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INTRODUCTION: Vaginal bleeding in the first trimester of pregnancy generates anxiety and uncertainty for expecting parents. The ability to determine pregnancy outcome through a first trimester ultrasound scan remains a challenge in obstetrics. Several first trimester ultrasound markers used individually or in combination, as well as ultrasound markers used in combination with biochemical markers, have been studied to determine their predictive value in pregnancy outcome. This scoping review was performed to determine which markers have already been investigated for this purpose. METHODS: An extensive and systematic database search was performed using four different categories of keywords which were combined using Boolean terms. A total of 14 variables were included on the final data charting forms. Data was synthesised collectively for each variable and then separately for the studies analysing only one marker. For the studies which analysed multiple markers, data was synthesised based on the number of markers per study. RESULTS: The search yielded 3608 studies, of which 128 were ultimately used for this review. Data extraction, based on predetermined eligibility criteria, was performed by two authors independently. Seventy-seven (62.6%) studies investigated the predictive value of a single ultrasound marker. The remaining 46 (37.4%) studies explored multiple markers, of which at least one was an ultrasound marker. CONCLUSION: This review identified several discrepancies among different studies. This highlights the need for better consensus among researchers to allow for the design of a predictive model which enables extrapolation of findings to all pregnant women. IMPLICATIONS FOR PRACTICE: Through the study of ultrasound and biochemical markers in the first trimester of pregnancy, clinicians may provide a more accurate prediction of pregnancy outcome following threatened miscarriage.
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BACKGROUND: Growth differentiation factor 15 (GDF15), a stress-responsive cytokine from transforming growth factor superfamily, is highly expressed in mammalian tissues, including pancreas, stomach and intestine under pathological conditions. In particular, elevated levels of GDF15 might play an important role in the development and progression of various gastrointestinal cancers (GCs), suggesting its potential as a promising target for disease prediction and treatment. METHODS: In this review, systematic reviews addressing the role of GDF15 in GCs were updated, along with the latest clinical trials focussing on the GDF15-associated digestive malignancies. RESULTS: The multiple cellular pathways through which GDF15 is involved in the regulation of physiological and pathological conditions were first summarized. Then, GDF15 was also established as a valuable clinical index, functioning as a predictive marker in diverse GCs. Notably, latest clinical treatments targeting GDF15 were also highlighted, demonstrating its promising potential in mitigating and curing digestive malignancies. CONCLUSIONS: This review unveils the pivotal roles of GDF15 and its potential as a promising target in the pathogenesis of GCs, which may provide insightful directions for future investigations.
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This letter addresses the study titled "Red cell distribution width: A predictor of the severity of hypertriglyceridemia-induced acute pancreatitis" by Lv et al published in the World Journal of Experimental Medicine. The study offers a valuable analysis of red cell distribution width (RDW) as a predictive marker for persistent organ failure in patients with hypertriglyceridemia-induced acute pancreatitis. The study results suggest that RDW, combined with the Bedside Index for Severity in Acute Pancreatitis score, could enhance the predictive accuracy for severe outcomes. Further investigation into the role of RDW in different severities of acute pancreatitis is recommended. Additionally, the need for large-scale and multicenter prospective studies to validate these findings is emphasized.
