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International Journal of Molecular... Apr 2021Polycystic ovarian syndrome (PCOS) is the most common endocrine-metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial... (Review)
Review
Polycystic ovarian syndrome (PCOS) is the most common endocrine-metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology and pathogenesis; however, their causative role in PCOS development requires further investigation. As a low-grade chronic inflammation disease, PCOS patients have permanently elevated levels of inflammatory markers (TNF-α, CRP, IL-6, IL-8, IL-18). In this review, we summarise recent data regarding the role of mtDNA mutations and mitochondrial malfunctions in PCOS pathogenesis. Furthermore, we discuss recent papers dedicated to the identification of novel biomarkers for early PCOS diagnosis. Finally, traditional and new mitochondria-targeted treatments are discussed. This review intends to emphasise the key role of oxidative stress and chronic inflammation in PCOS pathogenesis; however, the exact molecular mechanism is mostly unknown and requires further investigation.
Topics: DNA, Mitochondrial; Female; Humans; Inflammation; Mitochondria; Mutation; Oxidative Stress; Polycystic Ovary Syndrome
PubMed: 33920227
DOI: 10.3390/ijms22083923 -
Clinical Endocrinology Aug 2022Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic... (Review)
Review
Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Female; Hirsutism; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Virilism
PubMed: 35349173
DOI: 10.1111/cen.14710 -
Journal of Internal Medicine May 2022In line with increasing numbers of transgender (trans) and gender nonbinary people requesting hormone treatment, the body of available research is expanding. More... (Review)
Review
In line with increasing numbers of transgender (trans) and gender nonbinary people requesting hormone treatment, the body of available research is expanding. More clinical research groups are presenting data, and the numbers of participants in these studies are rising. Many previous review papers have focused on all available data, as these were scarce, but a more recent literature review is timely. Hormonal regimens have changed over time, and older data may be less relevant for today's practice. In recent literature, we have found that even though mental health problems are more prevalent in trans people compared to cisgender people, less psychological difficulties occur, and life satisfaction increases with gender-affirming hormone treatment (GAHT) for those who feel this is a necessity. With GAHT, body composition and contours change towards the affirmed sex. Studies in bone health are reassuring, but special attention is needed for adolescent and adult trans women, aiming at adequate dosage of hormonal supplementation and stimulating therapy compliance. Existing epidemiological data suggest that the use of (certain) estrogens in trans women induces an increased risk of myocardial infarction and stroke, the reason that lifestyle management can be an integral part of trans health care. The observed cancer risk in trans people does not exceed the known cancer-risk differences between men and women. Now it is time to integrate the mostly reassuring data, to leave the overly cautious approach behind, to not copy the same research questions repeatedly, and to focus on longer follow-up data with larger cohorts.
Topics: Adolescent; Adult; Female; Gender Identity; Humans; Male; Neoplasms; Testosterone; Transgender Persons; Transsexualism
PubMed: 34982475
DOI: 10.1111/joim.13441 -
Human Genomics Jun 2017Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable... (Review)
Review
BACKGROUND
Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1.
MAIN BODY
Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context.
CONCLUSION
As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.
Topics: Genes, Neurofibromatosis 1; Humans; Mutation; Neoplasms; Neurofibromatosis 1
PubMed: 28637487
DOI: 10.1186/s40246-017-0109-3 -
Ugeskrift For Laeger Oct 2022Physical function (PF) is a strong predictor for length of stay, complications, readmission, and mortality among patients across different diagnoses. Still, systematic...
Physical function (PF) is a strong predictor for length of stay, complications, readmission, and mortality among patients across different diagnoses. Still, systematic assessment of PF in hospitalised patients is not common, and if, only among the oldest. In this review, we suggest implementation of an easily applicable and validated test battery using the Cumulated Ambulation Score for basic mobility, Handgrip strength for general muscle strength, and the 30s Chair Stand Test for combined function and muscle strength for early identification and treatment of reduced PF in adult patients across diagnoses.
Topics: Female; Adult; Humans; Insulin Resistance; Diabetes Mellitus, Type 2; Risk Factors; Polycystic Ovary Syndrome; Obesity
PubMed: 36331169
DOI: No ID Found -
Current Opinion in Cell Biology Oct 2017Tumors are strongly influenced by the surrounding normal tissue, which forms a specialized niche termed the tumor microenvironment (TME). The TME is modeled by cancer... (Review)
Review
Tumors are strongly influenced by the surrounding normal tissue, which forms a specialized niche termed the tumor microenvironment (TME). The TME is modeled by cancer cells for their own benefit through a complex array of interactions. The identification of new forms of communication within the TME, which are dependent on the tumor's metabolic activity, has expanded our understanding of this heterocellular regulation and has revealed potential therapeutic targets. This review will summarize recent findings on the metabolic regulation of tumor cells by the TME. The concepts to be discussed include the existence of metabolic intratumoral heterogeneity, the contribution of cancer associated fibroblasts (CAFs) to tumor progression, and the regulation of tumor immunology by tumor-secreted metabolites.
