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Abstract Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.

Abstract We revisit Duff, Okun, and Veneziano’s divergent views on the number of fundamental constants and argue that the issue can be set to rest by having spacetime as the starting point. This procedure disentangles the resolution in what depends on the assumed spacetime (whether relativistic or not) from the theories built over it. By defining that the number of fundamental constants equals the minimal number of independent standards necessary to express all observables, as assumed by Duff, Okun, and Veneziano, it is shown that the same units fixed by the apparatuses used to construct the spacetimes are enough to express all observables of the physical laws defined over them. As a result, the number of fundamental constants equals one in relativistic spacetimes.

Fundamentally precision oncology illustrates the path in which molecular profiling of tumors can illuminate their biological behavior, diversity, and likely outcomes by identifying distinct genetic mutations, protein levels, and other biomarkers that underpin cancer progression. Next-generation sequencing became an indispensable diagnostic tool for diagnosis and treatment guidance in current clinical practice. Nowadays, tissue analysis benefits from further support through methods like comprehensive genomic profiling and liquid biopsies. However, precision medicine in the field of oncology presents specific hurdles, such as the cost-benefit balance and widespread accessibility, particularly in countries with low- and middle-income. A key issue is how to effectively extend next-generation sequencing to all cancer patients, thus empowering treatment decision-making. Concerns also extend to the quality and preservation of tissue samples, as well as the evaluation of health technologies. Moreover, as technology advances, novel next-generation sequencing assessments are being developed, including the study of Fragmentomics. Therefore, our objective was to delineate the primary uses of next-generation sequencing, discussing its’ applications, limitations, and prospective paths forward in Oncology.

[INLINE:1] We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the “weaver” mouse, a model of progressive nigrostriatal degeneration. Here, we extended our investigation in two clinically-relevant ways. First, we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors. Second, we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice, at late stages of degeneration. We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells, marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors. In agreement, we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice. However, the graft strongly induced an endogenous neurogenic response throughout the midbrain, which was significantly enhanced by the administration of microneurotrophin BNN-20. Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20. Interestingly, the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect.

Several studies and research papers have been published to elucidate and understand the mechanism of the coronavirus disease 2019 (COVID-19) pandemic and its long-term effects on the human body. COVID-19 affects a number of organs, including the female reproductive system. However, less attention has been given to the effects of COVID-19 on the female reproductive system due to their low morbidity. The results of studies investigating the relationship between COVID-19 infection and ovarian function in women of reproductive age have shown the harmless involvement of COVID-19 infection. Several studies have reported the involvement of COVID-19 infection in oocyte quality, ovarian function, and dysfunctions in the uterine endometrium and the menstrual cycle. The findings of these studies indicate that COVID-19 infection negatively affects the follicular microenvironment and dysregulate ovarian function. Although the COVID-19 pandemic and female reproductive health have been studied in humans and animals, very few studies have examined how COVID-19 affects the female reproductive system. The objective of this review is to summarize the current literature and categorize the effects of COVID-19 on the female reproductive system, including the ovaries, uterus, and hormonal profiles. The effects on oocyte maturation, oxidative stress, which causes chromosomal instability and apoptosis in ovaries, in vitro fertilization cycle, high-quality embryos, premature ovarian insufficiency, ovarian vein thrombosis, hypercoagulable state, women’s menstrual cycle, the hypothalamus-pituitary-ovary axis, and sex hormones, including estrogen, progesterone, and the anti-Müllerian hormone, are discussed in particular.

Gynecological cancers pose a significant burden on women’s health worldwide, necessitating innovative treatment approaches. Immunotherapy has emerged as a promising strategy, harnessing the body’s immune system to combat cancer. This review aims to provide a comprehensive overview of the current landscape and future directions of immunotherapy in cervical and endometrial cancer. Methods: A thorough literature search was conducted to identify relevant studies and clinical trials. The main methods and treatments employed in immunotherapy for cervical and endometrial cancer, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapies, are briefly described. Results: Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have shown remarkable clinical efficacy in certain gynecological malignancies, particularly in advanced or recurrent cases. Additionally, ongoing research on cancer vaccines and adoptive cell therapies holds promise for personalized and targeted treatment options.

