Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies.
Chromatin ; metabolism ; Chromatin Assembly and Disassembly ; DNA Methylation ; Enhancer of Zeste Homolog 2 Protein ; Epigenesis, Genetic ; Histones ; metabolism ; Humans ; Neoplasms ; genetics ; metabolism ; pathology ; Polycomb Repressive Complex 2 ; genetics ; metabolism

Testicular feminization is an uncommon genetic disorder with considerably familial predisposition and results in total feminization due to end-organ unresponsiveness to androgens. It is characterized by the presence of testes in phenotypically female with adequate breast development, normal extemal genitalia, absence of mullerian structures, and meager or absence of body hair. These patients characteristically have male karyotype(XY) and negative sex chromatin and are at increased risk of undergoing malignant transformation of the undescended gonad. In recent times, the malignant potential of the dysgenetic gonads in the intersex patients with a Y chromosome has been stressed by many authors, but few reports of an association between testicular feminization syndrome and benign tumors such as Sertoli cell adenomas. In the present study, postoperative pathology revealed that the gonads were Sertoli cell adenomas. The main features of clinical presentation and histological studies are briefly discussed with a review of the literature.
Adenoma* ; Androgen-Insensitivity Syndrome* ; Androgens ; Breast ; Female ; Feminization ; Genitalia ; Gonads ; Hair ; Humans ; Male ; Pathology ; Sex Chromatin ; Testis ; Y Chromosome

AIMTo investigate the prevalence of high levels of sperm DNA damage among men from infertile couples with both normal and abnormal standard semen parameters.

METHODSA total of 350 men from infertile couples were assessed. Standard semen analysis and sperm chromatin structure assay (SCSA) were carried out.

RESULTSNinety-seven men (28% of the whole study group) had a DNA fragmentation index (DFI)> 20%, and 43 men (12%) had a DFI>30%. In the group of men with abnormal semen parameters (n = 224), 35% had a DFI>20%, and 16% had a DFI>30%, whereas these numbers were 15% and 5%, respectively, in the group of men with normal semen parameters (n=126). Men with low sperm motility and abnormal morphology had significantly higher odds ratios (ORs) for having a DFI>20% (4.0 for motility and 1.9 for morphology) and DFI>30% (6.2 for motility and 2.8 for morphology) compared with men with normal sperm motility and morphology.

CONCLUSIONIn almost one-third of unselected men from infertile couples, the DFI exceeded the level of 20% above which, according to previous studies, the in vivo fertility is reduced. A significant proportion of men with otherwise normal semen parameters also had high sperm DNA damage levels. Thus, the SCSA test could add to explaining causes of infertility in cases where semen analysis has not shown any deviation from the norm. We also recommend running the SCSA test to choose the appropriate assisted reproductive technique (ART).

Chromatin ; pathology ; DNA Damage ; Female ; Humans ; Infertility, Male ; epidemiology ; genetics ; physiopathology ; Male ; Prevalence ; Semen ; cytology ; Spermatozoa ; physiology

Chromatin ; genetics ; metabolism ; Epigenesis, Genetic ; Genomic Instability ; Histones ; metabolism ; Humans ; Neoplasms ; metabolism ; pathology ; Ubiquitin-Protein Ligases ; genetics ; metabolism

OBJECTIVETo investigate changes in sperm chromosome and sperm DNA integrity of infertile males.

METHODSThe level of DNA fragmentation was determined by Sperm Chromatin Dispersion (SCD) test in infertile males with idiopathic severe oligoasthenozoospermia (ISOA, n= 19), couples with unexplained recurrent miscarriage (URM, n= 38) and adult healthy fertile men (control group, n= 32). Multi-color fluorescence in situ hybridization (FISH) was performed with probes specific for chromosomes 13, 18, 21, X and Y in the control group (n= 5), the ISOA (n= 10) and the URM (n= 12).