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Transmembrane protease/serine (TMPRSS2), a type II transmembrane serine protease, plays a crucial role in different stages of cancer. Recent studies have reported that the triggering epidermal growth factor receptor (EGFR) activation through protease action promotes metastasis. However, there are no reports on the interaction of TMPRSS2 with EGFR, especially in triple-negative triple negative (TNBC). The current study investigates the unexplored interaction between TMPRSS2 and EGFR, which are key partners mediating metastasis. This interaction is explored for potential targeting using quercetin (QUE) and taxifolin (TAX). TMPRSS2 expression patterns in breast cancer (BC) tissues and subtypes have been predicted, with the prognostic significance assessed using the GENT2.0 database. Validation of TMPRSS2 expression was performed in normal and TNBC tissues, including drug-resistant cell lines, utilizing GEO datasets. TMPRSS2 was further validated as a predictive biomarker for FDA-approved chemotherapeutics through transcriptomic data from BC patients. The study demonstrated the association of TMPRSS2 with EGFR through in silico analysis and validates the findings in TNBC cohorts using the TIMER2.0 web server and the TCGA dataset through C-Bioportal. Molecular docking and molecular dynamic simulation studies identified QUE and TAX as best leads targeting TMPRSS2. They inhibited cell-free TMPRSS2 activity like clinical inhibitor of TMPRSS2, Camostat mesylate. In cell-based assays focused on paclitaxel-resistant TNBC (TNBC/PR), QUE and TAX demonstrated potent inhibitory activity against extracellular and membrane-bound TMPRSS2, with low IC50 values. Furthermore, ELISA and cell-based AlphaLISA assays demonstrated that QUE and TAX inhibit the interaction of TMPRSS2 with EGFR. Additionally, QUE and TAX exhibited significant inhibition of proliferation and cell cycle accompanied by notable alterations in the morphology of TNBC/PR cells. This study provides valuable insights into potential of QUE and TAX targeting TMPRSS2 overexpressing TNBC.
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Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Simulação de Acoplamento Molecular , Paclitaxel , Quercetina , Serina Endopeptidases , Quercetina/farmacologia , Quercetina/química , Quercetina/metabolismo , Quercetina/análogos & derivados , Humanos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Paclitaxel/farmacologia , Paclitaxel/química , Feminino , Serina Endopeptidases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologiaRESUMO
Introduction Stroke is a leading cause of death and disability globally, with atrial fibrillation (AF) recognized as a significant risk factor due to its association with increased stroke recurrence and mortality. Timely detection of AF is crucial to prevent recurrent strokes and improve outcomes. This study primarily aimed to evaluate the utility of 24-hour Holter monitoring for AF detection in acute ischemic stroke patients. Methods This retrospective observational study examined data from 207 patients admitted with acute ischemic stroke to a tertiary-care hospital over a two-year period. Patients with pre-existing AF, transient ischemic attacks, unconfirmed diagnoses, and missing Holter reports were excluded. A total of 140 patients were included in the analysis. The study investigated AF detection rates, the relationship between AF and stroke risk factors, other Holter findings, and the time delay in attaching Holter monitors. Results Of the 140 patients evaluated, AF was detected in nine (6.4%), exclusively in those aged ≥65 years. The most prevalent risk factors among the study participants were hypertension (74.3%) and diabetes (61.4%). No significant correlations were observed between AF and the analyzed stroke risk factors. The median delay for Holter device attachment was 3,503 minutes (approximately two days and 10 hours), with longer delays noted in males (4,084 mins (approximately two days and 20 hours) vs. 2,565 mins (approximately one day and 18 hours), p=0.005). Premature atrial complexes (PACs) were notably associated with the absence of AF, suggesting their potential role as markers for undiagnosed AF. Conclusion The study highlights the limited utility of 24-hour Holter monitoring in detecting AF in acute ischemic stroke patients, advocating for extended monitoring durations, especially in older patients. To improve AF detection, potential strategies include using longer monitoring periods and optimizing hospital workflows to reduce delays in attaching Holter devices. These approaches can minimize the risk of underdiagnosing paroxysmal AF, thereby preventing recurrent strokes and improving patient outcomes. Further investigation into PACs as potential predictive markers for AF is warranted.
