Predictive Factors of Skip Metastasis in Papillary Thyroid Cancer.

BACKGROUND Skip metastasis is defined as metastasis incident to the lateral compartment without involvement of the central compartment, and is generally unpredictable in papillary thyroid cancer (PTC). The present study aimed to investigate the frequency and predictor value of skip metastasis in PTC patients. MATERIAL AND METHODS A total of 355 patients diagnosed with thyroid cancer who had received a prior complete thyroidectomy with bilateral central neck and ipsilateral lateral neck lymph node dissection were enrolled in this study. The clinicopathological and ultrasound features were analyzed. A univariate and multivariate analysis were performed to identify the risk factors of skip metastasis. RESULTS The frequency of skip metastasis was 12.4% (44/355). The PTC patients with skip metastasis exhibited fewer lymph node metastasis, which was more commonly detected in tumor size ≤1 cm (OR 9.354; p=0.001; 95% confidence interval (CI) 1.865-26.735), tumors located in upper pole (OR 3.822; p<0.001; 95% CI 1.935-7.549), without a well-defined margin (OR 2.528; p=0.016; CI 1.191-5.367), and extrathyroidal extension (OR 2.406; p=0.013; CI 1.691-4.367). CONCLUSIONS Skip metastasis was common in PTC. The PTC patients with a tumor size ≤1.0 cm, located in the upper pole, without a well-defined margin and extrathyroidal extension should be carefully evaluated for skip metastasis.

Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells.

The CD44 isoform containing variant exon v6 (CD44v6) plays an important role in the progression, metastasis, and prognosis of colorectal cancer (CRC). Recently, it was found that CD44v6 is involved in acquired drug resistance. This study aimed to investigate the molecular mechanism of CD44v6 in the resistance of CRC cells to chemotherapy. A stable CD44v6 overexpression model in SW480 cells was established via lentiviral transduction. The chemosensitivity of cells to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) was determined by cell counting kit (CCK)-8, lactate dehydrogenase (LDH) release, and colony formation assays. Immunohistochemical staining of CD44v6 was performed in human CRC tissues. The key components in cell apoptosis, drug efflux and metabolism, mismatch repair, autophagy, epithelial-mesenchymal transition (EMT), and the PI3K-Akt and MAPK-Ras-Erk1/2 pathways were assessed using flow cytometry, quantitative real-time polymerase chain reaction (PCR), and western blot assays. The CD44v6 overexpression cells showed a higher viability, a lower LDH release rate, and an increased clonogenicity than the control cells under drug treatment. Moreover, overexpression of CD44v6 resulted in enhanced autophagy flux, EMT, and phosphorylation of Akt and Erk in the presence of drugs. Furthermore, high CD44v6 expression in the primary tumor was closely associated with an early recurrence in CRC patients who underwent curative surgery and adjuvant chemotherapy. In conclusion, overexpression of CD44v6 contributes to chemoresistance in SW480 cells under cytotoxic stress via the modulation of autophagy, EMT, and activation of the PI3K-Akt and MAPK-Ras-Erk pathways.

Cancer stem cell subsets and their relationships.

Emerging evidence suggests that cancer stem cells account for the initiation and progression of cancer. While many types of cancer stem cells with specific markers have been isolated and identified, a variety of differences among them began to be appreciated. Cancer stem cells are hierarchical populations that consist of precancerous stem cells, primary cancer stem cells, migrating cancer stem cells and chemoradioresistant cancer stem cells, playing different roles in cancer initiation and progression. Here we propose a new concept "horizontal hierarchy of cancer stem cells" to distinguish them from vertical hierarchy cancer stem cells, cancer transient-amplifying cells and cancer differentiated cells, and summarize our current understanding of these subsets of cancer stem cells with the aim to open up novel therapeutic strategies for cancer based on this understanding.

XRCC3 5'-UTR and IVS5-14 polymorphisms and breast cancer susceptibility: a meta-analysis.

