Associations between Urinary Mercury/Cadmium Concentrations and Anthropometric Features in Korean Children.

Investigating the impact of urinary mercury and cadmium on anthropometric parameters in Korean children is crucial amid growing concerns about heavy metal exposure and childhood growth. Using data from the Korean National Environmental Health Survey (2015-2017), we assessed age- and sex-specific associations of urinary mercury and cadmium with height and body mass index (BMI) z-scores in 1458 children aged 3-5 (n = 571) and 6-11 years (n = 887). Overall, 5.0% had stunted height (3-5 years: 6.9%, 6-11 years: 3.8%), whereas older children exhibited higher overweight/obesity prevalence (29.2%) than younger ones did (22.2%). In 3-5-year-old boys, urinary mercury correlated negatively with height z-scores (p < 0.001), whereas in girls, urinary cadmium correlated positively (p = 0.015). Boys aged 6-11 years showed positive associations between mercury/cadmium levels and BMI z-scores (p = 0.012). Logistic regression indicated associations between urinary mercury and stunted height likelihood (p = 0.001) and between urinary cadmium and reduced overweight likelihood (p = 0.039) in 3-5-year-old boys. In boys aged 6-11 years, urinary cadmium levels were positively associated with overweight likelihood (p = 0.003). This study underscores the link between elevated urinary mercury, cadmium levels, and growth disruptions in Korean children, emphasizing the need for public health strategies for reducing childhood heavy metal exposure.

Insulin-like growth factor binding protein-3 induces senescence by inhibiting telomerase activity in MCF-7 breast cancer cells.

Insulin-like growth factor binding protein-3 (IGFBP-3) has been known to inhibit cell proliferation and exert tumor-suppressing effects depending on the cell type. In this study, we aimed to show that IGFBP-3 induces cellular senescence via suppression of the telomerase activity, thereby inhibiting MCF-7 breast cancer cell proliferation. We found that the induction of IGFBP-3 in MCF-7 cells enhanced the loss of cell viability. Flow cytometry revealed a higher percentage of non-cycling cells among IGFBP-3-expressing cells than among controls. IGFBP-3 induction also resulted in morphological alterations, such as a flattened cytoplasm and increased granularity, suggesting that IGFBP-3 induces a senescence-like phenotype. The percentage of IGFBP-3 expressing cells with senescence-associated ß-galactosidase activity was 3.4 times higher than control cells. Telomeric repeat amplification and real-time PCR showed that IGFBP-3 decreased telomerase activity by reducing the levels of the RNA component (hTR) and catalytic protein component with reverse transcriptase activity (hTERT) of telomerase in a dose-dependent manner. These results suggest that IGFBP-3 is a negative regulator of MCF-7 breast cancer cell growth by inducing senescence through telomerase suppression.

Microtubule Acetylation-Specific Inhibitors Induce Cell Death and Mitotic Arrest via JNK/AP-1 Activation in Triple-Negative Breast Cancer Cells.

Microtubule acetylation has been proposed as a marker of highly heterogeneous and aggressive triple-negative breast cancer (TNBC). The novel microtubule acetylation inhibitors GM-90257 and GM-90631 (GM compounds) cause TNBC cancer cell death but the underlying mechanisms are currently unknown. In this study, we demonstrated that GM compounds function as anti-TNBC agents through activation of the JNK/AP-1 pathway. RNA-seq and biochemical analyses of GM compound-treated cells revealed that c-Jun N-terminal kinase (JNK) and members of its downstream signaling pathway are potential targets for GM compounds. Mechanistically, JNK activation by GM compounds induced an increase in c-Jun phosphorylation and c-Fos protein levels, thereby activating the activator protein-1 (AP-1) transcription factor. Notably, direct suppression of JNK with a pharmacological inhibitor alleviated Bcl2 reduction and cell death caused by GM compounds. TNBC cell death and mitotic arrest were induced by GM compounds through AP-1 activation in vitro. These results were reproduced in vivo, validating the significance of microtubule acetylation/JNK/AP-1 axis activation in the anti-cancer activity of GM compounds. Moreover, GM compounds significantly attenuated tumor growth, metastasis, and cancer-related death in mice, demonstrating strong potential as therapeutic agents for TNBC.

