Background: Tendon-bone healing is an important factor in determining the success of ligament reconstruction. With the development of biomaterials science, the tissue engineering scaffold plays an extremely important role in tendon-bone healing and bone tissue engineering.Materials and Methods: Electronic databases  were systematically searched for relevant and qualitative studies published from 1 January 1990 to 31 December 2019. Only original articles that met eligibility criteria and evaluated the use of issue engineering scaffold especially biomaterials in tendon bone healing in vivo were selected for analysis.Results: The search strategy identified 506 articles, and 27 studies were included for full review including two human trials and 25 animal studies. Fifteen studies only used biomaterials like PLGA, collage, PCL, PLA, and PET as scaffolds to repair the tendon-bone defect, on this basis, the rest of the 11 studies using biological interventions like cells or cell factors to enhance the healing. The adverse events hardly ever occurred, and the tendon bone healing with tissue engineering scaffold was effective and superior, which could be enhanced by biological interventions.Conclusion: Although a number of tissue engineering scaffolds have been developed and applied in tendon bone healing, the researches are mainly focused on animal models which are with limitations in clinical application. Since the efficacy and safety of tissue engineering scaffold has been proved, and can be enhanced by biological interventions, substantial clinical trials remain to be done, continued progress in overcoming current tissue engineering challenges should allow for successful clinical practice. Usually, after arthroscopic surgery, there is a gap between the graft and bone healing in the bone tunnel. Therefore, researchers hope to obtain better healing effect through other ways such as tissue engineering, so as to improve the function recovery of ligament and joint postoperatively. In this paper, a systematic summary of the Tendon defect is one of the common clinical diseases  As a framework connecting cells and tissues, it can be used to guide tissues to grow into a specific shape  critique the evidence in vivo regarding the use of tissue engineering scaffold to achieve tendon-bone healing; (2) provide a descriptive summary of the current evidence for tissue engineering scaffold use in tendon-bone healing especially biomaterials, as this is the first systematic review on the topic; and (3) highlight areas of future research to facilitate clinical application.In recent years, studies on improving tendon-bone healing have mainly focused on promoting ligament-bone integration at tendon sites  scaffold which was manufactured using biomaterials. Studies reporting in vitro work without in vivo analysis were excluded. Only original peer-reviewed articles were included, so letters, editorials, review articles, conference, patents, and meeting abstracts and studies not involving tissue engineering scaffold were excluded.This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .” Because the scope of this review was large in terms of outcome measures, a systematic review, not a meta-analysis, was performed.Literature searches were conducted in three electronic databases  from 1 January 1990 to 31 December 2019. The following search terms were used for the literature search: “(tissue engineering OR tissue engineering scaffold OR scaffold for tissue engineering OR scaffold) AND  AND  utilized a rabbit model  possess three main structural forms . The degradation products of PLA and PGA are lactic acid and glycolic acid, respectively, which are intermediate metabolic products of the tricarboxylic acid cycle. They have good biodegradability and compatibility and will not cause inflammation, immune reactions, and cytotoxic reactions. The most widely used biodegradable biomaterials have been widely used in tissue engineering such as bone, cartilage, blood vessels, nerves, and skin  (PDLA), poly (l-lactic acid) (PLLA), poly (PDLLA)  (PLLA-CL), which could effectively augment the tendon-to-bone integration and improve gradient microstructure in a rabbit extra-articular model by inducing the new bone formation, increasing the area of fibrocartilage, and improving collagen organization and maturation.The PLA and PGA copolymers include PLGA, poly scaffolds have been extensively used as biomaterials in the field of tissue engineering in vivo at the end of the tendon can be resisted while the degradation products will not cause changes of the internal environment pH. Therefore, the widely developed biphasic and triphasic stents are very competitive (Atesok et al., In the past 10 years, the rapid degradation of various materials in the human body is still a major problem hindering its clinical application. Because the interface of tendon bone connection involves two different biological structures, the ideal biomaterial used for tendon bone healing should have a higher standard. In other words, it is necessary to ensure that the stress at the bone-tissue interface can be reduced while matching with the degradation rate during bone healing period, and the enzymatic hydrolysis Functional fibrocartilage regeneration is a choke point in tendon bone healing, and the currently available tissue-engineering strategies for fibrocartilage regeneration are insufficient because of a lack of appropriate scaffold that can load large seeding cells and induce chondrogenesis of stem cells. Numerous strategies have been employed to improve tendon bone junction healing, including delivery of stem cells, bioactive factors, and synthetic materials, but these are often inadequate at recapitulating the complex structure-function relationships at native tissue interfaces Based on the results of several studies, it is found that the challenges that may be faced in the clinical process of tendon bone healing include the following: the regeneration strategy may be overwhelmed by natural scar-mediated responses, BMP2 is not an effective growth factor to promote tendon bone healing, and scaffold materials may have a negative effect on tendon bone healing.At present, except for the periosteum which has been used clinically and the curative effect is clear, the remaining methods to promote tendon-bone healing have no definite conclusions, and further research is needed to provide a more stable healing effect after ligament or tendon repair and reconstruction. Although a number of tissue engineering scaffolds have been developed and investigated, whose efficacy and safety has been proved and can be enhanced by biological interventions in this review, the researches are mainly focused on animal models which are with limitations in clinical application. On the other hand, tendon tissue engineering has high requirements for scaffold materials, and the development and research of composite materials will continue to be a hotspot for future research. Therefore, substantial clinical trials remain to be done, and continued progress in overcoming current tissue engineering challenges should allow for successful clinical practice, which is also one of the main directions of tissue engineering material research and development in the future.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.ZM, BF, and XW: substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work. XH, JG, ZS, BX, MY, and ZC: drafting the work or revising it critically for important intellectual content. DJ and JY: final approval of the version to be published, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


With the development of nanotechnology, noble metal nanoparticles are widely used in the treatment of cancer due to their unique optical properties, excellent biocompatibility, surface effects, and small size effects. In recent years, researchers have designed and synthesized a large number of nanomedicines that can be used for cancer treatment based on the morphology, physical and chemical properties, mechanism of action, and toxicological studies of noble metal nanoparticles. Furthermore, the integration of diagnosis and treatment, hyperthermia, cytotoxicity research, and drug delivery system based on the study of noble metal nanoparticles can be used as effective means for cancer treatment. This article focuses on the analysis of noble metal nanoparticles that are widely used in the treatment of cancer, such as gold nanoparticles, silver nanoparticles, platinum nanoparticles, and palladium nanoparticles. The various methods and mechanisms of action of noble metal nanoparticles in the treatment of cancer are objectively summarized in detail. Based on the research on the therapeutic safety and toxicity of noble metal nanoparticles, the development prospect of noble metal nanoparticles in the future clinical application is prospected. Cancer is the biggest enemy of human health at present. According to the global cancer statistics, the mortality rate caused by cancer in China is 24%, and with the increase in the number of patients, China spends more than 220 billion yuan per year on cancer , 2. DrugThe emergence of nanodrugs effectively makes up for the shortcomings of traditional anticancer drugs. In 1964, nanoliposomes were first reported for the delivery of antitumor drugs. Researchers found that, compared with traditional antitumor drugs, nanoliposomes had more stable plasma concentration levels and lower toxic and side effects and were significantly superior to traditional drugs in pharmacokinetics and pharmacodynamics . Since tThe three-dimensional size of noble metal nanoparticles has at least one-dimensional distribution within 100 nm , as wellCroton caudatus Geisel leaf extract obtained by Vijaya Kumar et al. [In recent years, based on the excellent properties of gold nanoparticles, the synthesis and application of gold nanoparticles (GNPs) have become a research hotspot. At present, the efficient methods commonly used for the preparation of gold nanoparticles are the electrochemical method , two-phar et al.  are showGold nanoparticles are widely used in biomedical fields due to their small particle size, good monodispersity, high tissue