PF-429242 exhibits anticancer activity in hepatocellular carcinoma cells via FOXO1-dependent autophagic cell death and IGFBP1-dependent anti-survival signaling.

Effective therapies for hepatocellular carcinoma (HCC) are urgently needed, as it is a type of cancer resistant to chemotherapy. Recent evidence showed that PF-429242, a membrane-bound transcription factor site-1 protease (MBTPS1) inhibitor, exhibited anticancer activities against glioblastomas, renal cell carcinoma, and pancreatic cancer. However, its anticancer activity against HCC has yet to be investigated. In this study, we found that PF-429242 induced autophagy-dependent cell death in HCC cells. RNA-sequencing analysis indicated that the primary effect of PF-429242 was inhibition of the sterol regulatory element-binding protein (SREBP) signaling pathway. However, overexpression of SREBP proteins did not efficiently rescue PF-429242-induced autophagy and cell death. Mechanistically, PF-429242 induced forkhead box protein O1 (FOXO1)-dependent autophagic cell death. Additionally, PF-429242 caused FOXO1-independent upregulation of insulin-like growth factor-binding protein 1 (IGFBP1), ultimately leading to autophagy-independent cell death. The in vivo anticancer activity of PF-429242 against HCC cells was demonstrated in a tumor xenograft mouse model. Therefore, PF-429242 is a potential anticancer agent to treat HCC by triggering FOXO1-dependent autophagic cell death and IGFBP1-mediated anti-survival signaling in parallel.

Risk of Malnutrition in Adults Who Have Undergone Sleeve Gastrectomy: A Retrospective Study.

Sleeve gastrectomy achieves long-term weight control by reducing gastric volume. However, postoperative gastrointestinal symptoms and insufficient nutritional intake are likely to occur, which are not conducive to physical health. A retrospective study aimed to investigate changes in nutritional status and associated factors in patients after sleeve gastrectomy. Data were collected from the medical records of patients who underwent sleeve gastrectomy at a teaching hospital in Taiwan. Data from 120 patients who met the eligibility criteria were included in the analysis. The results show that sleeve gastrectomy has a strong weight loss effect. Within 12 months, the average body mass index of the patients decreased by 13.47 kg/m2. The number of morbidly obese patients decreased from 62 (51.7%) to 3 (2.5%). However, surgery is also associated with gastrointestinal symptoms and the threat of malnutrition. The number of patients with moderate to severe nutritional risk increased from 4 (3.3%) before surgery to 24 (20%) at 12-month follow-up. Likewise, the number of patients with anemia increased from 11 (9.2%) to 29 (24.17%). Gender, constipation, and diarrhea affected postoperative nutritional status. These findings suggest that patients after sleeve gastrectomy are at risk of malnutrition and require regular monitoring. Special attention should be given to women and patients with constipation or diarrhea, as they are at a particularly high risk of malnutrition.

Inhibition of CDK9 exhibits anticancer activity in hepatocellular carcinoma cells via targeting ribonucleotide reductase.

Cyclin-dependent kinase 9 (CDK9) inhibitors are a novel category of anticancer treatment for cancers. However, their effects on hepatocellular carcinoma (HCC) are rarely investigated. Human ribonucleotide reductase (RR, which consists of RRM1 and RRM2 subunits) catalyzes the conversion of ribonucleoside diphosphate into 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools, which play essential roles in DNA synthesis and DNA repair. In this study, we identified that CDK9 protein expression in adjacent non-tumor tissues predicted HCC patients' overall and progression-free survivals. The anticancer activity of a CDK9-selective inhibitor, LDC000067, on HCC cells was positively associated with its ability to inhibit the expression of RRM1 and RRM2. LDC000067 downregulated RRM1 and RRM2 expression through post-transcriptional pathway. Specifically, LDC000067 triggered RRM2 protein degradation via multiple pathways, including proteasome-, lysosome-, and calcium-dependent pathways. Furthermore, CDK9 positively correlates with RRM1 or RRM2 expression in HCC patients, and the expressions of these three genes were associated with the higher infiltration of immune cells in HCC. Taken together, this study identified the prognostic relevance of CDK9 in HCC and the molecular mechanism for the anticancer effect of CDK9 inhibitors on HCC.

