A family of Melnick-Needles syndrome: a case report.

BACKGROUND: Melnick-Needles syndrome (MNS) is an extremely rare osteochondrodysplasia caused by a mutation of FLNA, the gene encoding filamin A. MNS is inherited in an X-linked dominant manner. In this study, we describe three members of the same family with MNS, who exhibited different phenotypic severity despite having an identical FLNA gene mutation. CASE PRESENTATION: The patient was 16 months old, with a history of delayed physical development, multiple upper respiratory infections and otitis media episodes. She was referred to our orthopedic clinic because of bowed legs and an abnormal plain chest radiograph. Both upper and lower extremities were bowed. Plain X-rays showed thoracolumbar kyphoscoliosis, with anterior and posterior vertebral scalloping, and thin, wavy ribs. Hypoplasia of the pubis and ischium, with bilateral coxa valga, were also noted. Target exome sequencing revealed a heterozygous mutation of FLNA, c.3578 T > C, p.Lys1193Pro, which confirmed the diagnosis of MNS. Her older sister and mother had minimal deformities of the axial and extremity skeleton, but genetic analyses revealed the same FLNA mutation as the patient. The mutation identified in this family has not been previously reported. CONCLUSION: This report illustrates the potential inherited nature of MNS and the phenotypic variability of clinicoradiologic characteristics. In patients with traits suggestive of MNS, a careful medical and family history should be obtained, and genetic testing should be performed for the patient, as well as all family members.

Association between Five Common Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms and Colorectal Cancer Susceptibility.

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (-844G > A [rs2227631], -675 4G > 5G [rs1799889], +43G > A [rs6092], +9785G > A [rs2227694], and +11053T > G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 -675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556; 95% confidence interval (CI): 1.012-2.391; p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620; 95% CI: 0.413-0.932; p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662; 95% CI: 0.469-0.933; p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.

Genetic associations between the miRNA polymorphisms miR-130b (rs373001), miR-200b (rs7549819), and miR-495 (rs2281611) and colorectal cancer susceptibility.

BACKGROUND: Recent studies have extensively investigated the role of miRNAs in colorectal cancer (CRC), and several associations have been reported. In addition, single nucleotide polymorphisms (SNPs) in promoter regions of miRNAs have been shown to affect miRNA expression. Therefore, we aimed to analyze the effect of miRNA polymorphisms on CRC susceptibility. METHODS: We conducted association studies on the relationships between the miRNA polymorphisms miR-130bT > C rs373001, miR-200bT > C rs7549819, and miR-495A > C rs2281611 and CRC with 472 CRC patients and 399 control subjects in Korea. RESULTS: Multivariate logistic regressions of the CRC subgroups showed that the miR-495CC genotype associated with rectal cancer (AA+AC vs. CC; adjusted odds ratio (AOR) for CC, 1.592; 95% confidence interval (CI), 1.071-2.368; P = 0.022). The gene-environment combinatorial analysis showed that the combination of miR-495A > C and low plasma folate contributed to an increased risk of rectal cancer (AA+AC vs. CC; AOR for CC, 3.829; 95% CI, 1.577-9.300; P = 0.003). In the survival analysis, miR-200bT > C associated with CRC patient mortality (TT vs TC + CC; adjusted hazard ratio for TC + CC, 0.592; 95% CI, 0.373-0.940; P = 0.026). CONCLUSION: In this study, we found that miR-200b and miR-495 polymorphisms are involved in CRC susceptibility and prognosis.

Auranofin as a Novel Anticancer Drug for Anaplastic Thyroid Cancer.

