Association between triglyceride-glucose index and femoral bone mineral density in community-dwelling, nondiabetic men and women: a NHANES analysis of 1,928 US individuals.

OBJECTIVE: To determine the potential association between the triglyceride-glucose (TyG) index and bone mineral density (BMD) in community-dwelling adults without diabetes using a nationally representative database from the United States (US). METHODS: Data were extracted from the National Health and Nutrition Examination Survey (NHANES) 2005-2010, 2013-2014, and 2017-2018. Men and postmenopausal women aged ≥50 years with complete data on femoral neck BMD, triglycerides, and fasting plasma glucose levels were eligible for inclusion. Participants with diabetes, history of malignancy, thyroid disease, underweight status, end-stage kidney disease, rheumatoid arthritis, estrogen/selective estrogen receptor modulators, bisphosphonate or bone resorption inhibitors, or missing dataset weight values were excluded. Univariate and multivariable logistic regression analyses were performed to determine the associations between low BMD, TyG index, and other study variables. RESULTS: A total of 1,844 participants (1,161 men and 683 women) were included, representing 31,517,106 community-dwelling individuals in the US. The mean age of the study population was 60.7 years old, and 26.7% of the men and 60.4% of the women had low bone density. In both males and females, the mean TyG index was 8.6. After adjusting for demographic, lifestyle, and clinical factors, no significant association was observed between TyG and femoral neck BMD among men (adjusted odds ratio [aOR] = -0.0002, 95% confidence interval [CI]: -0.02 to 0.02) and women (aBeta = 0.005, 95% CI: -0.02 to 0.04). Similarly, no significant association was observed between TyG index and the odds for low bone density among men (aOR = 1.09, 95% CI: 0.73-1.63) and women (aOR = 0.99, 95% CI: 0.49-2.01). CONCLUSIONS: Based on data from a large sample in the US, this study did not find an association between the TyG index and femoral neck BMD or the occurrence of low bone density in community-dwelling males and females without diabetes.

Intracellular Delivery of Stabilized Peptide Blocking MTDH-SND1 Interaction for Breast Cancer Suppression.

Triple-negative breast cancer is one of the most prevalent malignant cancers worldwide. Disrupting the MTDH-SND1 protein-protein interaction has recently been shown to be a promising strategy for breast cancer therapy. In this work, a novel potent stabilized peptide with a stronger binding affinity was obtained through rational structure-based optimization. Furthermore, a sulfonium-based peptide delivery system was established to improve the cell penetration and antitumor effects of stabilized peptides in metastatic breast cancer. Our study further broadens the in vivo applications of the stabilized peptides for blocking MTDH-SND1 interaction and provides promising opportunities for breast cancer therapy.

Evaluation of sinonasal-related quality of life of 49 patients undergoing endoscopic skull base surgery.

OBJECTIVE: This study aimed to evaluate the sinonasal-related Quality of Life (QoL) in patients undergoing endoscopic skull base surgery. METHODS: A retrospective study was performed, including patients with benign and malignant tumors at a single institution. Each patient completed the 22-Item Sino-Nasal Outcome Test (SNOT-22) and the Empty Nose Syndrome 6 Item Questionnaires (ENS6Q) to assess their perceived QoL at least 2-months after treatment. RESULTS: Forty-nine patients were enrolled in this study. The average score was 25.1 (Stander Deviation [SD] 14.99) for SNOT-22 and 6.51 (SD=5.58) for ENS6Q. Analysis of the overall results for the SNOT-22 showed that olfactory damage was the most serious syndrome. The most frequently reported high-severity sub-domains in SNOT-22 were nasal symptoms and sleep symptoms. Nasal crusting was the most severe item in ENS6Q according to the report. Nine patients (18.4%) had a score higher than 10.5 which indicates the high risk of Empty Nose Syndrome (ENS). SNOT-22 score was related to the history of radiotherapy (p< 0.05), while the ENS6Q score was not. CONCLUSIONS: The possibility of patients suffering from ENS after nasal endoscopic skull base surgery is at a low level, although the nasal cavity structure is damaged to varying degrees. Meanwhile, patients undergoing endoscopic skull base surgery were likely to suffer nasal problems and sleep disorders. Patients who had received radiotherapy have a worse QoL than those without a history of radiotherapy. LEVEL OF EVIDENCE: Level 3.

