AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

Bladder paraganglioma: CT and MR imaging characteristics in 16 patients

Background Bladder paraganglioma (BPG) is a rare extra-adrenal pheochromocytoma with variable symptoms and easy to be misdiagnosed and mishandled. The aim of the study was to document the imaging features of BPG using computed tomography (CT) and magnetic resonance imaging (MRI). Patients and methods We retrospectively enrolled consecutive patients with pathology-proven BPG, who underwent CT or MRI examinations before surgery between October 2009 and October 2017. The clinical characteristics, CT, and MRI features of the patients were described and analysed. Results A total of 16 patients with 16 bladder tumours (median age 51 years, 9 females) were included. Among them, 13 patients underwent CT examinations and eight patients underwent MRI examinations preoperatively. Tumour diameters ranged from 1.6−5.4 cm. Most of the tumours grew into the bladder cavity (n = 11) with oval shapes (n = 10) and well-defined margins (n = 14). Intratumour cystic degeneration or necrosis (n = 2) was observed. Two lesions showed peripheral tissue invasion, suggesting malignant BPGs. All 13 lesions imaged with CT exhibited slight hypoattenuation and moderate to marked enhancement. Compared to the gluteus maximus, all lesions showed slight h yperintensity in T2-weighted images, hyperintensity on diffusion-weighted images (DWI), hypointensity on apparent diffusion coefficient maps, hyperintensity on T1-weighted images and a “fast in and slow out” enhanced pattern on contrast-enhanced MRI images. Conclusions BPGs are mostly oval-shaped, broadly-based and hypervascular bladder tumours with hypoattenuation on non-contrast CT, T2 hyperintensity, slight T1 hyperintensity compared to the muscle, marked restricted diffusion on DWI. Peripheral tissue invasion can suggest malignancy of the BPGs. All of these features contribute to preoperative decision-making.

Candida albicans PPG1, a serine/threonine phosphatase, plays a vital role in central carbon metabolisms under filament-inducing conditions: A multi-omics approach

Candida albicans is the leading cause of life-threatening bloodstream candidiasis, especially among immunocompromised patients. The reversible morphological transition from yeast to hyphal filaments in response to host environmental cues facilitates C. albicans tissue invasion, immune evasion, and dissemination. Hence, it is widely considered that filamentation represents one of the major virulence properties in C. albicans. We have previously characterized Ppg1, a PP2A-type protein phosphatase that controls filament extension and virulence in C. albicans. This study conducted RNA sequencing analysis of samples obtained from C. albicans wild type and ppg1Δ/Δ strains grown under filament-inducing conditions. Overall, ppg1Δ/Δ strain showed 1448 upregulated and 710 downregulated genes, representing approximately one-third of the entire annotated C. albicans genome. Transcriptomic analysis identified significant downregulation of well-characterized genes linked to filamentation and virulence, such as ALS3, HWP1, ECE1, and RBT1. Expression analysis showed that essential genes involved in C. albicans central carbon metabolisms, including GDH3, GPD1, GPD2, RHR2, INO1, AAH1, and MET14 were among the top upregulated genes. Subsequent metabolomics analysis of C. albicans ppg1Δ/Δ strain revealed a negative enrichment of metabolites with carboxylic acid substituents and a positive enrichment of metabolites with pyranose substituents. Altogether, Ppg1 in vitro analysis revealed a link between metabolites substituents and filament formation controlled by a phosphatase to regulate morphogenesis and virulence.

Delayed Initial Radioiodine Adjuvant Therapy Does Affect Biochemical Response in Intermediate- to High-Risk Differentiated Thyroid Cancer

BackgroundThere are no definite recommendations on the optimal time of initiating radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC) patients in current relevant guidelines. This study aimed to investigate the relationship between the timing of initiating radioiodine adjuvant therapy (RAT) and the clinical outcomes based on dynamic follow-ups and assessments in intermediate- to high-risk DTC patients.MethodsA total of 206 patients with intermediate- to high-risk DTC receiving RAT of 150 mCi were retrospectively reviewed. According to the time interval (TI: between thyroidectomy and initial RAT), the patients were divided into 2 groups: Group 1: TI < 3 months (n=148), and Group 2: TI ≥ 3 months (n=58). The RAT therapy response was evaluated as excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR), structural incomplete response (SIR). The univariate and multivariate analyses were conducted to screen out factors associated with incomplete response (IR= BIR+SIR). Finally, the prognostic nomogram was used to explain IR rates as a valuable tool in clinical practice.ResultsResponse to initial RAT was significantly different between 2 groups during dynamic follow-ups (all P<0.05). Group 2 had significantly lower ER rates (37.9 vs 63.5, 52.0 vs 73.9, 64.4 vs 80.3, all P<0.05, respectively) and higher IR rates (39.7 vs 14.9, 36.0 vs 9.7, 12.2 vs 3.9, all P<0.05, respectively) than group 1 during dynamic follow-ups. By univariate and multivariate analyses, prolonged TI (HR: 6.67, 95%CI: 2.241-19.857, P=0.001), soft tissue invasion (HR: 7.35, 95%CI: 1.624-33.296, P=0.010), higher sTg (HR: 7.21, 95%CI: 1.991-26.075, P=0.003) were manifested to be independent risk factors for IR. The nomogram showed that soft tissue invasion, sTg, and TI were the top 3 contributors to the IR.ConclusionsEarly RAT is associated with greater biochemical response but has no impact on SIR. Delayed initial RAT (≥3 months after thyroidectomy) related to IR in intermediate- to high-risk DTC.