Published data on the association between XRCC3 5'-UTR and IVS5-14 polymorphisms and breast cancer risk are inconclusive. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between these polymorphisms and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. A total of four studies were involved in the meta-analysis with 6,303 cases and 6,563 controls for XRCC3 5'-UTR polymorphism and with 6,270 cases and 6,682 controls for XRCC3 IVS5-14 polymorphism. For XRCC3 5'-UTR A/G polymorphism, significantly elevated breast cancer risk was associated with variant genotype when all studies were pooled into the meta-analysis (AG vs. AA: OR = 1.11, 95% CI = 1.03-1.19; dominant model: OR = 1.09, 95% CI = 1.01-1.17). For XRCC3 IVS5-14 A/G polymorphism, significantly decreased breast cancer risk was associated with variant genotype (GG vs. AA: OR = 0.86, 95% CI = 0.77-0.96). In conclusion, this meta-analysis suggests that the variant G allele of XRCC3 5'-UTR polymorphism is a low-penetrant risk factor for developing breast cancer, while the variant G allele of XRCC3 IVS5-14 polymorphism has a protective effect on breast cancer development.

Downregulation of CD44v6 Enhances Chemosensitivity by Promoting Apoptosis and Inhibiting Autophagy in Colorectal Cancer HT29 Cells.

BACKGROUND: Chemotherapy resistance reduces the effectiveness of chemotherapeutic drugs greatly, resulting in treatment failure. Therefore, exploring chemoresistance-related genes and the corresponding mechanism is extremely important. The central role of CD44v6 in colorectal cancer has been previously reported. However, the effects of CD44v6 gene knockdown on the chemosensitivity of colorectal cancer cells are not conclusive. MATERIAL AND METHODS: A stable CD44v6 knockdown cell model in HT29 cells (HT29-KD) was established via lentiviral transduction. A quantitative real-time polymerase chain reaction (PCR) was carried out to confirm the knockdown efficiency. The chemosensitivity of cells to 5-fluorouracil (5-FU) was determined by a cell counting kit (CCK)-8 assay. Cell apoptosis and the cell cycle were assessed by flow cytometry. RESULTS: The CD44v6 knockdown cell model was successfully constructed by using lentiviral transduction. Upon treatment with 5-FU, the inhibitory rate for cell activity of HT29-KD cells was significantly higher than that of the control group (HT29-NC). CD44v6 gene knockdown did not significantly affect HT-29 cell proliferation, according to the CCK-8 assay and cell cycle analysis. The cell apoptosis assay revealed that CD44v6 gene knockdown promoted HT-29 cell apoptosis. Without 5-FU treatment, there was no significant difference in terms of the relative expression level of the autophagy-related gene BECN1 between the two groups. However, with 5-FU treatment, the relative expression level of BECN1 in HT29-KD cells was much lower than that in HT29-NC cells. CONCLUSION: Our study confirms that CD44v6 gene knockdown can enhance chemosensitivity in HT29 cells by promoting apoptosis and inhibiting autophagy, thus affirming the effects of CD44v6 on the chemosensitivity of colorectal cancer.

Risk factors for hypocalcemia and hypoparathyroidism following thyroidectomy: a retrospective Chinese population study.

BACKGROUND: Hypocalcemia is one of the most common postoperative complications following thyroid surgery in clinical practice. The occurrence of hypocalcemia is mainly attributed to hypoparathyroidism when parathyroid glands are devascularized, injured, or dissected during the surgery. The aim of this study was to analyze the risk factors for hypocalcemia and hypoparathyroidism following thyroidectomy. PATIENTS AND METHODS: A total of 278 patients who underwent thyroid surgery were analyzed retrospectively. Univariate analysis and multivariable logistic regression were performed to discover the risk factors for hypocalcemia and hypoparathyroidism. RESULTS: Postoperative hypocalcemia occurred in 76 (27.3%) patients and hypoparathyroidism occurred in 42 (15.1%) patients. Seven factors were significantly related to the presence of postoperative hypocalcemia, namely, age (P=0.049), gender (P=0.015), lateral lymph node dissection (P=0.017), operation type (P<0.001), preoperative parathyroid hormone (PTH) level (P=0.035), operation time (P=0.001), and applying carbon nanoparticles (CNs; P=0.007). Our result revealed that gender (P=0.014), lateral lymph node dissection (P=0.038), operation type (P<0.001), operative time (P<0.001), and applying CNs (P=0.001) had a significant correlation with postoperative hypoparathyroidism. CONCLUSION: These findings were crucial for guiding surgeons to prevent the occurrence of hypocalcemia and hypoparathyroidism.

