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The sperm of infertile men have higher rates of chromosomal abnormalities than those of fertile men. Miscarriage rate is also higher following testicular sperm extraction combined with intracytoplasmic sperm injection (TESE-ICSI). Sperm chromosomal abnormalities are assumed to be the cause of miscarriages. Previous testicular sperm karyotyping studies have only examined a few selected chromosomes using fluorescence in situ hybridization. The aim of this study was to provide a more detailed analysis of sperm karyotyping by analyzing all chromosomes using next-generation sequencing (NGS) in clinically usable testicular sperm. Sperm discarded after clinical use was collected for NGS. Additionally, sperm were individually collected by micromanipulation from patients with obstructive azoospermia (OA) and non-obstructive azoospermia (NOA) who underwent TESE-ICSI. For comparison, ejaculated sperm from control and balanced translocation (BT) carriers were examined. Karyotyping was performed on individual sperm cells using NGS. The number of normal and aberrant sperm was compared. Seventeen patients participated in this study: control (n = 4), BT (n = 3), OA (n = 5), and NOA (n = 5). Ten sperm samples per patient were analyzed. The total acquisition rate for single sperm karyotyping was 85% (145/170). Karyotyping of sperm from the BT group revealed sperm with unbalanced chromosomes derived from carrier translocations. Among the NOA group, 7/41 (17%) sperm samples exhibited aberrant karyotypes, whereas no aberrant sperm were identified in the control and OA groups. Individual differences were observed in the frequency of sperm chromosomal abnormalities among patients with NOA. In conclusion, sperm chromosomal abnormalities are frequently observed in patients with NOA even after sperm selection for clinical use. As the frequency of chromosomal abnormalities varies among patients with NOA, single sperm sequencing may help identify patients with NOA most likely to benefit from PGT-A.

Background The growth of uterine leiomyomas is dependent on the levels of sex steroid hormones, and they usually shrink after menopause. However, there are cases in which leiomyomas continue to grow and/or surgery is required after menopause. In addition to estrogen, progesterone has recently been implicated in leiomyoma enlargement, but its relevance to postmenopausal leiomyoma remains unknown. Therefore, we investigated whether hormone receptor expression is associated with postmenopausal leiomyoma enlargement and characterized pathological findings of postmenopausal leiomyoma, which have not been clarified yet. Methods Nine cases that required total hysterectomy for leiomyomas after menopause were examined. Surgeries were conducted because of pelvic pressure, pelvic pain, suspected malignancy, or growing leiomyoma. Six cases of leiomyomas being incidentally found during total hysterectomy for postmenopausal uterine prolapse, and six patients who underwent hysterectomy for leiomyomas before menopause, were examined as controls. We evaluated the expression of estrogen receptor, progesterone receptor B, and progesterone receptor AB by immunohistochemical staining among the cases. We also analyzed the pathological findings of leiomyomas. Results In postmenopausal leiomyomas, the expression of progesterone receptor was higher than that in the adjacent myometrium. Compared with premenopausal leiomyomas, the expression of progesterone receptor decreased. Postmenopausal leiomyomas that required surgery did not show elevated sex steroid hormone receptor expression, compared with the leiomyomas that did not require surgery. The degeneration frequency of leiomyomas was 92% in the group that underwent surgery for postmenopausal leiomyomas, 65% in the group that underwent surgery for reasons other than the presence of leiomyomas after menopause, and 47% in the group operated for leiomyomas before menopause. Conclusions These results suggest that sex steroid hormones are unlikely to be associated with the growth of leiomyomas after menopause. Since leiomyoma degeneration with increased extracellular matrix is likely to occur in postmenopausal women, the degeneration of leiomyomas may be the main mechanism for the growth of postmenopausal leiomyomas.

Mitochondria contribute to cellular metabolism by providing a specialised milieu for energising cells by incorporating and processing the metabolites. However, heterogeneity between mitochondria has only partially been elucidated. Mitochondria dynamically alter their morphology and function during the life of an animal, when cells proliferate and grow. We here show that Kntc1, a highly evolutionarily conserved protein, translocates from the Golgi apparatus to linear mitochondrial segments (LMSs) upon glutamine deprivation and plays an essential role in maintaining LMSs. The LMSs to which Kntc1 localised exhibited an increase in the mitochondrial membrane potential, suggesting the role of Kntc1 in functioning as a reservoir for the energy-generating potential. Suppression of Kntc1 led to glutamine consumption and lactate production, thus impacting cellular metabolism, eventually leading to anchorage-independent growth of cells. Indeed, a KNTC1 variant was identified in a patient with ovarian cancer, suggesting that segmental regulation of the mitochondrial function is essential for maintaining tissue integrity.

IntroductionBisphosphonates and denosumab increase bone mineral density (BMD) for osteoporosis treatment in patients with aromatase inhibitor-associated bone loss (AIBL). This study aimed to directly compare bisphosphonates with denosumab in treating patients with AIBL and to determine the effect of denosumab on the trabecular bone score (TBS).Materials and methodsThirty-nine patients with AIBL receiving osteoporosis treatment (21 in the bisphosphonates group and 18 in the denosumab group) were retrospectively evaluated for changes in lumbar spine and femoral BMD, lumbar spine bone quality (assessed by TBS), and blood bone metabolic markers. The Mann–Whitney and Wilcoxon tests were used for statistical evaluation.ResultsAfter 24 months of treatment, the lumbar spine BMD change rate was 5.82 ± 1.10% with bisphosphonates and 10.49 ± 1.20% with denosumab, with the change rate of denosumab significantly increasing over that of bisphosphonates. The change rate in femoral BMD was 2.69 ± 1.16% with bisphosphonates and 2.95 ± 1.26% with denosumab, with no significant difference between the two groups. The rate of decrease in tartrate-resistant acid phosphatase isoform 5b was significantly higher in the denosumab group. The change rate in TBS at 24 months of treatment was 0.53 ± 1.26% in the bisphosphonates group and 1.08 ± 1.33% in the denosumab group, with no significant difference between the two groups. After 24 months, TBS remained stable.ConclusionBoth bisphosphonates and denosumab may increase BMD, improve bone metabolism, and inhibit bone quality loss in patients with AIBL.