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OBJECTIVE: Early diagnosis and prediction of organ dysfunction are critical for intervening and improving the outcomes of septic patients. The study aimed to find novel diagnostic and predictive biomarkers of organ dysfunction for perioperative septic patients. METHOD: This is a prospective, controlled, preliminary, and single-center study of emergency surgery patients. Mass spectrometry, Gene Ontology (GO) functional analysis, and the protein-protein interaction (PPI) network were performed to identify the differentially expressed proteins (DEPs) from sepsis patients, which were selected for further verification via enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to estimate the relative correlation of selected serum protein levels and clinical outcomes of septic patients. Calibration curves were plotted to assess the calibration of the models. RESULTS: Five randomized serum samples per group were analyzed via mass spectrometry, and 146 DEPs were identified. GO functional analysis and the PPI network were performed to evaluate the molecular mechanisms of the DEPs. Six DEPs were selected for further verification via ELISA. Cathepsin B (CatB), vascular cell adhesion protein 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL), protein S100-A9, prosaposin, and thrombospondin-1 levels were significantly increased in the patients with sepsis compared with those of the controls (p < 0.001). Logistic regression analysis showed that CatB, S100-A9, VCAM-1, prosaposin, and NGAL could be used for preoperative diagnosis and postoperative prediction of organ dysfunction. CatB and S100-A9 were possible predictive factors for preoperative diagnosis of renal failure in septic patients. Internal validation was assessed using the bootstrapping validation. The preoperative diagnosis of renal failure model displayed good discrimination with a C-index of 0.898 (95% confidence interval 0.843-0.954) and good calibration. CONCLUSION: Serum CatB, S100-A9, VCAM-1, prosaposin, and NGAL may be novel markers for preoperative diagnosis and postoperative prediction of organ dysfunction. Specifically, S100-A9 and CatB were indicators of preoperative renal dysfunction in septic patients. Combining these two biomarkers may improve the accuracy of predicting preoperative septic renal dysfunction. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trials Registry (ChiCTR2200060418) on June 1, 2022.
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BACKGROUND: TLR7 is a key player in the antiviral immunity. TLR7 signaling activates antigen-presenting cells including DCs and macrophages. This activation results in the adaptive immunity including T cells and B cells. Therefore, TLR7 is an important molecule of the immune system. Based on these observations, TLR7 agonists considered to become a therapy weaponize the immune system against cancer. Radiation therapy (RT) is one of the standard cancer therapies and is reported to modulate the tumor immune response. In this study, we aimed to investigate the anti-tumor activity in combination of TLR7 agonist, DSP-0509, with RT and underlying mechanism. RESULT: We showed that anti-tumor activity is enhanced by combining RT with the TLR7 agonist DSP-0509 in the CT26, LM8, and 4T1 inoculated mice models. We found that once- weekly (q1w) dosing of DSP-0509 rather than biweekly (q2w) dosing is needed to achieve superior anti-tumor activities in CT26 model. Spleen cells from the mice in RT/DSP-0509 combination treatment group showed increased tumor lytic activity, inversely correlated with tumor volume, as measured by the chromium-release cytotoxicity assay. We also found the level of cytotoxic T lymphocytes (CTLs) increased in the spleens of completely cured mice. When the mice completely cured by combination therapy were re-challenged with CT26 cells, all mice rejected CT26 cells but accepted Renca cells. This rejection was not observed with CD8 depletion. Furthermore, levels of splenic effector memory CD8 T cells were increased in the combination therapy group. To explore the factors responsible for complete cure by combination therapy, we analyzed peripheral blood leukocytes (PBLs) mRNA from completely cured mice. We found that Havcr2low, Cd274low, Cd80high, and Il6low were a predictive signature for the complete response to combination therapy. An analysis of tumor-derived mRNA showed that combination of RT and DSP-0509 strongly increased the expression of anti-tumor effector molecules including Gzmb and Il12. CONCLUSION: These data suggest that TLR7 agonist, DSP-0509, can be a promising concomitant when used in combination with RT by upregulating CTLs activity and gene expression of effector molecules. This combination can be an expecting new radio-immunotherapeutic strategy in clinical trials.