RESULTSPatients with ISOA and URM showed a significantly higher abnormality with total rate of 4.02% (n= 19) and 3.91%(n= 38) for chromosomes 13, 18 and 21, and 2.03%, 1.98% for chromosomes X and Y, respectively, in their spermatozoa compared to control (1.29% and 0.61%, P< 0.01). A significantly higher proportion of total sperm DNA fragmentation was detected in patients with ISOA (40.7%+/- 17.8%) and URM (22.1%+/- 10.3%) of sperm compared to the control group (12.1%+/- 5.2%, P< 0.01). Moreover, a positive correlation was found between the rate of sperm chromosomal aberration and the rate of sperm DNA fragmentation (gamma = 0.874, P< 0.01, n= 27). There were significant correlation between sperm DNA fragmentation and sperm density, sperm motility and abnormal sperm (gamma = - 0.571, gamma = - 0.616 and gamma = 0.637, respectively, P< 0.01).

CONCLUSIONThe result indicates that spermatozoa from patients with ISOA and URM contain greater DNA fragmentation and chromosomal aneuploidy and may lead to male infertility. Screening for sperm DNA damage may provide useful information in the diagnosis of male idiopathic infertility.

Abortion, Habitual ; pathology ; Adult ; Chromatin ; metabolism ; Chromosome Aberrations ; DNA Fragmentation ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infertility, Male ; genetics ; pathology ; physiopathology ; Male ; Sperm Count ; Sperm Motility ; Spermatozoa ; metabolism ; pathology

Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). This study investigated the role of glucose-regulated protein 78 (GRP78) in EBI after SAH. Male Sprague-Dawley rats (n=108) weighing 260±40 g were divided into control, sham-operated, and operated groups. Blood was injected into the prechiasmatic cistern of rats in the operated group. Neurological scores, ultrastructures of neurons, apoptosis, and GRP78 expression in the hippocampus were examined using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling, and Western blotting at 1, 6, 12, 24, 48, and 72 h after SAH, respectively. The results showed that neurological scores were significantly decreased in the operated group as compared with those in control and sham-operated groups at 12, 24, 48, and 72 h. Metachromatin, chromatin pyknosis at the edge, endoplasmic reticulum swelling, and invagination of nuclear membrane were observed at 24 h in the operated group, indicating the early morphological changes of apoptosis. The number of apoptotic cells was significantly increased in the operated group as compared with that in control and sham-operated groups at 6, 12, 24, 48, and 72 h. The GRP78 protein expression levels in the operated group were significantly elevated at all time points and reached the peak at 12 h. GRP78 expression was positively associated with apoptosis cells and negatively with neurological scores. In conclusion, EBI was demonstrated to occur after SAH and GRP78 was involved in the development of EBI after SAH.
Animals ; Apoptosis ; Brain Injuries ; complications ; metabolism ; pathology ; Chromatin ; pathology ; Endoplasmic Reticulum Stress ; Heat-Shock Proteins ; genetics ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage ; etiology ; metabolism ; pathology

Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.
Acetylation ; Chromatin Assembly and Disassembly* ; Chromatin* ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics* ; Gene Expression Regulation ; Genome ; Histones ; Learning* ; Memory* ; Memory, Long-Term ; Methylation ; Nervous System Diseases ; Neurosciences ; Pathology ; Protein Processing, Post-Translational

OBJECTIVETo investigate sperm DNA integrity in male infertility patients with hepatitis B virus (HBV) infection.

METHODSThis study included 90 infertile men with HBV infection (group A), 82 infertile men without HBV infection (group B) and 70 normal fertile men (group C). We detected sperm DNA integrity among the subjects, including DNA fragmentation index (DFI) and high DNA stainability (HDS), by sperm chromatin structure assay (SCSA), and compared them among the three groups.

RESULTSDFI was higher in group A ([28.17 +/- 13.06]%) than in B ([26.64 +/- 9.79]%) and C ([15.67 +/- 4.73]%), significantly higher in A and B than in C (P < 0.05) but with no significant difference between A and B (P > 0.05). HDS was higher in group A ([10.83 +/- 5.601]%) than in B ([9.04 +/- 3.48]%) and C ([8.04-2.25]%), with significant difference between A and C (P < 0.05).

CONCLUSIONSperm DNA integrity of infertile males is significantly different from that of normal fertile men, and infertility with HBV infection further impairs sperm DNA, which is manifested by abnormal sperm nuclear maturity.