Trial of labor after cesarean (TOLAC) is an alternative to repeated cesarean for women with singleton pregnancy and one previous transverse lower segment cesarean section (LSCS), resulting in most cases being a successful vaginal birth after cesarean section (VBAC). The primary objective of this study was to examine if the progress and the duration of the active first stage and the second stage of labor in nulliparous women with singleton pregnancy, spontaneous start of labor and vaginal birth differ from primiparous women succeeding VBAC after one previous elective LSCS in a country with a low cesarean section and high VBAC rate. Secondary objectives were to compare labor interventions and maternal–neonatal outcomes between the two groups. Methods: This is a retrospective comparative study. Data were collected in a four-year period at the departments of Obstetrics and Gynecology at Kristianstad and Ystad hospitals in Sweden. Out of 14,925 deliveries, 106 primipara women with one previous elective LSCS and a spontaneous labor onset in the subsequent singleton pregnancy were identified. Of these women, 94 (88.7%) delivered vaginally and were included in the study (VBAC group). The comparison group included 212 randomly selected nulliparous women that had a normal singleton pregnancy, spontaneous labor onset and delivered vaginally. Results: The rate of cervical dilation during the active first stage of labor as well as the duration of the second stage did not differ between the two groups. When adjusting for cervical dilation at admission, there was no significant difference between the two groups regarding the duration of the active phase of the first stage of labor. No significant differences were found in maternal–neonatal outcomes between the two groups except for higher birth weight in the VBAC group. The use of epidural analgesia was associated with slower dilation rhythm over the duration of the active phase and second stage of labor, need for labor augmentation, postpartum bleeding and need for transfusion at higher rates, irrespective of parity when epidural was used. Conclusions: Our study provides evidence that in women with one previous elective LSCS undergoing TOLAC in the subsequent pregnancy resulting in vaginal birth, the progress and duration of labor are not different from those in nulliparous women when labor is spontaneous and the it is a singleton pregnancy. The use of epidural was associated with prolonged labor, need for labor augmentation and higher postpartum bleeding, irrespective of parity. This information may be useful in patient counseling and labor management in TOLAC.

Abstract Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson’s disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.

Ovarian cancer (OC) is characterized by silent progression and late-stage diagnosis. It is critical to detect and accurately diagnose the disease early to improve survival rates. Tumor markers have emerged as valuable tools in the diagnosis and management of OC, offering non-invasive and cost-effective options for screening, monitoring, and prognosis. Purpose: This paper explores the diagnostic importance of various tumor markers including CA-125, CA15-3, CA 19-9, HE4,hCG, inhibin, AFP, and LDH, and their impact on disease monitoring and treatment response assessment. Methods: Article searches were performed on PubMed, Scopus, and Google Scholar. Keywords used for the searching process were “Ovarian cancer”, “Cancer biomarkers”, “Early detection”, “Cancer diagnosis”, “CA-125”,“CA 15-3”,“CA 19-9”, “HE4”,“hCG”, “inhibin”, “AFP”, “LDH”, and others. Results: HE4, when combined with CA-125, shows improved sensitivity and specificity, particularly in early-stage detection. Additionally, hCG holds promise as a prognostic marker, aiding treatment response prediction and outcome assessment. Novel markers like microRNAs, DNA methylation patterns, and circulating tumor cells offer potential for enhanced diagnostic accuracy and personalized management. Integrating these markers into a comprehensive panel may improve sensitivity and specificity in ovarian cancer diagnosis. However, careful interpretation of tumor marker results is necessary, considering factors such as age, menopausal status, and comorbidities. Further research is needed to validate and refine diagnostic algorithms, optimizing the clinical significance of tumor markers in ovarian cancer management. In conclusion, tumor markers such as CA-125, CA15-3, CA 19-9, HE4, and hCG provide valuable insights into ovarian cancer diagnosis, monitoring, and prognosis, with the potential to enhance early detection.

A growing body of evidence suggests that chemicals interfere with the age of onset of menarche. We conducted a review in order to demonstrate the relationship between several categories of chemicals and menarche. We searched for English language papers using the Medline/PubMed database until April 2023. The chemical factors found to affect menarche were prenatal and antenatal smoke, phthalates, phenols, organochlorines, perfluoroalkyls and polyfluoroalkyls, metals, air pollutants and polybrominated diphenyl ethers. Low or high exposure to each chemical compound could affect the age of menarche, leading to early or delayed menarche. Furthermore, the results show that intrauterine exposure may have a different impact from antenatal exposure. There is evidence that endocrine-disrupting chemicals affect the age of menarche, but more research needs to be conducted.

Central nervous system infections caused by pathogens crossing the blood–brain barrier are extremely damaging and trigger cellular alterations and neuroinflammation. Bacterial brain infection, in particular, is a major cause of hippocampal neuronal degeneration. Hippocampal neurogenesis, a continuous multistep process occurring throughout life in the adult brain, could compensate for such neuronal loss. However, the high rates of cognitive and other sequelae from bacterial meningitis/encephalitis suggest that endogenous repair mechanisms might be severely affected. In the current study, we used Group B Streptococcus (GBS) strain NEM316, to establish an adult mouse model of brain infection and determine its impact on adult neurogenesis. Experimental encephalitis elicited neurological deficits and death, induced inflammation, and affected neurogenesis in the dentate gyrus of the adult hippocampus by suppressing the proliferation of progenitor cells and the generation of newborn neurons. These effects were specifically associated with hippocampal neurogenesis while subventricular zone neurogenesis was not affected. Overall, our data provide new insights regarding the effect of GBS infection on adult brain neurogenesis.