Topics: Animals; Fibroblasts; Glucose; Humans; Metabolic Networks and Pathways; Neoplasms; Tumor Microenvironment
PubMed: 28605656
DOI: 10.1016/j.ceb.2017.05.006 -
Journal of Clinical Oncology : Official... Jul 2017Neurofibromatosis (NF) encompasses a group of distinct genetic disorders in which affected children and adults are prone to the development of benign and malignant... (Review)
Review
Neurofibromatosis (NF) encompasses a group of distinct genetic disorders in which affected children and adults are prone to the development of benign and malignant tumors of the nervous system. The purpose of this review is to discuss the spectrum of CNS tumors arising in individuals with NF type 1 (NF1) and NF type 2 (NF2), their pathogenic etiologies, and the rational treatment options for people with these neoplasms. This article is a review of preclinical and clinical data focused on the treatment of the most common CNS tumors encountered in children and adults with NF1 and NF2. Although children with NF1 are at risk for developing low-grade gliomas of the optic pathway and brainstem, individuals with NF2 typically manifest low-grade tumors affecting the cranial nerves (vestibular schwannomas), meninges (meningiomas), and spinal cord (ependymomas). With the identification of the NF1 and NF2 genes, molecularly targeted therapies are beginning to emerge, as a result of a deeper understanding of the mechanisms underlying NF1 and NF2 protein function. As we enter into an era of precision oncology, a more comprehensive awareness of the factors that increase the risk of developing CNS cancers in affected individuals, coupled with a greater appreciation of the cellular and molecular determinants that maintain tumor growth, will undoubtedly yield more effective therapies for these cancer predisposition syndromes.
Topics: Central Nervous System Neoplasms; Child; Clinical Trials as Topic; Combined Modality Therapy; Humans; Molecular Targeted Therapy; Neoplasm Grading; Neurofibromatoses; Neuroimaging; Risk Factors
PubMed: 28640700
DOI: 10.1200/JCO.2016.71.7199 -
Neurotherapeutics : the Journal of the... Oct 2022Genetic syndromes which develop one or more nervous system (NS) tumors as one of the manifestations can be grouped under the umbrella term of NS tumor predisposition... (Review)
Review
Genetic syndromes which develop one or more nervous system (NS) tumors as one of the manifestations can be grouped under the umbrella term of NS tumor predisposition syndromes. Understanding the underlying pathological pathways at the molecular level has led us to many radical discoveries, in understanding the mechanisms of tumorigenesis, tumor progression, interactions with the tumor microenvironment, and development of targeted therapies. Currently, at least 7-10% of all pediatric cancers are now recognized to occur in the setting of genetic predisposition to cancer or cancer predisposition syndromes. Specifically, the cancer predisposition rate in pediatric patients with NS tumors has been reported to be as high as 15%, though it can approach 50% in certain tumor types (i.e., choroid plexus carcinoma associated with Li Fraumeni Syndrome). Cancer predisposition syndromes are caused by pathogenic variation in genes that primarily function as tumor suppressors and proto-oncogenes. These variants are found in the germline or constitutional DNA. Mosaicism, however, can affect only certain tissues, resulting in varied manifestations. Increased understanding of the genetic underpinnings of cancer predisposition syndromes and the ability of clinical laboratories to offer molecular genetic testing allows for improvement in the identification of these patients. The identification of a cancer predisposition syndrome in a CNS tumor patient allows for changes to medical management to be made, including the initiation of cancer surveillance protocols. Finally, the identification of at-risk biologic relatives becomes feasible through cascade (genetic) testing. These fundamental discoveries have also broadened the horizon of novel therapeutic possibilities and have helped to be better predictors of prognosis and survival. The treatment paradigm of specific NS tumors may also vary based on the patient's cancer predisposition syndrome and may be used to guide therapy (i.e., immune checkpoint inhibitors in constitutional mismatch repair deficiency [CMMRD] predisposition syndrome) [8]. Early diagnosis of these cancer predisposition syndromes is therefore critical, in both unaffected and affected patients. Genetic counselors are uniquely trained master's level healthcare providers with a focus on the identification of hereditary disorders, including hereditary cancer, or cancer predisposition syndromes. Genetic counseling, defined as "the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease" plays a vital role in the adaptation to a genetic diagnosis and the overall management of these diseases. Cancer predisposition syndromes that increase risks for NS tumor development in childhood include classic neurocutaneous disorders like neurofibromatosis type 1 and type 2 (NF1, NF2) and tuberous sclerosis complex (TSC) type 1 and 2 (TSC1, TSC2). Li Fraumeni Syndrome, Constitutional Mismatch Repair Deficiency, Gorlin syndrome (Nevoid Basal Cell Carcinoma), Rhabdoid Tumor Predisposition syndrome, and Von Hippel-Lindau disease. Ataxia Telangiectasia will also be discussed given the profound neurological manifestations of this syndrome. In addition, there are other cancer predisposition syndromes like Cowden/PTEN Hamartoma Tumor Syndrome, DICER1 syndrome, among many others which also increase the risk of NS neoplasia and are briefly described. Herein, we discuss the NS tumor spectrum seen in the abovementioned cancer predisposition syndromes as with their respective germline genetic abnormalities and recommended surveillance guidelines when applicable. We conclude with a discussion of the importance and rationale for genetic counseling in these patients and their families.
