Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives.

The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included.

STEMI or not STEMI? A multimodality imaging approach to a challenging intracardiac mass with a tricky presentation.

Cardiac tumors, due to the various clinical scenarios and their histological subtypes, are still challenging for clinicians. They are differentiated into primary and secondary. The latest are more common and are usually lung and breast cancers, melanomas, and lymphoma metastasis. We present a case of a 73-year-old woman, with a history of breast cancer 10 years earlier, admitted to Cath lab for an elevation of the ST-segment of the electrocardiogram, myocardial infarction. Echocardiogram showed a curious abnormality in the myocardial wall. Thanks to a multimodality imaging strategy, including contrast-enhanced echocardiography and cardiac magnetic resonance, characterization of the underlying pathology was clear and, thus, the appropriate management and therapy.

This is the case of a cardiac metastatic tumor, whose certain diagnosis can only be made by myocardial biopsy ­ an invasive sample of heart tissue ­ unfortunately not available in our case. Alternatively, we puzzled data from two second-level imaging techniques: contrast-enhanced cardiac ultrasound and cardiac magnetic resonance, which allowed us to better evaluate the nature of this cardiac mass. The former gave information about its blood supply, the latter gave information about tissue characterization. In this paper, we show how a complete integration of data from clinical and a stepwise multimodality imaging-based approach may allow a diagnosis in a complex clinical case.

Complete agenesis of pericardium in a young asymptomatic woman.

Agenesis of pericardium is a rare finding resulting from alterations during embryologic formation. It is a congenital cardiac anomaly commonly asymptomatic. Cardiac magnetic resonance is actually considered the gold standard for diagnosis of pericardium agenesis. This report details the case of a 24-year-old woman who came to our clinic.

Colo-colic intussusception in an adult caused by lipoma: Case report of a rare condition.

This report describes the case of a 56-year-old woman who presented at the emergency room with a 3-week history of severe, intermittent abdominal pain. A CT scan revealed colo-colic intussusception caused by a large, substenosing mass with predominant adipose density. Subsequent endoscopic examination with biopsy revealed a necrotic tissue covering the mass, without definitive histological characterization. A second biopsy led to the extremely rare diagnosis of colo-colic lipoma. While intussusception is rare in adults, it's important to consider it as a differential diagnosis, especially when presenting with abdominal pain and signs of bowel obstruction. Timely diagnosis and appropriate treatment are essential to prevent complications.

Combined treatments with microballoon catheters and multiple cryoablation probes for shoulder-subclavian soft tissue hemangiopericytoma: A case report.

We describe a case of a 65-year-old woman affected by hemangiopericytoma/solitary fibrous tumor of the right shoulder-subclavian region. Hemangiopericytoma/solitary fibrous tumor is a rare tumor of uncertain malignancy. She reports shoulder pain and inability to abduct the arm and elevate the shoulder. Imaging showed erosion of the scapula. The patient underwent 5 sessions of "on demand" embolization in the previous 2 years scheduled for recurrence of symptoms-swelling of tissues. Further 2 treatments were achieved through embolization via 2 different microballoon catheter combined with percutaneous cryoablation with 5 probes. Images after the treatment demonstrate a marked reduction in the hypervascularized area and an increase in the necrosis area. So, this combined treatment is safety and reproducible also in extrahepatic tissue.

How many clues make an evidence? An unusual case of aborted cardiac arrest due to mitral valve prolapse.

There is an increasing awareness on the association between mitral valve prolapse (MVP) and sudden cardiac death. Mitral annular disjunction (MAD) is a phenotypic risk feature that can help in risk stratification. We present a case of a 58-year-old woman who experienced an out-of-hospital cardiac arrest caused by ventricular fibrillation interrupted by a direct current shock. No coronary lesions were documented. Echocardiogram showed myxomatous MVP. Nonsustained ventricular tachycardia have been registered during hospital stay. Interestingly, cardiac magnetic resonance revealed MAD and a late gadolinium enhancement area in inferior wall. Finally, a defibrillator has been implanted. For arrhythmic risk stratification of MVP with MAD, multimodality imaging is the diagnostic tool to find out the disease behind many cardiac arrests of unknown cause.

