Cytochalasins as Modulators of Stem Cell Differentiation.

Regenerative medicine aims to identify new research strategies for the repair and restoration of tissues damaged by pathological or accidental events. Mesenchymal stem cells (MSCs) play a key role in regenerative medicine approaches due to their specific properties, such as the high rate of proliferation, the ability to differentiate into several cell lineages, the immunomodulatory potential, and their easy isolation with minimal ethical issues. One of the main goals of regenerative medicine is to modulate, both in vitro and in vivo, the differentiation potential of MSCs to improve their use in the repair of damaged tissues. Over the years, much evidence has been collected about the ability of cytochalasins, a large family of 60 metabolites isolated mainly from fungi, to modulate multiple properties of stem cells (SCs), such as proliferation, migration, and differentiation, by altering the organization of the cyto- and the nucleo-skeleton. In this review, we discussed the ability of two different cytochalasins, cytochalasins D and B, to influence specific SC differentiation programs modulated by several agents (chemical or physical) or intra- and extra-cellular factors, with particular attention to human MSCs (hMSCs).

Non-response to first-line hormonal treatment for symptomatic endometriosis: overcoming tunnel vision. A narrative review.

One-fourth to one-third of women with endometriosis receiving first-line hormonal treatment lacks an adequate response in terms of resolution of painful symptoms. This phenomenon has been ascribed to "progesterone resistance", an entity that was theorized to explain the gap between the ubiquity of retrograde menstruation and the 10% prevalence of endometriosis among women of reproductive age.Nevertheless, the hypothesis of progesterone resistance is not free of controversies. As our understanding of endometriosis is increasing, authors are starting to set aside the traditionally accepted tunnel vision of endometriosis as a strictly pelvic disease, opening to a more comprehensive perspective of the condition. The question is: are patients not responding to first-line treatment because they have an altered signaling pathway for such treatment, or have we been overlooking a series of other pain contributors which may not be resolved by hormonal therapy?Finding an answer to this question is evermore impelling, for two reasons mainly. Firstly, because not recognizing the presence of further pain contributors adds a delay in treatment to the already existing delay in diagnosis of endometriosis. This may lead to chronicity of the untreated pain contributors as well as causing adverse consequences on quality of life and psychological health. Secondly, misinterpreting the consequences of untreated pain contributors as a non-response to standard first-line treatment may imply the adoption of second-line medical therapies or of surgery, which may entail non-negligible side effects and may not be free of physical, psychological and socioeconomic repercussions.The current narrative review aims at providing an overview of all the possible pain contributors in endometriosis, ranging from those strictly organic to those with a greater neuro-psychological component. Including these aspects in a broader psychobiological approach may provide useful suggestions for treating those patients who report persistent pain symptoms despite receiving first-line hormonal medical treatment.

Cytochalasin B Influences Cytoskeletal Organization and Osteogenic Potential of Human Wharton's Jelly Mesenchymal Stem Cells.

Among perinatal stem cells of the umbilical cord, human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) are of great interest for cell-based therapy approaches in regenerative medicine, showing some advantages over other MSCs. In fact, hWJ-MSCs, placed between embryonic and adult MSCs, are not tumorigenic and are harvested with few ethical concerns. Furthermore, these cells can be easily cultured in vitro, maintaining both stem properties and a high proliferative rate for several passages, as well as trilineage capacity of differentiation. Recently, it has been demonstrated that cytoskeletal organization influences stem cell biology. Among molecules able to modulate its dynamics, Cytochalasin B (CB), a cyto-permeable mycotoxin, influences actin microfilament polymerization, thus affecting several cell properties, such as the ability of MSCs to differentiate towards a specific commitment. Here, we investigated for the first time the effects of a 24 h-treatment with CB at different concentrations (0.1-3 µM) on hWJ-MSCs. CB influenced the cytoskeletal organization in a dose-dependent manner, inducing changes in cell number, proliferation, shape, and nanomechanical properties, thus promoting the osteogenic commitment of hWJ-MSCs, as confirmed by the expression analysis of osteogenic/autophagy markers.