Overcoming Cytosolic Delivery Barriers of Proteins Using Denatured Protein-Conjugated Mesoporous Silica Nanoparticles.

Intracellular delivery of therapeutic proteins has increased advantages over current small-molecule drugs and gene therapies, especially in therapeutic efficacies for a broad spectrum of diseases. Hence, developing the protein therapeutics approach provides a needed alternative. Here, we designed a mesoporous silica nanoparticle (MSN)-mediated protein delivery approach and demonstrated effective intracellular delivery of the denatured superoxide dismutase (SOD) protein, overcoming the delivery challenges and achieving higher enzymatic activity than native SOD-conjugated MSNs. The denatured SOD-conjugated MSN delivery strategy provides benefits of reduced size and steric hindrance, increased protein flexibility without distorting its secondary structure, exposure of the cell-penetrating peptide transactivator of transcription for enhanced efficient delivery, and a change in the corona protein composition, enabling cytosolic delivery. After delivery, SOD displayed a specific activity around threefold higher than in our previous reports. Furthermore, the in vivo biosafety and therapeutic potential for neuron therapy were evaluated, demonstrating the biocompatibility and the effective antioxidant effect in Neuro-2a cells that protected neurite outgrowth from paraquat-induced reactive oxygen species attack. This study offers an opportunity to realize the druggable possibility of cytosolic proteins using MSNs.

Bridging Size and Charge Effects of Mesoporous Silica Nanoparticles for Crossing the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a highly selective cellular barrier that tightly controls the microenvironment of the central nervous system to restrict the passage of substances, which is a primary challenge in delivering therapeutic drugs to treat brain diseases. This study aimed to develop simple surface modifications of mesoporous silica nanoparticles (MSNs) without external stimuli or receptor protein conjugation, which exhibited a critical surface charge and size allowing them to cross the BBB. A series of MSNs with various charges and two different sizes of 50 and 200 nm were synthesized, which showed a uniform mesoporous structure with various surface zeta potentials ranging from +42.3 to -51.6 mV. Confocal microscopic results showed that 50 nm of strongly negatively charged N4-RMSN50@PEG/THPMP (∼-40 mV) could be significantly observed outside blood vessels of the brain in Tg(zfli1:EGFP) transgenic zebrafish embryos superior to the other negatively charged MSNs. However, very few positively charged MSNs were found in the brain, indicating that negatively charged MSNs could successfully penetrate the BBB. The data were confirmed by high-resolution images of 3D deconvoluted confocal microscopy and two-photon microscopy and zebrafish brain tissue sections. In addition, while increasing the size to 200 nm but maintaining the similar negative charge (∼40 mV), MSNs could not be detected in the brain of zebrafish, suggesting that transport across the BBB based on MSNs occurred in charge- and size-dependent manners. No obvious cytotoxicity was observed in the CTX-TNA2 astrocyte cell line and U87-MG glioma cell line treated with MSNs. After doxorubicin (Dox) loading, N4-RMSN50@PEG/THPMP/Dox enabled drug delivery and pH-responsive release. The toxicity assay showed that N4-RMSN50@PEG/THPMP could reduce Dox release, resulting in the increase of the survival rate in zebrafish. Flow cytometry demonstrated N4-RMSN50@PEG/THPMP had few cellular uptakes. Protein corona analysis revealed three transporter proteins, such as afamin, apolipoprotein E, and basigin, could contribute to BBB penetration, validating the possible mechanism of N4-RMSN50@PEG/THPMP crossing the BBB. With this simple approach, MSNs with critical negative charge and size could overcome the BBB-limiting characteristics of therapeutic drug molecules; furthermore, their use may also cause drug sustained-release in the brain, decreasing peripheral toxicity.

Bioinformatics Analysis Identifies Precision Treatment with Paclitaxel for Hepatocellular Carcinoma Patients Harboring Mutant TP53 or Wild-Type CTNNB1 Gene.