Endothelial Dysfunction in COVID-19: Potential Mechanisms and Possible Therapeutic Options.

SARS-CoV-2, a novel coronavirus found in Wuhan (China) at the end of 2019, is the etiological agent of the current pandemic that is a heterogeneous disease, named coronavirus disease 2019 (COVID-19). SARS-CoV-2 affects primarily the lungs, but it can induce multi-organ involvement such as acute myocardial injury, myocarditis, thromboembolic eventsandrenal failure. Hypertension, chronic kidney disease, diabetes mellitus and obesity increase the risk of severe complications of COVID-19. There is no certain explanation for this systemic COVID-19 involvement, but it could be related to endothelial dysfunction, due to direct (endothelial cells are infected by the virus) and indirect damage (systemic inflammation) factors. Angiotensin-converting enzyme 2 (ACE2), expressed in human endothelium, has a fundamental role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In fact, ACE2 is used as a receptor by SARS-CoV-2, leading to the downregulation of these receptors on endothelial cells; once inside, this virus reduces the integrity of endothelial tissue, with exposure of prothrombotic molecules, platelet adhesion, activation of coagulation cascades and, consequently, vascular damage. Systemic microangiopathy and thromboembolism can lead to multi-organ failure with an elevated risk of death. Considering the crucial role of the immunological response and endothelial damage in developing the severe form of COVID-19, in this review, we will attempt to clarify the underlying pathophysiological mechanisms.

Effects of sacubitril/valsartan on both metabolic parameters and insulin resistance in prediabetic non-obese patients with heart failure and reduced ejection fraction.

Background: The effects of sacubitril/valsartan (sac/val) on metabolic parameters and insulin resistance (IR) in non-obese/prediabetic patients have not been previously described. Aim: To evaluate the effects of sac/val on glycemic and metabolic parameters, Homeostatic Model Assessment of IR (HOMA-IR), and echocardiographic parameters in prediabetic patients with heart failure with reduced ejection fraction (HFrEF). Methods: Fifty-nine patients with HFrEF (EF < 35%) but without obesity and/or type 2 diabetes mellitus have been enrolled. All the patients at baseline and week 24 underwent complete anthropometrical evaluation and were subjected to an echocardiogram test. IR has been assessed by HOMA-IR. Results: After 24-week of treatment with sac/val, a significant reduction in fasting plasma glucose (109 ± 9 vs 103 ± 8 mg/dl, p < 0.0001), fasting plasma insulin (16 ± 4 vs 10 ± 4 UI/L), and hemoglobin A1c (HbA1c) value (6% ± 0.5% vs 5.3% ± 0.3%, p < 0.0001) was observed. Similarly, we observed a significant improvement in IR (HOMA-IR, 4.4 ± 0.9 vs 2.5 ± 0.6, p < 0.0001). The echocardiogram evaluation showed a significant reduction of the left ventricular end-diastolic volume (168 ± 24 vs 158 ± 22 ml, p < 0.05), a significant reduction of the left ventricular end-systolic volume (111 ± 26 vs 98 ± 22 ml, p < 0.005), and a significant reduction of E/e' ratio. Sac/val use was also associated with an average 5.1% increase in ejection fraction. Conclusions: Our data seem to indicate that sal/val enhances metabolic control and improves insulin resistance also in prediabetic non-obese patients with HFrEF.

Cor triatriatum dexter: a rare incidentaloma.

Cor triatriatum dexter (CTD) is an extremely rare finding resulting from the persistence of the right valve of sinus venosus. It is a congenital cardiac anomaly defined by an abnormal septation of the atrium leading to inflow obstruction to the respective ventricle. Multimodal diagnostic modalities are necessary to characterize it for an optimal patient management. We report the case of a 68-year-old woman who presented to our clinic for further feedback of ventricular ectopic beats.