Plumbagin, a Natural Compound with Several Biological Effects and Anti-Inflammatory Properties.

Phytochemicals from various medicinal plants are well known for their antioxidant properties and anti-cancer effects. Many of these bioactive compounds or natural products have demonstrated effects against inflammation, while some showed a role that is only approximately described as anti-inflammatory. In particular, naphthoquinones are naturally-occurring compounds with different pharmacological activities and allow easy scaffold modification for drug design approaches. Among this class of compounds, Plumbagin, a plant-derived product, has shown interesting counteracting effects in many inflammation models. However, scientific knowledge about the beneficial effect of Plumbagin should be comprehensively reported before candidating this natural molecule into a future drug against specific human diseases. In this review, the most relevant mechanisms in which Plumbagin plays a role in the process of inflammation were summarized. Other relevant bioactive effects were reviewed to provide a complete and compact scenario of Plumbagin's potential therapeutic significance.

Melatonin finely tunes proliferation and senescence in hematopoietic stem cells.

Human hematopoietic stem/progenitor cells (HSPCs) are pluripotent cells that gradually lose their self-renewal and regenerative potential, to give rise to mature cells of the hematopoietic system by differentiation. HSPC infusion is used to restore hematopoietic function in patients with a variety of onco-hematologic and immune-mediated disorders. The functionality of these cells is therefore of great importance to ensure the homeostasis of the hematopoietic system. Melatonin plays an important role as immunomodulatory and oncostatic hormone. In the present manuscript, we aimed at evaluating the activity of melatonin in modulating HSPC senescence, in the attempt to improve their hemopoietic regenerative potential. We exposed HSPCs to melatonin, in different conditions, and then analyzed the expression of genes regulating cell cycle and cell senescence. Moreover, we assessed cell senescence by ß-galactosidase and telomerase activity. Our results showed the ability of melatonin to counteract HSPC senescence, thus paving the way for enhanced efficiency in their clinical application.

Cell Responsiveness to Physical Energies: Paving the Way to Decipher a Morphogenetic Code.

We discuss emerging views on the complexity of signals controlling the onset of biological shapes and functions, from the nanoarchitectonics arising from supramolecular interactions, to the cellular/multicellular tissue level, and up to the unfolding of complex anatomy. We highlight the fundamental role of physical forces in cellular decisions, stressing the intriguing similarities in early morphogenesis, tissue regeneration, and oncogenic drift. Compelling evidence is presented, showing that biological patterns are strongly embedded in the vibrational nature of the physical energies that permeate the entire universe. We describe biological dynamics as informational processes at which physics and chemistry converge, with nanomechanical motions, and electromagnetic waves, including light, forming an ensemble of vibrations, acting as a sort of control software for molecular patterning. Biomolecular recognition is approached within the establishment of coherent synchronizations among signaling players, whose physical nature can be equated to oscillators tending to the coherent synchronization of their vibrational modes. Cytoskeletal elements are now emerging as senders and receivers of physical signals, "shaping" biological identity from the cellular to the tissue/organ levels. We finally discuss the perspective of exploiting the diffusive features of physical energies to afford in situ stem/somatic cell reprogramming, and tissue regeneration, without stem cell transplantation.

First Case Report of Pregnancy on Alectinib in a Woman With Metastatic ALK-Rearranged Lung Cancer: A Case Report.

This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient's preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission.

"Lights and Shadows": An Interpretative Phenomenological Analysis of the Lived Experience of Being Diagnosed With Breast Cancer During Pregnancy.

