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1.
Acta Gastroenterol Belg ; 87(1): 37-39, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38431789

RESUMO

Acute colitis is a common feature of infection with Shiga-toxin producing Escherichia coli (STEC) and can mimic acute severe ulcerative colitis. Early recognition is important as there is a risk of developing Shiga toxin-induced haemolytic uremic syndrome (STEC-HUS), defined by the triad of microangiopathic haemolytic anemia, thrombocytopenia and organ damage. In severe cases STEC-HUS can cause severe neurological complications and can be fatal. We present a patient with a medical history of refractory ulcerative colitis, where making the diagnosis of STEC-HUS was challenging since the initial clinical presentation was difficult to differentiate from a flare of ulcerative colitis. This case illustrates that STEC induced colitis can mimic acute severe ulcerative colitis. This finding is of utmost clinical importance because of the potential life-threatening complications of STEC-HUS. Therefore it should be excluded promptly in patients with acute severe ulcerative colitis by using multiplex-PCR assay on a faecal sample.


Assuntos
Colite Ulcerativa , Colite , Infecções por Escherichia coli , Síndrome Hemolítico-Urêmica , Escherichia coli Shiga Toxigênica , Humanos , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/diagnóstico , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/complicações , Colite/diagnóstico
2.
Acta Gastroenterol Belg ; 87(1): 34-36, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38431788

RESUMO

Microscopic colitis is a chronic inflammatory disorder of the colon characterized by microscopic changes in the intestinal lining. Turmeric, a commonly used spice, is generally regarded as beneficial for digestive and articular health thanks to its anti-inflammatory properties. No cases of microscopic colitis under a food supplement containing turmeric has been previously described in the literature. This article highlights 3 cases where the consumption of a specific turmeric-based supplement caused microscopic colitis. Each of them complained about profuse watery diarrhea shortly after initiating the food supplement containing turmeric. Ileo-colonoscopies with biopsies confirmed the diagnosis of microscopic colitis, with two cases classified as lymphocytic colitis and the third as collagenous colitis. Following the discontinuation of the supplement, all patients experienced a resolution of their symptoms within a few days. Subsequent control biopsies for the three patients confirmed the resolution of microscopic colitis.


Assuntos
Colite Colagenosa , Colite Linfocítica , Colite Microscópica , Colite , Humanos , Curcuma/efeitos adversos , Colite Microscópica/induzido quimicamente , Colite Microscópica/diagnóstico , Colite Linfocítica/induzido quimicamente , Colite Linfocítica/diagnóstico , Colite Linfocítica/complicações , Colite Colagenosa/induzido quimicamente , Colite Colagenosa/diagnóstico , Colite Colagenosa/tratamento farmacológico , Diarreia/induzido quimicamente , Colite/induzido quimicamente , Colite/diagnóstico
3.
Front Immunol ; 15: 1297508, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38433841

RESUMO

Ulcerative colitis-related severe post-colectomy enteritis is a rare condition. A few cases have undergone successful treatment with corticosteroids, Cyclosporine, Azathioprine, and Infliximab. We aim to evaluate the treatment outcome of ustekinumab in this rare case. Here we describe a 56-year-old woman with post-colectomy enteritis refractory to multiple therapies. Finally, the patient was administered with ustekinumab treatment. Under monitoring, the feces volume of the patient decreased from 5000-7000 mL per day to 1700-2000 mL. Over a one-year follow-up period, the patient gradually gained body weight, with the stoma drainage of formed brown stool. And the villi of the small intestinal mucosa restore growth. To our knowledge, this is the first report that indicates ustekinumab could be a treatment selection for ulcerative colitis-related severe post-colectomy enteritis.