Serum kisspeptin levels mainly depend on ovarian expression of Kiss1 mRNA in female rats.

The hypothalamic kisspeptin/KISS1 receptor system is essential for puberty onset and reproductive development. Although serum kisspeptin might be associated with puberty, its levels, according to developmental stage, and its origin still remain unclear. This study evaluated the changes in serum kisspeptin levels during puberty and the corresponding Kiss1 mRNA and protein expression in various organs of female rats to identify the source of serum kisspeptin. Tissues from several organs, including the ovaries and anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) in the hypothalamus, were obtained for assessing Kiss1 mRNA and protein expressions. Serum kisspeptin levels progressively increased with developmental stages until the peripubertal stage. The ovaries showed the highest Kiss1 expression among the organs examined. Next, we explored the changes in serum kisspeptin levels and hypothalamic Kiss1 expression in ovariectomized and estradiol-treated ovariectomized rats. Serum kisspeptin levels decreased regardless of estradiol treatment; Kiss1 expression was enhanced by ovariectomy and estradiol treatment in the ARC, while it was decreased by ovariectomy and enhanced by estradiol in the AVPV, suggesting that serum kisspeptin may be associated with pubertal development and mainly depended on ovarian Kiss1 expression. Thus, serum kisspeptin levels are associated with puberty and may serve as a downstream marker of ovarian reproductive function.

Tumor-derived miR-130b-3p induces cancer-associated fibroblast activation by targeting SPIN90 in luminal A breast cancer.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) interact closely with cancer cells to promote tumor development. Downregulation of SPIN90 in CAFs has been reported to facilitate breast cancer progression, but the underlying mechanism has not been elucidated. Here, we demonstrate that miR-130b-3p directly downregulates SPIN90 in stromal fibroblasts, leading to their differentiation into CAFs. As the decrease of SPIN90 in CAFs was shown to be more prominent in estrogen receptor (ER)-positive breast tumors in this study, miR-130b-3p was selected by bioinformatics analysis of data from patients with ER-positive breast cancer. Ectopic expression of miR-130b-3p in fibroblasts accelerated their differentiation to CAFs that promote cancer cell motility; this was associated with SPIN90 downregulation. We also found that miR-130b-3p was generated in luminal A-type cancer cells and activated fibroblasts after being secreted via exosomes from cancer cells. Finally, miR-130b-3p increased in SPIN90-downregulated tumor stroma of luminal A breast cancer patients and MCF7 cell-xenograft model mice. Our data demonstrate that miR-130b-3p is a key modulator that downregulates SPIN90 in breast CAFs. The inverse correlation between miR-130b-3p and SPIN90 in tumor stroma suggests that the miR-130b-3p/SPIN90 axis is clinically significant for CAF activation during breast cancer progression.

Using Etomidate in a Two-month-old Infant with Cushing Syndrome due to Adrenocortical Carcinoma

Cushing syndrome (CS) is a rare disease caused by hypercortisolemia. Although surgical treatment is the first-line treatment in CS, the appropriate medication for the patient's condition should be selected when medical treatment is needed. Etomidate is an adrenal-blocking drug used to treat CS and the most suitable for severe hypercortisolemia and adrenocortical carcinoma (ACC), due to cardiovascular stability and an anti-tumorigenic effect. However, its use and safe recommended dosage in infants with CS is unreported. Here we describe the case of a 2-month-old girl treated with etomidate for CS caused by ACC. Even though radical mass excision was performed, severe hypercortisolemia persisted, resulting from metastatic lesions in the liver, and medical treatment was considered. The etomidate doses, no bolus dose and infusion rate of 0.03 mg/kg/hour, may be an appropriate dose for severe hypercortisolemia in infants. This case will help determine future treatment strategies for similar cases in infants.