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Receptor 7 Toll-Like , Animais , Receptor 7 Toll-Like/agonistas , Camundongos , Linhagem Celular Tumoral , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Glicoproteínas de Membrana/agonistas , Terapia Combinada , Humanos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Modelos Animais de Doenças , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
Growth hormone (GH) has a short half-life and declines abruptly following somatotropinoma surgery, enabling its prompt measurement as an indicator of surgical success. This study assesses the predictive value of early postoperative GH levels for 3-month and >1-year remission of acromegaly. We conducted a retrospective search in our database of patients who had undergone transsphenoidal surgery of GH-secreting pituitary adenoma from January 2011 to June 2022. Only the patients who underwent the first pituitary surgery and had GH measurements on the fifth postoperative day were included. The 3-month and >1-year remission of acromegaly was defined as achieving the GH nadir of <0.4 µg/L during an oral glucose tolerance test and maintaining normal insulin-like growth factor 1 levels at the initial follow-up visit 3 months after surgery and throughout at least the first year postoperation. We included 63 patients in the analysis, with a median follow-up of 51.8 (13-155) months. The 3-month remission was achieved in 42 (66.7%) patients, and >1-year remission without additional therapy in 38 (60.3%) patients. Those who achieved >1-year remission had significantly lower fifth-day postoperative GH levels (0.59 [0.09-8.92] vs. 2.63 [0.25-24.64] µg/L, p < .001). Receiver-operating characteristic analysis revealed a significant value of fifth-day postoperative GH levels regarding the prediction of 3-month (area under the curve [AUC], 0.834; p < .0001) and >1-year (AUC, 0.783; p < .0001) acromegaly remission. The GH threshold of ≤1.57 µg/L yielded a sensitivity of 90.5% and a specificity of 71.4% at 3 months and 89.5% sensitivity and 60% specificity at the >1-year remission, respectively. Notably, all patients with fifth-day postoperative GH levels ≤0.23 µg/L exhibited remission of acromegaly throughout the follow-up period. Early postoperative GH measurement could be a reliable predictor of both 3-month and >1-year remission of acromegaly.
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BACKGROUND: The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis. METHODS: sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis. FINDINGS: Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade. INTERPRETATION: sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis. FUNDING: F.B. was supported by the Else Kröner Foundation (Award 2016_kolleg.14). G.G. was supported by the Bristol Myers Squibb Foundation for Immuno-Oncology (Award FA-19-009). N.S. was supported by a Wellcome Trust Fellowship (211113/A/18/Z). J.A.H. received funding from the European Union's Horizon 2020 research and innovation programme (Award 860003). J.M.W. received funding from the Else Kröner Foundation (Award 2015_A10).
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Biomarcadores , Humanos , Masculino , Biomarcadores/sangue , Feminino , Pessoa de Meia-Idade , Células T Matadoras Naturais/metabolismo , Hepatócitos/metabolismo , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/sangue , Fígado Gorduroso/metabolismo , Adulto , IdosoRESUMO
AIM: The present cohort study explored whether specific gut microbiota (GM) profile would predict the development of impaired glucose tolerance (IGT) in individuals with normal glucose tolerance (NGT). METHODS: A total of 114 study subjects with NGT in Kumejima island, Japan participated in the present study and underwent 75 g oral glucose tolerance tests at baseline and one year later. We compared the profile of GM at baseline between individuals who consistently maintained NGT (NRN, n = 108) and those who transitioned from NGT to IGT (NTI, n = 6). RESULTS: Within-individual bacterial richness and evenness as well as inter-individual bacterial composition showed no significant differences between NRN and NTI. Of note, however, partial least squares discriminant analyses revealed distinct compositions of GM between groups, with no overlap in their 95 % confidence interval ellipses. Multi-factor analyses at the genus level demonstrated that the proportions of CF231, Corynebacterium, Succinivibrio, and Geobacillus were significantly elevated in NTI compared to NRN (p < 0.005, FDR < 0.1, respectively) after adjusting for age, sex, HbA1c level, and BMI. CONCLUSIONS: Our data suggest that increased proportion of specific GM is linked to the future deterioration of glucose tolerance, thereby serving as a promising predictive marker for type 2 diabetes mellitus.