Assuntos
Colite Ulcerativa , Colite , Enterite , Feminino , Humanos , Pessoa de Meia-Idade , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/cirurgia , Ustekinumab/uso terapêutico , Colectomia , Enterite/tratamento farmacológico , Enterite/etiologia
4.
World J Surg ; 48(1): 175-185, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38436211

RESUMO

BACKGROUND: Obesity worsens various gastrointestinal pathologies. While bariatric surgery ameliorates obesity, it substantially modifies the gastrointestinal system depending on surgery type, with limited data on subsequent impact on obesity-related gastrointestinal admissions. METHODS: Using the 2012-2014 Nationwide Readmission Database, we included individuals with obesity who received vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB), or hernia repair (HR-control surgery). Our main focus was the adjusted odds ratio (aOR) for gastrointestinal inpatient admissions within 6 months following surgery compared to the 6 months preceding it, while controlling for several confounding factors. Gastrointestinal admissions were grouped into postoperative complications or obesity-associated gastrointestinal conditions. RESULTS: Our cohort included 140,103 adults with RYGB, 132,253 with VSG, and 12,436 HR controls. Postoperative gastrointestinal complications were most common after RYGB, prominently obstruction (aOR = 33.17, 95%CI: 18.01, 61.10), and Clostridium difficile infection (aOR: 12.52, 95%CI: 6.22, 25.19). VSG also saw significantly increased but less frequent similar conditions. Notably, for gastrointestinal conditions associated with obesity, acute pancreatitis risk was higher post-VSG (aOR = 6.26, 95%CI: 4.02, 9.73). Post-RYGB patients were most likely to be admitted for cholelithiasis with cholecystitis (aOR: 4.15, 95% CI: 3.24, 5.31), followed by chronic liver disease (aOR: 3.00, 95% CI: 2.33, 3.87). The risk of noninfectious colitis admissions was threefold higher after RYGB and VSG. No gastrointestinal conditions showed an increase after HR. CONCLUSION: Despite weight loss, bariatric surgery was associated with an increased risk of hepato-pancreatobiliary and colitis admissions related to obesity in the first six postoperative months, with considerable variations in rates of gastrointestinal conditions by surgery type.


Assuntos
Cirurgia Bariátrica , Colite , Gastroenteropatias , Pancreatite , Adulto , Humanos , Doença Aguda , Cirurgia Bariátrica/efeitos adversos , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/cirurgia , Gastroenteropatias/epidemiologia , Gastroenteropatias/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia
6.
Cells ; 13(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474337

RESUMO

Inflammatory bowel disease (IBD) is marked by a state of chronic energy deficiency that limits gut tissue wound healing. This energy shortfall is partially due to microbiota dysbiosis, resulting in the loss of microbiota-derived metabolites, which the epithelium relies on for energy procurement. The role of microbiota-sourced purines, such as hypoxanthine, as substrates salvaged by the colonic epithelium for nucleotide biogenesis and energy balance, has recently been appreciated for homeostasis and wound healing. Allopurinol, a synthetic hypoxanthine isomer commonly prescribed to treat excess uric acid in the blood, inhibits the degradation of hypoxanthine by xanthine oxidase, but also inhibits purine salvage. Although the use of allopurinol is common, studies regarding how allopurinol influences the gastrointestinal tract during colitis are largely nonexistent. In this work, a series of in vitro and in vivo experiments were performed to dissect the relationship between allopurinol, allopurinol metabolites, and colonic epithelial metabolism and function in health and during disease. Of particular significance, the in vivo investigation identified that a therapeutically relevant allopurinol dose shifts adenylate and creatine metabolism, leading to AMPK dysregulation and disrupted proliferation to attenuate wound healing and increased tissue damage in murine experimental colitis. Collectively, these findings underscore the importance of purine salvage on cellular metabolism and gut health in the context of IBD and provide insight regarding the use of allopurinol in patients with IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Animais , Alopurinol , Purinas/metabolismo , Hipoxantina/metabolismo , Colite/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico
7.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474305