permeability, and colloidal stability . They ca3) added. This kind of peptide-directed hierarchical mineralized silver nanocages prepared by biomaterial template-directed mineralization has a high tumor-killing rate of 82.7% and a photothermal conversion rate of 46.1%, which belongs to the most powerful photothermal conversion of silver nanomaterials.Compared with gold nanoparticles, the stability of silver nanomaterials (AgNPs) is slightly poor and they will be oxidized gradually in oxygen-containing fluids . However+ but is caused by the oxidative stress of Ag nanoparticles [AgNPs have cytotoxicity, second only to mercury in antibacterial effect, and have the advantages of safety, slow release, and broad-spectrum antibacterial. The use of silver as a bactericidal material for the treatment of tumors has become a research hotspot since the 1990s. It is worth noting that the toxicity of AgNPs is not a direct effect of free Agarticles . Gurunatarticles  found tharticles  used doxSince scientists first discovered the antitumor effect of cisplatin in 1969 , the useCisplatin, as the first generation of platinum-based broad-spectrum antitumor drugs, has been one of the most widely used antitumor drugs since 1978. It is widely used in the clinical application treatment of prostate cancer, breast cancer, and bladder cancer . CisplatThe second-generation broad-spectrum antitumor drugs carboplatin and nedaplatin developed based on cisplatin have significantly improved their antitumor efficacy. Carboplatin is mainly used for the treatment of ovarian cancer and melanoma in the clinic. Its physicochemical properties, mechanism of action, antitumor spectrum, and anticancer activity are similar to those of cisplatin, and its nephrotoxicity, ototoxicity, and gastrointestinal side effects are weakened. But the administration is still intravenous administration and accompanied by serious bone marrow suppression and anemia and other adverse reactions . The phaThe third-generation antitumor drugs include oxaliplatin, lobaplatin, and heptaplatin. Compared with cisplatin and carboplatin, oxaliplatin has specific targets, mechanisms of action, and drug resistance mechanisms . OxaliplThe versatility and high selectivity of platinum nanoparticles make them a promising candidate in the field of cancer therapy . HoweverC. vulgaris extract, and the image is shown in Palladium nanomaterials are often used as substitutes for gold nanoparticles in the treatment of tumors because of their excellent photothermal stability, excellent catalytic activity, and significant price advantages . Arsiya With the vigorous development of nanotechnology, the research on the physicochemical properties, toxicology, and mechanism of action of noble metal nanoparticles in the treatment of tumors has become more and more thorough. Based on the LSPR effect , the SER3O4/Ag, which can be conjugated to an epidermal growth factor receptor-specific antibody (C225) as a high-sensitivity tracer and a potential radiosensitizer. Later, the magnetic resonance phenomenon is used for diagnosis. Using the noble metal nanoparticles can realize the real-time monitoring and evaluation of drug delivery processes and treatment status [The study has shown that the low diagnostic rate of early cancer may be the main reason for the high mortality of cancer patients in China . Becauset status . At the t status .Due to the rapid growth of the tumor site, the lack of lymphatic vascular reflux, vascular distortion, and aggregation, and slow blood flow velocity, the heat resistance of the tumor site is poor. Studies have shown that an elevated ambient temperature in tumor tissue can induce apoptosis of tumor cells . Noble m+ and polyvinylpyrrolidone on the human alveolar cell line A549. In the study, it was found that the treatment of antioxidant N-acetyl-cysteine significantly reduced the cytotoxicity of the two silver compounds, which further proved that AgNPs were the medium of ROS genetic toxicity. Studies have shown that the cytotoxicity of silver nanoparticles is closely related to their size and shape [μm in length, 100–160 nm in diameter) are more toxic than spherical nanowires (30 nm in diameter) [Silver nanoparticles have an excellent antibacterial effect, with cytotoxicity and heavy metal toxicity second only to mercury . Since tnd shape . Compareiameter) .In addition, cisplatin is also a representative drug for cytotoxicity research. Cisplatin selectively binds to tumor cell DNA, blocks cell cycle, and inhibits DNA replication and transcription of tumor cells, thereby exerting cytotoxicity . Shiny eAntitumor drug delivery systems are constructed by physical embedding, covalent binding, and electrostatic interaction of antitumor drugs and noble metal nanoparticles . SignifiAt present, cancer treatment still faces many challenges. But with the development of nanotechnology, the application of noble metal nanoparticles is expected to become an excellent weapon for the treatment of tumors. Noble metal nanoparticles have shown great potential in the biomedical field. The application of noble metal nanoparticles effectively overcomes the shortcomings of traditional tumor treatment methods and truly creates a new, safe, and minimally invasive tumor treatment system. In the diagnosis of cancer, based on the unique optical properties and excellent biocompatibility, researchers use advanced imaging technology to make noble metal nanoparticles as a contrast agent for self-imaging in vivo, which can significantly improve the signal intensity and enhance the contrast between normal tissues and tumor sites, to achieve the integration of diagnosis and treatment . In the


Long non-coding RNAs (lncRNAs) are a type of non-coding RNAs that act as molecular fingerprints and modulators of many pathophysiological processes, particularly in cancer. Specifically, lncRNAs can be involved in the pathogenesis and progression of brain tumors, affecting stemness/differentiation, replication, invasion, survival, DNA damage response, and chromatin dynamics. Furthermore, the aberrations in the expressions of these transcripts can promote treatment resistance, leading to tumor recurrence. The development of next-generation sequencing technologies and the creation of lncRNA-specific microarrays have boosted the study of lncRNA etiology. Cerebrospinal fluid (CSF) directly mirrors the biological fluid of biochemical processes in the brain. It can be enriched for small molecules, peptides, or proteins released by the neurons of the central nervous system (CNS) or immune cells. Therefore, strategies that identify and target CSF lncRNAs may be attractive as early diagnostic and therapeutic options. In this review, we have reviewed the studies on CSF lncRNAs in the context of brain tumor pathogenesis and progression and discuss their potential as biomarkers and therapeutic targets. Brain tumors refer to the primary intracranial tumors as well as the metastatic tumors in the brain with a primary lesion. They account for 1.8% of newly diagnosed cancers and 2.3% of cancer-related deaths worldwide . PatientWhile considerable advancements in fundamental scientific research and clinical practice have shed light on the brain tumor pathophysiology in the past decades, challenges remain in precise and early diagnosis . For insIn this scenario, it is essential to develop new methodologies to determine the diagnostic and prognostic parameters for various brain tumors and guide the individualized therapy . Non-codThe main limitation of blood biopsy for brain tumors is the low serum levels of tumor specific biomarkers, mainly caused by the brain blood barrier (BBB), which is formed by brain microvascular endothelial cells sealed by tight junctions . The BBBThe CSF is an ultrafiltrate of plasma surrounding the brain and spinal cord . The majvia abnormal epigenetic alterations in oncogene regulation pathways., including abnormal DNA methylation or histone changes at their gene promoters. More specifically, emerging data suggest that lncRNAs comprise a network of epigenetic modulators by creating platforms for chromatin-remodeling complexes and transcription factors capable of modulating the transcriptional state of lncRNA-controlled genomic loci  is the most devastating type of primary brain cancer, accounting for more than half of all primary CNS tumors . In 2016in vivo. Interestingly, MIR22HG was also enlisted in an immune-related lncRNA signature associated with glioblastoma prognosis, indicating its pathophysiological complexity in this malignancy , and pathological examination of tissues as the gold standard . In thisA cancer biomarker can be a substance naturally produced by a tumor or the body’s unique reaction to the presence of diseases . Regardiin vitro  of targeted mRNAs, thus reducing the mRNA stability or modulating gene translation. On the contrary, lncRNA might exert epigenetic functions in a more comprehensive and complex manner , antisense oligonucleotide (ASO), small molecule inhibitors, or even exosome-sealed ncRNAs, should be considered to reduce the expression of tissue lncRNAs or inhibit their functions within the tumor microenvironment. Finally, CSF lncRNAs cannot be the only answer for the diagnostics and treatment of brain tumors. Synergy between lncRNAs and other oncogenic regulators has been primarily documented . With prKX and SX conceived the structure of the manuscript and revised the manuscript. KX, XJ, and AAG designed and drafted the manuscript. XJ, YW, XL, and SX discussed and revised the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Physical inactivity and coronavirus disease 2019 (COVID-19) signify two pandemics with negative physical, mental, and economic consequences. Younger and older people have not reached the recommended physical activity level for years. Societal restrictions due to COVID-19 additionally reduce opportunities for physical activity, and they increase social isolation. Here, we outline how playing exergames with others  at home could foster physical and mental health and promote communication and discussions on exergaming. Accordingly, we highlight the educational and social benefits of exergaming at home and delineate the