Background: Primary dysmenorrhea is considered to be one of the most common gynecological complaints, affecting women’s daily activities and social life. The severity of dysmenorrhea varies among women, and its management is of high importance for them. Given that non-steroidal anti-inflammatory drugs (NSAIDs), the established treatment for dysmenorrhea, are associated with many adverse events, alternative therapeutic options are under evaluation. Emerging evidence correlates management of dysmenorrhea with micronutrients, especially vitamins. Purpose: The aim of this narrative review is to highlight and provide evidence of the potential benefits of vitamins for the management of dysmenorrhea. Methods: The articles were searched on PubMed, Scopus and Google Scholar. The searching process was based on keywords, such as “primary dysmenorrhea”, “vitamins”, “supplementation”, “vitamin D”, “vitamin E” and others. Our search focused on data derived from clinical trials, published only during the last decade (older articles were excluded). Results: In this review, 13 clinical trials were investigated. Most of them supported the anti-inflammatory, antioxidant and analgesic properties of vitamins. Particularly, vitamins D and E revealed a desirable effect on dysmenorrhea relief Conclusion: Despite the scarcity and heterogeneity of related research, the studies indicate a role of vitamins for the management of primary dysmenorrhea, proposing that they should be considered as alternative therapeutic candidates for clinical use. Nevertheless, this correlation warrants further research.

Clotting Factor deficiencies are rare disorders with variations in clinical presentation and severity of symptoms ranging from asymptomatic to mild to life-threatening bleeding. Thus, they pose a diagnostic and therapeutic challenge, mainly for the primary health care providers, general practitioners, and gynecologists who are more likely to first encounter these patients. An additional diagnostic challenge arises from the variable laboratory presentations, as PT, PTT, and BT are not always affected. The morbidity is higher among women of reproductive age since Abnormal Uterine Bleeding–specifically Heavy Menstrual Bleeding–is one of the most prevalent manifestations of these disorders, and in some cases of severe deficiencies has led to life-threatening episodes of bleeding requiring blood transfusions or even immediate surgical intervention. Physician awareness is important as, in the case of some of these disorders–i.e., Factor XIII deficiency–prophylactic treatment is available and recommended. Although uncommon, the potential for rare bleeding disorders and for hemophilia carrier states should be considered in women with HMB, after more prevalent causes have been excluded. Currently, there is no consensus on the management of women in these instances and it is reliant on the physicians’ knowledge.

Several factors during childhood and adolescence are thought to be associated with the development of proliferative benign breast diseases and breast cancer in adulthood. In order to identify them, the authors conducted an extensive review of the literature up to October 2022, searching for clinical studies, reports, and guidelines in English. A thorough Medline/Pubmed and Google scholar database research was performed, investigating the link between diet, exercise, age of menarche, body mass index, ionizing radiation exposure during childhood and adolescence, and proliferative breast diseases and breast cancer in adulthood. A list of keywords, including breast disorders, adolescence, childhood, and breast cancer was included in our search algorithm. Numerous studies concede that the development of breast disease in adulthood is influenced by various risk factors, whose influence begins during early childhood and adolescence.

Fundamentally precision oncology illustrates the path in which molecular profiling of tumors can illuminate their biological behavior, diversity, and likely outcomes by identifying distinct genetic mutations, protein levels, and other biomarkers that underpin cancer progression. Next-generation sequencing became an indispensable diagnostic tool for diagnosis and treatment guidance in current clinical practice. Nowadays, tissue analysis benefits from further support through methods like comprehensive genomic profiling and liquid biopsies. However, precision medicine in the field of oncology presents specific hurdles, such as the cost-benefit balance and widespread accessibility, particularly in countries with low- and middle-income. A key issue is how to effectively extend next-generation sequencing to all cancer patients, thus empowering treatment decision-making. Concerns also extend to the quality and preservation of tissue samples, as well as the evaluation of health technologies. Moreover, as technology advances, novel next-generation sequencing assessments are being developed, including the study of Fragmentomics. Therefore, our objective was to delineate the primary uses of next-generation sequencing, discussing its' applications, limitations, and prospective paths forward in Oncology. [ABSTRACT FROM AUTHOR]