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Microbioma Gastrointestinal , Intolerância à Glucose , Teste de Tolerância a Glucose , Humanos , Intolerância à Glucose/microbiologia , Intolerância à Glucose/sangue , Feminino , Masculino , Microbioma Gastrointestinal/fisiologia , Pessoa de Meia-Idade , Estudos de Coortes , Japão/epidemiologia , Glicemia/metabolismo , Glicemia/análise , Adulto , Idoso , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/sangueRESUMO
BACKGROUND: Kidney transplantation has emerged as the most effective treatment for patients with uremia. Advances in immunosuppressant medications have significantly reduced the risk of rejection. However, a notable increase in opportunistic infections, such as Pneumocystis jirovecii pneumonia (PJP), demands special attention in clinical practice. Our study aims to evaluate risk factors and identify predictive markers associated with PJP in kidney transplantation recipients. METHODS: We conducted a case-control study (1:2 ratio) involving kidney transplant recipients with and without PJP, matched based on the same surgical date. The study was carried out at Zhongnan Hospital of Wuhan University, China. RESULTS: Ninety-three participants were enrolled at Zhongnan Hospital of Wuhan University, comprising 31 with PJP and 62 without PJP. All patients tested negative for HIV. Our findings indicate that PJP patients exhibited lower levels of serum albumin (P = 0.001), reduced counts of total and CD3+ (P < 0.001), CD4+ (P = 0.001), and CD8+ T lymphocytes (P < 0.001), and a lower rate of prophylactic trimethoprim-sulfamethoxazole (TMP-SMZ) usage compared to non-PJP patients (P = 0.02). Conversely, urea levels in PJP patients were significantly higher than in non-PJP controls (P < 0.001). We developed a model combining CD8+ T cell count (< 241.11/µL, P < 0.001) and ALB levels (< 35.2 g/L, P = 0.003), which demonstrated excellent discriminatory power in distinguishing PJP from non-PJP cases, with an area under the curve (AUC) of 0. 920 (95% CI, 0.856-0.989). CONCLUSIONS: Our study suggests that a baseline CD8+ T cell count (< 241.11/µL) and serum ALB levels (< 35.2 g/L) offer robust predictive value for the occurrence of PJP infections in kidney transplant recipients.
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Biomarcadores , Transplante de Rim , Pneumocystis carinii , Pneumonia por Pneumocystis , Combinação Trimetoprima e Sulfametoxazol , Humanos , Transplante de Rim/efeitos adversos , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Adulto , Biomarcadores/sangue , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Fatores de Risco , China/epidemiologiaRESUMO
Background and Objective: Neoadjuvant chemoimmunotherapy (NACI) is the standard of care for patients with resectable non-small cell lung cancer (NSCLC). Although the pathological complete response (pCR) after NACI reportedly exceeds 20%, an optimal predictor of pCR is yet to be established. This review aims to examine the possible predictors of pCR after NACI. Methods: We identified research article published between 2018 and 2022 in English by the PubMed database. Fifty research studies were considered as relevant article, and were examined to edit information for this narrative review. Key Content and Findings: Recently, several studies have explored potential biomarkers for the pathological response after NACI. For example, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) imaging, tumor microenvironment (TME), genetic alternation such as circulating tumor DNA (ctDNA), and clinical markers such as neutrophil-to-lymphocyte ratio (NLR) and smoking signature were assessed in patients with resectable NSCLC to predict the pathological response after NACI. Based on the PET response criteria, the complete metabolic response (CMR) achieved a positive predictive value (PPV) of 71.4% for predicting pCR, and the decreasing rate of post-therapy maximum standardized uptake value (SUVmax) after NACI substantially correlated with the major pathological response (MPR). TME, as a significant marker for MPR in tumor specimens, was identified as an increase in CD8+ T cells and decrease in CD3+ T cells or Foxp3 T cells. Considering blood samples, TME comprised an increase in CD4+PD-1+ cells or natural killer cells and a decrease in CD3+CD56+CTLA4+ cells, total T cells, Th cells, myeloid-derived suppressor cells (MDSCs), or regulatory T cells. Although low pretreatment levels of ctDNA and undetectable ctDNA levels after NACI were markedly associated with survival, the relationship between ctDNA levels and pCR remains elusive. Moreover, the patients with a high baseline NLR had a low incidence of pCR. Heavy smoking (>40 pack-years) was favorable for predicting pathological response. Conclusions: A reduced rate of 18F-FDG uptake post-NACI and TME-related surface markers on lymphocytes could be optimal predictors for pCR. However, the role of these pCR predictors for NACI remains poorly validated, warranting further investigations. This review focuses on predictive biomarkers for pathological response after NACI in patients with resectable NSCLC.