Evaluation of sinonasal-related quality of life of 49 patients undergoing endoscopic skull base surgery

Abstract Objective This study aimed to evaluate the sinonasal-related Quality of Life (QoL) in patients undergoing endoscopic skull base surgery. Methods A retrospective study was performed, including patients with benign and malignant tumors at a single institution. Each patient completed the 22-Item Sino-Nasal Outcome Test (SNOT-22) and the Empty Nose Syndrome 6 Item Questionnaires (ENS6Q) to assess their perceived QoL at least 2-months after treatment. Results Forty-nine patients were enrolled in this study. The average score was 25.1 (Stander Deviation [SD] 14.99) for SNOT-22 and 6.51 (SD = 5.58) for ENS6Q. Analysis of the overall results for the SNOT-22 showed that olfactory damage was the most serious syndrome. The most frequently reported high-severity sub-domains in SNOT-22 were nasal symptoms and sleep symptoms. Nasal crusting was the most severe item in ENS6Q according to the report. Nine patients (18.4%) had a score higher than 10.5 which indicates the high risk of Empty Nose Syndrome (ENS). SNOT-22 score was related to the history of radiotherapy (p < 0.05), while the ENS6Q score was not. Conclusions The possibility of patients suffering from ENS after nasal endoscopic skull base surgery is at a low level, although the nasal cavity structure is damaged to varying degrees. Meanwhile, patients undergoing endoscopic skull base surgery were likely to suffer nasal problems and sleep disorders. Patients who had received radiotherapy have a worse QoL than those without a history of radiotherapy. Level of evidence Level 3.

The roles of lncRNA functions and regulatory mechanisms in the diagnosis and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent and deadly type of liver cancer. While the underlying molecular mechanisms are poorly understood, it is documented that lncRNAs may play key roles. Many HCC-associated lncRNAs have been linked to HBV and HCV infection, mediating gene expression, cell growth, development, and death. Studying the regulatory mechanisms and biological functions of HCC-related lncRNAs will assist our understanding of HCC pathogenesis as well as its diagnosis and management. Here, we address the potential of dysregulated lncRNAs in HCC as diagnostic and therapeutic biomarkers, and we evaluate the oncogenic or tumor-suppressive properties of these lncRNAs.

Structure-Based Design, Optimization, and Evaluation of Potent Stabilized Peptide Inhibitors Disrupting MTDH and SND1 Interaction.

Blocking the interaction of MTDH/SND1 complex is an attractive strategy for cancer therapeutics. In this work, we designed and obtained a novel class of potent stabilized peptide inhibitors derived from MTDH sequence to disrupt MTDH/SND1 interaction. Through structure-based optimization and biological evaluation, stabilized peptides were obtained with tight binding affinity, improved cell penetration, and antitumor effects in the triple-negative breast cancer (TNBC) cells without nonspecific toxicity. To date, our study was the first report to demonstrate that stabilized peptides truncated from MTDH could serve as promising candidates to disrupt the MTDH/SND1 interaction for potential breast cancer treatment.

Identification of an autoinhibitory, mitophagy-inducing peptide derived from the transmembrane domain of USP30.

