-
The Lancet. Oncology Dec 2023Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while... (Randomized Controlled Trial)
Randomized Controlled Trial
Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.
BACKGROUND
Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma.
METHODS
In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete.
FINDINGS
Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT.
INTERPRETATION
SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results.
FUNDING
Galera Therapeutics.
Topics: Humans; Male; Female; Aged; Adenocarcinoma; Pancreatic Neoplasms; Radiosurgery; Bayes Theorem; Carcinoma, Pancreatic Ductal; Double-Blind Method; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38039992
DOI: 10.1016/S1470-2045(23)00478-3 -
IScience Apr 2024Hepatitis B virus (HBV) infection generally elicits weak type-I interferon (IFN) immune response in hepatocytes, covering the regulatory effect of IFN-stimulated genes....
Hepatitis B virus (HBV) infection generally elicits weak type-I interferon (IFN) immune response in hepatocytes, covering the regulatory effect of IFN-stimulated genes. In this study, low level of IFN-stimulated gene 12a (ISG12a) predicted malignant transformation and poor prognosis of HBV-associated hepatocellular carcinoma (HCC), whereas high level of ISG12a indicated active NK cell phenotypes. ISG12a interacts with TRIM21 to inhibit the phosphorylation activation of protein kinase B (PKB, also known as AKT) and β-catenin, suppressing PD-L1 expression to block PD-1/PD-L1 signaling, thereby enhancing the anticancer effect of NK cells. The suppression of PD-1-deficient NK-92 cells on HBV-associated tumors was independent of ISG12a expression, whereas the anticancer effect of PD-1-expressed NK-92 cells on HBV-associated tumors was enhanced by ISG12a and treatments of atezolizumab and nivolumab. Thus, tumor intrinsic ISG12a promotes the anticancer effect of NK cells by regulating PD-1/PD-L1 signaling, presenting the significant role of innate immunity in defending against HBV-associated HCC.
PubMed: 38591006
DOI: 10.1016/j.isci.2024.109533 -
The American Journal of Gastroenterology Mar 2024
PubMed: 38534110
DOI: 10.14309/ajg.0000000000002779 -
Veterinary Parasitology Oct 2023Coccidiosis caused by Eimeria is one of the most severe chicken diseases and imposes huge economic losses to the poultry industry globally. Multi-Eimeria species...
Coccidiosis caused by Eimeria is one of the most severe chicken diseases and imposes huge economic losses to the poultry industry globally. Multi-Eimeria species coinfections are common with the most prevalent combination being mixtures of Eimeria acervulina and Eimeria tenella. Although detrimental impacts of either E. acervulina or E. tenella on chicken health are well recognized, no information is available regarding their coinfection effects so far. This study was designed to investigate the influence of coinfection with E. acervulina and E. tenella on broiler chickens. 144 one-day-old broiler chickens within each of trials (trial I or II) were divided into four groups, namely, control group (CG), E. acervulina infection group (EAIG), E. tenella infection group (ETIG) and dual (E. acervulina and E. tenella) infection group (DIG). Then, chickens were measured for weight loss, lesion scores, oocyst outputs, histological changes and expressions of pro-inflammatory (interleukin [IL]-6, IL-8 and IL-18), regulatory (IL-10 and IL-22) cytokines and Toll-like receptors (TLR; TLR2 and TLR4) as well as intestinal barrier (mucin 2 [MUC2] and fattey acid-bingding proteins 2 and 6 [FABP2 and FABP6])- and tight junction (TJ; zonula occluden-1 [ZO-1], occludin [OCLN], and claudins 1 and 5 [CLDN1 and CLDN5])-related proteins at 3, 5, 7, 10, 14 and 21 days post-infection, respectively. Our results consistently showed that although ETIG and DIG exhibited a higher level of weight loss and a more amount of oocyst excretion than EAIG, DIG had lighter lesions than EAIG in the early phase because of coinfection with E. tenella. A higher (P < 0.05) ratio of duodenal villous height to crypt depth was also observed in DIG than EAIG. Moreover, histological changes in the duodenum and cecum varied by single and dual Eimeria infections. Expressions of the intestinal barrier- and TJ-related genes of EAIG, ETIG and DIG were significantly (P < 0.05) upregulated but their levels exhibited differential changes among infected chickens. Similarly, the infected chickens showed significant (P < 0.05) inflammatory responses and higher (P < 0.05) expressions of TLRs in the intestines in comparison to CG. These results presented a comprehensive physiological, pathological and immunological characterization of E. acervulina and E. tenella coinfection in broiler chickens and also shed insights into pathogenesis of multi-coccidia coinfections.
Topics: Animals; Eimeria; Chickens; Coinfection; Coccidiosis; Intestines; Eimeria tenella; Immunity; Poultry Diseases
PubMed: 37666058
DOI: 10.1016/j.vetpar.2023.110019 -
Helicobacter Oct 2023Functional dyspepsia (FD) is a multifactorial disorder. Helicobacter pylori (H. pylori)-related dyspepsia (HpD) may be considered a separate entity. Duodenal...
