RESUMO
SignificanceWith obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage-inducing transmembrane protein 2 (FIT2)-facilitated, pancreatic ß cell LD biogenesis, which in turn induces ß cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)-associated degradation. Loss of ß cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.
Assuntos
Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Células Secretoras de Insulina/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Proteínas de Membrana/genética , Animais , Linhagem Celular , Estresse do Retículo Endoplasmático , Ácidos Graxos/metabolismo , Glucose/metabolismo , Intolerância à Glucose , Proteínas de Membrana/metabolismo , Camundongos , Mutação , Palmitatos/metabolismo , Estearatos/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide. Classically, HCC develops in genetically susceptible individuals who are exposed to risk factors, especially in the presence of liver cirrhosis. Significant temporal and geographic variations exist for HCC and its etiologies. Over time, the burden of HCC has shifted from the low-moderate to the high sociodemographic index regions, reflecting the transition from viral to nonviral causes. Geographically, the hepatitis viruses predominate as the causes of HCC in Asia and Africa. Although there are genetic conditions that confer increased risk for HCC, these diagnoses are rarely recognized outside North America and Europe. In this review, we will evaluate the epidemiologic trends and risk factors of HCC, and discuss the genetics of HCC, including monogenic diseases, single-nucleotide polymorphisms, gut microbiome, and somatic mutations.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/genética , Cirrose Hepática/epidemiologia , Cirrose Hepática/genética , Cirrose Hepática/complicações , Fatores de Risco , América do Norte/epidemiologiaRESUMO
BACKGROUND AND AIMS: Prospective long-term real-world safety data after fecal microbiota transplantation (FMT) remain limited. We reported long-term outcomes of FMT from a population-based FMT registry in Hong Kong. METHODS: We recruited patients undergoing FMT for recurrent Clostridioides difficile infection (CDI) and non-CDI indications from clinical trials, from June 2013 to April 2022 in Hong Kong. We captured data on demographics, FMT indications and procedures, clinical outcomes and short- to long-term safety. New medical diagnoses were obtained from electronic medical records and independently adjudicated by clinicians. Long-term safety in patients with recurrent CDI was compared with a control group treated with antibiotics. RESULTS: Overall, 123 subjects (median age 53 years, range 13-90 years; 52.0% male) underwent 510 FMTs and were prospectively followed up for a median of 30.3 (range, 1-57.9) months. The most common indication for FMT was type 2 diabetes mellitus. The most common short-term adverse events within 1 month of FMT included diarrhea and abdominal pain. At long-term follow-up beyond 12 months, 16 patients reported 21 new-onset medical conditions confirmed by electronic medical records. All were adjudicated to be unlikely to be related to FMT. There was no new case of inflammatory bowel disease, irritable bowel syndrome, allergy, diabetes mellitus, or psychiatric disorder. In a subgroup of patients with recurrent CDI, FMT was associated with a significantly higher cumulative survival probability compared with matched control subjects. CONCLUSIONS: This prospective real-world data from Asia's first FMT registry demonstrated that FMT has an excellent long-term safety profile. The risk of developing new medical conditions beyond 12 months after FMT is low.
Assuntos
Clostridioides difficile , Infecções por Clostridium , Diabetes Mellitus Tipo 2 , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Transplante de Microbiota Fecal/efeitos adversos , Transplante de Microbiota Fecal/métodos , Fezes , Hong Kong , Estudos Prospectivos , Resultado do Tratamento , Recidiva , Infecções por Clostridium/terapiaRESUMO
BACKGROUND & AIMS: The enteric mycobiota is a major component of the human gut microbiota, but its role in colorectal cancer (CRC) remains largely elusive. We conducted a meta-analysis to uncover the contribution of the fungal mycobiota to CRC. METHODS: We retrieved fecal metagenomic data sets from 7 previous publications and established an additional in-house cohort, totaling 1329 metagenomes (454 with CRC, 350 with adenoma, and 525 healthy individuals). Mycobiota composition and microbial interactions were analyzed. Candidate CRC-enriched fungal species (Aspergillus rambellii) was functionally validated in vitro and in vivo. RESULTS: Multicohort analysis revealed that the enteric mycobiota was altered in CRC. We identified fungi that were associated with patients with CRC or adenoma from multiple cohorts. Signature CRC-associated fungi included 6 enriched (A rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, Moniliophthora perniciosa, Sphaerulina musiva, and Phytophthora capsici) and 1 depleted species (A kawachii). Co-occurrent interactions among CRC-enriched fungi became stronger in CRC compared with adenoma and healthy individuals. Moreover, we reported the transkingdom interactions between enteric fungi and bacteria in CRC progression, of which A rambellii was closely associated with CRC-enriched bacteria Fusobacterium nucleatum. A rambellii promoted CRC cell growth in vitro and tumor growth in xenograft mice. We further identified that combined fungal and bacterial biomarkers were more accurate than panels with pure bacterial species to discriminate patients with CRC from healthy individuals (the area under the curve relative change increased by 1.44%-10.60%). CONCLUSIONS: This study reveals enteric mycobiota signatures and pathogenic fungi in stages of colorectal tumorigenesis. Fecal fungi can be used, in addition to bacteria, for noninvasive diagnosis of patients with CRC.