S. Giovanni Varieties (Pyrus communis L.): Antioxidant Properties and Phytochemical Characteristics.

In order to evaluate and identify the antioxidant properties and the phytochemical characteristics, as well as the role of the genetic background and the different fruit parts in the definition of fruit quality, we characterized the existing germplasm through nuclear simple sequence repeats (SSRs) and evaluated the genetic divergence between ancient S. Giovanni varieties (Pyrus communis L.) and different types of grafting in relation to some variables of fruit quality. On the peel and pulp of pear varieties, the contents of flavanols, flavonols, and hydroxycinnamic acids as well as total antioxidant capacity were assessed. Their role in plant defences was confirmed by a significantly higher amount in the peel (206.66 ± 44.27, 48.45 ± 13.65, and 31.11 ± 11.94 mg/100 g, respectively) of S. Giovanni pears than in the pulp (71.45 ± 34.94, 1.62 ± 0.83, and 17.05 ± 5.04 mg/100 g, respectively). Data obtained using capillary analysis of SSR indicate unequivocally that the four samples of San Giovanni varieties can be divided into 3 different genetic groups. Cultivar and the different parts of the fruit can exert an action in the definition of the quality product. The use of local varieties and ecotypes can be considered a valid tool to improve food quality and at the same time to support local agrobiodiversity.

α-Tocopherol, ß-carotene, lutein, squalene and secoiridoids in seven monocultivar Italian extra-virgin olive oils.

Fatty acids and bioactive lipophilic and hydrophilic compounds (tocopherols, ß-carotene, lutein, squalene, total polyphenols and secoiridoids) in monocultivar Italian extra-virgin olive oil (EVOO) samples produced from the Leccino cultivar and six other yet uncharacterised cultivars (Rustica, Carpinetana, Dritta, Gentile di Chieti and Intosso) were analysed, also taking into account the effect of the type of decanter used for the oil extraction. Significant differences among cultivars were found for α-tocopherol and squalene, but not for carotenoids. Among phenols, cultivars significantly influenced oleuropein and ligstroside aglycones contents, but not those of the dialdehydic form of decarboxymethyl elenolic acid linked neither to tyrosol nor hydroxytyrosol. As previously reported, phenol is quantitatively affected by the type of decanter used for oil extraction. Accordingly, we found that the two-phases decanter preserved in the oil 1.5 times more phenolic compounds as compared with three-phases, whereas it did not influence the amount of lipophilic compounds. Moreover, our data statistically support the finding that type of decanter affects phenols also qualitatively. In fact, the two-phases decanter preferably preserved more the hydroxytyrosol secoiridoid derivatives than the tyrosol ones. Our results from one hand characterise for the first time oils previously unreported, from the other give some new indications on the relative role of factors relevant for the achievement of biologically active extra-virgin oil, i.e. the cultivar and technological ones.

Negative feedback regulation of auxin signaling by ATHB8/ACL5-BUD2 transcription module.

The role of auxin as main regulator of vascular differentiation is well established, and a direct correlation between the rate of xylem differentiation and the amount of auxin reaching the (pro)cambial cells has been proposed. It has been suggested that thermospermine produced by ACAULIS5 (ACL5) and bushy and dwarf2 (BUD2) is one of the factors downstream to auxin contributing to the regulation of this process in Arabidopsis. Here, we provide an in-depth characterization of the mechanism through which ACL5 modulates xylem differentiation. We show that an increased level of ACL5 slows down xylem differentiation by negatively affecting the expression of homeodomain-leucine zipper (HD-ZIP) III and key auxin signaling genes. This mechanism involves the positive regulation of thermospermine biosynthesis by the HD-ZIP III protein Arabidopsis thaliana homeobox8 tightly controlling the expression of ACL5 and BUD2. In addition, we show that the HD-ZIP III protein REVOLUTA contributes to the increased leaf vascularization and long hypocotyl phenotype of acl5 likely by a direct regulation of auxin signaling genes such as like auxin resistant2 (LAX2) and LAX3. We propose that proper formation and differentiation of xylem depend on a balance between positive and negative feedback loops operating through HD-ZIP III genes.