Management of Central Precocious Puberty in Children with Hypothalamic Hamartoma.

Hypothalamic hamartoma (HH) is a rare, congenital, and benign lesion of the tuber cinereum, typically presenting with central precocious puberty (CPP), gelastic seizure, and developmental delay. This study aimed to investigate CPP in HH patients and compare clinical features between before and after gonadotropin-releasing hormone (GnRH) agonist treatment. A total of 30 HH patients under 18 years of age who visited Severance Children's Hospital between January 2005 and May 2020 were retrospectively reviewed. Fourteen patients were male (46.7%) and sixteen (53.3%) were female, with a mean age at diagnosis was4.2 ± 2.9 years. During follow-up, 24 patients (80.0%) were diagnosed with CPP, 15 patients (50.0%) had gelastic seizure, and 13 patients (43.3%) had developmental delay. The gelastic seizure was significantly associated with sessile type HH rather than pedunculated type HH (85.7% vs. 18.8%, p = 0.001). After GnRH agonist treatment, discrepancies between bone age and chronological age decreased (3.3 ± 1.3 years to 2.0 ± 1.7 years, p = 0.002). Additionally, height standard deviation score for bone age was increased, and predicted adult height increased significantly in females, while males showed an increasing trend. Clinical symptoms of HH were closely associated with the location of HH, and GnRH agonist treatment was safe and effective in the management of CPP caused by HH.

High Prevalence of Nonalcoholic Fatty Liver Disease Among Adolescents and Young Adults With Hypopituitarism due to Growth Hormone Deficiency.

OBJECTIVE: To investigate the prevalence of nonalcoholic fatty liver disease (NAFLD) in adolescents and young adults with hypopituitarism and to examine the associations of growth hormone (GH) deficiency with the occurrence of NAFLD. METHODS: A cross-sectional study for the determination of NAFLD prevalence included 76 patients with childhood-onset hypopituitarism and 74 controls matched by age and body mass index (BMI). We investigated the prevalence of NAFLD in adolescent and young adult patients with hypopituitarism as well as the age- and BMI-matched controls. Among patients with hypopituitarism, anthropometric, clinical, and biochemical assessments using transient elastography and magnetic resonance imaging were performed. Logistic regression was used to identify the factors associated with NAFLD. RESULTS: The adolescents and young adults with hypopituitarism exhibited higher prevalence of NAFLD than the age- and BMI-matched controls. Among patients with hypopituitarism, obesity and obesity-related metabolic derangements were significantly associated with liver steatosis and fibrosis, whereas lower insulin-like growth factor (IGF)-I standard deviation score (SDS) and IGF-I/IGF-binding protein 3 molar ratios were associated with steatosis. In regression analyses adjusted for BMI SDS, steatosis was found to be associated with a lower IGF-I SDS and IGF-I/IGF-binding protein 3 molar ratios, whereas liver fibrosis was found to be associated with a lower IGF-I SDS. CONCLUSION: Our results suggest that GH deficiency contributes to the occurrence of NAFLD, along with obesity and obesity-related metabolic changes. Because NAFLD occurs early in patients with hypopituitarism, the surveillance, weight control, and timely replacement of deficit hormones, including GH, are essential.

Central precocious puberty may be a manifestation of endocrine dysfunction in pediatric patients with mitochondrial disease.