•We analyzed population-based registry data in Kanagawa and Japan overall.•Cervical cancer mortality increased among women aged <50 years.•Cervical cancer mortality decreased among women aged >50 years.•Reclassification of uterine cancer provided exact cervical cancer mortality rates.•Unclassified uterine cancer rarely affected mortality for women aged <50. In Japan, cervical cancer (CC) deaths among women aged <50 years have doubled over the last three decades. Obtaining age-specific CC mortality rates among young women is important for taking measures against CC. Age-adjusted CC mortality rates for all ages are inadequate because of the classification of ‘uterine cancer, not otherwise specified’ (NOS uterine cancer) and CC mortality rates among elderly women. The aim of the present study was to calculate exact age-specific CC mortality rates in women aged <50 years in Kanagawa, taking into account the impact of NOS uterine cancer. Using the Kanagawa Cancer Registry, CC deaths (1975–2012) were analyzed and CC mortality rates (age-adjusted, 20–29, 30–49, and ≥50 years) were calculated. In addition, hospitals were surveyed to reclassify cases of NOS uterine cancer. After reclassification, chronological trends were also analyzed. Age-specific CC mortality rates in Kanagawa and Japan overall showed increasing trends for ages 20–29 (P for trend<0.001) and 30–49 (P for trend<0.001). Rates of NOS uterine cancer death were significantly lower in Kanagawa than in Japan overall (P<0.05), except for patients aged <50 years in 2005–2009 (P=0.159). The present study revealed concern for CC among Japanese women younger than 50 years. Well-organized CC screening and HPV vaccination should be provided to reduce CC mortality rates for these young women.

Small cell neuroendocrine carcinoma is rare among urinary bladder cancer types, and to date, there are no case reports of concurrent antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis. We describe the case of a 69-year-old Japanese man who presented with elevated creatine kinase levels and haematuria on medical examination. Approximately one month later, he developed dysphagia. Laryngoscopy confirmed laryngeal dysfunction. He also presented with muscle weakness and a skin rash. Magnetic resonance imaging of the upper extremities suggested bilateral brachial muscle myositis. He was diagnosed as having dermatomyositis and was later found to be positive for antitranscriptional intermediary factor 1-γ antibody. Computed tomography revealed an intravesical space-occupying lesion and right iliac lymphadenopathy, suggesting urinary bladder cancer. The patient was admitted to our hospital for treatment. Urinary bladder biopsy confirmed small cell neuroendocrine carcinoma because tumour cells were positive for synaptophysin, CD56, and chromogranin A. Thus, the patient was diagnosed as having an antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis concomitant with urinary bladder small cell neuroendocrine carcinoma. The patient was treated with glucocorticoid and intravenous immune globulin therapy for dermatomyositis. Radiotherapy was selected for the carcinoma. Although muscle weakness and skin symptoms improved with treatment, dysphagia persisted. Furthermore, expression of the transcriptional intermediary factor 1-γ protein in tumour cells was also confirmed by immunohistochemistry, but the significance is unknown. It should be noted that antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis can occur concomitantly with such a rare malignancy.

A 44-year-old woman presenting with pus-like discharge from the nipples visited our hospital for scleritis. Subcutaneous induration and ulceration were found on her breast. She was diagnosed with granulomatosis with polyangiitis (GPA) considering scleritis, sinusitis, cutaneous granuloma formation, and antiproteinase 3-antineutrophil cytoplasmic antibodies and was successfully treated with glucocorticoids. Fifteen months later, she developed pulmonary consolidation and a right breast nodule. Biopsies of the breast nodule showed granulomatous vasculitis, and she was treated with rituximab. While breast involvement in GPA is rare, unilateral breast mass is a typical clinical feature; thus, GPA should be considered in such cases.

MED12 exon 2 mutation is the most frequent mutation associated with uterine leiomyomas. MED12 wild-type leiomyomas have a higher growth potential than mutant leiomyomas, suggesting that the mutation limits leiomyoma growth. MED12 forms a complex with CDK8 and is involved in the phosphorylation of RNA polymerase II, playing a role in transcriptional regulation. However, its mechanism of action in leiomyoma growth is not clear. We aimed to clarify the relationship between MED12 mutation status, response to gonadotropin-releasing hormone (GnRH) agonist treatment, and CDK8 activity in leiomyomas. We also examined the effects of CDK8 inhibitors on primary cultured uterine leiomyoma cells. We classified 44 surgically removed uterine leiomyomas into four groups according to GnRH agonist use and MED12 mutation status. CDK8 was co-immunoprecipitated from leiomyoma tissue extracts using MED12 antibody to test its kinase activity in vitro , and the amount of phosphorylated substrate was measured. Cell proliferation and apoptosis of primary cultured MED12 wild-type leiomyoma cells were evaluated in the presence of a CDK8 inhibitor and sex steroid hormones. Of the 44 leiomyomas tested, 11 MED12 wild-type leiomyomas without preoperative GnRH agonist treatment had significantly higher CDK8 activity than nine GnRH agonist-treated MED12 wild-type leiomyomas and 15 leiomyomas with MED12 mutations without GnRH agonist treatment. Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis. MED12 wild-type leiomyoma cells without GnRH agonist treatment showed high CDK8 activity, and inhibition of CDK8 activity suppressed cell growth in vitro .