Mitochondrial Dynamics as Potential Modulators of Hormonal Therapy Effectiveness in Males.

Worldwide the incidence of andrological diseases is rising every year and, together with it, also the interest in them is increasing due to their strict association with disorders of the reproductive system, including impairment of male fertility, alterations of male hormones production, and/or sexual function. Prevention and early diagnosis of andrological dysfunctions have long been neglected, with the consequent increase in the incidence and prevalence of diseases otherwise easy to prevent and treat if diagnosed early. In this review, we report the latest evidence of the effect of andrological alterations on fertility potential in both young and adult patients, with a focus on the link between gonadotropins' mechanism of action and mitochondria. Indeed, mitochondria are highly dynamic cellular organelles that undergo rapid morphological adaptations, conditioning a multitude of aspects, including their size, shape, number, transport, cellular distribution, and, consequently, their function. Since the first step of steroidogenesis takes place in these organelles, we consider that mitochondria dynamics might have a possible role in a plethora of signaling cascades, including testosterone production. In addition, we also hypothesize a central role of mitochondria fission boost on the decreased response to the commonly administrated hormonal therapy used to treat urological disease in pediatric and adolescent patients as well as infertile adults.

Age-Related Mortality in STEMI Patients: Insight from One Year of HUB Centre Experience during the Pandemic.

Background: Old patients have a poor prognosis when affected by ST elevation myocardial infarction (STEMI). The aim of our study was to evaluate the impact of age on acute and mid-term mortality in STEMI patients over one year in the pandemic period. Methods: we collected data on 283 STEMI patients divided into three groups according to age (not old, "Not-O", ≤74 y/o; old, "O", 75−84 y/o; very old, "Very-O", ≥85 y/o). Results: the three groups did not differ in their clinical or procedural characteristics. The Very-O patients had a significantly increased incidence of in-hospital MACE (35%), mortality (30.0%), and percentage of cardiac death (25.0%). The only two independent predictors of in-hospital mortality were the ejection fraction (EF) [OR:0.902 (95% CI) 0.868−0.938; p < 0.0001] and COVID-19 infection [OR:3.177 (95% CI) 1.212−8.331; p = 0.019]. At follow-up (430 +/− days), the survival rates were decreased significatively among the age groups (Not-O 2.9% vs. O 14.8% vs. Very-O 28.6%; p < 0.0001), and the only two independent predictors of the follow-up mortality were the EF [OR:0.935 (95% CI) 0.891−0.982; p = 0.007] and age [OR:1.06 (95% CI) 1.018−1.110; p = 0.019]. Conclusions: in very old patients, all the accessory procedures that may be performed should be accurately and independently weighed up in terms of the risk−benefit balance and the real impact on the quality of life because of the poor mid-term prognosis.

Divergent Roles of Mitochondria Dynamics in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors; it is often diagnosed at an advanced stage and is hardly treatable. These issues are strictly linked to the absence of early diagnostic markers and the low efficacy of treatment approaches. Recently, the study of the metabolic alterations in cancer cells has opened the way to important findings that can be exploited to generate new potential therapies. Within this scenario, mitochondria represent important organelles within which many essential functions are necessary for cell survival, including some key reactions involved in energy metabolism. These organelles remodel their shape by dividing or fusing themselves in response to cellular needs or stimuli. Interestingly, many authors have shown that mitochondrial dynamic equilibrium is altered in many different tumor types. However, up to now, it is not clear whether PDAC cells preferentially take advantage of fusion or fission processes since some studies reported a wide range of different results. This review described the role of both mitochondria arrangement processes, i.e., fusion and fission events, in PDAC, showing that a preference for mitochondria fragmentation could sustain tumor needs. In addition, we also highlight the importance of considering the metabolic arrangement and mitochondria assessment of cancer stem cells, which represent the most aggressive tumor cell type that has been shown to have distinctive metabolic features to that of differentiated tumor cells.

Optical Coherence Tomography and Coronary Dissection: Precious Tool or Useless Surplus?

Spontaneous coronary artery dissection (SCAD) is a rare clinical condition, but frequently manifested as acute myocardial infarction. In this particular setting, in recent years, optical coherence tomography (OCT) has been established as a possible diagnostic method due to the high spatial resolution (10-20 µm), which can visualize the different layers of coronary vessels. OCT can better analyze the "binary" or double lumen morphology, typical of this entity. Furthermore, it can identify the entrance breach and the circumferential and longitudinal extension of the lesion. However, we have to emphasize that this technique is not free from complications. OCT could further aggravate a dissection or exacerbate a new intimal tear. Therefore, the use of OCT in the evaluation of SCAD should be defined by balancing the diagnostic benefits versus procedural risks. Moreover, we underline that as SCAD is a rare condition and OCT is a recently introduced technique in clinical practice, limited data is available in literature.

Testicular Torsion: Preliminary Results of In Vitro Cell Stimulation Using Chorionic Gonadotropin.