Background/Objectives: Anaplastic thyroid cancer (ATC) is an aggressive and rare cancer with a poor prognosis, and traditional therapies have limited efficacy. This study investigates drug repositioning, focusing on auranofin, a gold-based drug originally used for rheumatoid arthritis, as a potential treatment for ATC. Methods: Auranofin was identified from an FDA-approved drug library and tested on two thyroid cancer cell lines, 8505C and FRO. Antitumor efficacy was evaluated through gene and protein expression analysis using Western blot, FACS, and mRNA sequencing. In vivo experiments were conducted using subcutaneous injections in nude mice to confirm the anticancer effects of auranofin. Results: Auranofin induced reactive oxygen species (ROS) production and apoptosis, leading to a dose-dependent reduction in cell viability, G1/S phase cell cycle arrest, and altered expression of regulatory proteins. It also inhibited cancer stem cell activity and suppressed epithelial-mesenchymal transition. mRNA sequencing revealed significant changes in the extracellular matrix-receptor interaction pathway, supported by Western blot results. In vivo xenograft models demonstrated strong antitumor activity. Conclusions: Auranofin shows promise as a repurposed therapeutic agent for ATC, effectively inhibiting cell proliferation, reducing metastasis, and promoting apoptosis. These findings suggest that auranofin could play a key role in future ATC treatment strategies.

Genetic variants of MUC4 are associated with susceptibility to and mortality of colorectal cancer and exhibit synergistic effects with LDL-C levels.

As a disease with high mortality and prevalence rates worldwide, colorectal cancer (CRC) has been thoroughly investigated. Mucins are involved in the induction of CRC and the regulation of intestinal homeostasis but a member of the mucin gene family MUC4 has a controversial role in CRC. MUC4 has been associated with either decreased susceptibility to or a worse prognosis of CRC. In our study, the multifunctional aspects of MUC4 were elucidated by genetic polymorphism analysis in a case-control study of 420 controls and 464 CRC patients. MUC4 rs1104760 A>G polymorphism had a protective effect on CRC risk (AG, AOR = 0.537; GG, AOR = 0.297; dominant model, AOR = 0.493; recessive model, AOR = 0.382) and MUC4 rs2688513 A>G was associated with an increased mortality rate of CRC (5 years, GG, adjusted HR = 6.496; recessive model, adjusted HR = 5.848). In addition, MUC4 rs1104760 A>G showed a high probability of being a potential biomarker for CRC patients with low-density lipoprotein cholesterol (LDL-C) in the risk range while showing a significant synergistic effect with the LDL-C level. This is the first study to indicate a significant association between MUC4 genetic polymorphisms and CRC prevalence, suggesting a functional genetic variant with the LDL-C level, for CRC prevention.

Prognostic significance of three endothelial nitric oxide synthase (eNOS) polymorphisms and metabolic syndrome (MetS) in patients with colorectal cancer.

BACKGROUND: Polymorphisms of endothelial nitric oxide synthases (eNOS) have been associated with cancer susceptibility. Also, metabolic syndrome is associated with cancer malignancy. However, the effect of eNOS polymorphisms and metabolic syndrome on colorectal cancer (CRC) prognosis remains unclear. OBJECTIVE: To investigated whether three genetic polymorphisms (- 786 T > C rs2070744, 4a4b rs869109213, and 894G > T rs1799983) in the eNOS and metabolic syndrome (MetS) were associated with CRC patient survival. METHODS: We genotyped three polymorphisms of eNOS (- 786 T > C, 4a4b, and 894G > T) in 312 CRC cases from the Korean population by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Although the three eNOS polymorphisms were not causative of MetS, the TT genotype of the 894G > T polymorphism was associated with a worse survival rate compared with the GG genotype in the CRC group with MetS than in the CRC group without MetS (5-years survival; adjusted HR = 54.777; 95% CI 5.073-591.487 and RFS; adjusted HR = 14.909; 95% CI 1.571-141.528). CONCLUSIONS: The eNOS polymorphisms were not associated with metabolic syndrome prevalence in CRC patients. However, our findings suggest that the eNOS 894G > T polymorphism with MetS was associated with poor clinical outcomes.

Genetic Variants of HOTAIR Associated With Colorectal Cancer Susceptibility and Mortality.