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PURPOSE: Various studies have demonstrated the causal relationship between gut microbiota and efficacy of chemotherapy; however, the impact of gut microbiota on breast cancer has not been fully elucidated. This study aimed to evaluate the associations between the gut microbiota before neoadjuvant chemotherapy and its consequent efficacy in breast cancer. METHODS: This prospective observational study included patients who received neoadjuvant chemotherapy for primary early breast cancer at eight institutions between October 1, 2019, and March 31, 2022. We performed 16S rRNA analysis of fecal samples and α and ß diversity analyses of the gut microbiota. The primary endpoint was the association between the gut microbiota and pathological complete response (pCR) to neoadjuvant chemotherapy. RESULTS: Among the 183 patients, the pCR rate after neoadjuvant chemotherapy was 36.1% in all patients and 12.9% (9/70), 69.5% (41/59), and 29.6% (16/54) in those with the luminal, human epidermal growth factor receptor 2, and triple-negative types, respectively. The α diversity of the gut microbiota did not significantly differ between patients with pCR and those without pCR. Among the gut microbiota, two species (Victivallales, P = 0.001 and Anaerolineales, P = 0.001) were associated with pCR, and one (Gemellales, P = 0.002) was associated with non-pCR. CONCLUSION: Three species in the gut microbiota had potential associations with neoadjuvant chemotherapy efficacy, but the diversity of the gut microbiota was not associated with response to chemotherapy. Further research is needed to validate our findings.
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Hypertensive disorders of pregnancy (HDP) are among the major causes of high maternal and fetal/neonatal morbidity and mortality rates. Patients with HDP have significantly elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at diagnosis; however, the NT-proBNP levels during early pregnancy are largely unknown. This study aimed to validate the association between HDP and NT-proBNP levels. This retrospective study evaluated 103 pregnant women who developed HDP diagnosed after 35 weeks of gestation and 667 who did not. The HDP group had significantly lower early-pregnancy NT-proBNP levels than the without HDP group. However, the two groups did not significantly differ in terms of the late-pregnancy NT-proBNP levels. After adjusting for confounding factors such as age, body mass index, parity, and blood pressure levels, high early-pregnancy NT-proBNP levels were associated with a lower HDP risk. Early-pregnancy NT-proBNP levels ≥ 60.5 pg/mL had a negative predictive value of 97.0% for ruling out HDP, with a sensitivity of 87.4% and specificity of 62.5%. In conclusion, elevated early-pregnancy NT-proBNP levels were associated with a lower HDP risk. Moreover, a cutoff point of ≥ 60.5 pg/mL for early-pregnancy NT-proBNP levels had a high negative predictive value and sensitivity for ruling out HDP. These findings can provide new clinical implications.
