The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire Schwann cell lineage. While its importance in peripheral myelination is well established, little is known about its role in the early stages of Schwann cell development. In a search for direct target genes of Sox10 in Schwann cell precursors, the transcriptional co-repressor Tle4 was identified. At least two regions upstream of the Tle4 gene appear involved in mediating the Sox10-dependent activation. Once induced, Tle4 works in tandem with the bHLH transcriptional repressor Hes1 and exerts a dual inhibitory effect on Sox10 by preventing the Sox10 protein from transcriptionally activating maturation genes and by suppressing Sox10 expression through known enhancers of the gene. This mechanism establishes a regulatory barrier that prevents premature activation of factors involved in differentiation and myelin formation by Sox10 in immature Schwann cells. The identification of Tle4 as a critical downstream target of Sox10 sheds light on the gene regulatory network in the early phases of Schwann cell development. It unravels an elaborate regulatory circuitry that fine-tunes the timing and extent of Schwann cell differentiation and myelin gene expression.

Fine needle aspiration cytology (FNAC) is an established diagnostic modality today, but its utilization in skin tumors is limited by the fact that most of these lesions are small and easily accessible for clinicians to perform an excision biopsy. As a result, our knowledge of the cytological features of some of the uncommonly encountered skin tumors is still lacking. The aim of this study was to correlate the cytological features of cutaneous mixed tumors (CMTs) with histological and immunohistochemical findings in four cases of CMT in commonly and uncommonly encountered locations. We also review the recent updates highlighting the various genetic rearrangements and newer more specific immunohistochemical markers described so far. This was a retrospective study, and all the slides were taken from our departmental archives. Case 1 was a 25-year-old male who presented with a gradually increasing painless swelling over the right angle of the mouth of 1.5 years duration. Case 2 was a 45-year-old male with swelling on the right forearm for the last three years. Case 3 was a 35-year-old female with a forehead swelling of one year duration. Case 4 was a 55-year-old female with left cheek swelling for two years. On clinical examination, all four nodular swellings were predominantly in the skin/subcutaneous tissue. On cytology, all cases showed abundant chondromyxoid material with clusters of benign epithelial cells and a fair number of predominantly singly scattered myoepithelial cells. The diagnosis of all four cases was further confirmed on histopathology and immunohistochemistry, and the findings correlated well with cytology. The cytological features of CMT closely correlate with their histopathological and immunohistochemical features. Newer immunohistochemistry (IHC) marker pleomorphic adenoma gene 1 (PLAG1) may be helpful in making a definitive diagnosis of CMT on cytology and cell block preparation along with a good clinical correlation. Complete surgical excision is the treatment of choice, and recurrence is rare.

UNASSIGNED: Idiopathic hypogonadotropic hypogonadism (IHH) is a prevalent congenital genetic disorder with multiple inheritance patterns. IHH can manifest as normal hypogonadotrophic sexual hypofunction (nIHH) or with an abnormal sense of smell, known as Kallmann. It primarily affects the production and effectiveness of gonadotropin-releasing-hormone (GnRh), leading to reduced follicle-stimulating hormone and luteinizing hormone levels. This results in infertility and underdeveloped secondary sexual characteristics.
UNASSIGNED: A 29-year-old female presented with infertility.
UNASSIGNED: IHH diagnosis was confirmed through magnetic resonance (MR) scan, endocrine tests, physical examination, and B ultrasonic inspection. Additionally, genetic studies, including chromosome analysis, were conducted for the patient. The results confirmed no genetic abnormalities or concerns.
UNASSIGNED: The patient underwent multiple ovulation induction programs.
UNASSIGNED: After several ovulation induction cycles, the patient conceived and delivered a live baby.
UNASSIGNED: For IHH patients, a tailored human menopausal gonadotropin (HMG) dose is recommended. High-dose HMG can benefit those with poor follicular response. The addition of letrozole (5-7.5mg) may enhance follicular response during stimulation. Our approach, which emphasizes the combined use of high-dose HMG, letrozole, and the adjustment of FSH and LH ratios, offers a unique perspective compared to traditional treatments. If HMG treatment is ineffective, alternative ovulation induction methods, such as r-fsh combined with r-lh or HMG combined with rLH, can be considered. Adjusting the FSH and LH ratio and varying rFSH and rLH additions might help achieve dominant follicles and live birth in resistant cases. This case report underscores the potential benefits of our regimen, suggesting its consideration for future research and clinical applications.