concept of Educational and Social Exergaming (EASE). We outline specific benefits and pitfalls of exergaming regarding its physical and nonphysical effects, including educational values of discussing exergaming experiences and related topics. Moreover, we discuss the relevance of practical guidelines for educational and social exergaming at home as well as prospects for future research. Overall, educational and social exergaming could alleviate several detrimental effects of both pandemics on the health and well-being of people of all ages. Physical activity and exercising can promote health and well-being for people of all ages, but worldwide, recommended levels of physical activity are not reached by about 80% of adolescents  appears to be a suitable option to stay physically active at home, for instance, with balance training, dancing, boxing, and tennis   can be realized locally within a household or online via the internet. Social exergaming can not only foster physical activity but also provide social support and create valuable opportunities to communicate with others  see . AccordiPhysical effects of exergaming include (neuro-)plasticity and motor learning that take place via (neuro-)biological, physiological, and other mechanisms  effects on the motivational, emotional, and cognitive level in clinical and nonclinical populations  and/or with (cooperatively) other players. Compared to exergaming alone, competitive exergaming against peers was found to reduce perceived exertion and to increase affective outcomes of children and adolescents  is a basic human need besides competence (to perceive skill increase) and autonomy (to endorse activities oneself) in terms of self-determination theory  and related physical and nonphysical effects could serve as obvious conversation starters. Players could reflect on their physical activity, including motor and cognitive skills, values of physical activity, and motivational and social aspects Corbin, . Even beSecond, media-driven topics include understanding the exergames' features such as the motion sensors, which are often readily accessible in the form of visual, performance-based feedback. This could also facilitate a visual approach to complex topics such as the ubiquity of technology and the associated generation, measurement, and surveillance of data in daily life parents and their (grand)children, siblings, friends, and players from online communities. When older people play with younger people, it could also improve intergenerational communication (Costa and Veloso, potential benefits and pitfalls related to the concept of EASE, we now turn to its feasibility. Exergaming interventions should provide appropriate levels of physical activity, enjoyment, and adherence but low additional costs (LeBlanc et al., After outlining several EASE at home may benefit from structured programs and professional guidance. Therapeutic and rehabilitative applications would even require professional support (Ambrosino et al., There is a lack of research on exergaming in home environments, and the fidelity of interventions should be ensured (Gao et al., To conclude, EASE can alleviate detrimental effects of pandemic restrictions on physical and mental health and foster media competences in home environments. While the COVID-19 pandemic has severe consequences on daily lives and physical activity, its end will not put an end to the pandemic of physical inactivity. Therefore, this work is not limited to the current COVID-19 restrictions.The original contributions presented in the study are included in the article/MR and KK conceptualized the manuscript. MR drafted and revised the manuscript. KK revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of treatment in patients with hormone-sensitive prostate cancer (HSPC). However, treatment response is short-lived, and the majority of patients ultimately progress to castration-resistant prostate cancer (CRPC). Surmountable data from clinical trials have shown that the maintenance of AR signaling in the castration environment is accountable for disease progression. Study results indicate multiple factors and survival pathways involved in PCa. Based on these findings, the alternative molecular pathways involved in PCa progression can be manipulated to improve current regimens and develop novel treatment modalities in the management of CRPC. In this review, the interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition. Prostate cancer (PCa) is the most frequently diagnosed neoplasm in developed countries and is accountable for the second-highest rate of cancer-related deaths . SignifiThe underlying molecular mechanisms that lead to progression to CRPC are associated with the conservation of AR signaling in the castration-level androgen setting . ClinicaThe need to understand the intricate relationship between AR signaling and other molecular cascades involved with the pathogenesis of PCa and its therapeutic implications in advanced disease is of utmost importance, along with the familiarity of current and novel therapeutic approaches utilizing the AR signaling pathway for the treatment and management for patients with PCa in the advanced setting.Classified as a steroid hormone receptor, the AR is a ligand-activated nuclear transcription factor whose role is the regulation of target gene expression. The AR consists of a DNA-binding domain (DBD), along with a hinge region and ligand-binding domain (LBD) and an N-terminal domain (NTD) that consists of two repeated polymorphic trinucleotide segments. The repeat segments are constituted of random polyglutamine and polyglycine repeats, which are involved in the regulation of AR transcriptional activity ,19. AR eThe prostate tumor microenvironment (TME) harbors a various number of inflammatory cells and stromal components. Of these cellular constituents, cancer-associated fibroblasts (CAFs) are recruited and activated by factors secreted from the primary cancer, enabling molecular crosstalk with tumor cells. This interaction activates CAFs, which initiate cytokine release and extracellular matrix (ECM) deposition. This molecular cascade results in the reorganization of the structure and composition of the connective tissue along with the release of growth factors that influence the modification of the ECM. This alteration increases tumor stiffness and induces the proliferation and growth, along with drug-resistance of the newly transformed epithelial cells . The CAFIn the TME, tumor-associated macrophages (TAMs) comprise the majority of the population within the cellular milieu and are usually activated by a variety of chemokines, from chemokine C-C motif ligand 2 (CCL2) to CCL5 . DependeThe molecular crosstalk and relationship between the prostate TME and AR signaling are of an intricate nature, in which the AR and TME have both tumorigenic and anti-tumorigenic roles . The AR As the benign prostate cells transform into cancer cells, the structural and genomic transition of the stromal cells results in a progressive decrease in AR expression. Starting from low-grade PCa, there is a linear decrease in the mean AR stromal expression, which is almost entirely absent in high-grade disease . It has According to the study results of Abeshouse et al., AR gene mutations and amplifications are observed in 1% of patients with PCa , and appAs a therapeutic form of castration, ADT plays an essential role in the management of metastatic PCa and patients in the advanced setting. This chemical regimen inhibits the production of androgens and consists of anti-androgens that competitively bind to the C-terminal of the AR, resulting in activation blockage of the AR. The ADT regimen usually consists of gonadotropin-releasing hormone (GnRH) agonists that inhibit the production of androgens, such as leuprolide acetate, triptorelin, goserelin acetate, and histrelin ,67,68. ARecent studies and clinical trials have focused on other pathways of AR alterations to better comprehend the vast clinical spectrum of therapeutic resistance to ADT in the clinical setting of PCa. Several AR variants (AR-Vs) that result in natural resistance have been observed in CRPC cell lines . Most AREven in the setting of CRPC, AR signaling continues as a significant factor of tumor growth and disease development . The prop = 0.001). The most common adverse events (AE) were fatigue and musculoskeletal events, which occurred in 31% of the enzalutamide arm in comparison to 21% in the placebo group , p < 0.001). The therapeutic advantages of enzalutamide were observed in all specified subgroups, which consisted of patients with low-volume disease and patients who had received prior chemotherapy with docetaxel. Incidence of grade 3 or higher AE was comparable between the study groups at 24% for enzalutamide-treated patients and 25% for the placebo group. The study concluded that enzalutamide treatment significantly reduced metastatic progression or death, and due to its safety profile, enzalutamide should be considered a viable therapeutic option for patients with mHSPC p = 0.005) and rPFS at 24 months was 68.2% in the study drug cohort while 47.5% was noted in the placebo group. Grade 3 or 4 adverse events were observed with comparable frequency across the two study populations at 42.2% in the apalutamide group and 40.8% in the control group [The therapeutic benefit of apalutamide was explored in the phase III, double-blind, TITAN  NCT02489318) clinical trial [18 clinicThe expression of AR is crucial in the development and progression of PCa, and for this reason, ADT is considered the mainstream treatment of PCa. When stimulated, AR translocation to the nucleus is initiated, and regulation of the genetic code needed for cell growth and proliferation occurs . The purProteolysis-targeting chimeras (PROTACs) are molecular structures that consist of a trimeric complex between a target protein and an E3 ubiquitin ligase, which enables ubiquitination of the target followed by consequent AR degradation ,112. RecIn a phase I clinical trial of ARV-110 (NCT03888612), an orally bioavailable PROTAC, 18 patients with at least two prior therapies regarding mCRPC were administered 140 mg of ARV-110 