RESUMO

Patients with inflammatory bowel disease (IBD) who experience long-term chronic inflammation of the colon are at an increased risk of developing colorectal cancer (CRC). Mitotic spindle positioning (MISP), an actin-binding protein, plays a role in mitosis and spindle positioning. MISP is found on the apical membrane of the intestinal mucosa and helps stabilize and elongate microvilli, offering protection against colitis. This study explored the role of MISP in colorectal tumorigenesis using a database, human CRC cells, and a mouse model for colitis-induced colorectal tumors triggered by azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment. We found that MISP was highly expressed in colon cancer patient tissues and that reduced MISP expression inhibited cell proliferation. Notably, MISP-deficient mice showed reduced colon tumor formation in the AOM/DSS-induced colitis model. Furthermore, MISP was found to form a complex with Opa interacting protein 5 (OIP5) in the cytoplasm, influencing the expression of OIP5 in a unidirectional manner. We also observed that MISP increased the levels of phosphorylated STAT3 in the JAK2-STAT3 signaling pathway, which is linked to tumorigenesis. These findings indicate that MISP could be a risk factor for CRC, and targeting MISP might provide insights into the mechanisms of colitis-induced colorectal tumorigenesis.


Assuntos
Colite , Neoplasias Colorretais , Animais , Humanos , Camundongos , Azoximetano/efeitos adversos , Carcinogênese , Transformação Celular Neoplásica , Colite/patologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Janus Quinase 2/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Fuso Acromático/metabolismo , Fator de Transcrição STAT3/metabolismo
8.
Cells ; 13(5)2024 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-38474407

RESUMO

Inflammatory bowel disease (IBD) refers to a cluster of intractable gastrointestinal disorders with an undetermined etiology and a lack of effective therapeutic agents. Amygdalin (Amy) is a glycoside extracted from the seeds of apricot and other Rosaceae plants and it exhibits a wide range of pharmacological properties. Here, the effects and mechanisms of Amy on colitis were examined via 16S rRNA sequencing, ELISA, transmission electron microscopy, Western blot, and immunofluorescence. The results showed that Amy administration remarkably attenuated the signs of colitis (reduced body weight, increased disease activity index, and shortened colon length) and histopathological damage in dextran sodium sulfate (DSS)-challenged mice. Further studies revealed that Amy administration significantly diminished DSS-triggered gut barrier dysfunction by lowering pro-inflammatory mediator levels, inhibiting oxidative stress, and reducing intestinal epithelial apoptosis and ferroptosis. Notably, Amy administration remarkably lowered DSS-triggered TLR4 expression and the phosphorylation of proteins related to the NF-κB and MAPK pathways. Furthermore, Amy administration modulated the balance of intestinal flora, including a selective rise in the abundance of S24-7 and a decline in the abundance of Allobaculum, Oscillospira, Bacteroides, Sutterella, and Shigella. In conclusion, Amy can alleviate colitis, which provides data to support the utility of Amy in combating IBD.


Assuntos
Amigdalina , Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Camundongos , RNA Ribossômico 16S , Morte Celular , Sulfato de Dextrana
9.
Nutrients ; 16(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474712

RESUMO

The dysregulation of the intestinal epithelial barrier significantly contributes to the inflammatory progression of ulcerative colitis. Recent studies have indicated that lactate, produced by gut bacteria or derived from fermented foods, plays a key role in modulating inflammation via G-protein-coupled receptor 81 (GPR81). In this study, we aimed to investigate the potential role of GPR81 in the progression of colitis and to assess the impact of lactate/GPR81 signaling on intestinal epithelial barrier function. Our findings demonstrated a downregulation of GPR81 protein expression in patients with colitis. Functional verification experiments showed that Gpr81-deficient mice exhibited more severe damage to the intestinal epithelial barrier and increased susceptibility to DSS-induced colitis, characterized by exacerbated oxidative stress, elevated inflammatory cytokine secretion, and impaired expression of tight-junction proteins. Mechanistically, we found that lactate could suppress TNF-α-induced MMP-9 expression and prevent the disruption of tight-junction proteins by inhibiting NF-κB activation through GPR81 in vitro. Furthermore, our study showed that dietary lactate could preserve intestinal epithelial barrier function against DSS-induced damage in a GPR81-dependent manner in vivo. Collectively, these results underscore the crucial involvement of the lactate/GPR81 signaling pathway in maintaining intestinal epithelial barrier function, providing a potential therapeutic strategy for ulcerative colitis.