Testicular torsion is a pathology that occurs in young males generally before the age of 25. Despite surgery representing the only effective approach, there is still a need to identify a marker that can predict whether a preserved testicle will be functional. In addition, no therapeutic approach is currently considered in the post-operative phase. Through an approach based on the in vitro culture of a tissue strictly linked to the testicle, the gubernaculum, we defined the healthy state of the organ and the possible responsiveness to a therapy used in the andrology field, chorionic gonadotropin (hCG). Firstly, we optimized a protocol to obtain viable cells starting from a small piece of gubernacular tissue harvested during surgery with the aim to amplify cells in vitro. Intriguingly, only for a patient whose testicle had been removed during surgery due to an excessive necrotic area, gubernacular cells were not able to grow in culture. These data support the possibility of exploiting the gubernaculum to evaluate the healthy state of the testicle. Then, as we demonstrate that gubernacular cells express a luteinizing hormone receptor, to which hCG is specific, we analyzed the cellular response to hCG treatment on in vitro cultured cells derived from patients affected by testicular torsion. Our study opens the way for the possibility of evaluating testicle wellbeing after derotation through in vitro culture of a small piece of gubernaculum together with predicting the response to the treatment with hCG, which can have a positive effect on cell proliferation and vascularization.

Neurofibromin Deficiency and Extracellular Matrix Cooperate to Increase Transforming Potential through FAK-Dependent Signaling.

Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+/- milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell-cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM.

Gene and protein expression of mTOR and LC3 in hepatocellular carcinoma, colorectal liver metastasis and "normal" liver tissues.

The physiological role of autophagy in the progression of liver diseases is still debated. To understand the clinical relevance of autophagy in primary e secondary hepatic tumors, we analyzed the expression of mTOR (mammalian target of rapamycin), a key regulator of autophagy; Raptor (regulatory-associated protein of mTOR); ULK1 (Unc-51 like kinase 1) determinant in the autophagy initiation; LC3 (microtubule-associated protein 1A/1B-light chain 3), a specific marker of autophagosomes; and p62, a selective autophagy receptor. Samples from subjects with chronic hepatitis (n.58), cirrhosis (n.12), hepatocellular carcinoma (HCC, n.56), metastases (n.48) from colorectal cancer and hyperplasia or gallbladder stones (n.7), the latter considered as controls, were examined. Gene expression analysis was carried out in n.213 tissues by absolute q-PCR, while protein expression by Western Blot in n.191 lysates, including tumoral, surrounding tumoral and normal tissues. Nonparametric statistical tests were used for comparing expression levels in the above-mentioned groups. Subgroup analysis was performed considering viral infection and chemotherapy treatment. The mTOR transcriptional level was significantly lower in metastases compared to HCC (P = 0.0001). p-mTOR(Ser2448) and LC3II/LC3I protein levels were significantly higher in metastases compared to HCC (P = 0.008 and P<0.0001, respectively). ULK(Ser757) levels were significantly higher in HCC compared to metastases (P = 0.0002) while the HCV- and HBV- related HCC showed the highest p62 levels. Chemotherapy induced a down-regulation of the p-mTOR(Ser2448) in metastases and in non-tumor surrounding tissues in treated patients compared to untreated (P = 0.001 and P = 0.005, respectively). Conclusions: the different expression of proteins considered, owning their interaction and diverse tissue microenvironment, indicate an impairment of the autophagy flux in primary liver tumors that is critical for the promotion of tumorigenesis process and a coexistence of autophagy inhibition and activation mechanisms in secondary liver tumors. Differences in mTOR and LC3 transcripts emerged in tumor-free tissues, therefore particular attention should be considered in selecting the control group.

CT Perfusion Versus Coronary CT Angiography in Patients With Suspected In-Stent Restenosis or CAD Progression.

OBJECTIVES: The goal of this study was to assess the diagnostic performance of coronary computed tomography angiography (CTA) alone, adenosine-stress myocardial perfusion assessed by computed tomography (CTP) alone, and coronary CTA + CTP by using a 16-cm Z-axis coverage scanner versus invasive coronary angiography (ICA) and fractional flow reserve (FFR) as the clinical standard. BACKGROUND: Diagnostic performance of coronary CTA for in-stent restenosis detection is still challenging. Recently, CTP showed additional diagnostic power over coronary CTA in patients with suspected coronary artery disease. However, few data are available on CTP performance in patients with previous stent implantation. METHODS: Consecutive stable patients with previous coronary stenting referred for ICA were enrolled. All patients underwent stress myocardial CTP and rest CTP + coronary CTA. Invasive FFR was performed during ICA when clinically indicated. The diagnostic rate and diagnostic accuracy of coronary CTA, CTP, and coronary CTA + CTP were evaluated in stent-, territory-, and patient-based analyses. RESULTS: In the 150 enrolled patients (132 men; mean age 65.1 ± 9.1 years), the CTP diagnostic rate was significantly higher than that of coronary CTA in all analyses (territory based [96.7% vs. 91.1%; p < 0.0001] and patient based [96% vs. 68%; p < 0.0001]). When ICA was used as gold standard, CTP diagnostic accuracy was significantly higher than that of coronary CTA in all analyses (territory based [92.1% vs. 85.5%, p < 0.03] and patient based [86.7% vs. 76.7%, p < 0.03]). The concordant coronary CTA + CTP assessment exhibited the highest diagnostic accuracy values versus ICA (95.8% in the territory-based analysis). The diagnostic accuracy of CTP was significantly higher than that of coronary CTA (75% vs. 30.5%; p < 0.001). The radiation exposure of coronary CTA + CTP was 4.15 ± 1.5 mSv. CONCLUSIONS: In patients with coronary stents, CTP significantly improved the diagnostic rate and accuracy of coronary CTA alone compared with both ICA and invasive FFR as gold standard.