Hepatocellular carcinoma (HCC) is an aggressive and chemoresistant cancer type. The development of novel therapeutic strategies is still urgently needed. Personalized or precision medicine is a new trend in cancer therapy, which treats cancer patients with specific genetic alterations. In this study, a gene signature was identified from the transcriptome of HCC patients, which was correlated with the patients' poorer prognoses. This gene signature is functionally related to mitotic cell cycle regulation, and its higher or lower expression is linked to the mutation in tumor protein p53 (TP53) or catenin beta 1 (CTNNB1), respectively. Gene-drug association analysis indicated that the taxanes, such as the clinically approved anticancer drug paclitaxel, are potential drugs targeting this mitotic gene signature. Accordingly, HCC cell lines harboring mutant TP53 or wild-type CTNNB1 genes are more sensitive to paclitaxel treatment. Therefore, our results imply that HCC patients with mutant TP53 or wild-type CTNNB1 genes may benefit from the paclitaxel therapy.

PERK/ATF4-Dependent ZFAS1 Upregulation Is Associated with Sorafenib Resistance in Hepatocellular Carcinoma Cells.

Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced hepatocellular carcinoma (HCC) patients. However, this drug only provides a short improvement of patients' overall survival, and drug resistance is commonly developed. Thus, the identification of resistant factor(s) or biomarker(s) is needed to develop more efficient therapeutic strategies. Long, non-coding RNAs (lncRNAs) have recently been viewed as attractive cancer biomarkers and drive many important cancer phenotypes. A lncRNA, ZFAS1 (ZNFX1 antisense RNA 1) has been found to promote HCC metastasis. This study found that sorafenib induced ZFAS1 expression specifically in sorafenib-resistant HCC cells. Although ZFAS1 knockdown did not restore the sensitivity of HCC cells to sorafenib, its expression may act as a resistant biomarker for sorafenib therapy. Bioinformatics analysis predicted that sorafenib tended to induce pathways related to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in sorafenib-resistant HCC cells. In vitro experimental evidence suggested that sorafenib induced protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-dependent ZFAS1 expression, and sorafenib resistance could be overcome by PERK/ATF inhibitors. Therefore, PERK/ATF4/ZFAS1 signaling axis might be an attractive therapeutic and prognostic biomarker for sorafenib therapy in HCC.

STING Activator c-di-GMP-Loaded Mesoporous Silica Nanoparticles Enhance Immunotherapy Against Breast Cancer.

Reversing the immunosuppressive tumor microenvironment (TME) is a strategic initiative to sensitize cancer immunotherapy. Emerging evidence shows that cyclic diguanylate monophosphate (c-di-GMP or cdG) can induce the stimulator of interferon genes (STING) pathway activation of antigen-presenting cells (APCs) and upregulate expression of type I interferons (IFNs) to enhance tumor immunogenicity. In vitro anionic cdG revealed fast plasma clearance, poor membrane permeability, and inadequate cytosolic bioavailability. Therefore, we explored a comprehensive "in situ vaccination" strategy on the basis of nanomedicine to trigger robust antitumor immunity. Rhodamine B isothiocyanate (RITC) fluorescent mesoporous silica nanoparticles (MSN) synthesized and modified with poly(ethylene glycol) (PEG) and an ammonium-based cationic molecule (TA) were loaded with negatively charged cdG via electrostatic interactions to form cdG@RMSN-PEG-TA. Treatment of RAW 264.7 cells with cdG@RMSN-PEG-TA markedly stimulated the secretion of IL-6, IL-1ß, and IFN-ß along with phospho-STING (Ser365) protein expression. In vivo cdG@RMSN-PEG-TA enhanced infiltration of leukocytes, including CD11c+ dendritic cells, F4/80+ macrophages, CD4+ T cells, and CD8+ T cells within the tumor microenvironment (TME), resulting in dramatic tumor growth inhibition in 4T1 breast tumor-bearing Balb/c mice. Our findings suggest that a nanobased platform can overcome the obstacles bare cdG can face in the TME. Our approach of an in situ vaccination using a STING agonist provides an attractive immunotherapy-based strategy for treating breast cancer.

CDKN2A-Inactivated Pancreatic Ductal Adenocarcinoma Exhibits Therapeutic Sensitivity to Paclitaxel: A Bioinformatics Study.