The chemotherapy effect on embryonal rhabdomyosarcoma in a 2-year-old girl in a development country: A rare case

Rhabdomyosarcoma (RMS) is the third most common solid organ malignancy in children after Wilms tumor and neuroblastoma. It is a highly malignant tumor with local tissue invasion and lymphatic and hematogenous metastases. The main treatment for RMS is complete resection with a combination of chemotherapy and radiotherapy. Here, we present the case of a 2-year-old girl who came to the hospital with a complaint of noisy breathing (Stridor) for the past 2 weeks. Intraoral examination showed an oval mass at the base of the tongue that almost closed the airway, felt soft, and had a bump. A computed tomography scan of the neck was performed, and a solid lesion with clear irregular borders was found in the posterior lingua. Incisional biopsy was performed with histopathological results of embryonal RMS. Two weeks after the biopsy, chemotherapy was performed, and the evaluation after two chemotherapy sessions, the mass size was found to have decreased.

Transcriptomic Characterization of Postmolar Gestational Choriocarcinoma

The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the factors underlying the increased aggressiveness of choriocarcinoma arising after term delivery compared to those developing from hydatidiform moles, are unknown. Using a 730-gene panel covering 13 cancer-associated canonical pathways, we compared the transcriptomic profiles of complete moles to those of postmolar choriocarcinoma samples and those of postmolar to post-term delivery choriocarcinoma. We identified 33 genes differentially expressed between complete moles and postmolar choriocarcinoma, which revealed TGF-β pathway dysregulation. We found the strong expression of SALL4, an upstream regulator of TGF-β, in postmolar choriocarcinoma, compared to moles, in which its expression was almost null. Finally, there were no differentially expressed genes between postmolar and post-term delivery choriocarcinoma samples. To conclude, the TGF-β pathway appears to be a crucial step in the progression of placental malignancies. Further studies should investigate the value of TGF- β family members as biomarkers and new therapeutic targets.

Probing the Peculiarity of EhRabX10, a pseudoRab GTPase, from the Enteric Parasite Entamoeba histolytica through In Silico Modeling and Docking Studies

Entamoeba histolytica (Eh) is a pathogenic eukaryote that often resides silently in humans under asymptomatic stages. Upon indeterminate stimulus, it develops into fulminant amoebiasis that causes severe hepatic abscesses with 50% mortality. This neglected tropical pathogen relies massively on membrane modulation to flourish and cause disease; these modulations range from the phagocytic mode for food acquisition to a complex trogocytosis mechanism for tissue invasion. Rab GTPases form the largest branch of the Ras-like small GTPases, with a diverse set of roles across the eukaryotic kingdom. Rab GTPases are vital for the orchestration of membrane transport and the secretory pathway responsible for transporting the pathogenic effectors, such as cysteine proteases (EhCPs) which help in tissue invasion. Rab GTPases thus play a crucial role in executing the cytolytic effect of E. histolytica. First, they interact with Gal/Nac lectins required for adhering to the host cells, and then, they assist in the secretion of EhCPs. Additionally, amoebic Rab GTPases are vital for encystation because substantial vesicular trafficking is required to create dormant amoebic cysts. These cysts are the infective agent and help to spread the disease. The absence of a “bonafide” vesicular transport machinery in Eh and the existence of a diverse repertoire of amoebic Rab GTPases (EhRab) hint at their contribution in supporting this atypical machinery. Here, we provide insights into a pseudoRab GTPase, EhRabX10, by performing physicochemical analysis, predictive 3D structure modeling, protein-protein interaction studies, and in silico molecular docking. Our group is the first one to classify EhRabX10 as a pseudoRab GTPase with four nonconserved G-motifs. It possesses the basic fold of the P-loop containing nucleotide hydrolases. Through this in silico study, we provide an introduction to the characterization of the atypical EhRabX10 and set the stage for future explorations into the mechanisms of nucleotide recognition, binding, and hydrolysis employed by the pseudoEhRab GTPase family.

The microenvironment of DLBCL is characterized by non-canonical macrophages recruited by tumor-derived CCL5

Tissue invasion by tumor cells induces a host inflammatory response variably impacting tumorigenesis. This has been well documented for tumor-associated macrophages (TAM) that could either play a pro/M2 or an anti/M1-tumoral function. TAM frequently infiltrate diffuse large B-cell lymphoma (DLBCL), an aggressive neoplasm arising from germinal center-experienced B cells. However, the pathway leading to TAM presence in DLBCL remains unknown and their impact unclear. Here, we show that some DLBCL tumor cells expressed the chemokine CCL5, enabling the differential recruitment of blood monocytes through their expression of CCR1 and CCR5. CCL5 expression by DLBCL was not related to molecular subtypes and healthy tonsillar B cells did not produce this chemokine, implying a post-transformation event. A single-cell analysis revealed that most DLBCL TAM had a non-canonical gene signature with the concomitant expression of M1 and M2 genes. The presence of non-canonical TAM may explain the absence of impact reported for macrophages on DLBCL development in some survival studies.