In colorectal carcinogenesis, the unique molecular and genetic changes that occur within cells result in specific CRC phenotypes. The involvement of the long non-coding RNA, HOTAIR, in cancer development, progression, and metastasis is well-established. Various studies have reported on the contribution of HOTAIR to cancer pathogenesis. Therefore, we selected four HOTAIR polymorphisms (rs7958904G>C, rs1899663G>T, rs4759314A>G, and rs920778T>C) to evaluate the association of each variant with CRC prevalence and prognosis. We conducted a case-control study of 850 individuals to identify the genotype frequencies of each polymorphism. The study population included 450 CRC patients and 400 control individuals that were randomly selected following a health screening. Notably, rs7958904 and rs1899663, their hetero genotype, and the dominant model were significantly different when compared to the healthy control group (rs7958904; AOR = 1.392, 95% CI = 1.052-1.843, P = 0.021). To evaluate the effect of HOTAIR polymorphisms on the survival rate, we analyzed patient mortality and relapse occurrence within 3 and 5 years with Cox-regression analysis. The rs7958904 CC polymorphism mortality rate was significantly higher than the GG polymorphism mortality rate (adjusted HR = 2.995, 95% CI = 1.189-7.542, P = 0.021). In addition, the rs920778 CC genotype was significantly different than the TT genotype (adjusted HR = 3.639, 95% CI = 1.435-9.230, P = 0.007). In addition, this study confirmed that genetic variants of HOTAIR alter the mRNA expression level (P < 0.01). We suggest that HOTAIR rs7958904G>C which is associated with CRC prevalence and mortality is a potential biomarker for CRC. The association between HOTAIR gene polymorphisms and CRC prevalence were reported for the first time.

Association between TP53 genetic polymorphisms and the methylation and expression of miR-34a, 34b/c in colorectal cancer tissues.

Colorectal cancer (CRC) is one of the most common types of cancers, as evidenced by the >1.2 million patient diagnoses and 600,000 mortalities globally each year. Recently, the microRNA (miR/miRNA)-34 miRNA precursor family was revealed to participate in the tumor protein (TP)-53 pathway, which is frequently involved in CRC. Furthermore, the expression of miR-34 is reportedly regulated by DNA methylation. Accordingly, the present study investigated the correlation between the methylation status of miR-34 miRNAs and miR-34 expression in paired CRC tumor and normal tissues. The methylation status of miR-34a and miR-34b/c was determined using the MethyLight assay, and the expression of miR-34a and miR-34b/c in the same paired tissues was analyzed by reverse transcription-quantitative polymerase chain reaction. The results revealed significantly elevated miR-34a (P=0.012) and miR-34b/c (P<0.0001) methylation levels in tumor tissues when compared with normal tissues, whereas only the expression of miR-34b/c differed (P=0.005) between the paired tissues. In addition, an association between TP53 haplotypes and miR-34 family expression levels was observed. The miR-34a methylation levels in the TP53 PIN A1A1 (48.56±36.49) and TP53 MSP GG (49.00±36.44) genotypes were increased in the tumor tissues when compared with normal tissues. In conclusion, it was determined that miR-34 promoter methylation and TP53 polymorphisms may be associated with CRC pathogenesis.

Chloroquine and amodiaquine enhance AMPK phosphorylation and improve mitochondrial fragmentation in diabetic tubulopathy.

We investigated the effects of chloroquine (CQ) and amodiaquine (AQ) on AMPK phosphorylation in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether CQ- or AQ-mediated AMPK activity restoration attenuated diabetic tubulopathy by normalizing mitochondrial fragmentation. Human renal proximal epithelial cells (HKC8) were incubated in high-glucose conditions. Diabetes was induced with streptozotocin in male C57/BL6J mice. Treatment with CQ or AQ abolished high-glucose-induced phospho-AMPK and phosph-PGC1α down-regulation in HKC8 cells. Improvements in functional mitochondrial mass and balanced fusion/fission protein expression were observed in HKC8 cells after treatment with CQ or AQ in high-glucose conditions. Moreover, decreased mitochondrial ROS production and reduced apoptotic and fibrotic protein expression were noted in HKC8 cells after treatment with CQ or AQ, even in high-glucose conditions. CQ and AQ treatment effectively mitigated albuminuria and renal histopathologic changes and increased AMPK activity in the kidneys of diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased, and 8-OHdG content was low in the renal tubular cells of the CQ and AQ treatment groups compared with those of the diabetic control group. Our results suggest that CQ and AQ may be useful treatments for patients with diabetic kidney disease.