Assuntos
Adenoma , Neoplasias Colorretais , Adenoma/microbiologia , Animais , Aspergillus , Bactérias/genética , Biomarcadores , Transformação Celular Neoplásica , Neoplasias Colorretais/diagnóstico , Fezes/microbiologia , Humanos , Metagenoma , CamundongosRESUMO
Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.
Assuntos
COVID-19/virologia , Leucócitos Mononucleares/metabolismo , Lisossomos/metabolismo , Proteínas Associadas aos Microtúbulos/sangue , SARS-CoV-2/metabolismo , Adulto , Autofagia , Biomarcadores/sangue , COVID-19/sangue , Ciclo Celular , Colesterol/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/sangue , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Blood is conventionally thought to be sterile. However, emerging evidence on the blood microbiome has started to challenge this notion. Recent reports have revealed the presence of genetic materials of microbes or pathogens in the blood circulation, leading to the conceptualization of a blood microbiome that is vital for physical wellbeing. Dysbiosis of the blood microbial profile has been implicated in a wide range of health conditions. Our review aims to consolidate recent findings about the blood microbiome in human health and to highlight the existing controversies, prospects, and challenges around this topic. Current evidence does not seem to support the presence of a core healthy blood microbiome. Common microbial taxa have been identified in some diseases, for instance, Legionella and Devosia in kidney impairment, Bacteroides in cirrhosis, Escherichia/Shigella and Staphylococcus in inflammatory diseases, and Janthinobacterium in mood disorders. While the presence of culturable blood microbes remains debatable, their genetic materials in the blood could potentially be exploited to improve precision medicine for cancers, pregnancy-related complications, and asthma by augmenting patient stratification. Key controversies in blood microbiome research are the susceptibility of low-biomass samples to exogenous contamination and undetermined microbial viability from NGS-based microbial profiling, however, ongoing initiatives are attempting to mitigate these issues. We also envisage future blood microbiome research to adopt more robust and standardized approaches, to delve into the origins of these multibiome genetic materials and to focus on host-microbe interactions through the elaboration of causative and mechanistic relationships with the aid of more accurate and powerful analytical tools.
Assuntos
Legionella , Microbiota , Humanos , Interações entre Hospedeiro e Microrganismos , Disbiose/microbiologia , PrevisõesRESUMO
BACKGROUND & AIMS: Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. METHODS: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by ß-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. RESULTS: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. ß-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and ß-galactosidase activity assay. ß-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional ß-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via ß-galactosidase. ß-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. CONCLUSION: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of ß-galactosidase.
Assuntos
Proteínas de Bactérias/metabolismo , Neoplasias Colorretais/prevenção & controle , Probióticos/administração & dosagem , Streptococcus thermophilus/enzimologia , beta-Galactosidase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Proteínas de Bactérias/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Colo/microbiologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/microbiologia , Neoplasias Experimentais/prevenção & controle , Probióticos/metabolismo , Streptococcus thermophilus/genética , beta-Galactosidase/genéticaRESUMO
BACKGROUND & AIMS: Changes in the intestinal microbiota have been associated with development and progression of colorectal cancer (CRC). Archaea are stable components of the microbiota, but little is known about their composition or contribution to colorectal carcinogenesis. We analyzed archaea in fecal microbiomes of 2 large cohorts of patients with CRC. METHODS: We performed shotgun metagenomic analyses of fecal samples from 585 participants (184 patients with CRC, 197 patients with adenomas, and 204 healthy individuals) from discovery (165 individuals) and validation (420 individuals) cohorts. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database. RESULTS: Principal component analysis of archaeomes showed distinct clusters in fecal samples from patients with CRC, patients with adenomas, and control individuals (P < .001), indicating an alteration in the composition of enteric archaea during tumorigenesis. Fecal samples from patients with CRC had significant enrichment of halophilic and depletion of methanogenic archaea. The halophilic Natrinema sp. J7-2 increased progressively in samples from control individuals, to patients with adenomas, to patients with CRC. Abundances of 9 archaea species that were enriched in fecal samples from patients with CRC distinguished them from control individuals with areas under the receiver operating characteristic curve of 0.82 in the discovery cohort and 0.83 in the validation cohort. An association between archaea and bacteria diversities was observed in fecal samples from control individuals but not from patients with CRC. Archaea that were enriched in fecal samples from patients with CRC had an extensive mutual association with bacteria that were enriched in the same samples and exclusivity with bacteria that were lost from these samples. CONCLUSIONS: Archaeomes of fecal samples from patients with CRC are characterized by enrichment of halophiles and depletion of methanogens. Studies are needed to determine whether associations between specific archaea and bacteria species in samples from patients with CRC contribute to or are a response to colorectal tumorigenesis.