Designability and cooperative folding in a four-letter hydrophobic-polar model of proteins.

The two-letter hydrophobic-polar (HP) model of Lau and Dill [Macromolecules 22, 3986 (1989)] has been widely used in theoretical studies of protein folding due to its conceptual and computational simplicity. Despite its success in elucidating various aspects of the sequence-structure relationship, thermodynamic behavior of the model is not in agreement with a sharp two-state folding transition of many single-domain proteins. To gain a better understanding of this discrepancy, we consider an extension of the HP model by including an "antiferromagnetic" (AF) interaction in the contact potential that favors amino acid residues with complementary attributes. With an enlarged four-letter alphabet, the density of states on the low energy side can be significantly decreased. Computational studies of the four-letter HP model are performed on 36-mer sequences on a square lattice. It is found that the designability of folded structures in the extended model exhibits strong correlation with that of the two-letter HP model, while the AF interaction alone selects a very different class of structures that resembles the Greek key motif for beta sheets. A procedure is introduced to select sequences which have the largest energy gap to the native state. Based on density of states and specific heat calculations in the full configuration space, we show that the optimized sequence is able to fold nearly as cooperatively as a corresponding Go model.

Replantation with cryopreserved parathyroid for permanent hypoparathyroidism: a case report and review of literatures.

Permanent postsurgical hypoparathyroidism is defined as insufficient parathyroid hormone (PTH) to maintain normocalcemia 6 months after surgery. It occurs mostly in reoperation for persistent or recurrent hyperparathyroidism. The treatment of long-term calcium and vitamin D supplement is burdensome and may cause iatrogenic complications. PTH replacement is potential but still under trials. Only replantation with cryopreserved parathyroid is an available treatment for patients to reduce or stop long-term drug administration. However, this treatment is not applied widely in developing countries, due to lack of experiences and skills. Herein, we reported a 58-year-old male presented a continuous elevated parathyroid hormone up to about 2342 ng/L and bone pain during hemodialysis for 6 years due to chronic renal failure. He underwent the first operation total parathyroidectomy and autotransplantation. After this operation, he suffered from a persistent calcemia and permanent hypoparathyroidism. After three times of replantation with cryopreserved parathyroid and dialysis with a high calcium dialysate, the low concentration of calcium was elevated and symptoms of hypocalcemia disappeared. However, PTH was not elevated significantly in the long term. It might be related to our nonstandard cryopreservation protocol and no microbiological and histological examinations before replantation, compared with other successful reports. Therefore, we suggest a standard cryopreservation protocol should be followed by non-experienced institutions, especially in developing countries. Furthermore, a high calcium dialysate is efficient to increase calcium concentration and alleviate symptoms of hypocalcemia. It may be an available treatment of persistent hypocalcemia and permanent hypoparathyroidism in dialysis patients.

[Effect of 5-fluorouracil on the expression of ATP-binding cassette superfamily G member 2 in human colon cancer cell SW480].