The mitochondrial-anchored deubiquitinating enzyme USP30 (ubiquitin specific peptidase 30) antagonizes PRKN/parkin-mediated mitophagy, making it a potential target for treating Parkinson disease. However, few inhibitors targeting USP30 have been reported. Here, we report a novel peptide (Q14) derived from the transmembrane (TM) domain of USP30 that can target mitochondrial-anchored USP30 directly and increase mitophagy through two intriguing and distinct mechanisms: a novel autoinhibition mechanism in USP30 and accelerated autophagosome formation via the LC3-interacting region (LIR) of the Q14 peptide. We identified the potential binding sites between the Q14 peptide and USP30 and postulated that an allosteric autoinhibition mechanism regulates USP30 activity. Furthermore, the LIR motif in the Q14 peptide offers additional binding with LC3 and accelerated autophagosome formation. The two mechanisms synergistically enhance mitophagy. Our work provides novel insight and direction to the design of inhibitors for USP30 or other deubiquitinating enzymes (DUBs).Abbreviations: 3-MA: 3-methyladenine; ATTEC: autophagosome-tethering compound; BafA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DMSO: dimethyl sulfoxide; FP: fluorescence polarization; FUNDC1: FUN14 domain containing 1; HCQ: hydroxychloroquine; LIR: LC3-interacting region; MST: microscale thermophoresis; mtDNA: mitochondrial DNA; mtPA-GFP: mitochondria-targeted photoactive fluorescence protein; OMM: outer mitochondrial membrane; PINK1: PTEN induced kinase 1; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; Rap: rapamycin; SA: streptavidin; TM: transmembrane; Ub: ubiquitin; Ub-AMC: Ub-7-amido-4-methylcoumarin; UPS: ubiquitin-protease system; USP: ubiquitin specific peptidase; USP30: ubiquitin specific peptidase 30.

Radiomic Features of Multi-ROI and Multi-Phase MRI for the Prediction of Microvascular Invasion in Solitary Hepatocellular Carcinoma.

OBJECTIVES: To develop and validate an MR radiomics-based nomogram to predict the presence of MVI in patients with solitary HCC and further evaluate the performance of predictors for MVI in subgroups (HCC ≤ 3 cm and > 3 cm). MATERIALS AND METHODS: Between May 2015 and October 2020, 201 patients with solitary HCC were analysed. Radiomic features were extracted from precontrast T1WI, arterial phase, portal venous phase, delayed phase and hepatobiliary phase images in regions of the intratumoral, peritumoral and their combining areas. The mRMR and LASSO algorithms were used to select radiomic features related to MVI. Clinicoradiological factors were selected by using backward stepwise regression with AIC. A nomogram was developed by incorporating the clinicoradiological factors and radiomics signature. In addition, the radiomic features and clinicoradiological factors related to MVI were separately evaluated in the subgroups (HCC ≤ 3 cm and > 3 cm). RESULTS: Histopathological examinations confirmed MVI in 111 of the 201 patients (55.22%). The radiomics signature showed a favourable discriminatory ability for MVI in the training set (AUC, 0.896) and validation set (AUC, 0.788). The nomogram incorporating peritumoral enhancement, tumour growth type and radiomics signature showed good discrimination in the training (AUC, 0.932) and validation sets (AUC, 0.917) and achieved well-fitted calibration curves. Subgroup analysis showed that tumour growth type was a predictor for MVI in the HCC ≤ 3 cm cohort and peritumoral enhancement in the HCC > 3 cm cohort; radiomic features related to MVI varied between the HCC ≤ 3 cm and HCC > 3 cm cohort. The performance of the radiomics signature improved noticeably in both the HCC ≤ 3 cm (AUC, 0.953) and HCC > 3 cm cohorts (AUC, 0.993) compared to the original training set. CONCLUSIONS: The preoperative nomogram integrating clinicoradiological risk factors and the MR radiomics signature showed favourable predictive efficiency for predicting MVI in patients with solitary HCC. The clinicoradiological factors and radiomic features related to MVI varied between subgroups (HCC ≤ 3 cm and > 3 cm). The performance of radiomics signature for MVI prediction was improved in both the subgroups.

MRCP Combined With CT Promotes the Differentiation of Benign and Malignant Distal Bile Duct Strictures.