We retrospectively reviewed the data of 140 female pediatric patients with rare mitochondrial diseases (MDs) confirmed using muscle biopsy. We evaluated patients who were diagnosed with central precocious puberty (PP) with early pubertal development to determine whether PP is a clinical manifestation of MDs. We also examined the clinical, auxiological, laboratory, and radiological parameters after 1 year of gonadotropin-releasing hormone treatment for central PP. Among the 140 girls with MDs, 29 had early pubertal development and underwent endocrine evaluation. Ten (7.1%) patients were diagnosed with central PP; the prevalence of central PP was higher than was that previously thought. Patients with central PP exhibited bone age advancement over 1 year and increased sex hormone levels despite their young age at diagnosis. Serum estradiol levels were significantly higher in younger patients than in older patients (P = 0.004). Patients with central PP treated with gonadotropin-releasing hormone had favorable outcomes, and their pubertal development was suppressed for 1 year.Conclusion: Central PP may be a manifestation of endocrine dysfunction in young girls with MDs. What is Known: • The general characteristics of mitochondrial diseases include developmental delays and retarded growth. • Precocious puberty has rarely been suggested as a clinical manifestation of mitochondrial diseases. What is New: • Among the 140 girls with mitochondrial diseases, 10 (7.1%) were diagnosed with central precocious puberty. • Serum estradiol levels were significantly higher in younger patients than in older patients.

Association of Vitamin D Status and Physical Activity with Lipid Profile in Korean Children and Adolescents: A Population-Based Study.

Dyslipidemia is one of the important influencing factors of cardiovascular health in the youth, and thus, assessment of its etiology is important. We aimed to investigate the association of dyslipidemia with vitamin D and physical activity in Korean children and adolescents. Data of 3183 subjects aged 12-18 years in the Korea National Health and Nutrition Examination Survey were analyzed. Participants were divided into subgroups according to sex, body mass index, 25-hydroxyvitamin D levels, and lipid profile. The mean 25-hydroxyvitamin D level was 16.15 ng/mL, which was below normal. In total, 79.3% of the subjects had vitamin D deficiency. Females had lower vitamin D levels and a higher incidence of dyslipidemia compared to males. Vitamin D deficiency was significantly associated with high density lipoprotein cholesterol (HDL-C) levels. The low HDL-C group consisted of a higher proportion of subjects with vitamin D deficiency and low physical activity. This study suggests that vitamin D deficiency is prevalent in Korean children and adolescents. Vitamin D deficiency and low physical activity are related with low HDL-C levels. Maintaining sufficient vitamin D levels and physical activity may help prevent dyslipidemia.

Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer.

Microtubules are one of the major targets for anticancer drugs because of their role in cell proliferation and migration. However, as anticancer drugs targeting microtubules have side effects, including the death of normal cells, it is necessary to develop anticancer agents that can target microtubules by specifically acting on cancer cells only. In this study, we identified chemicals that can act as anticancer agents by specifically binding to acetylated microtubules, which are predominant in triple-negative breast cancer (TNBC). The chemical compounds disrupted acetylated microtubule lattices by interfering with microtubule access to alpha-tubulin acetyltransferase 1 (αTAT1), a major acetyltransferase of microtubules, resulting in the increased apoptotic cell death of MDA-MB-231 cells (a TNBC cell line) compared with other cells, such as MCF-10A and MCF-7, which lack microtubule acetylation. Moreover, mouse xenograft experiments showed that treatment with the chemical compounds markedly reduced tumor growth progression. Taken together, the newly identified chemical compounds can be selective for acetylated microtubules and act as potential therapeutic agents against microtubule acetylation enrichment in TNBC.

Cushing syndrome with acute kidney injury due to ureteral stones in a 6-year-old boy.

