Background: Cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) depends on binding of the viral spike (S) proteins to angiotensin-converting enzyme 2 and on S protein priming by TMPRSS2. Inhibition of TMPRSS2 may work to block or decrease the severity of SARS-CoV-2 infections. Intriguingly, TMPRSS2 is an androgen-regulated gene that is up-regulated in prostate cancer where it supports tumor progression and is involved in a frequent genetic translocation with the ERG gene. First-or second-generation androgen-deprivation therapies (ADTs) decrease the levels of TMPRSS2. Here we put forward the hypothesis that ADTs may protect patients affected by prostate cancer from SARS-CoV-2 infections. Materials and methods: We extracted data regarding 9280 patients (4532 males) with laboratory-confirmed SARS-CoV-2 infection from 68 hospitals in Veneto, one of the Italian regions that was most affected by the coronavirus disease 2019 (COVID-19) pandemic. The parameters used for each COVID-19-positive patient were sex, hospitalization, admission to intensive care unit, death, tumor diagnosis, prostate cancer diagnosis, and ADT. Results: There were evaluable 9280 SARS-CoV-2-positive patients in Veneto on 1 April 2020. Overall, males developed more severe complications, were more frequently hospitalized, and had a worse clinical outcome than females. Considering only the Veneto male population (2.4 million men), 0.2% and 0.3% of non-cancer and cancer patients, respectively, tested positive for SARS-CoV-2. Comparing the total number of SARS-CoV-2-positive cases, prostate cancer patients receiving ADT had a significantly lower risk of SARS-CoV-2 infection compared with patients who did not receive ADT (OR 4.05; 95% CI 1.55e10.59). A greater difference was found comparing prostate cancer patients receiving ADT with patients with any other type of cancer (OR 4.86; 95% CI 1.88e12.56). Conclusion: Our data suggest that cancer patients have an increased risk of SARS-CoV-2 infections compared with noncancer patients. However, prostate cancer patients receiving ADT appear to be partially protected from SARS-CoV-2 infections.

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Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

OBJECTIVES To investigate the incidence of urinary incontinence and its development over time, to compare the effects of alternative definitions on the incontinence rate and to explore risk factors for incontinence after radical retropubic prostatectomy (RRP) for clinically localized prostate cancer. PATIENTS AND METHODS Urinary continence was assessed using a questionnaire administered by a third party in 1144 consecutive patients after undergoing RRP at our department from January 1986 to December 2001. Overall, 985 men (86%) were suitable for evaluation (mean age 64.5 years, mean follow‐up 95.5 months). We compared the effects of three definitions on the actuarial rate of continence: (1) no or occasional pad use; (2) 0 or 1 pads used daily, but for occasional dribbling only; (3) 0–1 pads daily. The time to recovery of continence was defined as the date on which the patient met the continence definitions. The impact of incontinence on health‐related quality of life (HRQoL) was also evaluated. Univariate and multivariate analyses were used to identify predictors of incontinence, using data gathered prospectively. RESULTS At the last follow‐up at 24 months after RRP, 83%, 92.3% and 93.4% of men achieved continence according to definitions 1, 2 and 3, respectively. The difference in time to recovering continence was significant for definition 1 compared to the others (P < 0.001). Most men using 1 pad/day complained of occasional dribbling only (89.3%), considered themselves continent (98%) and their HRQoL was not as seriously affected as those requiring ≥ 2 pads/day. Men continent (by definition 3) at 2 years had an actuarial probability of preserving continence of 72.2% at the last follow‐up. On multivariate analysis the age at surgery (P = 0.009), anastomotic stricture and follow‐up interval (both P < 0.001) were independent prognostic factors. Bilateral neurovascular bundle resection was another independent predictive factor (P = 0.03) in the subset of the last 560 men with available data on surgical technique. The reduction in the incidence of incontinence over time was as high as 86%. CONCLUSIONS Continence improves progressively until 2 years from RRP but some patients can become incontinent later. The criterion of pad use discriminates well between men with a limited reduction in their QoL (no or one pad used) and those with a markedly affected QoL (≥2 pads/day). It could be clinically valid to consider users of 1 pad/day as continent. Age, bilateral neurovascular bundle resection and anastomotic stricture are significant risk factors for incontinence. There was a marked trend for the incidence of incontinence and anastomotic stricture to decrease with time.