OBJECTIVE: To determine whether contrast-enhanced computed tomography (CT) can promote the identification of malignant and benign distal biliary strictures (DBSs) compared to the use of magnetic resonance cholangiopancreatography (MRCP) alone and to identify imaging findings of malignant DBSs. MATERIALS AND METHODS: A total of 168 consecutive patients with confirmed DBSs were reviewed. MRCP alone and MRCP combined with CT images were blindly analyzed by two radiologists (e.g., stricture pattern, margins), and malignant or benign DBSs were identified based on surgical findings, endoscopy findings, or follow-up. The diagnostic accuracy of the two reviewers using MRCP alone and MRCP combined with CT were evaluated. MRCP and CT features of malignant and benign DBSs were compared using multiple logistic regression analysis to identify independent malignant risk factors. RESULTS: MRCP combined with CT examination could improve the diagnostic accuracy, which increased from 70.2% to 81.5% in Doctor A and from 85.1% to 89.3% in Doctor B. The multiple logistic regression model revealed that stricture length [odds ratio (OR) 1.070, P=0.016], angle of the DBS (OR 1.061, P<0.001), double duct sign (OR 4.312, P=0.003) and low density in the arterial phase (OR 0.319, P=0.018) were associated with malignant DBS. A scoring model incorporating these four factors was established; at a threshold value of 1.75, and the sensitivity and specificity for the detection of malignant DBSs were 73.5 and 85.9%, respectively. CONCLUSIONS: Compared to the use of MRCP alone, MRCP combined with contrast-enhanced CT can improve the accuracy of DBS diagnosis. The scoring model accurately predicts malignant DBSs and helps make treatment decisions.

Potent Inhibition of HIF1α and p300 Interaction by a Constrained Peptide Derived from CITED2.

Disrupting the interaction between HIF1α and p300 is a promising strategy to modulate the hypoxia response of tumor cells. Herein, we designed a constrained peptide inhibitor derived from the CITED2/p300 complex to disturb the HIF1α/p300 interaction. Through truncation/mutation screening and a terminal aspartic acid-stabilized strategy, a constrained peptide was constructed with outstanding biochemical/biophysical properties, especially in binding affinity, cell penetration, and serum stability. To date, our study was the first one to showcase that stabilized peptides derived from CITED2 using helix-stabilizing methods acted as a promising candidate for modulating hypoxia-inducible signaling.

Discrimination of serous cystadenoma from mucinous cystic neoplasm and branch duct intraductal papillary mucinous neoplasm in the pancreas with CT.

PURPOSE: The imaging features of serous cystadenomas (SCAs) overlap with those of mucinous cystic neoplasms (MCNs) and branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), and an accurate preoperative diagnosis is important for clinical treatment due to their different biological behaviors. The aim of this study was to provide a computed tomographic (CT) feature for the diagnosis of SCAs and estimate whether the "circumvascular sign" can contribute to the discrimination of SCAs from MCNs and BD-IPMNs. METHODS: From August 2011 through December 2019, a total of 71 patients (30 patients with 30 SCAs, 21 patients with 21 MCNs and 20 patients with 22 BP-IPMNs) were enrolled in this study. All patients underwent CT examination and were confirmed by surgical pathology. In addition to patient clinical information, CT features (e.g., location, shape) were evaluated via CT. RESULTS: Central scarring, central calcification and the circumvascular sign were found to be specific CT features for the diagnosis of SCAs and their differential diagnosis from MCNs and BD-IPMNs. All three CT features had high specificity, and both central scarring and central calcification had low sensitivity. When any one of these two features was combined with the circumvascular sign, the sensitivity increased to 83.3%. CONCLUSION: Pancreatic cystic neoplasms that show central scarring, central calcification or the circumvascular sign on CT could be diagnosed as SCAs. When either of the first two features is combined with the circumvascular sign, the diagnostic sensitivity could be increased.

Long-term defects of nasal epithelium barrier functions in patients with nasopharyngeal carcinoma post chemo-radiotherapy.