Cushing syndrome (CS) is rare in children. The clinical presentation of CS varies according to extent and duration of glucocorticoid excess, and urolithiasis is a common complication. We report the first case of a patient with CS associated with acute kidney injury (AKI) due to urolithiasis. A 6-year-old boy presented to the Emergency Department with seizure. On physical examination, he had clinical features of CS and high blood pressure. Brain computed tomography (CT) suggested posterior reversible encephalopathy syndrome due to hypertension. On evaluation of hypertension, laboratory tests suggested adrenocortical tumor, but abdominal CT suggested pheochromocytoma. During further evaluation, his condition deteriorated with AKI due to bilateral ureteral stones, for which the patient underwent continuous renal replacement therapy in the intensive care unit. After controlling hypercortisolism with etomidate and performing ureteral stent indwelling, an adrenal mass was resected and histologically confirmed as an adrenocortical adenoma. We review the clinical manifestations, diagnosis, and management of CS associated with urolithiasis and AKI. Early recognition and careful monitoring of urolithiasis in CS patients are important to avoid severe complications of urolithiasis.

A case of primary hyperparathyroidism due to an intrathymic ectopic parathyroid adenoma in a 15-year-old boy.

Hypercalcemia due to primary hyperparathyroidism (PHPT) is uncommon in children. PHPT is typically caused by a single parathyroid adenoma. Ectopic parathyroid adenomas account for 6%-16% of all parathyroid adenomas and are rare in children but should be considered in cases that present with hypercalcemia. We report the case of a 15-year-old boy with PHPT due to an intrathymic ectopic parathyroid adenoma. Neck ultrasonography and Tc-99m-sestamibi (MIBI) scanning with single-photon emission computed tomography/computed tomography (SPECT/CT) revealed ectopic parathyroid adenoma in the thymus. Video-assisted thoracoscopic surgery was performed to remove the ectopic parathyroid adenoma. Pathology showed intrathymic ectopic parathyroid adenoma. After surgery, the patient's serum calcium level immediately normalized. Intact parathyroid hormone (iPTH) and alkaline phosphatase levels returned to normal ranges within 3 months. Delayed diagnosis of PHPT can cause end-organ damage; a timely diagnosis is especially critical to preserve bone and renal function. If ectopic parathyroid adenomas are well localized in preoperative imaging evaluation and intraoperative iPTH level decreases after resection, ectopic parathyroidectomy without bilateral neck exploration may be performed to avoid unnecessary morbidity.

Extra domain A-containing fibronectin expression in Spin90-deficient fibroblasts mediates cancer-stroma interaction and promotes breast cancer progression.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment play major roles in supporting cancer progression. A previous report showed that SPIN90 downregulation is correlated with CAF activation and that SPIN90-deficient CAFs promote breast cancer progression. However, the mechanisms that mediate cancer-stroma interaction and how such interactions regulate cancer progression are not well understood. Here, we show that extra domain A (EDA)-containing fibronectin (FN), FN(+)EDA, produced by mouse embryonic fibroblasts (MEFs) derived from Spin90-knockout (KO) mice increases their own myofibroblast differentiation, which facilitates breast cancer progression. Increased FN(+)EDA in Spin90-KO MEFs promoted fibril formation in the extracellular matrix (ECM) and specifically interacted with integrin α4ß1 as the mediating receptor. Moreover, FN(+)EDA expression by Spin90-KO MEFs increased proliferation, migration, and invasion of breast cancer cells. Irigenin, a specific inhibitor of the interaction between integrin α4ß1 and FN(+)EDA, significantly blocked the effects of FN(+)EDA, such as fibril formation by Spin90-KO MEFs and proliferation, migration, and invasion of breast cancer cells. In orthotopic breast cancer mouse models, irigenin injection remarkably reduced tumor growth and lung metastases. It was supported by that FN(+)EDA in assembled fibrils was accumulated in cancer stroma of human breast cancer patients in which SPIN90 expression was downregulated. Our data suggest that SPIN90 downregulation increases FN(+)EDA and promotes ECM stiffening in breast cancer stroma through an assembly of long FN(+)EDA-rich fibrils; moreover, engagement of the Integrin α4ß1 receptor facilitates breast cancer progression. Inhibitory effects of irigenin on tumor growth and metastasis suggest the potential of this agent as an anticancer therapeutic.