Arabidopsis HD-Zip II transcription factors control apical embryo development and meristem function.

The Arabidopsis genome encodes ten Homeodomain-Leucine zipper (HD-Zip) II proteins. ARABIDOPSIS THALIANA HOMEOBOX 2 (ATHB2), HOMEOBOX ARABIDOPSIS THALIANA 1 (HAT1), HAT2, HAT3 and ATHB4 are regulated by changes in the red/far red light ratio that induce shade avoidance in most of the angiosperms. Here, we show that progressive loss of HAT3, ATHB4 and ATHB2 activity causes developmental defects from embryogenesis onwards in white light. Cotyledon development and number are altered in hat3 athb4 embryos, and these defects correlate with changes in auxin distribution and response. athb2 gain-of-function mutation and ATHB2 expression driven by its promoter in hat3 athb4 result in significant attenuation of phenotypes, thus demonstrating that ATHB2 is functionally redundant to HAT3 and ATHB4. In analogy to loss-of-function mutations in HD-Zip III genes, loss of HAT3 and ATHB4 results in organ polarity defects, whereas triple hat3 athb4 athb2 mutants develop one or two radialized cotyledons and lack an active shoot apical meristem (SAM). Consistent with overlapping expression pattern of HD-Zip II and HD-Zip III gene family members, bilateral symmetry and SAM defects are enhanced when hat3 athb4 is combined with mutations in PHABULOSA (PHB), PHAVOLUTA (PHV) or REVOLUTA (REV). Finally, we show that ATHB2 is part of a complex regulatory circuit directly involving both HD-Zip II and HD-Zip III proteins. Taken together, our study provides evidence that a genetic system consisting of HD-Zip II and HD-Zip III genes cooperates in establishing bilateral symmetry and patterning along the adaxial-abaxial axis in the embryo as well as in controlling SAM activity.

DNA integrity of onion root cells under catechol influence.

Catechol is a highly toxic organic pollutant, usually abundant in the waste effluents of industrial processes and agricultural activities. The environmental sources of catechol include pesticides, wood preservatives, tanning lotion, cosmetic creams, dyes, and synthetic intermediates. Genotoxicity of catechol at a concentration range 5 × 10(-1)-5 mM was evaluated by applying random amplified polymorphic DNA (RAPD) and time-lapse DNA laddering tests using onion (Allium cepa) root cells as the assay system. RAPD analysis revealed polymorphisms in the nucleotidic sequence of DNA that reflected the genotoxic potential of catechol to provoke point mutations, or deletions, or chromosomal rearrangements. Time-lapse DNA laddering test provided evidence that catechol provoked DNA necrosis and apoptosis. Acridine orange/ethidium bromide staining could distinguish apoptotic from necrotic cells in root cells of A. cepa.

Mutations of the RAG3 gene encoding a regulator of fermentation in Kluyveromyces lactis are suppressed by a mutation of the transcription factor gene KlGCR1.

In Kluyveromyces lactis, Rag3 regulates both fermentative metabolism and thiamine biosynthesis. Regulation of fermentation is exerted at the level of transcription of KlPDC1. We have isolated and identified a mutation of the transcription factor KlGCR1, Klgcr1-1, which suppressed the fermentative-deficient phenotype associated with the RAG3 deletion. In the mutant, the transcription of KlPDC1 was restored. However, we found that the suppression was not specific to the RAG3 mutation, as the Klgcr1-1 mutation could also suppress the fermentative defect associated with mutation of Sck1, another regulator of glycolysis.