HIF2 Regulates Intestinal Wnt5a Expression

Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.

Paracoccidioidomycosis in an Elderly Simulating Cholangiocarcinoma

Paracoccidioidomycosis, the most prevalent deep mycosis in Latin America, is caused by dimorphic species of the genus Paracoccidioides, affects predominantly male rural workers between 30-50 years of age and is an important cause of morbidity and mortality. It can present in two clinical forms: acute/subacute or chronic. In rare cases paracoccidioidomycosis may simulate neoplasia and must be considered as a differential diagnosis of intra-abdominal tumors in endemic areas. We report an exuberant case of subacute paracoccidioidomycosis in an elderly lady, although it is more frequent in the juvenile form. Multiple facial skin lesions were associated with a wasting syndrome and extensive adenopathy including in the hepatic area, causing bile duct dilatation simulating a cholangiocarcinoma. Skin histopathology was diagnostic and antifungal treatment allowed complete resolution of cutaneous and systemic lesions, thus highlighting the merit of the dermatologist, who was fundamental for the conclusive diagnosis and institution of specific therapy, resulting in a favorable outcome.

Large and acute symptomatic abdominal tumor in newborns: pitfalls, difficulties in management and surgical decision making.

Large and rapidly growing abdominal tumors endanger vital prognosis in neonates. Sometimes, quickly worsening patients’ clinical conditions demand surgical decision-making that cannot wait for precise histological diagnosis. There is neither consensus nor rules to manage these situations. We presented our experience with five patients and we looked in the literature for the best possible management of such rare disease. Laparostomy should be considered only as a safe-life procedure and if the liver is affected by the tumor and a coagulopathy is present, the prognosis is often compromised.

Spectral CT Hybrid Images in the Diagnostic Evaluation of Hypervascular Abdominal Tumors—Potential Advantages in Clinical Routine

Background: This study aimed to investigate the use of spectral computed tomography (SCT) hybrid images combining virtual monoenergetic images (VMIs) and iodine maps (IMs) as a potentially efficient search series for routine clinical imaging in patients with hypervascular abdominal tumors. Methods: A total of 69 patients with hypervascular abdominal tumors including neuroendocrine neoplasms (NENs, n = 48), renal cell carcinoma (RCC, n = 10), and primary hepatocellular carcinoma (HCC, n = 11) were analyzed retrospectively. Two radiological readers (blinded to clinical data) read three CT image sets (1st a reference set with 70 keV; 2nd a 50:50 hybrid 140 keV/40 keV set; 3rd a 50:50 hybrid140 keV/IM set). They assessed images subjectively by rating several parameters including image contrast, visibility of suspicious lesions, and diagnostic confidence on five-point Likert scales. In addition, reading time was estimated. Results: Median subjective Likert scores were highest for the 1st set, except for image contrast, for which the 2nd set was rated highest. Scores for diagnostic confidence, artifacts, noise, and visibility of suspicious lesions or small structures were significantly higher for the 1st set than for the 2nd or 3rd set (p < 0.001). Regarding image contrast, the 2nd set was rated significantly higher than the 3rd set (p < 0.001), while the median did not differ significantly compared with the 1st set. Agreement between the two readers was high for all sets. Estimated potential reading time was the same for hybrid and reference sets. Conclusions: Hybrid images have the potential to efficiently exploit the additional information provided by SCT in patients with hypervascular abdominal tumors. However, the use of rigid weighting did not significantly improve diagnostic performance in this study.

Preparation of Gd-Au Dendrimer-Entrapped Gold Nanoparticles-Folic Acid Nanoparticles and Its Application in Computed Tomography/Magnetic Resonance Imaging Dual-Modality Diagnosis of Abdominal Tumors

ABSTRACTThe development of nanomaterials, especially the development of multi-modality imaging nanoprobe technology has become a reality for tumor imaging diagnosis. In this study, the gadolinium ion chelating agent (2,2′,2′′-(10-(2-(2, 5-dioxopyrrolidin-1-oxyl)-2 oxoethyl)-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-tri)triacetic acid) (DOTA-NHS) and polyethylene glycol (PEG)-modified targeting ligand PEG-folic acid (FA) were grafted onto the PEG-modified fifth-generation polyamide-amine dendrimer (P5-NH2), which were undertaken as standards to wrap gold nanoparticles. Then, remaining amino group was acetylated to acquire Gd–Au DENPS-FA nanoparticles. Biocompatibility and cytotoxicity of nanoparticles were analyzed while characterizing them. The cases with unidentified tumors (mass diameter >4.5 cm) of abdominal or pelvic origin were selected and used for clinical study of computed tomography (CT)/magnetic resonance imaging (MRI) dual-modality abdominal tumors. In the test, average particle size of Gd-Au DENPs-FA nanoparticles was 4.2 nm, and they had good water solubility and stability in aqueous solution. When concentration of Au+ nanoparticles increased, the cell morphology remained normal, only a small number of round cells appeared, and the cell activity remained above 80%. GD-Au DENPs-FA nanoparticles had a good targeting specificity for KB cells with high folate receptor expression. During 6–24 hours of injection, the signal at the tumor site of the patient was enhanced markedly, namely the targeted gold nanoparticles were bound to the tumor tissue and the metabolic rate was slow. Based on this material, CT/MRI imaging could be performed in the patient’s body and further used for the early diagnosis of abdominal tumors.