been shown to protect against various liver diseases. However, the effect of OA on liver regeneration after partial hepatectomy (PHx) is still unclear. In this study, the results showed that OA (50 mg/kg, twice daily) treatment induced liver mass restoration and increased the liver-to-body weight ratio of mice following PHx. Meanwhile, OA promoted hepatocyte proliferation and increased the number of BrdU-, Ki67-and PCNA-positive cells. Furthermore, OA increased the nuclear accumulation of PXR and induced the expression of PXR downstream proteins such as CYP3A11, UGT1A1 and GSTM2 in mice, as well as in AML12 and HepRG cells. Luciferase reporter assay and nuclear localization of PXR further demonstrated the effect of OA on PXR activation in vitro. Molecular docking simulation showed that OA could interact with the PXR active sites. Moreover, OA inhibited the expression of FOXO1, RBL2 and CDKN1B, and increased the expression of PCNA, CCND1 and CCNE1 in vivo and in vitro. Silencing of Pxr further confirmed that OA-mediated upregulation of proliferation-related proteins depended on PXR. The current study illustrated that OA exhibited a significant promoting effect on liver regeneration following PHx, potentially through regulation of the PXR signaling pathway to accelerate liver recovery., Competing Interests: Declaration of competing interest Declarations of interest: none., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this work, a stable ratiometric nanofluorescent probe for the detection of 2,6-dipicolinic acid (DPA), a Bacillus anthracis biomarker, was developed based on confinement-induced emission enhancement of cationic styrylpyridine salt derivative L in MCM-22 molecular sieve pores. The cationic L and the lanthanide Tb 3+ were loaded into the pores of the molecular sieve by electrostatic interaction with the negatively charged AlO 4 tetrahedron unit, and L exhibited enhanced red fluorescence emission as a stable fluorescence reference mark in the nanoprobe platform due to the restricted molecular torsion of L in the pores of MCM-22. At the same time, the characteristic green fluorescence emission of Tb 3+ can be excited by energy transfer due to the "antenna effect" of DPA. The prepared Tb-L@MCM-22 nanoprobe showed specific selectivity and stable fluorescence ratiometric detection of DPA in tap water, lake water, bovine serum and actual bacterial spores. Benefiting from the confinement-induced fluorescence enhancement effect of L in the MCM-22 molecular sieve pores, the obtained Tb-L@MCM-22 can provide a stable reference signal for the fluorescence ratiometric detection of DPA with a limit of detection (LOD) of 78.6 nM and 1.310 × 10 4 spores per mL. More importantly, combining of the Tb-L@MCM-22 based DPA detection test strips with a smartphone app demonstrated a stable, convenient and rapid method for detecting of anthrax biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Polygonatum sibiricum is a plant with medicinal and nutritional properties. Saponins are the important biologically active components of Polygonatum sibiricum. In this study, the specific components of Polygonatum sibiricum saponins (PSS) were analyzed, and the regulation effect of PSS on intestinal flora in patients with ulcerative colitis (UC) was investigated by inducing male Kunming mice with dextran sulfate sodium (DSS). PSS could ameliorate the symptoms of weight loss, high DAI score and colon length reduction compared to DSS-induced treatment. Colonic fragments were taken for H&E staining and histopathological scoring. PSS could significantly improve the pathological abnormality of colitis mice. 16S rRNA analysis showed that the intestinal microbial community of mice treated with DSS was significantly damaged. PSS could restore the richness and diversity of intestinal microbial flora, reduce the number of pathogenic bacteria, and increase the abundance of Lactobacillus spp. and Muribaculaceae, and improve the intestinal microbial flora disorder. Generally, PSS had an obvious effect in relieving colitis in mice. This study confirmed that Polygonatum sibiricum saponins play a therapeutic and palliative role in ulcerative colitis by regulating the microbiome balance., Competing Interests: Declaration of competing interest These authors have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chitooligosaccharides (COS) possess versatile functional properties that have found extensive applications across various fields. Chitosanase can specifically hydrolyze β-1,4 glycosidic bonds in chitosan to produce COS. In this study, Csn-PD, a glycoside hydrolase family 46 chitosanase from Paenibacillus dendritiformis, which produces (GlcN) 2 as its main product, was rationally redesigned aiming to improve its catalytic performance. Based on the results of molecular docking analysis and multiple sequence alignment, four amino acid residues in Csn-PD (I101, T120, T220, and Y259) were pinpointed for targeted mutations. Beneficial mutations in terms of enhanced catalytic