Assuntos
Colite Ulcerativa , Colite , Humanos , Animais , Camundongos , Colite Ulcerativa/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Ácido Láctico/metabolismo , Mucosa Intestinal/metabolismo , Colite/induzido quimicamente , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colo/metabolismo , NF-kappa B/metabolismo
10.
Nutrients ; 16(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474718

RESUMO

Food-protein-induced allergic proctocolitis (FPIAP) is an increasingly reported transient and benign form of colitis that occurs commonly in the first weeks of life in healthy breastfed or formula-fed infants. Distal colon mucosal inflammation is caused by a non-IgE immune reaction to food allergens, more commonly to cow's milk protein. Rectal bleeding possibly associated with mucus and loose stools is the clinical hallmark of FPIAP. To date, no specific biomarker is available, and investigations are reserved for severe cases. Disappearance of blood in the stool may occur within days or weeks from starting the maternal or infant elimination diet, and tolerance to the food allergen is typically acquired before one year of life in most patients. In some infants, no relapse of bleeding occurs when the presumed offending food is reassumed after a few weeks of the elimination diet. Many guidelines and expert consensus on cow's milk allergy have recently been published. However, the role of diet is still debated, and recommendations on the appropriateness and duration of allergen elimination in FPIAP are heterogeneous. This review summarizes and compares the different proposed nutritional management of infants suffering from FPIAP, highlighting the pros and cons according to the most recent literature data.


Assuntos
Colite , Hipersensibilidade Alimentar , Hipersensibilidade a Leite , Proctocolite , Lactente , Feminino , Animais , Bovinos , Humanos , Dieta , Hipersensibilidade a Leite/complicações , Colite/complicações , Alérgenos
11.
Nutrients ; 16(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474831

RESUMO

Ulcerative colitis (UC) is a global intestinal disease, and conventional therapeutic drugs often fail to meet the needs of patients. There is an urgent need to find efficient and affordable novel biological therapies. Saccharomyces boulardii has been widely used in food and pharmaceutical research due to its anti-inflammatory properties and gut health benefits. However, there is still a relatively limited comparison and evaluation of different forms of S. boulardii treatment for UC. This study aimed to compare the therapeutic effects of S. boulardii, heat-killed S. boulardii, and S. boulardii ß-glucan on UC, to explore the potential of heat-killed S. boulardii as a new biological therapy. The results demonstrate that all three treatments were able to restore body weight, reduce the disease activity index (DAI), inhibit splenomegaly, shorten colon length, and alleviate histopathological damage to colonic epithelial tissues in DSS-induced colitis mice. The oral administration of S. boulardii, heat-killed S. boulardii, and S. boulardii ß-glucan also increased the levels of tight junction proteins (Occludin and ZO-1), decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in the serum, and suppressed the expressions of TNF-α, IL-1ß, and IL-6 mRNA in the colon. In particular, in terms of gut microbiota, S. boulardii, heat-killed S. boulardii, and S. boulardii ß-glucan exhibited varying degrees of modulation on DSS-induced dysbiosis. Among them, heat-killed S. boulardii maximally restored the composition, structure, and functionality of the intestinal microbiota to normal levels. In conclusion, heat-killed S. boulardii showed greater advantages over S. boulardii and S. boulardii ß-glucan in the treatment of intestinal diseases, and it holds promise as an effective novel biological therapy for UC. This study is of great importance in improving the quality of life for UC patients and reducing the burden of the disease.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Saccharomyces boulardii , beta-Glucanas , Humanos , Animais , Camundongos , Colite Ulcerativa/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversos , Interleucina-6 , Temperatura Alta , Qualidade de Vida , Inflamação/induzido quimicamente , Colite/induzido quimicamente , Colo/metabolismo , beta-Glucanas/farmacologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
12.
J Ethnopharmacol ; 326: 117995, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38428656

