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Cancer organoids are miniature, three-dimensional cell culture models that can be made from primary patient tumors and studied in the laboratory. Vlachogiannis et al. asked whether such “tumor-in-a-dish” approaches can be used to predict drug responses in the clinic. They generated a live organoid biobank from patients with metastatic gastrointestinal cancer who had previously been enrolled in phase I or II clinical trials. This allowed the authors to compare organoid drug responses with how the patient actually responded in the clinic. Encouragingly, the organoids had similar molecular profiles to those of the patient tumor, reinforcing their value as a platform for drug screening and development. Science , this issue p. 920 Organoids can recapitulate patient responses in the clinic, with potential for drug screening and personalized medicine. Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.

ObjectiveRegorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.DesignPatients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.ResultsTwenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA analysis revealed KRAS mutations that were not previously found in tissue. Twenty-two of these (84.6%) were detected following repeat tissue testing by ddPCR. Overall, the ctDNA detection rate in the KRAS mutant population was 66%. Detection of KRAS mutation in ctDNA failed to predict prognosis or refine patient selection for cetuximab. While this study confirms the feasibility of ctDNA analysis in LARC and the high sensitivity of ddPCR, larger series are needed to better address the role of ctDNA as a prognostic or predictive tool in this setting.

Background: Cisplatin (Cis) is potent chemotherapy used to treating already many different types of cancer; however, it is found to correlate with nephrotoxicity and other adverse health consequences. Thymoquinone (TQ) is an antioxidant and anti-inflammatory molecule that may defend against the consequences of different chemotherapies. Thymoquinone uses, although, are negatively impacted by its weak solubility and inadequate biological availability. Objectives: This investigation examined the efficacy of a new nanoparticle (NP) absorbing TQ in an Ehrlich Ascites Carcinoma (EAC) mice model to address its low solubility, enhance its bioavailability, and protect against Cis-induced nephrotoxicity. Methods: Following 4 treatment groups were included in this research: (1) control, (2) EAC, (3) EAC + Cis + Thymoquinone nanoparticle (TQ-NP) treated, and (4) EAC + Cis-treated. Results: The study revealed that TQ-NP was efficacious in avoiding Cis-induced kidney problems in EAC mice, as well as restoring kidney function and pathology. Thymoquinone nanoparticle considerably reduced Cis-induced oxidative damage in renal tissue by augmenting antioxidant levels. According to tumor weight and histological investigation results, TQ-NP did not impair Cis’s anticancer efficacy. Conclusion: Thymoquinone nanoparticle might be used as a potential drug along with Cis anticancer therapy to reduce nephrotoxicity and other side effects while maintaining Cis anticancer properties.

Background: Diet influences the symptoms of gastroesophageal reflux disease (GERD). Plant-based diets rich in vegetables, fruits, legumes, seeds, and nuts may reduce inflammation and improve gut health, while high-fat foods may worsen symptoms. Objective: We examined the association between plant-based and animal-based foods, selected demographic characteristics, and the likelihood of GERD in Al Madinah Al Munawarah, Saudi Arabia. Method: A cross-sectional study using the GerdQ tool assessed the GERD likelihood among 303 adults. Dietary diversity scores were used to assess the quality of their diet. quality. Results: The participants were predominantly women (68.6%) and had low education levels (88.4%). Cereals were the most consumed plant-based foods, while vitamin A-rich fruits and vegetables were the least consumed. There was significant variation in the consumption of legumes, nuts, seeds, and milk and milk products among the GERD groups. The participants with a 50% GERD likelihood had the highest consumption (34.5%), followed by the 89% likelihood group (21.4%) and the 79% likelihood group (14.5%). The lowest consumption of milk and milk products was among those with an 89% GERD likelihood who also consumed more organ meat. In addition, GERD likelihood was inversely associated with age (r = −0.153; p = 0.008). The likelihood of GERD was negatively correlated with the intake of legumes, nuts, and seeds (r = −0.163; p = 0.005). Furthermore, the intake of cereals and tubers (r = 0.114; p = 0.047) and legumes, nuts, and seeds (r = 0.231; p = 0.0001) increased significantly with education. Conclusion: GERD prevention programs should target women, those with a low education level, and individuals consuming fewer plant-based foods and more organ meats.

Background Esophageal cancer is a prevalent and highly lethal malignancy worldwide, comprising two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). While both subtypes are frequently encountered, ESCC has historically been more common globally. However, in recent decades, EAC has emerged as the predominant type in industrialized nations, often developing from Barrett's esophagus, a condition driven by chronic gastroesophageal reflux disease (GERD). ESCC typically occurs in the upper esophagus, whereas EAC arises near the lower gastroesophageal junction. The etiology of esophageal cancer is multifactorial, with diverse causes and clinical management strategies. Notably, diagnosing tumors located in the lower esophagus presents significant challenges. EAC is particularly prone to diagnostic errors, as it can be mistaken for ESCC. This study aims to investigate potential histological biomarkers for EAC to facilitate early and accurate identification of histological changes, especially in patients with GERD. Methods This cross-sectional study examined archival histological samples from patients with lower esophageal abnormalities. Immunohistochemistry was used to investigate the P63 marker, while Masson's trichrome stain was employed to evaluate cancer progression and associated microenvironmental changes. Results A total of 104 cases were analyzed, including 13 with known P63-positive staining and five P63-negative controls. The remaining cases consisted of both precancerous and cancerous tissues diagnosed as EAC. Among these, 86 cases showed negative P63 staining, confirming their origin from non-squamous cells and supporting their classification as true Barrett's-related epithelium. In contrast, five of the 13 SCC control cases exhibited P63 positivity, demonstrating a highly significant association (p < 0.00001). Additionally, Masson's trichrome staining revealed stromal collagen fibers infiltrating the malignant tissue areas. Conclusions This study highlights the significance of the P63 marker in distinguishing between ESCC and EAC. It also suggests a potential role for Masson's trichrome stain in identifying early microenvironmental changes associated with EAC progression.

Type 2 diabetes mellitus (T2DM) is common in the Arab population. Endothelin-1 (ET-1) is an a vasoconstrictor agent produced by the endothelin-1 gene ( ). Circulating ET-1 has been shown to be increased in T2DM. The current examined the association between the rs5370 polymorphism and T2DM. The investigation was a case-control study and included 190 T2DM patients and 120 healthy subjects. Polymerase chain reaction was employed to determine rs5370 genotypes among the study participants. The frequency of the G allele was 78.3% among the control group and 74.7% in T2DM (P=0.306). Plasma ET-1 protein levels were higher in T2DM than in controls (p<0.01). However, no association was found between rs5370 and T2DM. The frequencies of GG, GT, and TT genotypes were 60.8%, 35%, and 4.2% in the control group and 53.7%, 42.1%, and 4.2% in the patient group, respectively (P=0.447). With respect to T2DM complications, a significantly higher incidence of nephropathy was observed among patients with TT/GT genotypes compared to patients with the GG genotype (P<0.05). Furthermore, a marginal statistical significance was found between rs5370 and cardiovascular diseases in T2DM (P=0.06). Circulatory ET-1 levels were elevated in T2DM. The EDN1 rs5370 polymorphism might impact the development of nephropathy in T2DM.