Assuntos
Adenoma/microbiologia , Adenoma/patologia , Archaea/isolamento & purificação , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Microbioma Gastrointestinal , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Coronavirus disease 2019 (COVID-19) is affecting millions of patients worldwide. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the family Coronaviridae, with 80% genomic similarities to SARS-CoV. Lymphopenia was commonly seen in infected patients and has a correlation to disease severity. Thrombocytopenia, coagulation abnormalities, and disseminated intravascular coagulation were observed in COVID-19 patients, especially those with critical illness and non-survivors. This pandemic has caused disruption in communities and hospital services, as well as straining blood product supply, affecting chemotherapy treatment and haematopoietic stem cell transplantation schedule. In this article, we review the haematological manifestations of the disease and its implication on the management of patients with haematological disorders.
Assuntos
Coagulação Intravascular Disseminada , Transplante de Células-Tronco Hematopoéticas , Linfopenia , Pandemias , SARS-CoV-2/metabolismo , Trombocitopenia , COVID-19/sangue , COVID-19/mortalidade , COVID-19/terapia , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/terapia , Coagulação Intravascular Disseminada/virologia , Humanos , Linfopenia/sangue , Linfopenia/mortalidade , Linfopenia/terapia , Linfopenia/virologia , Trombocitopenia/sangue , Trombocitopenia/mortalidade , Trombocitopenia/terapia , Trombocitopenia/virologiaRESUMO
Worldwide cancer incidence and mortality have always been a concern to the community. The cancer mortality rate has generally declined over the years; however, there is still an increased mortality rate in poorer countries that receives considerable attention from healthcare professionals. This suggested the importance of the prompt detection, effective treatment, and prevention strategies. The genus Streptomyces has been documented as a prolific producer of biologically active secondary metabolites. Streptomycetes from mangrove environments attract researchers' attention due to their ability to synthesize diverse, interesting bioactive metabolites. The present review highlights research on mangrove-derived streptomycetes and the production of anticancer-related compounds from these microorganisms. Research studies conducted between 2008 and 2019, specifically mentioning the isolation of streptomycetes from mangrove areas and described the successful purification of compound(s) or generation of crude extracts with cytotoxic activity against human cancer cell lines, were compiled in this review. It is anticipated that there will be an increase in prospects for mangrove-derived streptomycetes as one of the natural resources for the isolation of chemotherapeutic agents.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Rhizophoraceae/microbiologia , Streptomyces/química , Animais , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Misturas Complexas , HumanosRESUMO
OBJECTIVES: Bacteriome and virome alterations are associated with colorectal cancer (CRC). Nevertheless, the gut fungal microbiota in CRC remains largely unexplored. We aimed to characterise enteric mycobiome in CRC. DESIGN: Faecal shotgun metagenomic sequences of 184 patients with CRC, 197 patients with adenoma and 204 control subjects from Hong Kong were analysed (discovery cohort: 73 patients with CRC and 92 control subjects; validation cohort: 111 patients with CRC, 197 patients with adenoma and 112 controls from Hong Kong). CRC-associated fungal markers and ecological changes were also validated in additional independent cohorts of 90 patients with CRC, 42 patients with adenoma and 66 control subjects of published repository sequences from Germany and France. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database. RESULTS: Principal component analysis revealed separate clusters for CRC and control (p<0.0001), with distinct mycobiomes in early-stage and late-stage CRC (p=0.0048). Basidiomycota:Ascomycota ratio was higher in CRC (p=0.0042), with increase in Malasseziomycetes (p<0.0001) and decrease in Saccharomycetes (p<0.0001) and Pneumocystidomycetes (p=0.0017). Abundances of 14 fungal biomarkers distinguished CRC from controls with an area under the receiver-operating characteristic curve (AUC) of 0.93 and validated AUCs of 0.82 and 0.74 in independent Chinese cohort V1 and European cohort V2, respectively. Further ecological analysis revealed higher numbers of co-occurring fungal intrakingdom and co-exclusive bacterial-fungal correlations in CRC (p<0.0001). Moreover, co-occurrence interactions between fungi and bacteria, mostly contributed by fungal Ascomycota and bacterial Proteobacteria in control, were reverted to co-exclusive interplay in CRC (p=0.00045). CONCLUSIONS: This study revealed CRC-associated mycobiome dysbiosis characterised by altered fungal composition and ecology, signifying that the gut mycobiome might play a role in CRC.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal , Micobioma , Idoso , Estudos de Casos e Controles , Feminino , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente PrincipalRESUMO