daily. The study reported that two patients achieved a reduction in PSA of ≥50%. Two patients developed grade 3/4 elevated hepatic enzyme levels, but the overall safety profile of the drug was tolerable . AlthougWith the continuous surge in the incidence of PCa, constant improvement in diagnostic modalities and therapeutic options in the clinical setting are mandatory. The significance of AR signaling in the disease continuum of advanced PCa and mCRPC certifies that the AR receptor will remain as the primary therapeutic target. Despite robust clinical research and developments in the pharmaceutical industry for novel anti-androgens, unmet clinical needs remain, and the various mechanisms of resistance that lead to CRPC suggest the requirement of a fundamentally distinct therapeutic approach with novel drug targets. Numerous mutations of the AR have been described as the underlying mechanism to treatment failure, which opens the opportunity for advances and improvements in the diagnosis of PCa at the molecular level. The clinical nature of PCa mandates the importance of identifying these mutations for a tailored-administration of androgen inhibitors most suitable to each patient. Due to its key role in the transcription process, the AR-NTD has become a target for potential novel inhibitors. Although it is a significant challenge, targeting AR degradation or signal blockage provides the potential for developing SARDs and novel inhibitors, such as PROTACs, to overcome drug resistance in patients with PCa in the advanced and metastatic setting. Despite promising results for both modalities mentioned above, further studies and clinical trials would be needed for these novel approaches to be fully utilized in the everyday clinical setting. The development of novel pharmaceuticals based on the accumulated information regarding AR will ultimately reshape future treatment paradigms and clinical decisions in the ongoing treatment advancement for metastatic and advanced PCa.Due to the advances of modern medicine, improvements in traditional therapies and novel treatments have evolved for the treatment of PCa and the therapeutic armory is continuously increasing. AR signaling is a crucial factor involved in the growth and progression of PCa. Therefore, in accordance with this disease spectrum, anti-AR molecules are in development to target the whole disease spectrum of PCa, from high-risk tumors to CRPC in the metastatic setting. However, there is a need for novel therapeutic approaches to improve the overall outcomes in patients with PCa. Many therapeutic agents with different AR-inhibiting mechanisms have shown efficacy in various clinical trials. Moreover, novel AR inhibitors, such as PROTACs and SARDs, have shown promising preclinical efficacy and safety profiles, therefore providing another option for overcoming resistance to current androgen-targeted therapeutics. Further prospective studies and accumulation of data from ongoing clinical trials will provide elucidation of the resistance mechanism of prostate tumors and the underlying molecular pathways for better treatment response.


Cognitive decline is often present in stroke survivors, with a significant impact on motor recovery. However, how specific cognitive domains could impact motor recovery after robotic rehabilitation in patients with stroke is still not well understood. In this study, we analyzed the relationship between cognitive impairment and the outcome of a robot-mediated upper limb rehabilitation intervention in a sample of 51 subacute stroke patients. Participants were enrolled and treated with a set of robotic and sensor-based devices. Before the intervention, patients underwent a cognitive assessment by means of the Oxford Cognitive Screen. To assess the effect of the 30-session rehabilitation intervention, patients were assessed twice with the following outcome measures: the Fugl-Meyer Assessment for Upper Extremity (FMA-UE), to evaluate motor function; the Upper limb Motricity Index (MI), to evaluate upper limb muscle strength; the Modified Barthel Index (mBI), to evaluate activities of daily living and mobility. We found that deficits in spatial attention and executive functions impacted the mBI improvement, while language, number processing, and spatial attention deficits reduced the gains in the FMA-UE. These results suggest the importance to evaluate the cognitive functions using an adequate tool in patients with stroke undergoing a robotic rehabilitation intervention. Robotic therapy is a well-established approach for upper limb rehabilitation after stroke, to increase the amount and intensity of the therapy and to standardize the treatment . RecentlBesides motor impairment, cognitive decline is often present in stroke survivors. Several studies confirmed the high prevalence of cognitive impairment after stroke ,7,8,9,10However, the impact of cognitive decline on the clinical outcome of a robotic intervention is scarcely considered; therefore, few data on the topic are available. A recent systematic review  on 66 arWe hypothesize that cognitive decline deeply impacts motor recovery after robotic rehabilitation in patients with stroke. The aim of this paper is to evaluate if the impairment of the cognitive functions influences the recovery of the upper limb motor performance in patients after stroke undergoing robotic rehabilitation.This is a secondary analysis of a longitudinal study  approvedAt baseline, demographic and clinical data were recorded; Moreover, patients underwent a cognitive screening: specifically, we used the Italian version of the Oxford Cognitive Screen (OCS), recently developed with the specific aim to describe the cognitive deficits after stroke . The scaTo assess the effect of the rehabilitation intervention, patients were assessed before and after robotic rehabilitation with the following outcome measures: the Fugl-Meyer Assessment for Upper Extremity (FMA-UE) , to evalPatients were treated with a set of robotic and sensor-based devices showed in The upper limb treatment was performed daily for 45 min, 5 days a week, for 30 sessions. More details on the treatment are reported elsewhere . FurtherVisual inspection and the Shapiro–Wilk test showed that data did not meet the criteria for parametric analysis, and therefore, non-parametric tests were used.The percentages of patients with cognitive impairment, according to the OCS scores, were summarized for the whole sample, and patients with a left or a right hemiparesis, separately. The percentage of patients with cognitive impairments were compared according to the affected side, by means of the Fisher Exact test.p-value of 0.05 was deemed significant. Statistical analysis was performed with SPSS .To investigate the impact of cognitive deficits on the recovery of upper limb motor performance, strength, and activities of daily living, the change from baseline of the clinical scales  were compared between patients with or without cognitive deficits, according to the OCS domains, using the Mann-Whitney U test. When significant, the Cohen’s d was computed to assess the effect size . For all the statistical analyses, a The demographic and clinical characteristics of the sample are given in calculation task, about 70%); spatial attention ; language, memory, and executive functions . Lower percentages were found in praxis  and perception . Comparing patients with right and left hemiparesis, a statistically significant difference were detected in sentence reading, recall and recognition, and number writing tasks  and object asymmetry task .emantics, number writing, heart cancelation, and space asymmetry. Similarly, the improvement in the activities of daily living, as assessed by the mBI, was lower in patients showing a pathological score in the object asymmetry and the executive function (baseline score) tasks. On the contrary, the improvement in motor strength, as measured by the MI, did not differ between patients with or without a pathological score in the OCS tests. As showed in heart cancellation task, change in the FMA-UE) and strong for the remaining five tasks.Cognitive impairment is considered a priority in the rehabilitation path of patients after stroke  because In this context, the robotic treatment has been proposed as a viable approach to improve motor performance and activities of daily living; however, the same attention was not paid to the cognitive area. Our results showed that the cognitive status can impact the gain in motor and activities of daily living performance after a robotic rehabilitation intervention. To the best of our knowledge, only one study focused on the influence of cognitive status on motor recovery after robotic upper limb rehabilitation in stroke patients . The autTo better understand our results it is important to describe the clinical, motor, and cognitive function of our sample. About half of the sample was affected by right hemisphere damage, while half was affected by left hemisphere damage; moreover, as expected, ischemic stroke was prevalent. Regarding the activities of daily living dependence and the motor performance of the upper limb, our sample showed a severe disability, associated with a moderate to severe impairment in upper limb motor function and strength.With regard to the assessment of cognitive functions, we used, as a screening tool, the Oxford Cognitive Screening. It is important to note that our group was part of the Italian OCS Group and participated in the study detecting cognitive impairment in stroke patients using the OCS  and, thesentence reading task) and in the memory  domains. In the hearts cancellation task, a higher percentage of right-hemisphere damage patients showed inattention for left space (64.3%), but also a higher percentage of left-hemisphere damage patients showed a higher percentage of right inattention for the right space (60.9%). On the contrary, we detected a higher percentage of failure in the number domain (43.5%) in left-hemisphere damage patients than right-hemisphere damaged patients (14.3%); moreover, left-hemisphere damage patients had a significantly worse performance in the object asymmetry task of the spatial attention (32.1%) than