The mutation of cyclin dependent kinase inhibitor 2A (CDKN2A) is frequently found in pancreatic ductal adenocarcinoma (PDAC). However, its prognostic and therapeutic roles in PDAC have not been extensively investigated yet. In this study, we mined and integrated the cancer genomics and chemogenomics data to investigate the roles of CDKN2A genetic alterations in PDAC patients' prognosis and treatment. We found that functional CDKN2A inactivation caused by mutations and deep deletions predicted poor prognosis in PDAC patients. CDKN2A inactivation was associated with the upregulation of genes related to estrogen response, which can be overcome by CDKN2A restoration. Chemosensitivity profiling of PDAC cell lines and patient-derived organoids found that CDKN2A inactivation was associated with the increased sensitivity to paclitaxel and SN-38 (the active metabolite of irinotecan). However, only paclitaxel can mimic the effect of CDKN2A restoration, and its drug sensitivity was correlated with genes related to estrogen response. Therefore, our study suggested that CDKN2A-inactivated PDAC patients could benefit from the precision treatment with paclitaxel, whose albumin-stabilized nanoparticle formulation (nab-paclitaxel) has been approved for treating PDAC.

Catcher in the rel: Nanoparticles-antibody conjugate as NF-κB nuclear translocation blocker.

Transcription factor complex NF-κB (p65/p50) is localized to the cytoplasm by its inhibitor IκBα. Upon activation, the Rel proteins p65/p50 are released from IκBα and transported through nuclear pore to affect many gene expressions. While inhibitions of up or down stream signal pathways are often ineffective due to crosstalks and compensations, direct blocking of the Rel proteins p65/p50 has long been proposed as a potential target for cancer therapy. In this work, a nanoparticle/antibody complex targeting NF-κB is employed to catch the Rel protein p65 in perinuclear region and thus blocking the translocation near the nuclear pore gate. TAT peptide conjugated on mesoporous silica nanoparticles (MSN) help non-endocytosis cell-membrane transducing and converge toward perinuclear region, where the p65 specific antibody performed the targeting and catching against active NF-κB p65 effectively. The size of the p65 bound nanoparticle becomes too big to enter nucleus. Simultaneous treatment of mice with the hybrid MSN and doxorubicin conferred a significant therapeutic effect against 4T1 tumor-bearing mice. The new approach of anti-body therapy targeting on transcription factor with "nucleus focusing" and "size exclusion blocking" effects of the antibody-conjugated nanoparticle is general and may be applicable to modulating other transcription factors.

Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells.

The main curative treatments for hepatocellular carcinoma (HCC) are surgical resection and liver transplantation, which only benefits 15% to 25% of patients. In addition, HCC is highly refractory and resistant to cytotoxic chemotherapy. Although several multi-kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for treating advanced HCC, only a short increase of median overall survival in HCC patients was achieved. Therefore, there is an urgent need to design more effective strategies for advanced HCC patients. Human ribonucleotide reductase is responsible for the conversion of ribonucleoside diphosphate to 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. In this study, mining the cancer genomics and proteomics data revealed that ribonucleotide reductase regulatory subunit M2 (RRM2) serves as a prognosis biomarker and a therapeutic target for HCC. The RNA sequencing (RNA-Seq) analysis and public microarray data mining found that RRM2 was a novel molecular target of sorafenib in HCC cells. In vitro experiments validated that sorafenib inhibits RRM2 expression in HCC cells, which is positively associated with the anticancer activity of sorafenib. Although both RRM2 knockdown and sorafenib induced autophagy in HCC cells, restoration of RRM2 expression did not rescue HCC cells from sorafenib-induced autophagy and growth inhibition. However, long-term colony formation assay indicated that RRM2 overexpression partially rescues HCC cells from the cytotoxicity of sorafenib. Therefore, this study identifies that RRM2 is a novel target of sorafenib, partially contributing to its anticancer activity in HCC cells.

Osteocalcin is an Independent Predictor for Hungry Bone Syndrome After Parathyroidectomy.