Adolescents with thyroid nodules: retrospective analysis of factors predicting malignancy.

Thyroid nodules are less common in children than in adults. However, pediatric thyroid nodules have a higher rate of malignancy compared to those in adults, and increased risk of metastasis and recurrence. In the present study, we analyzed the clinical features as well as laboratory and thyroid ultrasound (US) findings of children and adolescents with thyroid nodules to identify predictive factors of thyroid cancer. We retrospectively analyzed 275 patients with thyroid nodules under 18 years of age who visited Severance Children's Hospital between January 2005 and May 2017. Among them, 141 patients who underwent ultrasonography-guided fine needle aspiration biopsy (FNAB), and four patients without FNAB who underwent surgical resection, were included in this study. The remaining 125 patients without FNAB and five patients with follow-up loss after FNAB were excluded. Clinical, laboratory, and US data were evaluated in 145 patients to establish the potential predictive factors of thyroid cancer. Thyroid malignancies were observed in 101 patients. Grade 2 goiters were seen more often in benign nodule group. Hypoechoic nodules, nodules with microcalcifications, abnormal lymph nodes, and irregular margins were findings significantly associated with thyroid cancer. The findings of hypoechoic nodule, nodule with microcalcifications, and abnormal lymph nodes showed statistical significance in predicting thyroid cancer.Conclusion: Hypoechoic nodules, nodules with microcalcifications, and abnormal lymph nodes are predictive factors for thyroid cancer in children. Therefore, further diagnostic evaluations, including FNAB, should be considered in patients with such findings.What is Known:• Thyroid nodules are less common in children than in adults, but pediatric thyroid nodules have a higher rate of malignancy, and also have increased risk of metastasis and recurrence.• Research on ways to predict thyroid cancer have mostly been accomplished in adult patients, and the application of risk stratification system has not been fully satisfactory in children, which requires further studies in pediatric thyroid nodules.What is New:• Hypoechoic nodules, nodules with microcalcifications, and abnormal lymph nodes are predictive factors for thyroid cancer in Korean children.

Incidence and Prevalence of Central Precocious Puberty in Korea: An Epidemiologic Study Based on a National Database.

OBJECTIVES: To investigate the prevalence and incidence of central precocious puberty in Korea using claims data provided by the Health Insurance Review and Assessment Service in Korea as the population-based epidemiologic study. STUDY DESIGN: In this national registry-based, longitudinal, epidemiologic study, patients who were registered with an International Classifications of Diseases, Tenth Revision diagnosis of central precocious puberty (E22.8 according to International Classifications of Diseases, Tenth Revision) and treated with gonadotropin-releasing hormone agonist were included. We assessed the age- and sex-specific prevalence and incidence rates of central precocious puberty in Korea from 2008 to 2014. RESULTS: A total of 37 890 girls and 1220 boys were newly registered with a diagnosis of central precocious puberty from 2008 to 2014. The overall incidence of central precocious puberty during the study period was 122.8 per 100 000 persons (girls, 262.8; boys, 7.0). The overall prevalence of central precocious puberty during the study period was 193.2 per 100 000 persons (girls, 410.6; boys, 10.9). The incidence and prevalence of central precocious puberty steeply increased during the study period in both girls and boys. CONCLUSIONS: This epidemiologic study, based on a national registry that included Korean children, demonstrated that the incidence and prevalence rates of central precocious puberty were high and increased steeply during the study period. Further investigations to determine the underlying causes for this rapid increase in central precocious puberty are needed.

Clinical manifestations of Rathke's cleft cysts and their natural progression during 2 years in children and adolescents.