BACKGROUND AND PURPOSE: Chronic and recurrent upper respiratory tract infection and inflammation is common in patients with nasopharyngeal carcinoma (NPC) post chemo-radiotherapy (CRT). Whether it is due to intrinsic (e.g., host-defense mechanisms of the epithelium), epigenetic or extrinsic factors is not fully understood. MATERIALS AND METHODS: Tissue biopsies of the middle turbinate (MT) and inferior turbinate (IT) from NPC patients after CRT (mean of 3 years, n = 39) were compared with the IT biopsies from healthy subjects (n = 44). The epithelial ultrastructure was examined by transmission electron microscope (TEM). mRNA and protein expressions of epithelial stem/progenitor cells markers, as well markers of cell proliferation and differentiation markers was analyzed. RESULTS: Abnormal epithelial architecture was observed in all tissue samples of NPC patients. Significantly decreased expression levels of mRNA and protein levels for p63 (basal cells), Ki67 (cell proliferation), p63+/KRT5+ (epithelial stem/progenitor cells), MUC5AC and MUC5B (secretary proteins from goblet cells), alpha-tubulin, beta-tubulin and TAp73 (ciliated cells), DNAH5 and DNAI1 and RSPH4A (microtubule assemblies of motile cilia), FOXJ1 and CP110 (ciliogenesis-associated markers) were evident in MT and IT biopsies from NPC patients when compared to healthy controls. CONCLUSION: CRT causes long-term defects of epithelial barrier functions and increases the susceptibility of these patients to upper respiratory tract infection and inflammation.

Comparison of Diagnostic Accuracy of Thyroid Cancer With Ultrasound-Guided Fine-Needle Aspiration and Core-Needle Biopsy: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to evaluate the accuracy of fine-needle aspiration (FNA) and core-needle biopsy (CNB) in diagnosing thyroid cancer. The PubMed, Embase, and Cochrane Library databases were retrieved up to May 2019, and the overall accuracy of FNA and CNB in diagnosing thyroid cancer was evaluated by meta-analysis. The sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated. The summary receiver operating characteristic (ROC) curve was estimated, and the area under the ROC curve (AUC) was calculated. Ten eligible studies, involving 10,078 patients with 10,842 thyroid nodules, were included. The overall sensitivity and specificity of FNA and CNB for thyroid cancer were 0.72 [95 % confidence interval (CI): 0.69-0.74], 0.99 (95% CI: 0.98-0.99), and 0.83 (95% CI: 0.81-0.85), 0.99 (95% CI: 0.98-0.99), respectively. Other parameters used to assess efficacy included PLR 41.71 (2.15-808.27) and 51.56 (3.20-841.47), NLR 0.31 (0.22-0.42) and 0.22 (0.15-0.32), for FNA and CNB, respectively. Overall, the pooled summary ROC (AUC) value of FNA and CNB was 0.9025 and 0.7926, respectively. No significant difference was observed between the two AUCs of FNA and CNB (P = 0.164). FNA and CNB are still similar as first-line diagnostic tools. FNA remains a good first-line method for detecting thyroid malignancies.

SKA3 promotes lung adenocarcinoma metastasis through the EGFR-PI3K-Akt axis.

The processes that lead to lung adenocarcinoma (LUAD) metastasis are poorly characterized. Spindle and kinetochore associated complex subunit 3 (SKA3) plays a key role in cervical cancer development, but its contribution to LUAD is unknown. Here, we found that SKA3 is overexpressed in LUAD and its expression correlates with lymph node metastasis and poor prognosis. SKA3 silencing experiments identified SKA3 as an oncogene that promotes the metastasis of LUAD cell lines and tissues. SKA3 was found to induce the expression of matrix metalloproteinase (MMP)-2, -7, and -9, which activate PI3K-AKT. SKA3 was also found to bind and activate EGFR to activate PI3K-AKT. In summary, we identify a role for SKA3 in LUAD metastasis through its ability to bind EFGR and activate PI3K-AKT signaling.

Experimental and theoretical validations of a one-pot sequential sensing of Hg2+ and biothiols by a 3D Cu-based zwitterionic metal-organic framework.