left-hemisphere damaged patients (4.3%). This means that more than 50% of our sample showed an impairment of the attention (measured by heart cancellation task), independently of the side of the lesion. In addition, half of the patients with left-hemisphere damage and about 30% of the patients with right-hemisphere damage showed an impairment of the spatial exploration, while a significantly high percentage of patients with left-hemisphere damage showed a severe deficit seeing the object in its left side. Likely the differences between our and Mancuso’s sample are due to the difference in the time since the stroke onset, higher in Mancuso’s sample than in ours.Similar to the results of the paper of Mancuso et al. , in our The main result of our study was that the impairment in specific cognitive functions, evaluated using a specific tool, negatively influences the post-stroke recovery of the upper limb motor performance and ability in activities of daily living after upper limb robotic rehabilitation. In particular, the improvement in patients with language impairment (semantic functions and abilities to understand and write the numbers heard) was significantly lower than in unimpaired patients. This result can be due to the difficulty of the patient with language impairment to correctly understand the proposed exercises and tasks during upper limb robotic rehabilitation. As expected, patients with an impairment in attention and visuospatial functions showed a lower improvement of the upper limb performance than patients in which these cognitive functions were spared. Similarly, the impairment of visual-spatial functions and executive functions negatively influenced the improvement in the ability of the daily living activities.These results were identified since the OCS was able to separately assess memory, language, number cognition, praxis, executive functions, and attention. Moreover, it is important to note that the administration of OCS is compatible with the presence of severe language impairments, as it includes items that do not require language-based answers ; similarly, the influence of left unilateral spatial neglect is minimized by arranging targets vertically, whenever appropriate.Our result underlined that a cognitive evaluation is important to better address the rehabilitation treatment since the cognitive impairment can negatively influence the upper limb motor performance; however, it is important to highlight that cognitive impairment  in patients after stroke can improve after robotic upper limb rehabilitation. Indeed, as shown in our previous study, upper limb robotic rehabilitation can improve cognitive function as attention and visual-spatial function .In conclusion, this study confirmed our hypothesis, since in our sample we found a relationship between cognitive impairment and post-stroke upper limb motor recovery. In addition, this study confirmed the importance to evaluate cognitive functions in patients with stroke undergoing rehabilitation, using an adequate and specific tool. On the basis of our data, we believe that new robotic exercises, enriched by visual and acoustic feedback, virtual reality application, and cognitive goals, and, therefore, able to combine motor and cognitive training, could enhance the outcome of the treatment.


Compared to other regions of the world, sub-Saharan Africa has made limited progress in the implementation and performance of nationwide human papillomavirus (HPV) vaccination programmes. Without urgent intervention, this will serve to undermine cervical cancer elimination efforts in this region. The primary intent of this narrative review is to highlight the programmatic successes and challenges of the school-based HPV vaccination programme in South Africa since its inception in 2014, with the aim of contributing to the evidence base needed to accelerate implementation and improve programme performance in other sub-Saharan African countries. As of 2020, the proportion of adolescent girls aged 15 years who had received at least one dose of the HPV vaccine at any time between ages 9–14 years was 75%, while 61% had completed the full recommended two-dose schedule. This gives some indication of the reach of the South African HPV vaccination programme over the past 6 years. Despite this, vaccine coverage and dose completion rates have persistently followed a downward trend, slowing progress toward attaining global elimination targets. There is evidence suggesting that declining public demand for the HPV vaccine may be a result of weakening social mobilization over time, inadequate reminder and tracking systems, and vaccine hesitancy. Another concern is the disproportionate burden of HPV and HIV co-infections among adolescent girls and young women in South Africa, which predisposes them to early development of invasive cervical cancer. Moving forward, national policy makers and implementers will have to explore reforms to current age eligibility criteria and vaccine dose schedules, as well as implement strategies to support vaccine uptake among populations like out-of-school girls, girls attending private schools, and HIV positive young women. Additional opportunities to strengthen the South African HPV vaccination programme can be achieved by scaling up the co-delivery of other adolescent health services such as comprehensive sexual and reproductive health and rights education, deworming, and health screening. This calls for reinforcing implementation of the integrated school health policy and leveraging existing adolescent health programmes and initiatives in South Africa. Ultimately, establishing tailored, adolescent-centered, integrated health programmes will require guidance from further operational research. Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related death among women worldwide . The bruRecognizing the devastating impact of cervical cancer on public health, the World Health Assembly passed a resolution in August 2020 to accelerate the elimination of cervical cancer, calling for all member states to adopt multi-sectoral and integrated healthcare approaches aimed at achieving the following triple-intervention coverage targets by 2030; (i) vaccination: 90% of adolescent girls fully vaccinated with the HPV vaccine by the age of 15 years, (ii) screening: 70% of women screened using a high-performance test by the age of 35, and again by the age of 45 years, and (iii) treatment: 90% of women with cervical pre-cancer treated and 90% of women with invasive cervical cancer managed . CurrentThree licensed prophylactic HPV vaccines – the bivalent, quadrivalent and nonavalent HPV vaccines – with excellent safety profiles and relatively similar effectiveness in preventing cervical cancer are currently available for use. As of June 2020, the proportion of countries that had introduced the HPV vaccine partially or nationwide as part of their national immunization programme per region was as follows: 85% in the Americas, 77% in Europe, 56% in Oceania, 40% in Asia, and finally 31% in Africa . Where tIn South Africa, the bivalent and quadrivalent HPV vaccines were first approved for use in 2008, although only available at a cost through the private health sector at the time. In April 2014, South Africa joined countries like Rwanda and Seychelles as one of the first few sub-Saharan African countries to roll-out nationwide HPV vaccination, offered free of charge to grade 4 adolescent girls ≥9 years of age, attending public schools across the country . The schIt is also worth noting that adolescents in South Africa constitute about 19% of the overall population . The burOf the 503,507 eligible grade 4 girls aged ≥9 years attending South African public schools in April 2014, 419,520 were vaccinated with the first dose of the bivalent HPV vaccine during the first round of the nationwide HPV vaccination programme, achieving a high coverage rate of 83% . The secThe disparity in coverage rates between the first and last vaccine doses is also worth noting and suggests an increasing dropout rate over time, ranging from 18% in 2014 to as high as 26% in both 2018 and 2019 . The chaWhere South Africa's progress toward achieving the 2030 vaccine coverage target is concerned, the WHO-UNICEF cumulative data collected by 2020 show that the proportion of adolescent girls aged 15 years who had received at least one dose of the HPV vaccine at any time between ages 9–14 years was 75% while 61% had received the full recommended schedule . It is iOverall, coverage rates over the past 6 years of the nationwide HPV vaccination programme in South Africa are lower than anticipated, given the high uptake rates (>90%) reported during early demonstration projects and feasibility studies , 30. ThiThe successful implementation of the nationwide HPV vaccination programme in South Africa has been largely attributed to the strong political commitment, intersectoral collaboration among the National Departments of Health, Basic Education and Social Development, careful planning and coordination at provincial and district levels, and strong leadership from the National Department of Health . This stOn the supply side, factors such as appropriate vaccine dose schedules, eligibility, cost, vaccine delivery strategies, vaccine availability and accessibility, partnerships with key stakeholders, quality of health infrastructure, and capacity of vaccinators including staffing, capability, and level of knowledge, can all influence HPV vaccine uptake and completion rates. Although the bivalent and quadrivalent HPV vaccines were initially licensed as three-dose vaccines, a two-dose schedule was widely adopted following demonstration of non-inferior immunogenicity between both schedules , 31. ThePolicy decisions on the eligibility for the HPV vaccine is another critical supply-side factor as limited and missed opportunities for vaccination could contribute to suboptimal vaccine uptake and compromise elimination efforts. There have been calls to expand the reach of the South African HPV vaccination programme given the unique epidemiology of HPV infection and co-burden of other sexually transmitted infections  among AGYW >15 years of age . SeveralIn terms