To evaluate the outcomes of a long GnRH agonist protocol with corifollitropin alfa followed by hMG in low responders.
Retrospective cohort study. Patients with a suboptimal previous ovarian response (<9 oocytes) and a normal ovarian reserve (Poseidon groups 1 and 2) were classified in 1) Group 1 (n=88), submitted to a second cycle with a GnRH antagonist protocol using rFSH/hMG; 2) Group 2 (n=66), submitted to a long GnRH agonist protocol with corifollitropin alfa followed by hMG (named as simplified long protocol). Clinical outcomes were compared between groups and between the first/second cycle of each group.
Clinical outcomes were similar between groups. There were no differences in the number of oocytes [7(5-11.75) versus 7(5-10), p=0.802], clinical pregnancy (19.3% versus 18.2%, p=0.858) and live birth rates (18.2% versus 15.2%, p=0.619). However, baseline characteristics were different, decoding a poor prognosis among women in group 2. Both groups (1 and 2) had significantly higher number of oocytes, pregnancy, and live birth rates in the second cycle. In group 2, there was a higher rate of embryo transfer (56.1% versus 27.3%, p<0.001). In group 1, despite the similar rate of embryo transfer, there was a higher positive hCG (23.9% versus 8.0%, p=0.004).
Both simplified long protocol and GnRH antagonist protocol are suitable for low responders. The best second cycle clinical outcomes experienced in a population with worse prognosis (group 2) suggests that the simplified long protocol may be a better option, although prospective well-conducted studies must explore this hypothesis.

Isolated follicle-stimulating hormone (FSH) deficiency is a rare cause of infertility in both sexes, and only a few cases have been reported in Japan. This is a case report of a young male patient with isolated FSH deficiency and azoospermia who was successfully treated with human menopausal gonadotropin (hMG). A 28-year-old male patient was referred for azoospermia. The delivery at his birth was uneventful and a family history of infertility or hypogonadism was not observed. The testes volume was 22/24 mL (right/left). No varicocele was observed in the ultrasound, and no sign or symptom of hypogonadism was found. In the semen analysis, however, the sperm concentration was as low as 2.5×106/mL and the motility was less than 1%. The endocrine panel revealed luteinizing hormone (LH) (2.1 mUI/mL, normal values 0.8-5.7 mUI/mL) and testosterone (6.57 ng/ml, normal values 1.42-9.23 ng/mL) were normal, while the FSH level was very low (0.6 mUI/mL, normal values 2.0-8.3 mIU/mL). The odor and the karyotype 46, XY, were normal. The brain MRI scans showed no abnormal findings. Genitalia and potency were normal. The diagnosis was made of isolated FSH with severe oligoastenozoospermia clinically.  FSH replacement therapy was employed. The patient self-injected 150 units of hMG three times a week. After 3 months of the treatment, the sperm concentration and motility went up to 264×106/mL and 12%, respectively. At 5 months, the patient\'s spouse conceived naturally, and at 7 months the treatment was terminated. During the treatment, FSH rose to the normal range, while other test items showed no change. The patient\'s health condition was uneventful. The spouse delivered a healthy boy. In conclusion, for isolated FSH with severe oligoastenozoospermia, hMG can be as effective as recombinant human FSH (rh-FSH), although the dosage remains a matter of discussion.

The transcription factor Sox10 is an essential regulator of genes that code for structural components of the myelin sheath and for lipid metabolic enzymes in both types of myelinating glia in the central and peripheral nervous systems. In an attempt to characterize additional Sox10 target genes in Schwann cells, we identified in this study a strong influence of Sox10 on the expression of genes associated with adhesion in the MSC80 Schwann cell line. These included the genes for Gliomedin, Neuronal cell adhesion molecule and Neurofascin that together constitute essential Schwann cell contributions to paranode and node of Ranvier. Using bioinformatics and molecular biology techniques we provide evidence that Sox10 directly activates these genes by binding to conserved regulatory regions. For activation, Sox10 cooperates with Krox20, a transcription factor previously identified as the central regulator of Schwann cell myelination. Both the activating function of Sox10 as well as its cooperation with Krox20 were confirmed in vivo. We conclude that the employment of Sox10 and Krox20 as regulators of structural myelin sheath components and genes associated with the node of Ranvier is one way of ensuring a biologically meaningful coordinated formation of both structures during peripheral myelination.