BACKGROUND & AIMS: Patients with colorectal cancer (CRC) have a different gut microbiome signature than individuals without CRC. Little is known about the viral component of CRC-associated microbiome. We aimed to identify and validate viral taxonomic markers of CRC that might be used in detection of the disease or predicting outcome. METHODS: We performed shotgun metagenomic analyses of viromes of fecal samples from 74 patients with CRC (cases) and 92 individuals without CRC (controls) in Hong Kong (discovery cohort). Viral sequences were classified by taxonomic alignment against an integrated microbial reference genome database. Viral markers associated with CRC were validated using fecal samples from 3 separate cohorts: 111 patients with CRC and 112 controls in Hong Kong, 46 patients with CRC and 63 controls in Austria, and 91 patients with CRC and 66 controls in France and Germany. Using abundance profiles of CRC-associated virome genera, we constructed random survival forest models to identify those associated with patient survival times. RESULTS: The diversity of the gut bacteriophage community was significantly increased in patients with CRC compared with controls. Twenty-two viral taxa discriminated cases from controls with an area under the receiver operating characteristic curve of 0.802 in the discovery cohort. The viral markers were validated in 3 cohorts, with area under the receiver operating characteristic curves of 0.763, 0.736, and 0.715, respectively. Clinical subgroup analysis showed that dysbiosis of the gut virome was associated with early- and late-stage CRC. A combination of 4 taxonomic markers associated with reduced survival of patients with CRC (log-rank test, P = 8.1 × 10-6) independently of tumor stage, lymph node metastases, or clinical parameters. We found altered interactions between bacteriophages and oral bacterial commensals in fecal samples from patients with CRC compared with controls. CONCLUSIONS: In a metagenomic analysis of fecal samples from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify individuals with CRC or predict outcomes.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/virologia , Disbiose/virologia , Microbioma Gastrointestinal/genética , Vírus/genética , Áustria/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Colonoscopia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Estudos Transversais , Disbiose/diagnóstico por imagem , Fezes/virologia , Feminino , França/epidemiologia , Alemanha/epidemiologia , Hong Kong/epidemiologia , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
BACKGROUND AND AIM: Comorbid generalized anxiety disorder and irritable bowel syndrome are common and therapeutically challenging. We aimed to assess the effectiveness of electroacupuncture in relieving anxiety and bowel symptoms in Chinese adults with this form of comorbidity. METHODS: In a single-blind randomized sham-controlled trial, subjects with comorbid generalized anxiety disorder and irritable bowel syndrome were randomly assigned to receive 10 weekly sessions of electroacupuncture or sham electroacupuncture. Patients were assessed at baseline, immediately after intervention and at 6-week follow-up. Primary outcome was anxiety (7-item Patient Health Questionnaire section for anxiety). Secondary outcomes included bowel symptoms (bowel symptoms questionnaire), depressive symptoms (9-item Patient Health Questionnaire), somatic symptoms (15-item Patient Health Questionnaire), and health-related quality of life (EuroQol-5 Dimensions). RESULTS: Eighty subjects, 40 in each arm, were randomized. All but two in the sham group completed 10 weekly sessions. There was no significant difference in the proportion of patients experiencing significant (≥ 50%) reduction of anxiety symptoms between the two groups immediately after intervention (32.4% vs 21.6%, P = 0.06) and at 6-week follow-up (25.7% in electroacupuncture vs 27% in sham, P = 0.65). Anxiety, depressive symptom, and bowel symptom severity did not differ significantly between electroacupuncture and sham groups. CONCLUSIONS: Findings failed to support the effectiveness of electroacupuncture for comorbid generalized anxiety disorder and irritable bowel syndrome. Further studies are needed to identify effective acupuncture treatment protocols for such comorbidity.