Adult ; Case-Control Studies ; Chromatin ; DNA ; genetics ; DNA Damage ; Hepatitis B ; pathology ; Hepatitis B virus ; Humans ; Infertility, Male ; genetics ; virology ; Male ; Sperm Count ; Spermatozoa ; pathology ; Young Adult

OBJECTIVETo evaluate the role of flow cytometry in semen assessment.

METHODSSemen samples from 104 infertile male patients (as the case group) and 10 fertilized donors (as the control group) were analyzed for the volume of ejaculate and sperm concentration, motility and atypical morphology by computer-assisted semen analysis (CASA), the viability, chromatin structure and mitochondrial membrane potential (MMP) of the sperm stained by SYBR-14/PI, AO and JC-1 respectively, and assessed with flow cytometry. The results were analyzed through SAS software.

RESULTSU tests indicated that the semen from the infertile patients had not only lower concentration (U = 2.51, P = 0.0143), lower motility (U = 3.44, P = 0.001) and higher rate of atypical morphology (U = -5.88, P < 0.0001), but also lower viability (U = 4.72, P < 0.0001), MMP (U = -2.53, P = 0.0309), and chromatin integrity (alpha t: U = -3.82, P = 0.0003; SD alpha t: U = -3.98, P = 0.0001; COMP alpha t: U = -3.57, P = 0.0005). The multiple stepwise regression analysis revealed that sperm motility was positively correlated with sperm membrane integrity (t = 1.66, P = 0.1016), sperm MMP (t = 3.33, P = 0.0014) and sperm acrosome integrity (t = 3.24, P = 0.0019), while sperm MMP was negatively correlated with the rates of sperm neck and tail defects (t = -3.44, P = 0.001).

CONCLUSIONFlow cytometry plays a significant role in the evaluation of the quality of human sperm, and can be adopted as a useful tool in the diagnosis and treatment of male infertility.

Adult ; Case-Control Studies ; Cell Survival ; physiology ; Chromatin ; pathology ; Flow Cytometry ; Humans ; Infertility, Male ; physiopathology ; Male ; Membrane Potentials ; Middle Aged ; Sperm Motility ; Spermatozoa ; abnormalities ; pathology ; physiology

OBJECTIVETo evaluate the sperm DNA fragmentation index (DFI) and sperm malformation rate (SMR) before intracytoplasmic sperm injection (ICSI) and their impact on the clinical outcome of ICSI.

METHODSThis study included 79 cycles of ICSI because of oligoasthenozoospermia. We detected the sperm concentration, percentage of progressively motile sperm, DFI and SMR at 3 to 6 months before ICSI, and analyzed the relationship of DFI and SMR with the outcome parameters.

RESULTSOf the 79 oligoasthenozoospermia cases, DFI was found to be normal (< or = 25%) in 51 and abnormal (> 25%) in the other 28, significantly increased in the latter (14.18% vs 41.47%), and coincidently, SMR, too, was normal (< or = 96%) in 51 cases and abnormal (> 96%) in 28, significantly higher in the abnormal than in the normal cases (87.88% vs 98.46%). There were no significant differences between the normal and abnormal DFI groups in age, females'BMI, number of oocytes retrieved, and number of embryos transferred, nor between the normal and abnormal SMR groups in the number of fertilized oocytes and quality embryos, biochemical pregnancy, clinical pregnancy, and early pregnancy loss. Sperm DFI was significantly positively correlated with SMR (r = 0.231, P < 0.05).

CONCLUSIONICSI may reduce the rates of biochemical pregnancy and clinical pregnancy for men with increased sperm DFI (> 25%) and SMR (> 96%) by strict detection criteria, but with no statistically significant difference from normal males. Our findings need to be supported by further studies with larger sample sizes.

Adult ; Chromatin ; DNA Fragmentation ; Female ; Humans ; Male ; Middle Aged ; Pregnancy ; Pregnancy Rate ; Sperm Injections, Intracytoplasmic ; Spermatozoa ; pathology ; Treatment Outcome ; Young Adult