A zwitterionic three-dimensional (3D) metal-organic framework (MOF) of {[Cu(Cdcbp)(bipy)]·4H2O}n (1) has been synthesized and characterized (H3CdcbpBr = 3-carboxyl-(3,5-dicarboxybenzyl)-pyridinium bromide; bipy = 4,4'-bipyridine). MOF 1 exhibits a variety of structural traits, such as ligand conjugated, positively charged pyridinium center, and Cu(II) cations that collectively enable its efficient hybridization with the flexible, negatively charged, single-stranded, and thymine-rich (T-rich) DNA. The T-rich DNA is labeled with carboxyfluorescein (FAM) fluorescent probe (characterized as P-DNA), but the resultant MOF 1 - P-DNA hybrid (characterized as P-DNA@1) is non-emissive (off-state) because of the fluorescent quenching by MOF 1. The P-DNA@1 hybrid functions as an effective and selective sensor for Hg2+ due to the formation of rigid hairpin-like T-Hg2+-T double-stranded DNA (ds-DNA@Hg2+) which is subsequently ejected by MOF 1, triggering a recovery of the P-DNA fluorescence (on-state). Subsequent addition of biothiols further sequestrates Hg2+ from the ds-DNA@Hg2+ duplex driven by the stronger Hg-S coordination, thus release the P-DNA and, in turn, resorbed by MOF 1 to regain the initial hybrid (off-state). P-DNA@1 hybrid thus detects Hg2+ and biothiols sequentially via a fluorescence "off-on-off" mechanism. The limits of detection (LOD) for Hg2+, biothiols, including cysteine (Cys), glutathione (GSH) and homocysteine (Hcy) are 3.0, 14.2, 15.1 and 8.0 nM, respectively, with the detection time of 60 min for Hg2+, and instantaneous detection for all the three biothiols. The detection mechanism is further confirmed by circular dichroism (CD), fluorescence anisotropy (FA), binding constant and molecular simulation. This sequential detection of Hg2+ and biothiols counter-proofs the presence of each other and may shed light to the occurrence of related diseases, such as neurodegenerative disorders of Parkinson's disease (PD), and Alzheimer's disease (AD).

Changes of Vitamin D-Binding Protein, and Total, Bioavailable, and Free 25-Hydroxyvitamin D in Transgender People.

CONTEXT: Total 25-hydroxyvitamin D [25(OH)D] is mainly bound to vitamin d-binding protein (DBP). Bioavailable 25(OH)D consists of albumin-bound and free 25(OH)D and is available for metabolic processes. As sex steroids influence DBP, hormonal treatment (HT) in transgender people might affect DBP and consequently the available 25(OH)D. Total 25(OH)D might therefore not well represent bioavailable and free 25(OH)D. OBJECTIVE: To investigate the effects of HT on DBP, and total, bioavailable, and free 25(OH)D, and to assess whether total 25(OH)D well represents bioavailable and free 25(OH)D. DESIGN: A prospective study. SETTING: A university hospital. PARTICIPANTS: Twenty-nine transwomen and 30 transmen. INTERVENTION: Estradiol and cyproterone acetate in transwomen, and testosterone in transmen. MAIN OUTCOME MEASURES: DBP, total 25(OH)D, free 25(OH)D, and albumin were measured at baseline and after 3 months of HT, and deseasonalized total 25(OH)D and bioavailable 25(OH)D were calculated. RESULTS: DBP changed with +5% (95% CI, -0% to 10%; P = 0.06) in transwomen and with -3% (95% CI: -9% to 3%; P = 0.34) in transmen. No significant changes were found in total 25(OH)D, free, and bioavailable 25(OH)D concentrations. Total 25(OH)D was well correlated with bioavailable (R2, 0.75) and free (R2, 0.76) 25(OH)D. CONCLUSIONS: DBP tended to increase in transwomen, but did not change in transmen. HT did not influence free 25(OH)D, total 25(OH)D, and bioavailable 25(OH)D concentrations in transwomen and transmen. As total 25(OH)D represents bioavailable and free 25(OH)D well, HT in transgender people does not interfere with the assessment of vitamin D status.