Assuntos
Transtornos de Ansiedade/terapia , Eletroacupuntura , Síndrome do Intestino Irritável/terapia , Adulto , Idoso , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Comorbidade , Eletroacupuntura/efeitos adversos , Feminino , Hong Kong/epidemiologia , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/epidemiologia , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Fatores de Tempo , Falha de TratamentoRESUMO
OBJECTIVES: We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. DESIGN: We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi'an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China. RESULTS: We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q<0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p<0.001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p<0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori-negative samples compared with H. pylori-positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. CONCLUSIONS: In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis, D. pneumosintes, S. exigua, P. micra and S. anginosus in GC progression.
Assuntos
Carcinogênese/patologia , Disbiose/microbiologia , Mucosa Gástrica/patologia , Microbiota/genética , Neoplasias Gástricas/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Transformação Celular Neoplásica/patologia , China , Feminino , Mucosa Gástrica/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/patologia , Adulto JovemRESUMO
AIMS: Previous trials on the effectiveness of genotype-guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta-analysis of randomized trials comparing genotype-guided to conventional dosing strategies. METHODS: PubMed and the Cochrane Library were searched up to 23 October 2017. RESULTS: A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype-guided dosing (mean age 63.3 ± 5.8 years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 ± 6.1 years; 46% male) groups (mean follow-up duration 64 days) from 18 trials were included. Compared with conventional dosing, genotype-guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6 days, standard error 0.3 days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9 days, standard error 2.0 days; P < 0.01; I2 94%). Genotype-guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR ≥4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2 : 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. CONCLUSIONS: Genotype-guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident.
Assuntos
Anticoagulantes/administração & dosagem , Hemorragia/prevenção & controle , Medicina de Precisão/métodos , Tromboembolia/tratamento farmacológico , Varfarina/administração & dosagem , Anticoagulantes/efeitos adversos , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Relação Dose-Resposta a Droga , Genótipo , Técnicas de Genotipagem , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Coeficiente Internacional Normatizado , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Tromboembolia/mortalidade , Fatores de Tempo , Resultado do Tratamento , Vitamina K Epóxido Redutases/genética , Varfarina/efeitos adversosRESUMO
OBJECTIVE: To evaluate the potential for diagnosing colorectal cancer (CRC) from faecal metagenomes. DESIGN: We performed metagenome-wide association studies on faecal samples from 74 patients with CRC and 54 controls from China, and validated the results in 16 patients and 24 controls from Denmark. We further validated the biomarkers in two published cohorts from France and Austria. Finally, we employed targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers in an independent Chinese cohort of 47 patients and 109 controls. RESULTS: Besides confirming known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4 markers in the Danish cohort. In the French and Austrian cohorts, these four genes distinguished CRC metagenomes from controls with areas under the receiver-operating curve (AUC) of 0.72 and 0.77, respectively. qPCR measurements of two of these genes accurately classified patients with CRC in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes to discover and validate microbial biomarkers in ethnically different cohorts, and to independently validate selected biomarkers using an affordable clinically relevant technology. Our study thus takes a step further towards affordable non-invasive early diagnostic biomarkers for CRC from faecal samples.
Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Disbiose/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Idoso , Área Sob a Curva , Áustria , Estudos de Casos e Controles , China , Estudos de Coortes , Neoplasias Colorretais/complicações , Dinamarca , Disbiose/complicações , Feminino , Firmicutes/isolamento & purificação , França , Fusobacterium nucleatum/isolamento & purificação , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , Peptostreptococcus/isolamento & purificação , Curva ROCRESUMO
Human appendix is critical for the maintenance of intestinal homeostasis. Appendicectomy has been the optimal treatment of acute appendicitis, yet the cancer incidence after appendix removal remains unclear. In this territory-wide retrospective cohort study, adult participants who underwent appendicectomy from 2000 to 2018 were retrieved from a population database (n = 43,983), while matched reference participants were retrieved as controls (n = 85,853). After appendicectomy, the overall cancer risk was significantly increased (subdistribution hazard ratio (SHR) = 1.124) compared to the non-appendicectomy group. Appendicectomy-treated males had higher cancer risk than males without appendicectomy (SHR = 1.197), while such difference was not observed in female participants. Significant increase in cancer risk was also observed in elder participants (age >60) with appendicectomy (SHR = 1.390). Appendicectomy was positively correlated with the risk of digestive tract and respiratory cancers including colon (SHR = 1.440), pancreas (SHR = 1.930), and trachea, bronchus, and lung (SHR = 1.394). In contrast, the risk of liver cancer was markedly decreased after appendicectomy (SHR = 0.713). In conclusion, we reported the association of appendicectomy with subsequent cancer incidence. These findings highlight the potential complication after appendix removal and the necessity of post-operative management to monitor and prevent long-term adverse events.