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be the driving factor of colitis carcinogenesis. Effective control of inflammation is helpful to prevent and treat colitis-related colorectal cancer (CAC). Anchang Yuyang Decoction (AYD), a traditional Chinese medicine (TCM) formula, is originated from the ancient prescription of TCM for treating colitis and colorectal cancer. AYD has demonstrated efficacy in treating IBD and potential anti-carcinogenic properties. AIM OF THE STUDY: This research aims to assess the therapeutic efficacy of AYD in ameliorating experimental colitis-related carcinogenesis induced by AOM/DSS. It further seeks to elucidate its potential mechanisms by integrating multiple omics sequencing approaches. MATERIALS AND METHODS: A rat model for colitis-related carcinogenesis was developed using azoxymethane (AOM)/dextran sulfate sodium (DSS). UPLC-MS identified AYD's chemical constituents. Rats were administered varying doses of AYD (18.37, 9.19 and 4.59 g/kg) orally for 53 days, with mesalazine as a positive control. The study evaluated anti-carcinogenic effects by examining adenoma number, adenoma load, abnormal crypt foci (ACF), histopathological damage, and tumor-related protein expression. Anti-inflammatory and reparative effects were assessed through body weight, disease activity index (DAI), colon length, spleen index, inflammatory cytokine levels, and tight junction protein expression. The effects on intestinal microbiota and host metabolism were explored through 16S rRNA sequencing, targeted short-chain fatty acid (SCFA) metabonomics, and non-targeted colon metabolomics. Potential AYD targets were identified through transcriptomic sequencing and validated by qRT-PCR and western blotting. RESULTS: AYD significantly reduced adenoma number, adenoma load, neoplasm-associated lesions, ACF, and tumor-related protein expression (e.g., p53, PCNA) in AOM/DSS-induced rats, thus impeding colitis-related carcinogenesis progression. AYD also alleviated histopathological damage and inflammation, promoting intestinal mucosal barrier repair. Furthermore, AYD modulated intestinal flora structure, enhanced SCFA production, and regulated colon metabolites. Transcriptomic sequencing revealed a significant impact on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Subsequent qRT-PCR and western blotting experiments indicated AYD's influence in up-regulating PPAR-γ and down-regulating PPAR-α, PPAR-ß/δ, and related proteins (thrombomodulin [Thbd], fatty acid binding protein 5 [Fabp5], stearoyl-CoA desaturase 2 [Scd2], phospholipid transfer protein [Pltp]). CONCLUSIONS: This study demonstrates AYD's ability to inhibit experimental colitis-related carcinogenesis induced by AOM/DSS. Its mechanism likely involves modulation of the PPAR signaling pathway, impacting intestinal microbiota and host metabolic equilibrium.


Assuntos
Adenoma , Colite , Neoplasias Colorretais , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Ratos , Animais , Camundongos , Receptores Ativados por Proliferador de Peroxissomo , RNA Ribossômico 16S , Cromatografia Líquida , Espectrometria de Massas em Tandem , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/patologia , Transdução de Sinais , Carcinogênese , Azoximetano/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Homeostase , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Colo
13.
Nihon Shokakibyo Gakkai Zasshi ; 121(3): 221-229, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38462470