BACKGROUND
Functional dyspepsia (FD) is a multifactorial disorder. Helicobacter pylori (H. pylori)-related dyspepsia (HpD) may be considered a separate entity. Duodenal eosinophilia is a potential pathogenic mechanism in FD. However, the impact of duodenal eosinophilia and host genetic polymorphism of innate and pro-inflammatory cascade, nucleotide-binding oligomerization domain 1 (NOD-1), and interleukin-1 beta (IL-1β) in HpD was not explored.
AIM
To evaluate the association of NOD1-796G>A and IL-1B-511C>T gene variants and low-grade duodenal eosinophilia in HpD.
METHODS
A multicenter cross-sectional study was conducted. A total of 253 patients who met Rome-IV criteria were selected before upper endoscopy and 98 patients were included after unremarkable upper endoscopy and positive H. pylori in gastric biopsies were assessed. Clinical parameters, H. pylori cagA and duodenal histology, were evaluated.
RESULTS
Sixty-four (65%) patients had epigastric pain syndrome (EPS), 24 (25%) postprandial distress syndrome (PDS), and 10 (10%) EPS/PDS overlap. FD subtypes were not associated with NOD1-796G>A and IL-1B-511C>T gene variants. Low-grade duodenal eosinophilia was significantly increased in NOD1-796 GG versus single A-allele, but not in IL-1B-511 single T-allele or CC-allele. This association is dependent of cagA infection, since harboring cagA strain was significantly associated with low-grade duodenal eosinophilia with isolated variants NOD1-796 GG and IL-1B-511 single T-allele, but not without cagA. When we performed combined polymorphism analysis with NOD1-796 GG/IL-1B-511 single T-allele, a synergistic effect on low-grade duodenal eosinophilia was found between these two loci irrespective of cagA strain status in HpD.
CONCLUSION
Our findings suggest that low-grade duodenal eosinophilia is significantly associated with NOD1-796 GG allele specially in cagA strain and with allelic combination NOD1-796 GG/IL-1B-511 single T-allele independent of cagA strain infection in HpD patients.
Topics: Humans; Antigens, Bacterial; Bacterial Proteins; Cross-Sectional Studies; Dyspepsia; Eosinophilia; Gastritis; Helicobacter Infections; Helicobacter pylori; Nod1 Signaling Adaptor Protein; Polymorphism, Genetic
PubMed: 37350445
DOI: 10.1111/hel.13002 -
Journal of Medical Case Reports Oct 2023Plasmablastic lymphoma is a rare type of non-Hodgkin lymphoma that generally presents an aggressive clinical course. It is strongly associated with human immunodeficency... (Review)
Review
BACKGROUND
Plasmablastic lymphoma is a rare type of non-Hodgkin lymphoma that generally presents an aggressive clinical course. It is strongly associated with human immunodeficency virus (HIV) infection, and the most common site of involvement is the oral cavity. Although extraoral PBL has been reported in several places, small intestine involvement is extremely rare.
CASE PRESENTATION
Here, we describe an exceptionally rare case of a 24-year-old immunocompetent Asian Male patient with newly diagnosed plasmablastic lymphoma of the duodenum. The patient was admitted to our oncology facility due to the patient's clinical course, which included persistent vomiting, hematemesis, weight loss, and generalized weakness. Computed tomography of the abdomen (triphasic) of the patient showed thickness at the 2nd part of the duodenum measuring 2.6 cm in width and 16 cm in length blocking the pancreatic and common bile ducts by entering the second section of the duodenum. The biopsy specimen's pathological investigation indicated abnormal cells with plasmacytoid characteristics and a high proliferation index. The diagnosis of PBL was confirmed by immunohistochemical profiling. Supportive therapies like blood transfusions, antacids, and antiemetics were started to manage the patient's symptoms. Palliative radiation was also anticipated for the lesion site.
CONCLUSIONS
Duodenal involvement to the extent seen in our patient is exceptionally rare and, to the best of our knowledge, has hardly been described. The main goal of the article is to review the literature and report a case.
Topics: Humans; Male; Young Adult; Adult; Plasmablastic Lymphoma; Lymphoma, Large-Cell, Immunoblastic; Duodenum; Lymphoma, Non-Hodgkin; Disease Progression
PubMed: 37777745
DOI: 10.1186/s13256-023-04143-1 -
Frontiers in Veterinary Science 2023Porcine epidemic diarrhea virus (PEDV) causes porcine epidemic diarrhea (PED), a highly infectious disease, which has resulted in huge economic losses for the pig...