Cancer diagnosed during pregnancy is a rare event. The most common type of malignancy diagnosed in pregnant women is breast cancer, whose incidence is expected to raise in the next future due to delayed childbirth, as well as to the increased occurrence of the disease at young age. Pregnant women diagnosed with breast cancer are exposed to multiple sources of stress, which may lead to poorer obstetric outcomes, such as preterm birth and low birth weight. In addition, pregnancy involves physiological changes in the breasts that may blur the signs of cancer, with delayed diagnosis and poor prognosis. However, the lived experience of these women was investigated in very few studies. Given this scenario, we conducted this qualitative study to describe and understand women's subjective experience of being diagnosed with breast cancer during pregnancy. The study was conducted following the principles of Interpretative Phenomenological Analysis. Participants were five women with breast cancer diagnosed during pregnancy, purposefully recruited at a public hospital during medical visits and interviewed at treatment initiation. The interview transcripts were analyzed using thematic analysis. The textual analysis led to the identification of three main themes related to: (1) the emotional storm experienced after cancer diagnosis, and the importance of receiving appropriate information and being focused on treatment decisions; (2) physical changes and comparisons with healthy women, associated with feelings of sadness and inadequacy; (3) being positive, feeling free to disclose all kinds of emotions, religion and spirituality as sources of strength. The paradoxical coexistence of pregnancy and cancer represents a stressful experience for women and their loved ones. Adopting a systemic perspective may be important to understand the effects of such a complex condition, also considering its impact on healthcare workers.

Sex-Specific Transcriptome Differences in Human Adipose Mesenchymal Stem Cells.

In humans, sexual dimorphism can manifest in many ways and it is widely studied in several knowledge fields. It is increasing the evidence that also cells differ according to sex, a correlation still little studied and poorly considered when cells are used in scientific research. Specifically, our interest is on the sex-related dimorphism on the human mesenchymal stem cells (hMSCs) transcriptome. A systematic meta-analysis of hMSC microarrays was performed by using the Transcriptome Mapper (TRAM) software. This bioinformatic tool was used to integrate and normalize datasets from multiple sources and allowed us to highlight chromosomal segments and genes differently expressed in hMSCs derived from adipose tissue (hADSCs) of male and female donors. Chromosomal segments and differentially expressed genes in male and female hADSCs resulted to be related to several processes as inflammation, adipogenic and neurogenic differentiation and cell communication. Obtained results lead us to hypothesize that the donor sex of hADSCs is a variable influencing a wide range of stem cell biologic processes. We believe that it should be considered in biologic research and stem cell therapy.

Physical energies to the rescue of damaged tissues.

Rhythmic oscillatory patterns sustain cellular dynamics, driving the concerted action of regulatory molecules, microtubules, and molecular motors. We describe cellular microtubules as oscillators capable of synchronization and swarming, generating mechanical and electric patterns that impact biomolecular recognition. We consider the biological relevance of seeing the inside of cells populated by a network of molecules that behave as bioelectronic circuits and chromophores. We discuss the novel perspectives disclosed by mechanobiology, bioelectromagnetism, and photobiomodulation, both in term of fundamental basic science and in light of the biomedical implication of using physical energies to govern (stem) cell fate. We focus on the feasibility of exploiting atomic force microscopy and hyperspectral imaging to detect signatures of nanomotions and electromagnetic radiation (light), respectively, generated by the stem cells across the specification of their multilineage repertoire. The chance is reported of using these signatures and the diffusive features of physical waves to direct specifically the differentiation program of stem cells in situ, where they already are resident in all the tissues of the human body. We discuss how this strategy may pave the way to a regenerative and precision medicine without the needs for (stem) cell or tissue transplantation. We describe a novel paradigm based upon boosting our inherent ability for self-healing.

Early Developmental Zebrafish Embryo Extract to Modulate Senescence in Multisource Human Mesenchymal Stem Cells.