Topics: Humans; Child; Li-Fraumeni Syndrome; Neoplastic Syndromes, Hereditary; Brain Neoplasms; Genetic Predisposition to Disease; Neurofibromatosis 1; Tumor Microenvironment; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 36056180
DOI: 10.1007/s13311-022-01277-w -
Orphanet Journal of Rare Diseases Sep 2023To obtain updated estimates of the incidence and prevalence of neurofibromatosis type 1 (NF1) and type 2 (NF2). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To obtain updated estimates of the incidence and prevalence of neurofibromatosis type 1 (NF1) and type 2 (NF2).
STUDY DESIGN
We conducted a systematic search of NF1 and NF2 incidence or prevalence studies, in OVID Medline, OVID Embase, Web of Science, and Cinahl. Studies were appraised with the Joanna Briggs Institute Prevalence Critical Appraisal tool. Pooled incidence and prevalence rates were estimated through random-effects meta-analysis.
RESULTS
From 1,939 abstracts, 20 studies were fully appraised and 12 were included in the final review. Pooled NF1 prevalence was 1 in 3,164 (95%CI: 1 in 2,132-1 in 4,712). This was higher in studies that screened for NF1, compared to identification of NF1 through medical records (1 in 2,020 and 1 in 4,329, respectively). NF1 pooled birth incidence was 1 in 2,662 (95%CI: 1 in 1,968-1 in 3,601). There were only 2 studies on NF2 prevalence, so data were not pooled. Pooled NF2 birth incidence was 1.08 per 50,000 births (95%CI: 1 in 32,829-1 in 65,019).
CONCLUSION
We present updated estimates of the incidence and prevalence of NF1 and NF2, to help plan for healthcare access and allocation. The prevalence of NF1 from screening studies is higher than from medical record studies, suggesting that the disease may be under recognized. More studies are needed regarding the prevalence of NF2.
Topics: Humans; Incidence; Neurofibromatosis 1; Prevalence; Health Services Accessibility; Medical Records
PubMed: 37710322
DOI: 10.1186/s13023-023-02911-2 -
Biology of Sex Differences May 2020Immunotherapies are often used for the treatment, remission, and possible cure of autoimmune diseases, infectious diseases, and cancers. Empirical evidence illustrates... (Review)
Review
Immunotherapies are often used for the treatment, remission, and possible cure of autoimmune diseases, infectious diseases, and cancers. Empirical evidence illustrates that females and males differ in outcomes following the use of biologics for the treatment of autoimmune diseases, e.g., rheumatoid arthritis (RA), infectious diseases, e.g., influenza, and solid tumor cancers. Females tend to experience more adverse reactions than males following the use of a class of biologics referred to as immunotherapies. For immunotherapies aimed at stimulating an immune response, e.g., influenza vaccines, females develop greater responses and may experience greater efficacy than males. In contrast, for immunotherapies that repress an immune response, e.g., tumor necrosis factor (TNF) inhibitors for RA or checkpoint inhibitors for melanoma, the efficacy is reportedly greater for males than females. Despite these differences, discrepancies in reporting differences between females and males exist, with females have been historically excluded from biomedical and clinical studies. There is a critical need for research that addresses the biological (i.e., sex) as well as sociocultural (i.e., gender) causes of male-female disparities in immunotherapy responses, toxicities, and outcomes. One-size-fits-all approaches to immunotherapies will not work, and sex/gender may contribute to variable treatment success, including adherence, in clinical settings.
Topics: Animals; Arthritis, Rheumatoid; Gender Identity; Humans; Immunotherapy; Influenza Vaccines; Neoplasms; Sex Characteristics
PubMed: 32366281
DOI: 10.1186/s13293-020-00301-y