of HPV vaccine availability and accessibility in South Africa, providing free HPV vaccination to eligible girls continues to be a major driver of vaccine uptake. According to the 2019 School Realities Report by the Department of Basic Education , of the Given the current context, it is worth highlighting how South Africa has approached the school-based HPV vaccination programme during the COVID-19 pandemic. Intermittent school closures in response to multiple waves of the COVID-19 pandemic disrupted HPV vaccine delivery particularly in 2020 and may have even led to wasted doses. Without appropriately adapting the HPV vaccination programme amid the COVID-19 context, South Africa would have gone on to lose a year's worth of the programme with half a million eligible girls missing out on lifesaving vaccination. Fortunately, the South African National Advisory Group on Immunization recommended pivoting the HPV vaccination programme to prioritize adolescent girls in grade 5, most of whom may have missed their scheduled doses in 2020 due to the pandemic . It is aPublic demand for the HPV vaccine may be influenced by the level of knowledge, awareness and attitudes of the various stakeholders involved in the HPV vaccination programme. These stakeholders include, the parents or caregivers of adolescent girls, adolescent girls themselves, their peers, teachers, and healthcare providers. The influence of these stakeholders on the performance of the vaccination programme stresses the need for sustained, inclusive, and strengthened vaccine communication, education and promotional campaigns aimed at increasing stakeholders' knowledge and awareness about the life-time risk of HPV infection and the risks and benefits of the HPV vaccine in an effort to increase public trust and encourage positive attitudes toward the vaccination programme. Previous systematic reviews , 45 haveTo improve HPV vaccine acceptance and uptake, the WHO recommends that national immunization programmes invest in effective vaccine communication strategies and provides clear guidance on developing and delivering such strategies . In SoutOne of the persistent reasons for reluctance or non-acceptance of the HPV vaccine among stakeholders has been the misconceptions about the safety of the vaccine. Even among parents and caregivers with high levels of education, unaddressed safety concerns about the HPV vaccine may fuel negative attitudes like hesitancy or unacceptance . Our revWithout easy access to careful and transparent information about the safety and benefits of the HPV vaccine, stakeholders may not be able to demand lifesaving HPV vaccines, instead turning to readily available false and often dangerous information in making the decision to refuse the vaccine altogether. Although difficult to quantify, it has been suggested that vaccine hesitancy may play an important role in the suboptimal HPV vaccine coverage and completion rates observed in South Africa, however this is yet to be comprehensively researched . Among ahttp://sheconquerssa.co.za/) and B-Wise , as well as others with similar mandates.Demand generation for the HPV vaccine in South Africa can be improved through continued multi-level engagements with the full scope of stakeholders. Such engagements should adopt tailored, community-based communication and sensitization campaigns with the goal of increasing public awareness and trust in the HPV vaccine. In the current COVID-19 context, clear and effective communication strategies will be important in ensuring that adolescent girls and their parents or caregivers do not confuse ongoing COVID-19 vaccine roll-out with the HPV vaccination programme. The need to empower adolescent girls to demand lifesaving HPV vaccines cannot be overstated. Opportunities exist for creating national spaces and platforms which encourage adolescent girls to be at the forefront of HPV and cervical cancer advocacy and awareness campaigns which can be linked with existing initiatives like the She Conquers campaign   makes prThere is limited evidence in the published literature on the co-delivery of HPV vaccines and other adolescent health services in South Africa. Further operational research studies are required to improve our limited understanding of the successes and challenges of such integrated programmes. Evidence from elsewhere suggests that while delivering the HPV vaccine alongside other adolescent health services in schools offers significant prospects in terms of adolescent health and wellbeing, such programmes come with substantial financial, logistical, and operational challenges . In thisWe present recommendations for expanding current research and practice aimed at scaling up the delivery and uptake of adolescent health services alongside the HPV vaccination programme in South Africa . DrawingAlthough a systematic literature search was performed as part of this narrative review, it is possible that the strategy used may have excluded key literature sources. While we attempted to adequately capture core themes and trends emerging from the pre-HPV vaccine introduction era to date by expanding the scope of the review to include literature sources published between 2010 and 2021, the findings may not comprehensively capture the real-world experiences of the HPV vaccination programme in South Africa. In addition, the review findings may not be generalizable to all settings and calls for further systematic reviews and syntheses to be conducted.Overall, sustained implementation of a nationwide school-based HPV vaccination programme in South Africa has been successful, at least over the past 6 years. Moving forward, improving demand generation will be crucial in recovering optimal HPV vaccine coverage and completion rates among eligible adolescent girls. This will have to be supported by up-to-date research evidence on the determinants of HPV vaccine uptake and dose completion. Maximizing the utility of the HPV vaccination programme as an entry point for delivering comprehensive adolescent health care will require, (i) further high-level political commitment and multi-sectoral collaboration, aimed at scaling up the HPV vaccination programme with the local unique disease epidemiology in mind, (ii) reinforcing the implementation of the integrated school health policy, and (iii) appropriately linking adolescents to existing programmes and initiatives which meet their expressed healthcare needs.As more countries in sub-Saharan Africa prepare to introduce nationwide HPV vaccination programmes, policymakers and immunization managers will rely on the lessons learned in countries with existing and mature programmes. While the South African HPV vaccination programme may be unique for several reasons including the fact that it is fully funded by the national government, the experiences gained over the past 6 years are worth sharing and could make useful contributions to the body of evidence needed to accelerate HPV vaccination and cervical cancer elimination efforts across sub-Saharan Africa. Future HPV vaccination programmes in sub-Saharan Africa will have to secure the involvement of policy makers and influencers, including adolescents, to support and sustain implementation. Furthermore, future, and existing HPV vaccination programmes in sub-Saharan Africa will need to strengthen the implementation of context-specific and adolescent-centered strategies needed to maintain high demand for HPV vaccination and reduce missed opportunities for vaccination and dropout rates. It is also important to stress the need for adaptable HPV vaccination programmes which can withstand acute and prolonged health systems shocks such as those caused by disease outbreaks and pandemics. Finally, given that the widely observed inequitable distribution of COVID-19 vaccines has strengthened calls to invest in scaling up vaccine manufacturing capacity within sub-Saharan Africa, it is imperative that the production of low-cost generic HPV vaccines form part of this regional policy agenda as an avenue to address vaccine supply challenges.EA-D developed the review concept and wrote the initial draft of the manuscript. EA-D, NB, VVN, and VC contributed to the overall review process, including the literature search, screening, data extraction, and analysis. All authors approved the final version of the manuscript.EA-D was supported by funding from the Harry Crossley Postdoctoral Research Fellowship, 2021. The funder had no role in the conception of the review, data collection and analysis, preparation of the manuscript, or the decision to publish.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Since the first evidence suggesting that maternal nutrition can impact the development of diseases in the offspring, much has been elucidated about its effects on the offspring’s nervous system. Animal studies demonstrated that maternal obesity can predispose the offspring to greater chances of metabolic and neurodevelopmental diseases. However, the mechanisms underlying these responses are not well established. In recent years, the role of the gut-brain axis in the development of anxiety and depression in people with obesity has emerged. Studies investigating changes in the maternal microbiota during pregnancy and also in the offspring demonstrate that conditions such as maternal obesity can modulate the microbiota, leading to long-term outcomes in the offspring. Considering that maternal obesity has also been linked to the development of psychiatric conditions (anxiety and depression), the gut-brain axis is a promising target to be further explored in these neuropsychiatric contexts. In the present study, we review the relationship between maternal obesity and anxious and depressive features, exploring the gut-brain axis as a potential mechanism underlying this relationship. The Developmental Origins of Health and Disease (DOHaD) theory brought by Neurodevelopmental disorders are well documented in the offspring of obese mothers in humans and animal models . HoweverConsidering that obesity during pregnancy is increasing globally , as wellThis review will discuss the influence of maternal overnutrition on the development of depression and anxiety in the