Stem cells undergo senescence both in vivo, contributing to the progressive decline in self-healing mechanisms, and in vitro during prolonged expansion. Here, we show that an early developmental zebrafish embryo extract (ZF1) could act as a modulator of senescence in human mesenchymal stem cells (hMSCs) isolated from both adult tissues, including adipose tissue (hASCs), bone marrow (hBM-MSCs), dental pulp (hDP-MSCs), and a perinatal tissue such as the Wharton's Jelly (hWJ-MSCs). In all the investigated hMSCs, ZF1 decreased senescence-associated ß-galactosidase (SA ß-gal) activity and enhanced the transcription of TERT, encoding the catalytic telomerase core. In addition, it was associated, only in hASCs, with a transcriptional induction of BMI1, a pleiotropic repressor of senescence. In hBM-MSCs, hDP-MSCs, and hWJ-MSCs, TERT over-expression was concomitant with a down-regulation of two repressors of TERT, TP53 (p53), and CDKN1A (p21). Furthermore, ZF1 increased the natural ability of hASCs to perform adipogenesis. These results indicate the chance of using ZF1 to modulate stem cell senescence in a source-related manner, to be potentially used as a tool to affect stem cell senescence in vitro. In addition, its anti-senescence action could also set the basis for future in vivo approaches promoting tissue rejuvenation bypassing stem cell transplantation.

Zebrafish embryo extract counteracts human stem cell senescence.

Human adult stem cells hold promise for regenerative medicine. They are usually expanded for multiple passages in vitro to increase cell yield prior to transplantation. Unfortunately, prolonged culture leads to cell senescence, a major drawback from successful outcomes in cell therapy approaches. Here, we show that an extract from early Zebrafish embryo (ZF1) counteracted senescence progression in human adipose-derived stem cells (hASCs) along multiple culture passages (from the 5th to the 20th). Exposure to ZF1 strongly reduced the expression of senescence marker beta-galactosidase. Both stemness (NANOG, OCT4, and MYC) and anti-senescence (BMI1, and telomerase reverse transcriptase - TERT) related genes were overexpressed at specific experimental points, without recruitment of the cyclin-dependent kinase Inhibitor 2A (CDKN2A, ali-as p16). Increased telomerase activity was associatt-ed with TERT overexpression. Both osteogenic and adipogenic abilities were enhanced. In conclusion, hASCs exposure to ZF1 is a feasible tool to counteract and reverse human stem cell senescence in long-term culturing conditions.

Psychosexual Consequences of Female Genital Mutilation and the Impact of Reconstructive Surgery: A Narrative Review.

Purpose: We aim to provide a comprehensive overview of the health consequences of female genital mutilation/cutting (FGM/C), with a particular focus on the psychosexual implications of this practice and the overall impact of reconstructive plastic surgery. Methods: A MEDLINE search through PubMed was performed to identify the best quality evidence published studies in English language on long-term health consequences of FGM/C. Results: Women with FGM/C are more likely to develop psychological disorders, such as post-traumatic stress disorder, anxiety, somatization, phobia, and low self-esteem, than those without FGM/C. Most studies showed impaired sexual function in women with FGM/C. In particular, women with FGM/C may be physiologically less capable of becoming sexually stimulated than uncut women. Reconstructive surgery could be beneficial, in terms of both enhanced sexual function and body image. However, prospective studies on the impact of reconstructive surgery are limited, and safety issues should be addressed. Conclusion: Although it is clear that FGM/C can cause devastating immediate and long-term health consequences for girls and women, high-quality data on these issues are limited. Psychosexual complications need to be further analyzed to provide evidence-based guidelines and to improve the health care of women and girls with FGM/C. The best treatment approach involves a multidisciplinary team to deal with the multifaceted FGM/C repercussions.

Lessons from human umbilical cord: gender differences in stem cells from Wharton's jelly.

OBJECTIVE: To study the molecular features of mesenchymal stem cells from Wharton Jelly (WJ-MSCs) of umbilical cord to predict their differentiation capacity. DESIGN: Comparison of gene expression from mesenchymal stem cells of male and female umbilical cord SETTING: University hospital PATIENT (S): umbilical cords (n = 12, 6 males and 6 females) retrieved from spontaneous full-term vaginal delivery of healthy women INTERVENTION: we analyzed the expression of the stemness related genes C-MYC, OCT4, SOX2 and NANOG and of the epigenetic modulating gene DNA-methyltransferase 1 (DNMT1). MEAN OUTCOME MEASURE: WJ-MSCs were isolated by standard procedures and immunophenotypically characterized. Gene expression analysis of stemness related genes and the epigenetic modulating gene DNMT1 were performed by real-time PCR RESULTS: expression of the OCT4 and DNMT1 genes was significantly higher in WJ- MSCs isolated from male subjects, as compared to MSCs isolated from female-derived WJ. The resulting higher expression of OCT4 and DNMT1 in WJ-MSCs from males as compared with female WJ-MSCs for the first time identifies a specific relationship between stemness genes, an epigenetic modulator, and gender differences. CONCLUSION: our findings disclose novel biomedical implications in WJ-MSCs related to the sex of the donor, thus providing additional cues to exploit their regenerative potential in allogenic transplantation.