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Hipertensão Induzida pela Gravidez , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Humanos , Feminino , Gravidez , Peptídeo Natriurético Encefálico/sangue , Adulto , Fragmentos de Peptídeos/sangue , Hipertensão Induzida pela Gravidez/sangue , Hipertensão Induzida pela Gravidez/diagnóstico , Estudos Retrospectivos , Biomarcadores/sangue , Idade GestacionalRESUMO
Triple-negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC include surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with a worse prognosis in TNBC. MCL1 inhibitors are in clinical trials for TNBC, but response rates to these inhibitors can vary and predictive markers are lacking. Currently, we identified a 4-member (AXL, ETS1, IL6, EFEMP1) gene signature (GS) that predicts MCL1 inhibitor sensitivity in TNBC cells. Factors encoded by these genes regulate signaling pathways to promote MCL1 inhibitor resistance. Small molecule inhibitors of the GS factors can overcome resistance and sensitize otherwise resistant TNBC cells to MCL1 inhibitor treatment. These findings offer insights into potential therapeutic strategies and tumor stratification for MCL1 inhibitor use in TNBC.
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Resistencia a Medicamentos Antineoplásicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Neoplasias de Mama Triplo Negativas , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Feminino , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Interleucina-6/metabolismo , Interleucina-6/genética , Proteína Proto-Oncogênica c-ets-1RESUMO
BACKGROUND: Microsatellite instability-high (MSI-H) colorectal cancer (CRC) is known for its heightened responsiveness to immunotherapy. However, establishing robust predictive markers for immunotherapy efficacy remains imperative. This retrospective study aimed to elucidate the genetic landscape of MSI-H CRC and correlate these genetic alterations with immunotherapy outcomes in a cohort of 121 patients. METHODS: We analyzed clinical and molecular data from 121 patients with MSI-H CRC. We conducted a thorough genetic analysis of MSI-H CRC patients, with a specific emphasis on the APC, TP53, RAS, and MMR genes. We further analyzed the relationship between gene mutations and immunotherapy efficacy. The primary endpoints analyzed were objective response rate (ORR) and progression-free survival (PFS). All statistical analysis was conducted using SPSS26.0 and R 4.2.0 software. RESULTS: Our findings underscored the complexity of the genetic landscape in MSI-H CRC, shedding light on the intricate interplay of these genes in CRC development. Notably, mutations in MMR genes exhibited a distinctive pattern, providing insights into the underlying mechanisms of MSI-H. Furthermore, our results revealed correlations between specific genetic alterations and immunotherapy outcomes, with a particular focus on treatment response rates and progression-free survival. CONCLUSION: This study represents a significant step toward unraveling the genetic nuances of MSI-H CRC. The distinctive pattern of MMR gene mutations not only adds depth to our understanding of MSI-H CRC but also hints at potential avenues for targeted therapies. This research sets the stage for future investigations aimed at refining therapeutic strategies and improving outcomes for patients with MSI-H CRC.