activity were then combined by site-directed mutagenesis. Notably, the most promising variant, Csn-PDT6 (Csn-PD I101M/T120E/T220G), exhibited an impressive eight-fold surge in activity compared to the wild-type Csn-PD. This heightened enzymatic activity was complemented by an enhanced pH stability profile. A compelling feature of Csn-PDT6 is its preservation of the hydrolytic product profile observed in Csn-PD. This characteristic further accentuates its candidacy for the targeted production of (GlcN) 2 . The success of our strategic approach is vividly illustrated by the significant improvements achieved in the catalytic performance of the chitosanase, encompassing both its activity and stability. These developments offer a valuable model that may have implications for the semi-rational design of other enzymes., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Goose astrovirus (GAstV)-2, a novel pathogen identified in 2018, mainly causes visceral gout in goslings, leading to approximately 50% mortality. At present, no commercial veterinary products are available to prevent and treat the disease. Our previous studies showed that nitric oxide (NO) and inducible NO synthase (iNOS) were markedly higher in the kidney and spleen of goslings infected with GAstV-2, but their effects during GAstV-2 infection remain unclear. In the present study, goslings were intraperitoneally injected with aminoguanidine (AG)-an iNOS inhibitor-to examine the role of NO during GAstV-2 infection. AG significantly decreased the serum NO concentration and iNOS mRNA expression in the kidney. Moreover, AG reduced the mortality, serum uric acid and creatinine content, and urate deposition in visceral organs and joints. Histopathological analysis demonstrated that AG reduced renal tubular cell necrosis, inflammatory cell infiltration, glycogen deposition in glomerular mesangium, and interstitial fibrosis, suggesting alleviation of kidney lesions. Furthermore, AG decreased the expression of renal injury markers such as KIM-1 and desmin; inflammatory cytokine-related genes such as IL-1β, IL-8, and MMP-9; and autophagy-related genes and proteins such as LC3II, ATG5, and Beclin1. However, quantitative real-time PCR and immunohistochemistry showed that treatment with AG did not affect the kidney and liver viral load. These findings suggest that AG decreases the mortality rate and kidney lesions in goslings infected with GAstV-2 through mechanisms associated with autophagy and inhibition of inflammatory cytokine production in the kidney but not with GAstV-2 replication., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The more severe the acute stroke is, the more serious myocardial damage is. This study aimed to determine the relationship between myocardial work and S100β, a quantitative biomarker of active cerebral lesions, in patients with acute ischemic stroke (AIS)., Methods: A total of 63 patients with AIS were examined by myocardial work echocardiography, 4D echocardiography with the measurement of left ventricular (LV) myocardial work, volume and function within 24-48 h of symptom onset, respectively. Their plasma S100β was measured from a peripheral blood sample within 2-6 h of symptom onset., Results: Patients with elevated S-100β level had significantly increased ratios of peak early diastolic transmitral filling velocity to peak early diastolic lateral mitral annulus tissue velocity(E/e') and global longitudinal strain (GLS), and significantly reduced global work index(GWI) and global constructive work (GCW) compared with those with normal S-100β level (p < 0.05). S-100β positively correlated with E/e'(r = 0.878, p < 0.0001) and GLS (r = 0.511, p = 0.002) but negatively correlated with GWI(r = -0.409, p = 0.034) and GCW(r = -0.353, p = 0.041). S-100β showed an excellent ability to differentiate if a reduced GWI [cut-off value, 120.79 pg/mL; area under receiver operating characteristic curve (AUC), 1.000; sensitivity, 100%; specificity, 100%], GCW (cut-off value, 120.79 pg/mL;AUC,1.000; sensitivity,100%; specificity, 100%) and an increased E/e' (cut-off value, 91.1 pg/mL;AUC,0.913; sensitivity,80%; specificity, 100%) or not, but poor ability to differentiate if an increased GLS(cut-off value, 91.1 pg/mL; AUC,0.576; sensitivity,63.64%; specificity, 83.33%) or not., Conclusion: S-100β level is closely associated with LV function. It is highly competent in determining an impaired myocardial work in patients with AIS., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Several microRNAs (miRNAs) are expressed at lower levels in specific tumors, e.g., miR-let-7a in non-small cell lung cancer (NSCLC). This makes it challenging to analyze their lower abundance versus specifically elevated miRNAs. Here, we describe a novel fluorescent biosensor for the highly selective and sensitive detection of miR-let-7a constructed by combining miRNA screening assisted by a duplex-specific nuclease (DSN) with CRISPR-Cas12a system signal amplification. We meticulously designed a