Comparison of Oxidative Stress Effects on Senescence Patterning of Human Adult and Perinatal Tissue-Derived Stem Cells in Short and Long-term Cultures.

Human Mesenchymal Stem Cells (hMSCs) undergo senescence in lifespan. In most clinical trials, hMSCs experience long-term expansion ex vivo to increase cell number prior to transplantation, which unfortunately leads to cell senescence, hampering post-transplant outcomes. Hydrogen peroxide (H2O2) in vitro represents a rapid, time and cost-effective tool, commonly used as oxidative stress tantalizing the stem cell ability to cope with a hostile environment, recapitulating the onset and progression of cellular senescence. Here, H2O2 at different concentrations (ranging from 50 to 400 µM) and time exposures (1 or 2 hours - h), was used for the first time to compare the behavior of human Adipose tissue-derived Stem Cells (hASCs) and human Wharton's Jelly-derived MSCs (hWJ-MSCs), as representative of adult and perinatal tissue-derived stem cells, respectively. We showed timely different responses of hASCs and hWJ-MSCs at low and high subculture passages, concerning the cell proliferation, the cell senescence-associated ß-Galactosidase activity, the capability of these cells to undergo passages, the morphological changes and the gene expression of tumor protein p53 (TP53, alias p53) and cyclin dependent kinase inhibitor 1A (CDKN1A, alias p21) post H2O2 treatments. The comparison between the hASC and hWJ-MSC response to oxidative stress induced by H2O2 is a useful tool to assess the biological mechanisms at the basis of hMSC senescence, but it could also provide two models amenable to test in vitro putative anti-senescence modulators and develop anti-senescence strategies.

Potential benefits of pregnancy on endometriosis symptoms.

OBJECTIVE: To explore the potential benefits of pregnancy on endometriosis symptoms. This is a retrospective study that has been conducted at Academic department and referral center for endometriosis. STUDY DESIGN: We included all conservative women who had a live birth after at least one surgery for endometriosis and who reported pre-pregnancy moderate to severe pelvic pain symptoms (at least one among dysmenorrhea, deep dyspareunia, non menstrual pelvic pain and dyschezia). Data were collected before pregnancy and two years after delivery. The main aim of the study was comparing endometriosis-related pain symptoms before and after pregnancy. Mental health and quality of life were also assessed to investigate the possible psychological benefits of pregnancy. RESULTS: One-hundred thirty- one women were identified. Forty- nine women (37%, 95% CI: 29-47%) had a clinically relevant recurrence of symptoms requiring medical or surgical treatment. Two years after delivery, 84% of women (95% CI 77-90%) reported at least one moderate-severe pain symptom. A statistically significant improvement was observed for HADS and SF-12 scores but not for FSFI. CONCLUSION: Women with endometriosis experiencesymptoms relief during and immediately after pregnancy. However, as for hormonal medical therapy, symptoms rapidly recur in the vast majority of cases.

Tissue Regeneration without Stem Cell Transplantation: Self-Healing Potential from Ancestral Chemistry and Physical Energies.