Porcine epidemic diarrhea virus (PEDV) causes porcine epidemic diarrhea (PED), a highly infectious disease, which has resulted in huge economic losses for the pig industry. To date, the pathogenic and immune response mechanism was not particularly clear. The purpose of this study was to investigate the pathogenic and immune responses of pigs infected with PEDV.In this study, 12 Min pigs were randomly selected without taking colostrum. At 3 days old, eight piglets were infected with 1 mL of PEDV solution (10 TCID50/ml), and the remaining four piglets were handled by 1 mL of 0.9% normal saline. Within the age of 7 days old, four piglets died and were considered as the death group. Correspondingly, four alive individuals were classified into the resistance group. Tissues of the duodenum, jejunum, ileum, colon, cecum, and rectum of piglets in the three groups were collected to measure the PEDV content. Additionally, the jejunum was used for the measurements and analyses of Hematoxylin-eosinstaining (HE), immunohistochemical sections, and transcriptomics. The phenotypes of Min piglets infected with PEDV showed that the viral copy numbers and jejunal damage had significant differences between the death and resistance groups. We also observed the transcriptome of the jejunum, and the differentially expressed (DE) analysis observed 6,585 DE protein-coding genes (PCGs), 3,188 DE long non-coding RNAs (lncRNAs), and 350 DE microRNAs (miRNAs), which were mainly involved in immune response and metabolic pathways. Furthermore, the specific expressed molecules for each group were identified, and 97 PCGs,108 lncRNAs, and 51 miRNAs were included in the ceRNA-regulated networks. By weighted gene co-expression network analysis (WGCNA) and transcription factor (TF) prediction, 27 significant modules and 32 significant motifs (-value < 0.05) annotated with 519 TFs were detected. Of these TFs, 53 were DE PCGs. In summary, the promising key PCGs, lncRNAs, and miRNAs related to the pathogenic and immunological response of pigs infected with PEDV were detected and provided new insights into the pathogenesis of PEDV.
PubMed: 38192721
DOI: 10.3389/fvets.2023.1295723 -
Internal Medicine (Tokyo, Japan) May 2024A 64-year-old woman was transported to the emergency room with a headache and fever. She presented with a right ocular protrusion, hyperemia, and tenderness in the neck....
A 64-year-old woman was transported to the emergency room with a headache and fever. She presented with a right ocular protrusion, hyperemia, and tenderness in the neck. Contrast-enhanced MRI of the head showed a high DWI signal in the bilateral sphenoid sinuses and contrast defects along the bilateral internal jugular and superior ophthalmic veins. Blood and CSF cultures revealed Streptococcus milleri group. Surgery was performed for Lemierre's syndrome secondary to sphenoid sinusitis. The patient was treated with antibiotics and anticoagulant therapy, but a duodenal ulcer and brain abscess thereafter developed. However, multidisciplinary endoscopic and surgical treatment saved her life.
Topics: Humans; Female; Lemierre Syndrome; Middle Aged; Streptococcus milleri Group; Streptococcal Infections
PubMed: 37743513
DOI: 10.2169/internalmedicine.2311-23 -
Journal of Virology Oct 2023Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for...
Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum-derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models. We show that viral host cell factors required for virus entry differ between cell lines from distinct origins and demonstrate the importance of clathrin-mediated endocytosis.
Topics: Humans; Adenoviridae; Clathrin; Duodenum; Endocytosis; Virus Internalization
PubMed: 37823645
DOI: 10.1128/jvi.00770-23 -
Asian Pacific Journal of Cancer... Dec 2023Helicobacter pylori (H. pylori) have been accepted as having an etiologic role in gastro-duodenal diseases as chronic gastritis, peptic ulcer, and gastric carcinoma....
BACKGROUND
Helicobacter pylori (H. pylori) have been accepted as having an etiologic role in gastro-duodenal diseases as chronic gastritis, peptic ulcer, and gastric carcinoma. Methylation of CGI has been correlated with the tumorigenic process since it can inactivate tumor suppressor genes. CDH1 is a tumor suppressor gene that encodes the E-cadherin protein, which is preserving cell-cell connections. Early stages of gastric carcinogenesis may be affected by the promoter methylation-mediated inactivation of this gene.
OBJECTIVE
This study aimed to investigate the methylation status of CDH1 using Methylation-Specific PCR (MSP) technique in clinical suspected patients with H. pylori infection who undergoing upper gastrointestinal endoscopy and correlated it with H. pylori detection by glmM PCR test.
METHODS
Fifty gastric mucosal biopsies were selected from one hundred and five samples included in this study. The detection of H. pylori was performed with the PCR primers specific to glmM gene. Bisulfite modification was done and the methylation status of the CDH1 gene was detected using MSP reaction.
RESULTS
H. pylori was detected in 36% (18/50) of study population using glmM gene PCR test, 89% (16/18) of H. pylori positive cases were CDH1 methylated positive (chi-square, p-value=0.002). CDH1 methylation can be present in cancerous and noncancerous gastric mucosa, where 60% (18/30) of CDH1 methylation positive gastric mucosa showed gastritis as an endoscopy finding and gastric cancer in 6% (2/30). There was a significant correlation between and CDH1 methylation positive results and age group (P-value = 0.02). There was no significant correlation between CDH1 methylation positive results and participants gender (p-value=0.431) and clinical symptoms (all P-value > 0.05).
CONCLUSION
This work suggested strong significance association between H. pylori infection and CDH1 methylation.
Topics: Humans; Helicobacter pylori; DNA Methylation; Gastritis; Gastritis, Atrophic; Gastric Mucosa; Stomach Neoplasms; Biopsy; Transcription Factors; Helicobacter Infections; Antigens, CD; Cadherins
PubMed: 38156839
DOI: 10.31557/APJCP.2023.24.12.4071