The aim of the study is to compare the qualitative and semi-quantitative profile of the polyphenol fraction purified from the leaf (BLPF) and fruit (BFPF) of bergamot (Citrus bergamia), and to evaluate their antioxidant and anti-inflammatory activity. The analytical qualitative profile was carried out by LC-ESI/MS using three different approaches: targeted (searching analytes already reported in bergamot extract), semi-targeted (a selective search of 3-hydroxy-3-methylglutarate [HMG] derivatives involved in the cholesterol reducing activity of BPF) and untargeted. A total number of 108 compounds were identified by using the three approaches, 100 of which are present in both the extracts thus demonstrating a good qualitative overlapping of polyphenols between the two extracts. The antioxidant activity was higher for BLPF in respect to BFPF but when normalized in respect to the polyphenol content they were almost overlapping. Both the extracts were found to dose dependently inhibit cell inflammation stimulated with IL-1α. In conclusion, the comparison of the qualitative and quantitative profile of polyphenols as well as of the antioxidant and anti-inflammatory activity of bergamot leaf and fruit well indicates that leaf is a valid source of bergamot polyphenol extraction and an even richer source of polyphenol in respect to the fruit.

The aim of the present study is to investigate embryo quality (score) after controlled ovarian stimulation for IVF using rFSH or hMG with the GnRH antagonist protocol.
Open, randomized, single center study. The patients were randomized to receive rFSH or hMG according to randomized cards inside a black envelope with the name of the respective treatment following a computer generated list (85 patients were allocated to rFSH group and 83 patients to hMG group). Inclusion criteria were patients with IVF indication and normal ovarian reserve. Embryo evaluation was performed on day three, after fertilization based on the Graduated Embryo Score (GES).
There were no relevant differences in demographic characteristics. There was no difference in pregnancy rates with 27 (31%) and 25 (30.1%) pregnancies for rFSH and hMG, respectively (p=0.87). The total embryo score was the same for both groups, but the best embryo score was significant higher for the rFSH group (77.33±34.0 x 65.07±33.2 p=0.03). The total number of embryos was statistical different, also in favor of the rFSH group (4.17±3.1 x 3.26±2.4 p=0.04).
The total embryo score was the same for both groups, but the best embryo score was significantly higher for the rFSH group. Moreover, rFSH was associated with an increased number of embryos.

Commercial hMG drugs are marketed for the treatment of infertility and consist of highly purified hormones acting on receptors expressed in target gonadal cells. Menopur® and Meriofert® are combined preparation of FSH and hCG and are compared in vitro herein. To this purpose, the molecular composition of the two drugs was analyzed by immunoassay. The formation of FSH receptor and LH/hCG receptor (FSHR; LHCGR) heteromer, intracellular Ca2+ and cAMP activation, β-arrestin 2 recruitment and the synthesis of progesterone and estradiol were evaluated in transfected HEK293 and human primary granulosa lutein cells treated by drugs administered within the pg-mg/ml concentration range. Molecular characterization revealed that Meriofert® has a higher FSH:hCG ratio than Menopur® which, in turn, displays the presence of LH molecules. While both drugs induced similar FSHR-LHCGR heteromeric formations and intracellular Ca2+ increase, Meriofert® had a higher potency than Menopur® in inducing a cAMP increase. Moreover, Meriofert® revealed a higher potency than Menopur® in recruiting β-arrestin 2, likely due to different FSH content modulating the tridimensional structure of FSHR-LHCGR-β-arrestin 2 complexes, as evidenced by a decrease in bioluminescence resonance energy transfer signal. This drug-specific activation of intracellular signaling pathways is consistent with the molecular composition of these preparations and impacts downstream progesterone and estradiol production, with Menopur® more potent than Meriofert® in inducing the synthesis of both the steroids. These findings are suggestive of distinct in-vivo activities of these preparations, but require cautious interpretation and further validation from clinical studies.

Ribosome biogenesis is tightly regulated through stress-sensing pathways that impact genome stability, aging and senescence. In Saccharomyces cerevisiae, ribosomal RNAs are transcribed from rDNA located on the right arm of chromosome XII. Numerous studies reveal that rDNA decondenses into a puff-like structure during interphase, and condenses into a tight loop-like structure during mitosis. Intriguingly, a novel and additional mechanism of increased mitotic rDNA compaction (termed hypercondensation) was recently discovered that occurs in response to temperature stress (hyperthermic-induced) and is rapidly reversible. Here, we report that neither changes in condensin binding or release of DNA during mitosis, nor mutation of factors that regulate cohesin binding and release, appear to play a critical role in hyperthermic-induced rDNA hypercondensation. A candidate genetic approach revealed that deletion of either HSP82 or HSC82 (Hsp90 encoding heat shock paralogs) result in significantly reduced hyperthermic-induced rDNA hypercondensation. Intriguingly, Hsp inhibitors do not impact rDNA hypercondensation. In combination, these findings suggest that Hsp90 either stabilizes client proteins, which are sensitive to very transient thermic challenges, or directly promotes rDNA hypercondensation during preanaphase. Our findings further reveal that the high mobility group protein Hmo1 is a negative regulator of mitotic rDNA condensation, distinct from its role in promoting premature condensation of rDNA during interphase upon nutrient starvation.