The Emerging Role of p38 Alpha in Cancer Specific Metabolism and Therapy: Analysis of Autophagic and Apoptotic Pathways in Response to Its Inhibition

Cancer is one of the leading cause of death in the world. Since tumorigenesis was described as a multistep mechanism in 1958 by Foulds, important progresses are obtained in the research field. Through these years many altered mechanisms were discovered revealing a very intricate picture of this disease. Mutations, epigenetic changes, aneuploidy imply severe modifications in naive cellular pathways involved in every feature of cell life. p38 MAPK is a family of kinases composed by four isoforms: alpha, beta, delta and gamma. These kinases are involved in several important cellular pathways, from the differentiation of muscle cells to inflammation and also in cancer progression. The pharmacologic and genetic inhibition of p38 alpha in colorectal cancer cells induced cell cycle arrest, autophagy and then cell death with autophagic features. My PhD project is focused on the understanding the role of p38 alpha in the autophagic activation in colorectal cancer cell lines, finding that its inhibition induced the decrease of HIF-1 alpha protein levels and its glycolytic transcriptional program. Moreover, p38 alpha inhibition trigger the activation of FoxO3A-dependent transcription, which is related to cell cycle arrest, autopahgy and cell death. We checked for other HIF-1 alpha-dependent tumors which shown also overactivation of p38 alpha, such as ovarian cancer and prostate cancer. In these kind of tumors we obtained the same encouraging results. However, in the DU 145 prostate cancer cell line, the inhibition of p38 alpha failed to activate autophagic pathway due to the lack of LKB1 kinase, which is the upstream activator of AMPK. In this cell line the inhibition of p38 alpha triggered apoptotic pathway. Chemoresistance is one of the main obstacle in the treatment of cancer. A part of my PhD project is based on the study of p38 alpha role in cisplatin chemoresistance in colorectal cancer cells. Surprisingly, we found that its inhibition, together with the administration of cisplatin, induced apoptotic cell death in the resistant HT29 cell line and increased the effect of cell death in the responsive HCT116 cell line, through the activation of FoxO3A. All these evidences indicated that inhibition of p38 alpha could be used as a promising therapeutic approaches for colorectal cancer and other malignancy, through the activation of FoxO3A-dependent transcription program

Calcitonina elevata e gozzo nodulare: che fare?

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Qualità della vita nei pazienti con microcarcinoma papillare della tiroide in funzione del trattamento: tiroidectomia totale con o senza terapia radiometabolica ablativa

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A functional connection between dyskerin and energy metabolism

The human DKC1 gene encodes dyskerin, an evolutionarily conserved nuclear protein whose overexpression represents a common trait of many types of aggressive sporadic cancers. As a crucial component of the nuclear H/ACA snoRNP complexes, dyskerin is involved in a variety of essential processes, including telomere maintenance, splicing efficiency, ribosome biogenesis, snoRNAs stabilization and stress response. Although multiple minor dyskerin splicing isoforms have been identified, their functions remain to be defined. Considering that low-abundance splice variants could contribute to the wide functional repertoire attributed to dyskerin, possibly having more specialized tasks or playing significant roles in changing cell status, we investigated in more detail the biological roles of a truncated dyskerin isoform that lacks the C-terminal nuclear localization signal and shows a prevalent cytoplasmic localization. Here we show that this dyskerin variant can boost energy metabolism and improve respiration, ultimately conferring a ROS adaptive response and a growth advantage to cells. These results reveal an unexpected involvement of DKC1 in energy metabolism, highlighting a previously underscored role in the regulation of metabolic cell homeostasis

A patient with MEN1 and end‑stage chronic kidney disease due to Alport syndrome: Decision making on the eligibility of transplantation

Absence of neoplastic disease in the organ‑recipient is required in order to allow organ transplantation. Due to its rarity, no data regarding management of patients with Multiple endocrine neoplasia type 1 (MEN1) and end‑stage renal failure candidates for kidney transplantation are available. A 36 year‑old man was referred to the present hospital with MEN1, with a neuroendocrine pancreatic tumor and primary hyperparathyroidism and associated Alport syndrome with end stage renal failure. The present study aimed to establish the eligibility of the patient for a kidney transplantation. The neuroendocrine tumor had been treated with duodenopancreatectomy two years earlier and hyperparathyroidism by parathyroidectomy. The review of the literature did not provide data regarding the eligibility for kidney transplantation of patients harboring a neuroendocrine pancreatic tumor in the context of MEN1. Due to the end‑stage renal failure, neuroendocrine markers were unreliable and the investigation therefore relied on imaging studies, which were unremarkable. Young age, low‑grade tumor, low expression of Ki67, absence of metastatic lymph nodes, onset in the setting of a MEN1 were all positive prognostic factors of the neuroendocrine tumor. Normal serum calcium ruled out persistent primary hyperparathyroidism. Overall, hemodyalisis is known to significantly reduce life expectancy. Benefits of kidney transplantation overcome the risk of neuroendocrine tumor recurrence in a young patient bearing MEN1