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Neoplasias Colorretais , Instabilidade de Microssatélites , Mutação , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/imunologia , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Imunoterapia/métodos , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA , Resultado do TratamentoRESUMO
BACKGROUND: Recurrent malignant pleural effusion (MPE) resulting from non-small-cell lung cancer (NSCLC) is easily refractory to conventional therapeutics and lacks predictive markers. The cellular or genetic signatures of recurrent MPE still remain largely uncertain. METHODS: 16 NSCLC patients with pleural effusions were recruited, followed by corresponding treatments based on primary tumours. Non-recurrent or recurrent MPE was determined after 3-6 weeks of treatments. The status of MPE was verified by computer tomography (CT) and cytopathology, and the baseline pleural fluids were collected for single-cell RNA sequencing (scRNA-seq). Samples were then integrated and profiled. Cellular communications and trajectories were inferred by bioinformatic algorithms. Comparative analysis was conducted and the results were further validated by quantitative polymerase chain reaction (qPCR) in a larger MPE cohort from the authors' centre (n = 64). RESULTS: The scRNA-seq revealed that 33 590 cells were annotated as 7 major cell types and further characterized into 14 cell clusters precisely. The cell cluster C1, classified as Epithelial Cell Adhesion Molecule (EpCAM)+ metastatic cancer cell and correlated with activation of tight junction and adherence junction, was significantly enriched in the recurrent MPE group, in which Claudin-4 (CLDN4) was identified. The subset cell cluster C3 of C1, which was enriched in recurrent MPE and demonstrated a phenotype of ameboidal-type cell migration, also showed a markedly higher expression of CLDN4. Meanwhile, the expression of CLDN4 was positively correlated with E74 Like ETS Transcription Factor 3 (ELF3), EpCAM and Tumour Associated Calcium Signal Transducer 2 (TACSTD2), independent of driver-gene status. CLDN4 was also found to be associated with the expression of Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A) and Vascular Endothelial Growth Factor A (VEGFA), and the cell cluster C1 was the major mediator in cellular communication of VEGFA signalling. In the extensive MPE cohort, a notably increased expression of CLDN4 in cells from pleural effusion among patients diagnosed with recurrent MPE was observed, compared with the non-recurrent group, which was also associated with a trend towards worse overall survival (OS). CONCLUSIONS: CLDN4 could be considered as a predictive marker of recurrent MPE among patients with advanced NSCLC. Further validation for its clinical value in cohorts with larger sample size and in-depth mechanism studies on its biological function are warranted. TRIAL REGISTRATION: Not applicable.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Derrame Pleural Maligno , Humanos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/metabolismo , Fator A de Crescimento do Endotélio Vascular , Claudina-4/genética , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Molécula de Adesão da Célula Epitelial , Perfilação da Expressão GênicaRESUMO
Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial-mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications.
RESUMO
BACKGROUND: Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. METHODS: Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. RESULTS: This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. CONCLUSIONS: Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.
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Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Estudos Retrospectivos , Taxoides/farmacologia , Taxoides/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Linhagem Celular TumoralRESUMO
Introduction: The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors of the efficacy of ICI monotherapy after platinum-based chemotherapy in NSCLC with ≤ 49% PD-L1 expression remain scarce. Methods: This multicenter retrospective study evaluated 54 advanced or recurrent NSCLC patients with ≤ 49% PD-L1 expression who were treated with second-line ICI monotherapy following disease progression on first-line platinum-based chemotherapy at nine hospitals in Japan. The impact of response to platinum-based chemotherapy on the efficacy of subsequent ICI monotherapy was investigated. Results: The response to first-line platinum-based chemotherapy was divided into two groups: the non-progressive disease (PD) group, which included patients who did not experience disease progression after four cycles of chemotherapy, and the PD group, which included patients who showed initial PD or could not maintain disease control during the four cycles of chemotherapy and switched to second-line ICI monotherapy. Among the 54 patients, 32 and 22 were classified into the non-PD and PD groups, respectively. The non-PD group showed better response rates (p = 0.038) and longer overall survival (OS) with ICI monotherapy (p = 0.023) than the PD group. Multivariate analysis identified that maintaining a non-PD status after four cycles of chemotherapy was an independent prognostic factor for ICI monotherapy (p = 0.046). Moreover, patients with a modified Glasgow Prognostic Score (mGPS) of 0 showed a tendency for longer OS with ICI monotherapy (p = 0.079), and there was a significant correlation between maintaining non-PD after four cycles of chemotherapy and an mGPS of 0 (p = 0.045). Conclusion: Maintaining a non-PD status after four cycles of platinum-based chemotherapy was a predictor of OS after second-line ICI monotherapy. These findings will help physicians select the most suitable treatment option for NSCLC patients who were treated with platinum-based chemotherapy and switched to second-line treatment. Those who experienced early PD during platinum-based chemotherapy should not be treated with ICI monotherapy in the second-line setting.