RESUMO

With the advent of immune checkpoint inhibitors (ICI), cancer treatment options have widened in recent years. However, ICI-specific adverse events (irAEs) have been reported. Lower gastrointestinal lesions, such as colitis and enteritis, account for most gastrointestinal irAEs, and reports of upper gastrointestinal lesions are rare. We report a rare case of gastroesophagitis associated with ICI. The patient was a 64-year-old male. He was diagnosed with lung adenocarcinoma stage IIIB (cT2aN3M0), and pembrolizumab (PEM) was started as a first-line treatment. Severe gastroesophagitis with laryngopharyngitis was confirmed 5 months after PEM administration. These improved after withdrawal of PEM and steroid administration. Reports of ICI-associated gastritis remain limited, especially with laryngopharyngitis;therefore, we consider this case as valuable, in which we confirmed the clinical features of ICI-associated gastroesophagitis and its therapeutic effects.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Colite , Esofagite , Neoplasias Pulmonares , Masculino , Humanos , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico
14.
Gut Microbes ; 16(1): 2323231, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38436673

RESUMO

Rapid and accurate clinical staging of pediatric patients with inflammatory bowel disease (IBD) is crucial to determine the appropriate therapeutic approach. This study aimed to identify effective, convenient biomarkers for staging IBD in pediatric patients. We recruited cohorts of pediatric patients with varying severities of IBD to compare the features of the intestinal microbiota and metabolites between the active and remitting disease stages. Metabolites with potential for staging were targeted for further assessment in both patients and colitis model mice. The performance of these markers was determined using machine learning and was validated in a separate patient cohort. Pediatric patients with IBD exhibited distinct gut microbiota structures at different stages of disease activity. The enterotypes of patients with remitting and active disease were Bacteroides-dominant and Escherichia-Shigella-dominant, respectively. The bile secretion pathway showed the most significant differences between the two stages. Fecal and serum bile acid (BA) levels were strongly related to disease activity in both children and mice. The ratio of primary BAs to secondary BAs in serum was developed as a novel comprehensive index, showing excellent diagnostic performance in stratifying IBD activity (0.84 area under the receiver operating characteristic curve in the primary cohort; 77% accuracy in the validation cohort). In conclusion, we report profound insights into the interactions between the gut microbiota and metabolites in pediatric IBD. Serum BAs have potential as biomarkers for classifying disease activity, and may facilitate the personalization of treatment for IBD.


Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Animais , Criança , Camundongos , Ácidos e Sais Biliares , Biomarcadores
15.
JCO Clin Cancer Inform ; 8: e2300207, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38427922

RESUMO

PURPOSE: Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We aimed to build a machine learning (ML) framework using routine electronic health record (EHR) data to predict hepatitis, colitis, pneumonitis, and 1-year overall survival. METHODS: Real-world EHR data of more than 2,200 patients treated with ICI through December 31, 2018, were used to develop predictive models. Using a prediction time point of ICI initiation, a 1-year prediction time window was applied to create binary labels for the four outcomes for each patient. Feature engineering involved aggregating laboratory measurements over appropriate time windows (60-365 days). Patients were randomly partitioned into training (80%) and test (20%) sets. Random forest classifiers were developed using a rigorous model development framework. RESULTS: The patient cohort had a median age of 63 years and was 61.8% male. Patients predominantly had melanoma (37.8%), lung cancer (27.3%), or genitourinary cancer (16.4%). They were treated with PD-1 (60.4%), PD-L1 (9.0%), and CTLA-4 (19.7%) ICIs. Our models demonstrate reasonably strong performance, with AUCs of 0.739, 0.729, 0.755, and 0.752 for the pneumonitis, hepatitis, colitis, and 1-year overall survival models, respectively. Each model relies on an outcome-specific feature set, though some features are shared among models. CONCLUSION: To our knowledge, this is the first ML solution that assesses individual ICI risk-benefit profiles based predominantly on routine structured EHR data. As such, use of our ML solution will not require additional data collection or documentation in the clinic.