No difference in the outcome of metastatic thyroid cancer patients when using recombinant or endogenous TSH

Objective: At the present, recombinant TSH cannot be used for the treatment of metastatic differentiated thyroid cancer patients. Aim of this study was to evaluate if the type of TSH stimulation, recombinant or endogenous, had an impact on the outcome of these patients. Design and methods: We compared the outcome of two propensity score-matched groups of metastatic patients, stimulated by either only recombinant TSH (n=43) or only endogenous TSH (n=34). Results: As expected from the matching procedure, the clinical-pathological features and the cumulative 131I-activities administered of the two groups were very similar. After 4 years of follow-up 4% of patients were cured, 3% had biochemical disease and 93% had structural disease. However, 91% of patients obtained a clinical benefit from this therapy in terms of stabilization of the disease or complete remission or partial response. When considering the two groups separately we did not find any difference in their outcome. When considering the response to 131-I therapy of the single type of metastases, 8% of lymph node metastases and 8% of lung metastases disappeared but none of bone metastases. The response to 131-I therapy of the single type of metastases was similar when we looked at the two groups separately. Conclusions: this study shows a) an overall clinical benefit of the 131-I therapy since the majority of patients remained affected but with a stable disease b) the preparation with either recombinant or endogenous TSH has no impact on the 131-I therapy efficacy and the outcome of our two groups of patients

COVID-19 outbreak in Italy: an opportunity to evaluate extended interval dosing of ocrelizumab in MS patients

introduction during the COVID-19 pandemic, ocrelizumab (OCR) infusions for MS patients were often re-scheduled because of MS center's disruption and concerns regarding immunosuppression. The aim of the present study was to assess changes in OCR schedule during the first wave of pandemic in italy and to evaluate the effect of delayed infusion on clinical/radiological endpoints.methods data were extracted from the Italian MS register database. standard interval dosing was defined as an infusion interval <= 30 weeks, while extended interval dosing was defined as an infusion interval > 30 weeks at the time of the observation period. clinico-demographics variables were tested as potential predictors for treatment delay. time to first relapse and time to first MRI event were evaluated. Cumulative hazard curves were reported along their 95% confidence intervals. a final sample of one-thousand two patients with MS from 65 centers was included in the analysis: 599 pwMS were selected to evaluate the modification of OCR infusion intervals, while 717 pwRMS were selected to analyze the effect of infusion delay on clinical/MRI activity. results mean interval between two OCR infusions was 28.1 weeks before pandemic compared to 30.8 weeks during the observation period, with a mean delay of 2.74 weeks (p < 0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the north of italy. clinical relapses (4 in SID, 0 in EID) and 17 MRI activity reports (4 in SID, 13 in EID) were recorded during follow-up period. discussion despite the significant extension of OCR infusion interval during the first wave of pandemic in Italy, a very small incidence of clinical/radiological events was observed, thus suggesting durable efficacy of OCR, as well as the absence of rebound after its short-term suspension

Dual inhibition of TGFβ and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype

A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFβ signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFβ inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFβ as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFβ receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFβ galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFβ receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFβ could represent a novel therapeutic strategy for patients with this aggressive disease

Active surveillance in differentiated thyroid cancer: a strategy applicable to all treatment categories response

Currently, the differentiated thyroid cancer (DTC) management is shifted toward a tailored approach based on the estimated risks of recurrence and disease-specific mortality. While the current recommendations on the management of metastatic and progressive DTC are clear and unambiguous, the management of slowly progressive or indeterminate disease varies according to different centers and different physicians. In this context, active surveillance (AS) becomes the main tool for clinicians, allowing them to plan a personalized therapeutic strategy, based on the risk of an unfavorable prognosis, and to avoid unnecessary treatment. This review analyzes the main possible scenarios in treated DTC patients who could take advantage of AS