mismatch in the first three to four bases at the 5'-end of the capture DNA to improve the signal-to-noise ratio of the CRISPR-Cas12a system. Within this "DSN-mismatched CRISPR" fluorescence strategy, miR-let-7a was accurately screened by DSN-assisted cleavage, and the mismatched capture DNA unbound to target miRNA could trigger the CRISPR-Cas12a system to produce a mass of trans-cleave fluorescence signals. This "turn-off" approach was suitable for detecting decreased levels of miRNAs. This approach can not only discriminate the single-base mismatched let-7 family but also reach a limit of detection at 64.17 fM as well as be quantified from 100 fM to 500 pM. The miR-let-7a levels were then measured in clinical serum samples from healthy volunteers and patients with NSCLC. This study holds promise for the development of a universal under-expressed miRNA assay for early diagnosis and treatment of cancers., Competing Interests: Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Manure application improves soil fertility, yet its implications on the success of invasion of manure-borne microorganisms in the soil are poorly understood. Here, we assessed the importance of abiotic and biotic factors in modulating the extent to which manure-borne fungal and bacterial communities can invade resident soil microbial communities. For this purpose, we applied varying frequencies of two different amounts of manure to nine soils differing in physico-chemical properties, as well as in land-use history, over 180 days and monitored changes in bacterial and fungal communities. Variance partitioning revealed differential contributions of abiotic and biotic factors to invasion success, which together accounted for up to 82 % of the variance explained. We showed that the effects of interactions between biotic and abiotic factors increased with coalescence frequency and manure amount for the bacterial and fungal communities, respectively. Both abiotic and biotic factors were important for modulating coalescence asymmetry for the bacterial community, whereas abiotic factors had a greater effect on the fungal community. These results provide new insights into the drivers of coalescence events between manure and resident soil microbial communities. Moreover, our findings highlight the roles of the mixing ratio and frequency of coalescence events in modulating the survival of manure-borne microorganisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Bifidobacterium animalis ssp. lactis DN-173 010/CNCM I-2494 (B. animalis) is a probiotic strain commonly added to yogurt. Yogurt and honey are a popular culinary pairing. Honey improves bifidobacteria survival in vitro. However, probiotic survival in yogurt with honey during in vitro digestion has not been investigated., Objectives: The study aimed to evaluate the effects of different honey varietals and concentrations on B. animalis survivability in yogurt through in vitro digestion., Methods: Yogurt with honey or control-treated samples underwent in vitro simulated oral, gastric, and intestinal digestion. B. animalis cells were enumerated on de Man Rogosa and Sharpe (MRS) medium followed by an overlay with a modified selective MRS medium; all underwent anaerobic incubation. B. animalis were enumerated predigestion and after oral, gastric, and intestinal digestion. There were 2 study phases: Phase 1 tested 4 honey varietals at 20% wt/wt per 170 g yogurt, and Phase 2 tested 7 dosages of clover honey (20, 14, 10, 9, 8, 6, and 4% wt/wt) per 170 g yogurt., Results: Similar B. animalis counts were observed between all treatments after oral and gastric digestion (<1 Log colony forming units (CFU)/g probiotic reduction). Higher B. animalis survivability was observed in yogurt with clover honey after exposure to simulated intestinal fluids (∼3.5 Log CFU/g reduction; P < 0.05) compared to all control treatments (∼5.5 Log CFU/g reduction; P < 0.05). Yogurt with 10-20% wt/wt clover honey increased B. animalis survivability after simulated in vitro digestion (≤ ∼4.7 Log CFU/g survival; P < 0.05)., Conclusions: Yogurt with added honey improves probiotic survivability during in vitro digestion. The effective dose of clover honey in yogurt was 10-20% wt/wt per serving (1-2 tablespoons per 170 g yogurt) for increased probiotic survivability during in vitro digestion., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the medical field, the application of machine learning technology in the automatic diagnosis and monitoring of osteoporosis often faces challenges related to domain adaptation in drug therapy research. The existing neural networks used for the diagnosis of osteoporosis may experience a decrease in model performance when applied to new data domains due to changes in radiation dose and equipment. To address this issue, in this study, we propose a new method for multi domain diagnostic and quantitative computed tomography (QCT) images, called DeepmdQCT. This method adopts a domain invariant feature strategy and integrates a