Associations between bone-alkaline phosphatase and bone mineral density in adults with and without diabetes.

Insufficient evidence is available to reliably compare the roles of bone alkaline phosphatase (BAP) and bone mineral density (BMD) in diabetes. This study aimed to compare associations between BAP and BMD in adults with and without diabetes to elucidate fracture risk in diabetes.Data were extracted from the National Health and Nutrition Examination Survey (NHANES), 2001-2004, including 4197 adults aged 20 to 49 years, 143 with diabetes (DM group), and 4054 without (non-DM group). Main outcome measure was BMD and regression analyses were performed to identify serum BAP and other covariates associated with total BMD.BMD decreased significantly in DM patients when BAP was increased. In the non-DM group, all BMD results were significantly decreased when BAP was increased. Factors associated with total BMD varied with DM status. Lifestyle measures such as smoking and physical activity were also associated with BMD in the non-DM group.BAP and BMD are inversely associated in DM and non-DM patients. BAP is significantly associated with BMD after controlling for other variables, suggesting that BAP may interact with other factors altering bone metabolism in DM patients.

An in-tether chiral center modulates the proapoptotic activity of the KLA peptide.

The helical peptide KLA (KLAKLAKKLAKLAK) is a well-known inducer of cellular apoptosis, acting to disrupt the mitochondrial membrane. However, its weak cellular uptake impedes development of any further applications. Here, we have utilized a novel in-tether chiral center induced helicity strategy (CIH) to develop a potent apoptosis inducer based on this KLA sequence. Notably, for the two resulting epimers of the CIH-KLA peptide, the CIH-KLA-(R) epimer exhibited superior cellular uptakes and special mitochondrial targeting when compared with its S counterpart. This work provides a promising and versatile method to modify the KLA peptide and a proof-of-concept application for the CIH strategy in modifying bioactive peptides.

ATRA increases iodine uptake and inhibits the proliferation and invasiveness of human anaplastic thyroid carcinoma SW1736 cells: Involvement of ß-catenin phosphorylation inhibition.

All-trans-retinoic acid (ATRA) can enhance iodine uptake capability of thyroid tumors, but the mechanisms remain poorly understood. The aim of the present study was to investigate the effects of ATRA on isotope susceptibility, proliferation and invasion of anaplastic thyroid carcinoma (ATC) and potential mechanisms. SW1736 cells were treated with 1 µmol/l ATRA or 1% ethanol for 5 days. A cell line stably expressing ß-catenin-shRNA was established. An iodine uptake assay was performed using 125I. Proliferation and invasiveness were tested using MTT and Transwell assays, respectively. Western blotting was used to assess the expression of ß-catenin, glycogen synthase kinase-3ß (GSK-3ß), sodium/iodine symporter (NIS) and proteins involved in epithelial-mesenchymal transition. Cells pretreated with ATRA were injected subcutaneously into SCID mice. Mice were intraperitoneally injected with 131I once on the first day of treatment, and tumor growth was then assessed. After 35 days of 131I treatment, ATRA-pretreated tumor volume and weight were decreased compared with the 131I alone group (163.32±19.57 vs. 332.06±21.37 mm3; 0.35±0.14 vs. 0.67±0.23 g, both P<0.05). Similar results were observed in the ß-catenin shRNA-pretreated tumors. ATRA also increased the uptake of iodine by SW1736 cells (P<0.01), and similar results were observed in ß-catenin shRNA cells. ATRA treatment decreased the cell proliferation and invasion compared with control cells (all P<0.05), similar to ß-catenin shRNA. ATRA treatment decreased the expression of phosphorylated (p-)ß-catenin, p-GSK-3ß, vimentin, and fibronectin, and increased the expression of NIS and E-cadherin, compared with the control. ATRA increased the iodine uptake and inhibited the proliferation and invasion of SW1736 cells, involving ß-catenin phosphorylation. In conclusion, ATRA could be used to improve the isotope sensitivity of ATC.