offspring. We will emphasize the role of the gut-brain axis in the mechanisms linking maternal obesity to the harmful neurodevelopment of the progeny.Intrauterine overnutrition could affect the fetal programming, increasing the risk of the newborn developing neuropsychiatric conditions such as depression .Offspring of rodent mothers fed with a high-fat diet (HFD) during pregnancy and lactation shows increased depressive-like behaviour in adolescence and adulthood , even ifMaternal exposure to HFD, or a carbohydrate-rich diet, also affects the dopaminergic (DA) system by changing the amount of dopamine and its metabolite DOPAC  in the nucleus accumbens and the expression of dopamine receptors D1/D2 in the ventral tegmental area . DysreguClinical studies have reported that elevated levels of proinflammatory cytokines in obese pregnant women can lead to placental dysfunction and are related to neurodevelopmental and neuropsychiatric disorders in the offspring [for review see ]. EvidenFurthermore, emotional changes in the progeny were associated with maternal nutritional status  and highMaternal obesity has been associated with offspring’s anxiety independently of sex, species, and age . HoweverDuring adolescence, there is an increase in anxiety in the offspring of HFD-fed dams, shown in the light-dark transition task, but a decrease in anxiety in the open field and elevated plus-maze, which could be interpreted as an increased risky behaviour rather than decreased anxiety. Importantly, an increase in the expression of nuclear factor kappa B (NF-kB) and IL-6 genes, responsible for inflammatory responses, was found in the hippocampus of adolescent offspring of dams fed with a hypercaloric diet. But an increase in the expression of anti-inflammatory genes such as IkBα and mitogen-activated protein kinase MKP-1 was also seen, suggesting a disturbance in the expression of inflammatory mediators in the brain of these animals . On the Most studies involving maternal consumption of obesogenic diets use the HFD model. However, the cafeteria diet (CAF) model provides animals with ultra-processed human food consumption and has translational potential . Wright Otherwise, consuming CAF exclusively during pregnancy increased maternal behaviours such as licking pups, arched nursing, and nest building after 2- and 8-days following birth. Interestingly, even with increased maternal behaviour, the offspring demonstrated behavioural disturbances in adolescence such as increased anxiety-like manifestations during light-dark tests .Data presented so far reinforce a causative relationship between maternal diet and neurologic programming in offspring. However, the underlying mechanism involved in this phenomenon remains elusive. Despite that, the influence of maternal microbiota on the development of anxious behaviours in the offspring has emerged as a mechanism that is sufficient to disrupt behavioural function in murine offspring in a sex-specific manner . It suggIn addition to fermenting non-digestible fibers from the diet, which increases energy extraction from food, the influence of the gut microbiota on the host’s physiology has been gaining notoriety from studies that demonstrate a bi-directional relationship with the brain, a pathway coined as the gut-brain axis . AlthougAkkermansia, Clostridium, Bacteroides, and Bifidobacterium genera was found in C57BL/6 pregnant mice, supporting the idea of gut microbiome changes during pregnancy  and Bifidobacterium compared to lean pregnant animals  reach the circulation, where they activate inflammatory responses that can become chronic and lead to psychiatric manifestations . YucatanLactobacillus rhamnosus and Bifidobacterium lactis supplementation in obese pregnant women regarding depression and well-being (Therefore, microbiota and its metabolites may provide an interesting mechanism of how the gut-brain axis is involved in the effects of obesity on the offspring’s brain and also provide a potential therapeutic target. The use of prebiotics and probiotics has provoked interest in the scientific community in recent years. While probiotics can modulate the composition of intestinal bacteria, prebiotics are the substrate used for fermentation and production of metabolites with an interest to improve host health. Recent research data indicate positive impacts of these strategies regarding metabolic diseases and also in the CNS, including improvement of cognitive impairment, anxiety, and depression [for a review see ]. The gell-being . TherefoAs already mentioned, dysbiosis may be related to the genesis of chronic inflammation in obesity and, through the gut-brain axis, trigger neuroinflammation and the development of psychiatric manifestations . MaternaIn this review, we highlighted the influence of maternal overnutrition and obesity on offspring’s CNS manifestations, mainly on depression and anxiety, psychiatric disorders increasingly prevalent in the world. We also show how the gut-brain axis is altered during pregnancy and obesity. Accordingly, healthier food consumption during pregnancy must be encouraged to prevent this global health issue .Depression and anxiety may manifest at different stages of life, either in childhood, adulthood, or aging. Whenever it happens, the causes regarding maternal exposure cannot be excluded. Thus, a particularly productive focus for research would be to better understand the influence of the microbiota of obese mothers on the offspring’s brain, allowing the establishment of the importance of therapeutic interventions in this context. Modulating the microbiota through a healthier diet can be beneficial to the offspring, as maternal and offspring dietary fiber consumption was demonstrated to diminish cognitive and social disabilities while improving synaptic function and microglia maturation in the offspring . The use


Admixed populations arise when two or more ancestral populations interbreed. As a result of this admixture, the genome of admixed populations is defined by tracts of variable size inherited from these parental groups and has particular genetic features that provide valuable information about their demographic history. Diverse methods can be used to derive the ancestry apportionment of admixed individuals, and such inferences can be leveraged for the discovery of genetic loci associated with diseases and traits, therefore having important biomedical implications. In this review article, we summarize the most common methods of global and local genetic ancestry estimation and discuss the use of admixture mapping studies in human diseases. Admixed populations are the result of gene flow between reproductively isolated groups, owing to events that have occurred throughout human history, including migratory events, the discovery of new territories, or the slave trade. As a result of the intermixture and recombination, over time, the genomes of individuals in the hybrid population will contain a mosaic of ancestries from different population sources in their chromosomes. The length of the chromosome segments inherited from the different ancestral populations will be proportional to the time elapsed since the admixture event. These tracts shorten over the generations by the meiotic recombination process, so that the most recently admixed populations, such as the Canary Islanders in Spain or the Latino populations, would retain longer ancestral tracts, while the populations that mixed more distantly in time, such as the Uyghur in China, would harbor shorter ancestry segments in their chromosomes ,2.As such, the admixture proportions and the elapsed time since the admixture event can be inferred based on linkage disequilibrium (LD) ,4. When Several studies support that genetic ancestry and admixture can partially explain the differences in the prevalence of complex diseases and treatment responses between population groups, due to the unequal distribution of allelic frequencies of the underlying causal variants across populations. As such, and given that the prevalence of many traits and diseases differs between populations, the analysis of genetic ancestry differences between affected and nonaffected subjects, as well as the link of these differences with the pathogenesis, and with evolutionary, environmental, or behavioral factors, plays an important role in biomedical research. Some examples are the high prevalence of multiple sclerosis among Europeans , of diabCYP2C19) and Paraoxonase 1 (PON1) genes, which are highly structured by ancestry, modify the response of the antiplatelet agent clopidogrel in Puerto Ricans [Many studies also support the existence of genetic variants affecting drug metabolism, transport, and toxicity, which vary widely among populations and ethnic groups ,11. In to Ricans . Additioo Ricans  or to tro Ricans .Given the importance of genetic ancestry in medicine, here, we provide an updated review of the most common methods for global and local genetic ancestry estimation, and of their use in admixture mapping approaches, highlighting a few key findings from the recent literature. We also discuss the potential of Next Generation Sequencing (NGS) data for ancestry estimation.Global ancestry (GA) is the fraction of genomic ancestry from each admixed individual that can be ascribed to each of the ancestral populations contributing to the recently admixed population A. The esLocal ancestry (LA) is a term commonly used to refer to the ancestry in each of the chromosome blocks, also known as ancestral tracks, in recently admixed individuals B. For thSome of the genetic characteristics of recently admixed populations described above (chromosome blocks and ALD distribution) allow the estimation of ancestry with a relatively small number of genetic markers. These markers are usually single nucleotide polymorphisms (SNPs) with a different distribution between populations, known as ancestry informative markers (AIMs). Their number will also depend on the assessed population, the ancestral groups, and the time since the admixture event . In ordeThe use of genotyping microarrays has also led to the development of improved methods to infer LA, such as LAMP-LD , RFMix , and HAPIn order to