Assuntos
Apendicectomia , Apendicite , Humanos , Apendicectomia/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Incidência , Apendicite/cirurgia , Apendicite/epidemiologia , Fatores de Risco , Idoso , Neoplasias/epidemiologia , Povo Asiático , Apêndice/cirurgia , Apêndice/patologia , Adulto JovemRESUMO
Sepsis is a life-threatening illness caused by the dysregulated host response to infection. Nevertheless, our current knowledge of the microbial landscape in the blood of septic patients is still limited. Next-generation sequencing (NGS) is a sensitive method to quantitatively characterize microbiomes at various sites of the human body. In this study, we analyzed the blood microbial DNA of 22 adult patients with sepsis and 3 healthy subjects. The presence of non-human DNA was identified in both healthy and septic subjects. Septic patients had a markedly altered microbial DNA profile compared to healthy subjects over α- and ß-diversity. Unexpectedly, the patients could be further divided into two subgroups (C1 and C2) based on ß-diversity analysis. C1 patients showed much higher bacteria, viruses, fungi, and archaea abundance, and a higher level of α-diversity (Chao1, Observed and Shannon index) than both C2 patients and healthy subjects. The most striking difference was seen in the case of Streptomyces violaceusniger, Phenylobacterium sp. HYN0004, Caulobacter flavus, Streptomyces sp. 11-1-2, and Phenylobacterium zucineum, the abundance of which was the highest in the C1 group. Notably, C1 patients had a significantly poorer outcome than C2 patients. Moreover, by analyzing the patterns of microbe-microbe interactions in healthy and septic subjects, we revealed that C1 and C2 patients exhibited distinct co-occurrence and co-exclusion relationships. Together, our study uncovered two distinct microbial signatures in the blood of septic patients. Compositional and ecological analysis of blood microbial DNA may thus be useful in predicting mortality of septic patients.
RESUMO
The human microbiome is an emerging research frontier due to its profound impacts on health. High-throughput microbiome sequencing enables studying microbial communities but suffers from analytical challenges. In particular, the lack of dedicated preprocessing methods to improve data quality impedes effective minimization of biases prior to downstream analysis. This review aims to address this gap by providing a comprehensive overview of preprocessing techniques relevant to microbiome research. We outline a typical workflow for microbiome data analysis. Preprocessing methods discussed include quality filtering, batch effect correction, imputation of missing values, normalization, and data transformation. We highlight strengths and limitations of each technique to serve as a practical guide for researchers and identify areas needing further methodological development. Establishing robust, standardized preprocessing will be essential for drawing valid biological conclusions from microbiome studies.
RESUMO
The outbreak of coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality worldwide. Vaccination against coronavirus disease 2019 is a useful weapon to combat the virus. Patients with chronic liver diseases (CLDs), including compensated or decompensated liver cirrhosis and noncirrhotic diseases, have a decreased immunologic response to coronavirus disease 2019 vaccines. At the same time, they have increased mortality if infected. Current data show a reduction in mortality when patients with chronic liver diseases are vaccinated. A suboptimal vaccine response has been observed in liver transplant recipients, especially those receiving immunosuppressive therapy, so an early booster dose is recommended to achieve a better protective effect. Currently, there are no clinical data comparing the protective efficacy of different vaccines in patients with chronic liver diseases. Patient preference, availability of the vaccine in the country or area, and adverse effect profiles are factors to consider when choosing a vaccine. There have been reports of immune-mediated hepatitis after coronavirus disease 2019 vaccination, and clinicians should be aware of that potential side effect. Most patients who developed hepatitis after vaccination responded well to treatment with prednisolone, but an alternative type of vaccine should be considered for subsequent booster doses. Further prospective studies are required to investigate the duration of immunity and protection against different viral variants in patients with chronic liver diseases or liver transplant recipients, as well as the effect of heterologous vaccination.