We have investigated the effects of arachidonic and palmitic acids in isolated rat liver mitochondria and in rat hepatoma MH1C1 cells. We show that both compounds induce the mitochondrial permeability transition (PT). At variance from palmitic acid, however, arachidonic acid causes a PT at concentrations that do not cause PT-independent depolarization or respiratory inhibition, suggesting a specific effect on the PT pore. When added to intact MH1C1 cells, arachidonic acid but not palmitic acid caused a mitochondrial PT in situ that was accompanied by cytochrome c release and rapidly followed by cell death. All these effects of arachidonic acid could be prevented by cyclosporin A but not by the phospholipase A 2 inhibitor aristolochic acid. In contrast, tumor necrosis factor ␣ caused phospholipid hydrolysis, induction of the PT, cytochrome c release, and cell death that could be inhibited by both cyclosporin A and aristolochic acid. These findings suggest that arachidonic acid produced by cytosolic phospholipase A 2 may be a mediator of tumor necrosis factor ␣ cytotoxicity in situ through induction of the mitochondrial PT.The mitochondrial PT 1 is a regulated permeability increase to solutes with molecular masses up to 1,500 Da mediated by opening of a high conductance channel, the PTP, whose molecular nature remains debated (1). The PT is modulated by a variety of effectors of cell death, including reactive oxygen species that are produced early by mitochondria after stimulation of the TNF␣ receptor (2). Early evidence indicated that PTP opening can mediate cell death caused by oxidative stress and anoxia through ATP depletion and dysregulation of Ca 2ϩ homeostasis (3-5). The PT could also be instrumental in the release of intermembrane proteins such as cytochrome c (6, 7), which plays a key role in caspase 9 activation (8), and apoptosis-inducing factor (9), which causes nuclear degradation independent of caspase activation (10).Mitochondria play a role in apoptotic signaling in the TNF␣ pathway, which is activated by ligand binding to the TNF␣ receptor. Several cytosolic proteins are recruited to the receptor death domain, which in turn leads to the production of a variety of second messengers. As a result, multiple protein-mediated signaling cascades are activated, including caspase-dependent and caspase-independent pathways, phospholipases, protein kinases, and protein phosphatases (see Ref. 11 for a critical and comprehensive review). Lipid mediators may be involved both in signaling and in the late cellular responses by receptors of the TNF␣ superfamily, and solid evidence indicates that mitochondria can be the target of lipid mediators of pathophysiological relevance. Ceramide produced by acidic sphingomyelinase is essential for production of GD3 ganglioside, a cell death inducer (12) that is able to cause PT-dependent apoptosis (13) with cytochrome c release and caspase activation (14). Ceramide itself has prominent effects on mitochondria (14 -19) and may turn physiological Ca 2ϩ signals acting through ...

Tumor stage and nodal involvement are the only independent predictors of survival to be used to select the optimal therapy after radical cystectomy, stratify patients in controlled trials and evaluate new prognostic factors.

For survivors of severe COVID-19 disease, having defeated the virus is just the beginning of an uncharted recovery path. What follows after the acute phase of SARS-CoV-2 infection depends on the extension and severity of viral attacks in different cell types and organs. Despite the ridiculously large number of papers that have flooded scientific journals and preprinthosting websites, a clear clinical picture of COVID-19 aftermath is vague at best. Without larger prospective observational studies that are only now being started, clinicians can retrieve information just from case reports and or small studies. This is the time to understand how COVID-19 goes forward and what consequences survivors may expect to experience. To this aim, a multidisciplinary post-acute care service involving several specialists has been established at the Fondazione Policlinico Universitario A. Gemelli IRCSS (Rome, Italy). Although COVID-19 is an infectious disease primarily affecting the lung, its multi-organ involvement requires an interdisciplinary approach encompassing virtually all branches of internal medicine and geriatrics. In particular, during the post-acute phase, the geriatrician may serve as the case manager of a multidisciplinary team. The aim of this article is to describe the importance of the interdisciplinary approach-coordinated by geriatrician-to cope the potential post-acute care needs of recovered COVID-19 patients.

We studied the effects of the divalent cation ionophore A23187 on apoptotic signaling in MH1C1 cells. Addition of A23187 caused a fast rise of cytosolic Ca(2+) ([Ca(2+)](c)), which returned close to the resting level within about 40 s. The [Ca(2+)](c) rise was immediately followed by phospholipid hydrolysis, which could be inhibited by aristolochic acid or by pretreatment with thapsigargin in Ca(2+)-free medium, indicating that the Ca(2+)-dependent cytosolic phospholipase A(2) (cPLA(2)) was involved. These early events were followed by opening of the mitochondrial permeability transition pore (PTP) and by apoptosis in about 30% of the cell population. In keeping with a cause-effect relationship between addition of A23187, activation of cPLA(2), PTP opening, and cell death, all events but the [Ca(2+)](c) rise were prevented by aristolochic acid. The number of cells killed by A23187 was doubled by treatment with 0.5 microm MK886 and 5 microm indomethacin, which inhibit arachidonic acid metabolism through the 5-lipoxygenase and cyclooxygenase pathway, respectively. Consistent with the key role of free arachidonic acid, its levels increased within minutes of treatment with A23187; the increase being more pronounced in the presence of MK886 plus indomethacin. Cell death was preceded by cytochrome c release and cleavage of caspase 9 and 3, but not of caspase 8. All these events were prevented by aristolochic acid and by the PTP inhibitor cyclosporin A. Thus, A23187 triggers the apoptotic cascade through the release of arachidonic acid by cPLA(2) in a process that is amplified when transformation of arachidonic acid into prostaglandins and leukotrienes is inhibited. These findings identify arachidonic acid as the causal link between A23187-dependent perturbation of Ca(2+) homeostasis and the effector mechanisms of cell death.