PURPOSE: Rathke's cleft cyst (RCC) is an asymptomatic benign lesion. With increased interest in pediatric endocrinology, the prevalence of RCCs in children is also increasing. However, the clinical relevance and proper management of RCC is not well defined in children. Therefore, we investigated the clinical manifestations and radiologic features of RCC in children and adolescents, as well as the natural progression of RCC. METHODS: We retrospectively reviewed the medical records of 91 children and adolescents with RCC diagnosed with magnetic resonance imaging (MRI) in Severance Children's Hospital from January 2006 to December 2015. The clinical, hormonal, and imaging findings were analyzed in patient groups classified according to age. The size of each cyst was assessed in sixty patients who underwent follow-up MRI during the 2 years. RESULTS: Female patients were predominant (64 vs. 27). The common clinical features at presentation were endocrine dysfunction (59.3%), headache (23.0%), and dizziness (4.4%). Symptoms related to endocrine disorders were more frequent in younger patients. In 7 patients managed surgically, the cysts were significantly larger and more frequently located in the suprasellar region. Of 60 nonsurgical patients with a follow-up MRI performed within 2 years after the diagnosis, the RCC size increased in about 26.7% (n=16). CONCLUSIONS: Although 94.4% of the patients with RCC had clinical symptoms, surgery was performed in only about 7.5% of patients. RCC is associated with pituitary insufficiency, thus, baseline and follow-up endocrine function tests are required. Additionally, regular MRI follow-up is required in long-term period to monitor change in size.

Diabetes mellitus due to agenesis of the dorsal pancreas in a patient with heterotaxy syndrome.

Heterotaxy syndrome (HS) is a congenital disorder resulting from an abnormal arrangement of visceral organs across the normal left-right axis in the embryonic period. HS is usually associated with multiple anomalies, including defects of the major cardiovascular system and the extracardiovascular system such as intestinal malrotation, abnormal lung lobulation, bronchus anomalies, and pancreatic dysplasia. Although pancreatic dysplasia is occasionally accompanied with HS, the occurrence of diabetes mellitus (DM) due to pancreatic dysplasia in HS is rarely reported. We here report a case involving 13-year-old girl with DM caused by agenesis of the dorsal pancreas and HS diagnosed on the basis of the presence of a double-outlet right ventricle with bilateral pulmonary stenosis and intestinal malrotation with duodenal cyst. Timely diagnosis and treatment with insulin improved glycemic control.

SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression.

Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710-22. ©2017 AACR.

Risk of Gonadoblastoma Development in Patients with Turner Syndrome with Cryptic Y Chromosome Material.

Current guidelines recommend that testing for Y chromosome material should be performed only in patients with Turner syndrome harboring a marker chromosome and exhibiting virilization in order to detect individuals who are at high risk of gonadoblastoma. However, cryptic Y chromosome material is suggested to be a risk factor for gonadoblastoma in patients with Turner syndrome. Here, we aimed to estimate the frequency of cryptic Y chromosome material in patients with Turner syndrome and determine whether Y chromosome material increased the risk for development of gonadoblastoma. A total of 124 patients who were diagnosed with Turner syndrome by conventional cytogenetic techniques underwent additional molecular analysis to detect cryptic Y chromosome material. In addition, patients with Turner syndrome harboring Y chromosome cell lines had their ovaries removed prophylactically. Finally, we assessed the occurrence of gonadoblastoma in patients with Turner syndrome. Molecular analysis demonstrated that 10 patients had Y chromosome material among 118 patients without overt Y chromosome (8.5%). Six patients with overt Y chromosome and four patients with cryptic Y chromosome material underwent oophorectomy. Histopathological analysis revealed that the occurrence of gonadoblastoma in the total group was 2.4%, and gonadoblastoma occurred in one of six patients with an overt Y chromosome (16.7%) and 2 of 10 patients with cryptic Y chromosome material (20.0%). The risk of developing gonadoblastoma in patients with cryptic Y chromosome material was similar to that in patients with overt Y chromosome. Therefore, molecular screening for Y chromosome material should be recommended for all patients with Turner syndrome to detect individuals at a high risk of gonadoblastoma and to facilitate proper management of the disease.