Assuntos
Colite , Hepatite , Pneumonia , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Inibidores de Checkpoint Imunológico , Instituições de Assistência Ambulatorial , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico
16.
PLoS One ; 19(3): e0295814, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38446811

RESUMO

BACKGROUND: The prospective cohort study PROTECT is the largest study in pediatric ulcerative colitis (UC) with standardized treatments, providing valuable data for predicting clinical outcomes. PROTECT and previous studies have identified characteristics associated with clinical outcomes. In this study, we aimed to compare predictive modeling between Bayesian analysis including machine learning and frequentist analysis. METHODS: The key outcomes for this analysis were week 4, 12 and 52 corticosteroid (CS)-free remission following standardized treatment from diagnosis. We developed predictive modeling with multivariable Bayesian logistic regression (BLR), Bayesian additive regression trees (BART) and frequentist logistic regression (FLR). The effect estimate of each risk factor was estimated and compared between the BLR and FLR models. The predictive performance of the models was assessed including area under curve (AUC) of the receiver operating characteristic (ROC) curve. Ten-fold cross-validation was performed for internal validation of the models. The estimation contained 95% credible (or confidence) interval (CI). RESULTS: The statistically significant associations between the risk factors and early or late outcomes were consistent between all BLR and FLR models. The model performance was similar while BLR and BART models had narrower credible intervals of AUCs. To predict week 4 CS-free remission, the BLR model had AUC of 0.69 (95% CI 0.67-0.70), the BART model had AUC of 0.70 (0.67-0.72), and the FLR had AUC of 0.70 (0.65-0.76). To predict week 12 CS-free remission, the BLR model had AUC of 0.78 (0.77-0.79), the BART model had AUC of 0.78 (0.77-0.79), and the FLR model had AUC of 0.79 (0.74-0.83). To predict week 52 CS-free remission, the BLR model had AUC of 0.69 (0.68-0.70), the BART model had AUC of 0.69 (0.67-0.70), and the FLR model had AUC of 0.69 (0.64-0.74). The BART model identified nonlinear associations. CONCLUSIONS: BLR and BART models had intuitive interpretation on interval estimation, better precision in estimating the AUC and can be alternatives for predicting clinical outcomes in pediatric patients with UC. BART model can estimate nonlinear nonparametric association.


Assuntos
Colite Ulcerativa , Colite , Humanos , Criança , Teorema de Bayes , Estudos Prospectivos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Área Sob a Curva
17.
Sci Rep ; 14(1): 5517, 2024 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448514

RESUMO

Ulcerative colitis (UC) is a chronic, recurrent inflammatory bowel disease. UC confronts with severe challenges including the unclear pathogenesis and lack of specific diagnostic markers, demanding for identifying predictive biomarkers for UC diagnosis and treatment. We perform immune infiltration and weighted gene co-expression network analysis on gene expression profiles of active UC, inactive UC, and normal controls to identify UC related immune cell and hub genes. Neutrophils, M1 macrophages, activated dendritic cells, and activated mast cells are significantly enriched in active UC. MMP-9, CHI3L1, CXCL9, CXCL10, CXCR2 and S100A9 are identified as hub genes in active UC. Specifically, S100A9 is significantly overexpressed in mice with colitis. The receiver operating characteristic curve demonstrates the excellent performance of S100A9 expression in diagnosing active UC. Inhibition of S100A9 expression reduces DSS-induced colonic inflammation. These identified biomarkers associated with activity in UC patients enlighten the new insights of UC diagnosis and treatment.


Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Colite Ulcerativa/terapia , Calgranulina B/genética , Biologia Computacional , Biomarcadores
18.
Nat Commun ; 15(1): 2083, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453952

RESUMO

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.


Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Humanos , Masculino , Animais , Camundongos , Colite Ulcerativa/patologia , Necroptose , Colite/patologia , Células Epiteliais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colo/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
19.
Stem Cell Res Ther ; 15(1): 69, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38454492

RESUMO

BACKGROUND: A significant unmet need in inflammatory bowel disease is the lack of anti-fibrotic agents targeting intestinal fibrosis. This study aimed to investigate the anti-fibrogenic properties and mechanisms of the conditioned medium (CM) from human umbilical cord/placenta-derived mesenchymal stem cells (UC/PL-MSC-CM) in a murine intestinal fibrosis model and human primary intestinal myofibroblasts (HIMFs). METHODS: UC/PL-MSC-CM was concentrated 15-fold using a 3 kDa cut-off filter. C57BL/6 mice aged 7 weeks old were randomly assigned to one of four groups: (1) control, (2) dextran sulfate sodium (DSS), (3) DSS + CM (late-phase treatment), and (4) DSS + CM (early-phase treatment). Chronic DSS colitis and intestinal fibrosis was induced by three cycles of DSS administration. One DSS cycle consisted of 7 days of oral DSS administration (1.75%, 2%, and 2.5% DSS), followed by 14 days of drinking water. UC/PL-MSC-CM was intraperitoneally administered in the late phase (from day 50, 10 times) or early phase (from day 29, 10 times) of DSS cycles. HIMFs were treated with TGF-ß1 and co-treated with UC/PL-MSC-CM (10% of culture media) in the cellular model. RESULTS: In the animal study, UC/PL-MSC-CM reduced submucosa/muscularis propria thickness and collagen deposition, which improved intestinal fibrosis in chronic DSS colitis. The UC/PL-MSC-CM significantly reduced the expressions of procollagen1A1 and α-smooth muscle actin, which DSS significantly elevated. The anti-fibrogenic effect was more apparent in the UC-MSC-CM or early-phase treatment model. The UC/PL-MSC-CM reduced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs in the cellular model. The UC/PL-MSC-CM downregulated fibrogenesis by suppressing RhoA, MRTF-A, and SRF expression. CONCLUSIONS: Human UC/PL-MSC-CM inhibits TGF-ß1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and chronic DSS colitis-induced intestinal fibrosis. Thus, it may be regarded as a novel candidate for stem cell-based therapy of intestinal fibrosis.


Assuntos
Colite , Células-Tronco Mesenquimais , Humanos , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Meios de Cultivo Condicionados/farmacologia , Meios de Cultivo Condicionados/metabolismo , Actinas/metabolismo , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/terapia , Colite/metabolismo , Fatores Imunológicos , Fibrose , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças
20.
Int J Colorectal Dis ; 39(1): 36, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38456914

RESUMO

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease of a multifactorial pathogenesis. Recently numerous genetic variants linked to an aggressive phenotype were identified, leading to a progress in therapeutic options, resulting in a decreased necessity for surgery. Nevertheless, surgery is often inevitable. The aim of the study was to evaluate possible risk factors for postoperative complications and disease recurrence specifically after colonic resections for CD. PATIENTS AND METHODS: A total of 241 patients who underwent colonic and ileocaecal resections for CD at our instiution between 2008 and 2018 were included. All data was extracted from clinical charts. RESULTS: Major complications occurred in 23.8% of all patients. Patients after colonic resections showed a significantly higher rate of major postoperative complications compared to patients after ICR (p = < 0.0001). The most common complications after colonic resections were postoperative bleeding (22.2%), the need for revision surgery (27.4%) and ICU (17.2%) or hospital readmission (15%). As risk factors for the latter, we identified time interval between admission and surgery (p = 0.015) and the duration of the surgery (p = 0.001). Isolated distal resections had a higher risk for revision surgery and a secondary stoma (p = 0.019). Within the total study population, previous bowel resections (p = 0.037) were identified as independent risk factors for major perioperative complications. CONCLUSION: The results indicate that both a complex surgical site and a complex surgical procedure lead to a higher perioperative morbidity in colonic resections for Crohn's colitis.


Assuntos
Colite , Doença de Crohn , Humanos , Doença de Crohn/complicações , Doença de Crohn/cirurgia , Doença de Crohn/patologia , Colectomia/efeitos adversos , Colectomia/métodos , Recidiva Local de Neoplasia/cirurgia , Complicações Pós-Operatórias/epidemiologia , Colite/cirurgia , Colite/complicações , Morbidade
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