comprehensive attention mechanism to guide the fusion of global and local features, effectively improving the diagnostic performance of multi domain CT images. We conducted experimental evaluations on a self-created OQCT dataset, and the results showed that for dose domain images, the average accuracy reached 91%, while for device domain images, the accuracy reached 90.5%. our method successfully estimated bone density values, with a fit of 0.95 to the gold standard. Our method not only achieved high accuracy in CT images in the dose and equipment fields, but also successfully estimated key bone density values, which is crucial for evaluating the effectiveness of osteoporosis drug treatment. In addition, we validated the effectiveness of our architecture in feature extraction using three publicly available datasets. We also encourage the application of the DeepmdQCT method to a wider range of medical image analysis fields to improve the performance of multi-domain images., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Triggerable coatings, such as pH-responsive polymethacrylate copolymers, can be used to protect the active pharmaceutical ingredients contained within oral solid dosage forms from the acidic gastric environment and to facilitate drug delivery directly to the intestine. However, gastrointestinal pH can be highly variable, which can reduce delivery efficiency when using pH-responsive drug delivery technologies. We hypothesized that biomaterials susceptible to proteolysis could be used in combination with other triggerable polymers to develop novel enteric coatings. Bioinformatic analysis suggested that silk fibroin is selectively degradable by enzymes in the small intestine, including chymotrypsin, but resilient to gastric pepsin. Based on the analysis, we developed a silk fibroin-polymethacrylate copolymer coating for oral dosage forms. In vitro and in vivo studies demonstrated that capsules coated with this novel silk fibroin formulation enable pancreatin-dependent drug release. We believe that this novel formulation and extensions thereof have the potential to produce more effective and personalized oral drug delivery systems for vulnerable populations including patients that have impaired and highly variable intestinal physiology., Competing Interests: Declaration of Competing Interest C.S. is currently employed by Bayer pharmaceuticals and has been listed as a co-inventor on multiple patent applications for drug delivery systems.. D.R., R.L. and G.T. are co-inventors on multiple patent applications describing novel drug delivery systems and interactions between excipients and drugs. D.R. acts as a mentor for the German Accelerator Life Sciences and acts as a scientific consultant for pharmaceutical and biotechnology companies. Complete details of all relationships for profit and not for profit for G.T. can found at the following link: https://www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0. For a list of entities to which R.L. is involved, compensated or uncompensated, see https://www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Gene selection is a process of selecting discriminative genes from microarray data that helps to diagnose and classify cancer samples effectively. Swarm intelligence evolution-based gene selection algorithms can never circumvent the problem that the population is prone to local optima in the process of gene selection. To tackle this challenge, previous research has focused primarily on two aspects: mitigating premature convergence to local optima and escaping from local optima. In contrast to these strategies, this paper introduces a novel perspective by adopting reverse thinking, where the issue of local optima is seen as an opportunity rather than an obstacle. Building on this foundation, we propose MOMOGS-PCE, a novel gene selection approach that effectively exploits the advantageous characteristics of populations trapped in local optima to uncover global optimal solutions. Specifically, MOMOGS-PCE employs a novel population initialization strategy, which involves the initialization of multiple populations that explore diverse orientations to foster distinct population characteristics. The subsequent step involved the utilization of an enhanced NSGA-II algorithm to amplify the advantageous characteristics exhibited by the population. Finally, a novel exchange strategy is proposed to facilitate the transfer of characteristics between populations that have reached near maturity in evolution, thereby promoting further population evolution and enhancing the search for more optimal gene subsets. The experimental results demonstrated that MOMOGS-PCE exhibited significant advantages in comprehensive indicators compared with six competitive multi-objective gene selection algorithms. It is confirmed that the "reverse-thinking" approach not only avoids local optima but also leverages it to uncover superior gene subsets for cancer diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)