25-hydroxyvitamin D Levels was not Associated with Blood Pressure and Arterial Stiffness in Patients with Chronic Kidney Disease.

BACKGROUND: We investigated the effect of vitamin D deficiency on cardiovascular risk profiles in an Asian population with chronic kidney disease (CKD). METHODS: A total of 210 participants (62 non-dialysis CKD patients and 148 hemodialysis [HD] patients) were enrolled between December 2009 and February 2010. Vitamin D deficiency was determined using the serum 25-hydroxyvitamin D [25(OH)D] concentration. Blood pressure and arterial stiffness were measured. Subjects were divided into groups according to 25(OH)D concentration based on a cut-off of 13.5 ng/mL in non-dialysis CKD patients and 11.3 ng/mL in HD patients. RESULTS: The mean age was 61.7±12.3 years in non-dialysis CKD patients and 57.0±12.7 years in HD patients. In the non-dialysis CKD group, mean estimated glomerular filtration rate (eGFR) was 29.7±15.4 mL/min/1.73 m2. Mean 25(OH)D concentration was 13.6±7.8 ng/mL in non-dialysis CKD patients and 11.3±6.7 ng/mL in HD patients. More than half of the subjects had vitamin D deficiency (67.6% in non-dialysis CKD patients and 80.4% in HD patients). There were no significant differences in systolic blood pressure, pulse pressure, and arterial stiffness between higher and lower 25(OH)D groups among non-dialysis CKD and HD patients. Multivariate analysis revealed that female sex (odds ratio [OR]: 5.890; 95% confidence interval [CI]: 2.597-13.387; p<0.001) and presence of diabetes (OR: 2.434; 95% CI: 1.103-5.370; p=0.028) were significantly associated with lower serum 25(OH)D levels in HD patients. CONCLUSION: The prevalence of vitamin D deficiency was high in both nondialysis CKD patients and HD patients. Serum 25(OH)D concentration was not a significant factor associated with blood pressure and arterial stiffness among non-dialysis CKD and HD patients.

Warthin-like variant of papillary thyroid carcinoma: single institution experience.

BACKGROUND: Correct diagnosis of the variants of papillary thyroid carcinoma (PTC) is important because these variants differ in clinical course. The Warthin-like variant (WLV) is relatively uncommon and is recognized as not different from conventional PTC. We therefore assessed the clinicopathological features of patients with WLV of PTC who were diagnosed and treated at our institution. METHODS: Of the 8179 patients treated for PTC at the Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, between January 2007 and December 2012, 16 patients (0.2%) were pathologically diagnosed with WLV of PTC. Their clinicopathological features and post-operative follow-up for local recurrence and distant metastasis were retrospectively investigated. RESULT: Mean patient age was 44.9 years (range: 23-61 years), with seven (44%) being younger than 45 years. Only one of the 16 patients was male (6%). Mean tumour size was 8.9 mm (range: 3-22 mm). Extrathyroidal extension was observed in seven patients (44%), associated thyroiditis in 11 (69%) and lymph node metastasis in six (38%). The mean follow-up period was 37 months (range: 13-78 months), during which none of the 16 patients experienced recurrence or metastasis. Fifteen patients (94%) had MACIS score <6, with the remaining patient having a MACIS score of 6.33. CONCLUSION: WLV of PTC is rare, with favourable prognosis. Nevertheless, it is important to determine the histopathological features of these tumours.

Tuberculosis cervical lymphadenopathy mimics lateral neck metastasis from papillary thyroid carcinoma.