OBJECTIVE: To investigate the effect of 5-fluorouracil (5-FU) on the expression of ATP-binding cassette superfamily G member 2 (ABCG2) in human colon cancer cell SW480. METHODS: SW480 cells were treated with various concentrations of 5-FU. CCK8 assay was utilized to detect the 5-FU IC50 to SW480 cells. Positive expression of ABCG2 was detected by flow cytometry, and mRNA expression of ABCG2 was detected by real time polymerase chain reaction (RT-PCR). RESULTS: The 5-FU IC50 to SW480 cells increased as the drug concentration increased (P<0.05). Flow cytometry revealed that positive expression rate of ABCG2 in normal SW480 cells (group A) was (6.26±0.86)%. Immediately after treatment with 5-FU for 48 hours, the positive expression rate of ABCG2 (group B) was (3.43±1.18)% (P<0.05). In the second passage of cells after treatment with 5-FU for 48 hours, the positive expression rate of ABCG2 (group C) was (12.91±3.42)% (P<0.05). The mRNA expression of ABCG2 detected by RT-PCR was in accordance with the results from flow cytometry. CONCLUSION: Expression of ABCG2 in SW480 cells can be affected by various concentrations of 5-FU.

Expression of ABCG2 and its significance in colorectal cancer.

The expression of ABCG2 in colorectal cancer and its relationship with invasion and metastasis is still not clear. In our study, immunohistochemical staining of ABCG2 was therefore performed for 60 cases of primary colorectal cancer. ABCG2 positive cancer cells were found to be mainly positioned in the front of carcinomatous tissue or between carcinomatous and non-carcinomatous margin tissues. In carcinomatous tissues and non-carcinomatous margin tissues, high expression rates forABCG2 were 36.7% (22/60) and 3.3% (2/60) respectively, with significant difference (chi2=5773.3, P<0.001). The rates of high expression of ABCG2 were 30% (9/30) and 6.7% (2/30) in 30 cases with and without positive lymph nodes, respectively. (chi2=5.45, P<0.025). From the present results expression of ABCG2 may be important in the progression and metastasis of colorectal cancer.

Prognostic and metastatic value of phosphatase of regenerating liver-3 in invasive breast cancer.

PURPOSE: The aim of this study was to investigate the expression of the PRL-3 in human invasive breast cancer and to evaluate its clinical and prognostic significance. Its potential role in the invasive-metastatic properties of invasive breast cancer was also investigated. METHODS: Protein expression of PRL-3 was evaluated by immunohistochemistry for a consecutive series of 82 invasive human breast cancer tissues and 63 matched lymph node metastases, including PRL-3 mRNA expression analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) in malignant, nonmalignant breast tissue samples and lymph node metastases. We investigated the correlation of PRL-3 with clinicopathologic features, Overall and recurrence-free survival distribution curves were assessed using the Kaplan-Meier test and log-rank statistics, followed by Cox proportional hazards regression model. RESULTS: We found that 70.7% patients expressed a high level of PRL-3 protein in their tumors, and its over expression was positive correlated with lymph node metastasis (LNM) (P = 0.011). Moreover, The PRL-3 mRNA expression was significantly higher in malignant compared to benign breast tissue, while increased expression of PRL-3 mRNA was significantly associated with LNM (P = 0.002). Univariate analysis showed that the positive expression of PRL-3 was a poor risk prognostic factor (OS, P = 0.045; RFS, P = 0.034). Multivariate analysis using the Cox regression model indicated that high PRL-3 expression was an independent unfavorable prognostic factor for RFS. CONCLUSIONS: These results strongly suggest that PRL-3 expression can indicate the potential role of LNM to some extent. Increasing the risk of tumor metastasis (OR = 3.889). Our results also imply that PRL-3 might be a novel molecular marker for predicting relapse of invasive breast cancer.

How to search for specific markers of cancer stem cells.

According to the cancer stem cell hypothesis, cancer stem cells with unlimited self-renewal and multi-differentiation properties such as adult stem cells are the root cause of cancer initiation and progression, and targeted therapy to cancer stem cells is to become the most efficient therapy of cancer. However, specific markers should be discovered to define cancer stem cells accurately before targeted therapy. Therefore, we propose a model of specific markers of cancer stem cells and how to search for such markers.