Verso una definizione delle “near-death experiences”: dimensioni fisiologiche, psicologiche e culturali

Riassunto: Il fenomeno delle “near-death experiences” (NDE), esperienze soggettive intense e profonde, è caratterizzato dalla percezione di essere in una dimensione diversa da quella ordinaria, di aver abbandonato il proprio corpo e, con esso, la dimensione spazio-temporale del mondo fisico. Il termine NDE è utilizzato per indicare esperienze simili occorse in condizioni cliniche molto diverse, ad esempio l’arresto cardiaco, il coma, lo svenimento o l’assunzione di sostanze psicotrope. In questo lavoro si considerano esclusivamente quelle esperienze sperimentate in condizioni di prossimità alla morte. Il fenomeno viene discusso confrontando gli elementi più comunemente presenti nelle NDE di soggetti occidentali con quelli riportati da soggetti di altre culture. Le varie esperienze pre-morte sono discusse in funzione dei contenuti riportati e delle modalità con cui si sono verificate. Infine, lo stato di coma è stato valutato come condizione di “near-death” nell’ottica di considerare la morte come un processo.Parole chiave: Near-death Experiences; Cultura; Coscienza; Memoria; Arresto cardiaco; Coma Towards a definition of “near-death experiences”: Physiologic, psychologic and cultural dimensionsAbstract: The phenomenon of near-death experiences (NDE), intense and profound subjective experiences, is characterized by the perception of being in a different dimension from the ordinary one, of having abandoned one’s body and, with it, the space-time dimension of the physical world. The term NDE has been used to indicate similar experiences that occurred in very different clinical conditions, namely cardiac arrest, coma, fainting, use of psychotropic substances, etc. In what follows will be considered only experiences taking place in conditions of proximity to death. The phenomenon will be discussed comparing elements most commonly present in NDEs of Western subjects with those reported by subjects from other cultures. The various near-death experiences will be discussed in according to the contents reported and the ways in which they occurred. Finally, the state of coma was considered as a near-death condition under the assumption of death as a process.Keywords: Near-Death Experiences; Culture; Consciousness; Memory; Cardiac Arrest; Com

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer is a heterogeneous disease that still lacks specific therapeutic approaches. The identification of new biomarkers, predictive of the disease’s aggressiveness and pharmacological response, is a challenge for a more tailored approach in the clinical management of patients. Nerve growth factor, initially identified as a key factor for neuronal survival and differentiation, turned out to be a multifaceted molecule with pleiotropic effects in quite divergent cell types, including cancer cells. Many solid tumors exhibit derangements of the nerve growth factor and its receptors, including the tropomyosin receptor kinase A. This receptor is expressed in triple-negative breast cancer, although its role in the pathogenesis and aggressiveness of this disease is still under investigation. We now report that triple-negative breast cancer-derived MDAMB- 231 and MDA-MB-453 cells express appreciable levels of tropomyosin receptor kinase A and release a biologically active nerve growth factor. Activation of tropomyosin receptor kinase by nerve growth factor treatment positively affects the migration, invasion, and proliferation of triple-negative breast cancer cells. An increase in the size of triple-negative breast cancer cell spheroids is also detected. This latter effect might occur through the nerve growth factor-induced release of matrix metalloproteinase 9, which contributes to the reorganization of the extracellular matrix and cell invasiveness. The tropomyosin receptor kinase A inhibitor GW441756 reverses all these responses. Co-immunoprecipitation experiments in both cell lines show that nerve growth factor triggers the assembly of the TrkA/b1-integrin/FAK/Src complex, thereby activating several downstream effectors. GW441756 prevents the complex assembly induced by nerve growth factor as well as the activation of its dependent signaling. Pharmacological inhibition of the tyrosine kinases Src and FAK (focal adhesion kinase), together with the silencing of b1-integrin, shows that the tyrosine kinases impinge on both proliferation and motility, while b1-integrin is needed for motility induced by nerve growth factor in triple-negative breast cancer cells. The present data support the key role of the nerve growth factor/tropomyosin receptor kinase A pathway in triple-negative breast cancer and offer new hints in the diagnostic and therapeutic management of patients

A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells

:Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. We report here that the AR associates with Filamin A (FlnA) promoting migration and invasiveness of various PC-derived cells after androgen challenging. Inhibition of the AR/FlnA complex assembly by a very low concentration of Rh-2025u, an AR-derived peptide specifically interfering with this association, impairs such phenotype in monolayer cells and in 3D models. This study, together with our recent data in cancer-associated fibroblasts (CAFs), indicates that targeting the AR/FlnA complex could improve the clinical management of invasive PC, as the limited number of new drugs reaching the market suggests that we must re-examine the way invasive PC is currently treated. In this context, the synthesis of new biologically active molecules, such as the Rh-2025u peptide, which has been shown to efficiently interfere in the complex assembly in CAFs and PC cells, should overcome the limits of current available therapies, mostly based on hormone hormone antagonists

Communication between cells: exosomes as a delivery system in prostate cancer.

Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database (https:// pubmed. ncbi. nlm. nih. gov) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented

Penile, Uretral and Seminal Sampling for Diagnosis of Human Papillomavirus Infection in Men.

Methods that used specimens from three genital sites (penile brushing [PB], urethral brushing [UB], and the retrieval of semen [SE]) from 50 men were examined for human papillomavirus (HPV) DNA detection. The rates of detection by PB, UB, SE, PB and UB, and PB and SE were 88.9%, 50.0%, 33.3%, 100%, and 97.2%, respectively. The use of PB and UB appears to be the most accurate method; as an alternative to UB, the use of SE with PB could be used to improve the rate of HPV DNA detection in men

Therapeutic potential of TRPM8 antagonists in prostate cancer.

Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior of in various PC-derived cells, at different degree of malignancy. The effect of the compounds was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected compounds were lastly identified using transcriptional and non-transcriptional reporter assays. TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a ‘druggable’ target in the androgen receptor-expressing prostate cancers

The androgen receptor/filamin A complex as a target in prostate cancer microenvironment.

Prostate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signalling pathways. Tumour microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumour area in androgen-treated 3D co-culture. The androgen receptor in association with β1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. The present study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer

On the characterization of GJ 504: a magnetically active planet-host star observed by the Transiting Exoplanet Survey Satellite (TESS)

We present the results of the analysis of the photometric data collected in long and short-cadence mode by the Transiting Exoplanet Survey Satellite (TESS) for GJ 504, a well studied planet-hosting solar-like star, whose fundamental parameters have been largely debated during the last decade. Several attempts have been made by the present authors to isolate the oscillatory properties expected on this main-sequence star, but we did not find any presence of solar-like pulsations. The suppression of the amplitude of the acoustic modes can be explained by the high level of magnetic activity revealed for this target, not only by the study of the photometric light-curve, but also by the analysis of three decades available of Mount Wilson spectroscopic data. In particular, our measurements of the stellar rotational period Prot=3.4 d and of the main principal magnetic cycle of 12 a confirm previous findings and allow us to locate this star in the early main sequence phase of its evolution during which the chromospheric activity is dominated by the superposition of several cycles before the transition to the phase of the magnetic-braking shutdown with the subsequent decrease of the magnetic activity