BACKGROUND: Tuberculosis (TB) lymphadenitis is a frequent cause of lymphadenopathy in areas in which TB is endemic. Cervical lymphadenopathy in TB can mimic lateral neck metastasis (LNM) from papillary thyroid carcinoma (PTC). This study evaluated the clinicopathological features of patients with PTC and TB lateral neck lymphadenopathy. METHODS: Of the 9098 thyroid cancer patients who underwent thyroid cancer surgery at the Thyroid Cancer Center of Gangnam Severance Hospital between January 2009 and April 2013, 28 had PTC and showed TB lymphadenopathy of the lateral neck node. The clinicopathological features of these 28 patients were evaluated. RESULTS: Preoperatively, all 28 patients were diagnosed with PTC and showed cervical lymphadenopathy. All had radiological characteristics suspicious of metastasis in lateral neck nodes. Based upon the results from intraoperative frozen sections, lymph node dissection (LND) was not performed on 19 patients. Seven of eight patients who underwent LND had metastasis combined with tuberculous lymphadenopathy, with the remaining patient negative for LNM. CONCLUSIONS: Intraoperative sampling and frozen sectioning of lymph nodes suspicious of metastasis can help avoid unnecessary LND for tuberculous lymphadenopathy.

Overcoming the limitations of fine needle aspiration biopsy: detection of lateral neck node metastasis in papillary thyroid carcinoma.

PURPOSE: Ultrasound (US) and US-guided fine needle aspiration biopsies (FNAB) are considered the modalities of choice for assessing lymph nodes suspected of containing metastases, but the sensitivity of FNAB varies and is specific to the operator. We analyzed the risk of FNAB providing false negative results of lateral neck node metastasis, and evaluated diagnostic accuracy of FNAB, in patients with papillary thyroid cancer. MATERIALS AND METHODS: FNAB was performed in 242 patients suspected of having lateral neck node metastasis on preoperative imaging. Thyroglobulin in the fine-needle aspirate washout (FNA wash-out Tg) and computed tomography enhancement (Hounsfield units) were measured. Patients with negative results on FNAB were examined by intraoperative frozen section. The false negative and true negative groups were compared. RESULTS: Of the 242 patients, 130 were confirmed as having lateral neck node metastases. In 74 patients, the metastasis was identified by FNAB. False positive results were observed in 2 patients (0.8%) and false negatives in 58 (44.6%). Risk analysis showed that patient age <45 years (p=0.006), tumor size >1 cm (p=0.008) and elevated FNA wash-out Tg (p=0.004) were significantly associated with false negative results on FNAB. The accuracy of FNAB increased significantly when combined with FNA wash-out Tg (p=0.003). CONCLUSION: To reduce the false negative rate of FNAB, patient age (<45 years), tumor size (>1 cm) and FNA wash-out Tg (>34.8 ng/mL) should be considered in preoperative planning. Accuracy may be improved by combining the results of FNAB and FNA wash-out Tg.

Cervical bronchogenic cysts mimic metastatic lymph nodes during thyroid cancer surgery.

PURPOSE: Although congenital bronchogenic cysts in the cervical region, especially in the thyroid or perithyroidal area, are rare, distinguishing them from other cervical cystic lesions (e.g., thyroglossal duct and branchial cleft cysts) and metastatic cervical lymph nodes is difficult preoperatively. Additionally, cystic degeneration of metastatic lymph nodes is common in patients with thyroid cancer. We investigated the clinical characteristics and proper treatment for individuals with cervical bronchogenic cysts. METHODS: Of the 18,900 patients treated for thyroid cancer, 18 patients with pathologically confirmed bronchogenic cysts were retrospectively reviewed. Bilateral total thyroidectomy or less than total thyroidectomy with central compartment node dissection, including cystic mass excision was done and cystic mass was confirmed by postoperative pathologic examination. RESULTS: All cervical bronchogenic cysts were asymptomatic. Their mean size was 1.2 cm (range, 0.3 to 3 cm). Of these 18 patients, 15 did not have any abnormal radiological findings, except for lymphadenopathy during preoperative evaluations. Most bronchogenic cysts were detected around the thyroid and paratracheal areas. On preoperative imaging and intraoperatively, most were indistinguishable from metastatic cervical lymph nodes or other cystic lesions. CONCLUSION: Although cervical bronchogenic cysts are rare and benign, they should be distinguished from other cystic cervical masses, especially metastatic cervical lymph nodes associated with thyroid cancer. Possible cervical bronchogenic cysts found during thyroid cancer evaluation or surgery should be surgically excised.