identify the optimal approach for each scenario, benchmarking the different algorithms and reference panels is necessary. Previous reviews have compared the characteristics and effectiveness of local ancestry estimators ,44,45,46Regarding the necessary requirements for the use of each estimator, it must be considered, for example, whether a phasing step is needed prior to ancestry estimation. This step is crucial for an accurate estimate of ancestry and is closely linked to the density of available markers . TherefoMoreover, the inherent characteristics of the population under study can also influence software selection. For example, although RFMIX  or LAMP-Finally, another important aspect that must be considered is the computational requirements of each software, such as the execution time or memory used, which is strongly conditioned by the sample size of the admixed sample under study ,44. In tThe distribution of allelic frequencies in recently admixed populations is closely related to those frequencies found in their ancestral populations ,49. WhenAdmixture mapping studies can be performed using case-only or case-control approaches. The case-only design is based on the comparison between observed and average expected ancestry to detect loci enriched in one of the ancestries, while the case-control approach consists of comparing LA pointwise between cases and controls ,54. AlthSince 2005, genome-wide association studies (GWAS) have allowed the identification of thousands of genetic loci associated with many traits, including complex diseases . HoweverOn the contrary, admixture mapping studies lose efficiency when allele frequencies are similarly distributed among ancestral populations and when the LD in the parental populations is unknown ,65. FurtBased on admixed populations, several studies have implemented admixture mapping approaches to reveal novel risk factors associated with complex diseases, including cancer, hypertension, and autoimmune, respiratory, and infectious diseases. Primarily, these studies have been widely applied in African Americans and Hispanic/Latino populations. The genetic contribution of each of the parental populations has been estimated for African Americans from four different states, providing an estimate of average ancestry corresponding to 76.4% African, 20.9% European, and 2.7% Native American . A similMycobacterium tuberculosis in the South African Colored population [Staphylococcus aureus in African Americans [Zhu and colleagues performed an admixture mapping in African Americans, identifying an excess of African ancestry at 6p24 and 21p21 associated with hypertension . Gignouxpulation  and the mericans , allowinmericans ,11. Thermericans .EYS) gene significantly associated with type 2 diabetes [PLCG2) gene, located in that region, was enriched of deleterious variants among asthma cases [Additionally, although less frequently, admixture mapping studies have also been performed in admixed populations other than Latinos or African Americans. For instance, Sun and colleagues recently performed an admixture mapping approach in the Hawaiian population in order to determine the relation of the genetic admixture with different cardiovascular traits. Interestingly, this admixed population  has a hdiabetes . Moreovediabetes . This stma cases . Likewisma cases , and thema cases . GeneticThe technological development of NGS over the years, together with the reduction in the sequencing costs, offers a great opportunity for genetic ancestry studies to develop further. Among the major advantages of this technology compared to microarrays  is its hHowever, although the application of NGS implies important advances, its use to estimate LA still has important limitations . First, Although the blooming use of NGS represents a great opportunity for population studies improvement, only two NGS-based admixture mapping studies have been published to date ,91. Liu Genetic ancestry studies and admixture mapping approaches have expanded genetic knowledge in biomedical research, revealing new loci associated with traits and diseases that could not have been detected by conventional association studies. Despite this, the available genomic resources need to be improved to obtain more accurate ancestry inferences. For instance, WGS data for African or Middle Eastern populations are still limited. Interestingly, the genetic features of Arab populations could be a valuable opportunity, especially in the study of recessive traits given the high rate of consanguinity that could be overlooked in other population groups . In thisConsequently, a more equitable representation of the ancestral groups in association studies will improve the development of personalized medicine. The unequal proportion in European-based GWAS is known to generate a bias in the findings that could lead to misinterpretations and hamper the risk prediction, prognosis, or response to drugs in under-represented populations . In thisThere are other approaches currently used in biomedical research that would benefit from taking genetic ancestry into account. Gene expression studies, which seek to explain how the expression of certain genes influences the development or severity of a trait, are an example. Based on the evidence that gene expression levels also differ between populations, in recent years, there has been a need to incorporate ancestry in expression studies and generate ancestry-dependent transcriptomic profiles ,98,99. AIn summary, promoting genetic studies in admixed populations, and the use of admixture mapping studies, combined with the alternative approaches described, promise the identification of novel disease associations and a better understanding of complex trait genetics. Eventually, these results will translate into a more equitable representation of the catalogs of genetic variation across populations.


Polyaromatic hydrocarbons (PAHs) are hazardous organic molecules with mutagenic, carcinogenic and genotoxic effects. According to the United States Environmental Protection Agency (USEPA) total 16 PAHs are considered as priority pollutants and are toxic for living organisms  in contaminated sites have also emerged to be highly effective and provide a considerable amount of PAH removal . In this technique, a solid anode is utilized as an inexhaustible electron acceptor and microbial activity is enriched by biocurrent in situ to confirm removal of PAHs. The review elaborates the degradation of PAHs using MES, as well as its effectiveness in different settings, such as modification of the anode, improvement of substrate and transfer of an electron, supplementation of chemical reagents. The mass transfer of PAHs combined with phytoremediation, functional microorganisms and exoelectrogens, electrochemical activity and internal resistance, the power density and current density of the PAH removal system have also been explained . Further, an overview of physical and chemical techniques for the remediation of PAHs such as adsorption, soil filtration, membrane filtration, thermal-, or electrokinetic- oxidation and photocatalytic treatments has been discussed. In addition, a detailed systematic compilation of the use of microbial treatments, in-situ and ex-situ biological treatments like bioaugmentation, land-farming, biostimulation, phytoremediation, bioreactor, vermiremediation and generation of value-added by-products during degradation of PAHs has been elaborated, which will be highly useful for scale-up of technologies at commercial level . Rhizoremediation is one of the strategies in bioremediation that uses plant-microbe interaction for the removal of higher-molecular-weight PAHs In this issue, in one of the articles, the microbial electrochemical system (MES) of specific designs for PAH removal has been elaborated with unique details One of the main sources of PAH contamination is the use of crude oil. The process by which crude oil is sourced and available for use is known as the oil supply chain during which crude oil is subjected to acidification, bio-deterioration, which affects the environment and economy. Genes and pathways involved in PAH degradation in different stages of the oil supply chain had been described that adversely affect various environments  and present challenges for PAH bioremediation for oil spills  In another paper, the potential of fungal bioaugmentation was utilized as an efficient strategy to improve the bioremediation of an aged industrially polluted soil enriched with heavy hydrocarbon. A consortium of six potentially hydrocarbonoclastic fungi was applied, and compared with soil biostimulation process (water and nutrient addition). Bioaugmentation of indigenous fungi resulted in an important shift of the bacterial populations, which was also linked to HMW-PAHs biodegradation efficiency, compared to biostimulation. Also, the fungal bioaugmentation with indigenous fungi exerted an influence on the soil bacterial populations toward a more diverse microbial community Not only bacteria but fungi have also been exploited for PAH removal from contaminated environments. The role of fungi in the long-term natural bioremediation of contaminated soils has been assessed, and reported, and summarized as it could also contribute to the development of a fungal community adapted to the contaminated soils. Next-generation sequencing is accompanied with the microbiome and functional diversity of fungi based on Biolog FFPlates, glomalin-related soil protein (GRSP) content, trace element and PAH concentration. In this study, soils collected from oil wells had shown to be more diversified with higher biological activity (35% share the PAHs degrading population) as compared with 3 m radius of the oil wells (<5% share the PAHs degrading population) (Innovative strategies are being devised for removal of HMW-PAHs from the contaminated environments. Some of the recent and promising technologies have been described in this issue. However, there had been concerns for the efficiency of each such technology (Gan et al., PP prepared the draft and finalized the manuscript. AK and SB edited and corrected the draft. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.