The human body constantly regenerates after damage due to the self-renewing and differentiating properties of its resident stem cells. To recover the damaged tissues and regenerate functional organs, scientific research in the field of regenerative medicine is firmly trying to understand the molecular mechanisms through which the regenerative potential of stem cells may be unfolded into a clinical application. The finding that some organisms are capable of regenerative processes and the study of conserved evolutionary patterns in tissue regeneration may lead to the identification of natural molecules of ancestral species capable to extend their regenerative potential to human tissues. Such a possibility has also been strongly suggested as a result of the use of physical energies, such as electromagnetic fields and mechanical vibrations in human adult stem cells. Results from scientific studies on stem cell modulation confirm the possibility to afford a chemical manipulation of stem cell fate in vitro and pave the way to the use of natural molecules, as well as electromagnetic fields and mechanical vibrations to target human stem cells in their niche inside the body, enhancing human natural ability for self-healing.

Management of Endometriosis: Toward Value-Based, Cost-Effective, Affordable Care.

Endometriosis management seems to be influenced by outcome-independent biomedical, pharmacological, and technological developments. The propensity towards doing more affects several aspects of care, sometimes translating into proposals that are not based on sound epidemiological principles and robust evidence. Different stakeholders share the interest for doing more testing and using novel and costly drugs or devices in patients with endometriosis. Although some women may benefit from such an approach, the majority do not, and some may be harmed. Moreover, an uncontrolled increase in expenditures for endometriosis management without demonstrated and proportional health benefits would waste the finite resources of national health care services and would risk cost-related non-adherence. Cost-effectiveness analyses should be systematically pre-planned in future trials on endometriosis, and the concept of "value" of medical interventions should guide investigators and health care policymakers. Reducing low-value care, financial toxicity, and the burden of treatment is respectful not only of endometriosis patients, but also of the entire society. Whenever possible, long-term therapeutic strategies should be tailored to each woman's needs, and high-value tests and treatments should be chosen based on her priorities and preferences. Moreover, listening to patients, understanding their concerns, avoiding disease labelling, explaining plainly what is known and what is unknown, and giving constant reassurance and encouragement may be exceedingly important for the successful management of endometriosis and may change the patient's perception of her clinical condition. Physician empathy has no untoward effects, does not cause harms, and may determine whether a woman successfully copes or desperately struggles with her disease during reproductive life.

Vaginal rejuvenation: current perspectives.

Female genital cosmetic surgery includes several procedures aimed at reaching better female genital appearance and/or improved sexual functioning. Among these procedures, vaginal rejuvenation is considered as one of the most controversial genital cosmetic surgical interventions and involves a range of surgical procedures performed by gynecologists or plastic surgeons to decrease the average diameter of the vagina, mainly for sexual reasons. In this narrative review, vaginal rejuvenation outcomes are examined in order to clarify the current scenario of the different vaginal rejuvenation techniques, as well as their effectiveness and associated complications. Psychological and ethical issues linked to these procedures are also addressed.

When love hurts. A systematic review on the effects of surgical and pharmacological treatments for endometriosis on female sexual functioning.

INTRODUCTION: Endometriosis is associated with an increased risk of dyspareunia, therefore this chronic gynecologic disease should be considered as a major cause of sexual dysfunctions. The aims of this study were to review the literature on the effects of surgical and pharmacological treatments for endometriosis on female sexual functioning, and to provide suggestions for future treatment strategies. MATERIAL AND METHODS: We followed the PRISMA guidelines to conduct this systematic review, which involved an electronic database search of studies on the association between endometriosis and sexuality published between 2000 and 2016. RESULTS: As a result of the screening process, 22 studies were included in this systematic review. The 22 studies included were divided into two categories: (a) surgical intervention studies (n = 17), examining postoperative sexual outcomes of surgery for endometriosis; (b) pharmacological intervention studies (n = 5), evaluating the effects of pharmacological endometriosis treatments on sexual functioning. The studies considered showed that overall surgical and pharmacological interventions for endometriosis can lead to medium-/long-term improvement, but not necessarily to a definitive resolution of female sexual dysfunctions due to endometriosis. CONCLUSIONS: Sexual functioning is a multidimensional phenomenon and the ideal treatment for endometriosis-related sexual dysfunctions should be conducted by a multidisciplinary team that involves not only gynecologists, but also sexologists and psychologists/psychotherapists. Improving global sexual functioning, and not just reducing pain at intercourse, should be considered as a major clinical goal of endometriosis treatment.