BACKGROUND: Hungry bone syndrome is characterized by prolonged and severe hypocalcemia following parathyroidectomy. Previously, we reported that preoperative alkaline phosphatase is a major factor predicting prolonged hospital stay. Nonetheless, some patients with low alkaline phosphatase levels presented with hungry bone syndrome, suggesting that additional factors may play a role. METHODS: From September 2010 to December 2017, consecutive dialysis patients who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Length of hospital stay was used as a surrogate marker for postoperative bone hunger. RESULTS: A total of 260 patients were included in the study. The median postoperative hospital stay was 3 days, and 69 (27%) patients had a stay longer than 3 days. Multivariate logistic regression analysis revealed that alkaline phosphatase (odds ratio [OR] = 1.005), osteocalcin (OR = 1.001), and subtotal parathyroidectomy (OR = 0.061) were associated with prolonged hospital stay. Multivariate linear regression analysis indicated that age (ß = - 0.170), alkaline phosphatase (ß = 0.430), and osteocalcin (ß = 0.166) were correlated with the length of stay. After surgery, the median osteocalcin level increased from 264 to 478 ng/mL (P < 0.001). CONCLUSIONS: Alkaline phosphatase is the main predictor of hungry bone syndrome after parathyroidectomy, and preoperative osteocalcin is an additional independent predictor. Patients with a high osteocalcin level may prone to have a higher demand for calcium supplementation.

p38α/S1P/SREBP2 activation by the SAM-competitive EZH2 inhibitor GSK343 limits its anticancer activity but creates a druggable vulnerability in hepatocellular carcinoma.

Enhancer of zeste homolog 2 (EZH2) mediates epigenetic gene silencing via tri-methylation of histone H3 lysine 27 (H3K27-me3). Increased expression of EZH2 is frequently detected in various cancers including hepatocellular carcinoma (HCC), which is associated with the silencing of tumor suppressor genes. S-adenosyl-L-methionine (SAM)-competitive EZH2 inhibitors fall into the major category of EZH2 inhibitors for cancer therapy. In this study, microarray analyses found that induction of genes related to cholesterol homeostasis is a common effect of SAM-competitive EZH2 inhibitors in cancer cells. As a representative, GSK343 induced lipid accumulation which promoted cancer cell survival. GSK343 selectively activated sterol regulatory element-binding protein 2 (SREBP2), but not SREBP1, in HCC cells. Inhibition of SREBP2 by siRNA reduced cell viability and enhanced the anticancer effect of GSK343. Cancer genomics analysis indicated that SREBP2 upregulation was associated with the poor overall survival of HCC patients. Mechanistically, GSK343-induced SREBP2 activation was unrelated to its original ability to compete with SAM and inhibit EZH2 activity. Instead, GSK343 activated SREBP2 in p38α- and site-1 protease (S1P)-dependent manners. Inhibition of p38α and S1P by SB-202190 and PF-429242, respectively, enhanced the in vitro anticancer activity of GSK343, thereby creating a vulnerability for treating HCC.

Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFß) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.

Codelivery of Plasmid and Curcumin with Mesoporous Silica Nanoparticles for Promoting Neurite Outgrowth.

Reactive oxygen species (ROS)-induced oxidative stress leads to neuron damage and is involved in the pathogenesis of chronic inflammation in neurodegenerative diseases (NDs), such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Researchers, therefore, are looking for antiinflammatory drugs and gene therapy approaches to slow down or even prevent neurological disorders. Combining therapeutics has shown a synergistic effect in the treatment of human diseases. Many nanocarriers could be designed for the simultaneous codelivery of drugs with genes to fight diseases. However, only a few researches have been performed in NDs. In this study, we developed a mesoporous silica nanoparticle (MSN)-based approach for neurodegenerative therapy. This MSN-based platform involved multiple designs in the targeted codelivery of (1) curcumin, a natural antioxidant product, to protect ROS-induced cell damage and (2) plasmid RhoG-DsRed, which is associated with the formation of lamellipodia and filopodia for promoting neurite outgrowth. At the same time, TAT peptide was introduced to the plasmid RhoG-DsRed via electrostatic interaction to elevate the efficiency of nonendocytic pathways and the nuclear plasmid delivery of RhoG-DsRed in cells for enhanced gene expression. Besides, such a plasmid RhoG-DsRed/TAT complex could work as a noncovalent gatekeeper. The release of curcumin inside the channel of the MSN could be triggered when the complex was dissociated from the MSN surface. Taken together, this MSN-based platform combining genetic and pharmacological manipulations of an actin cytoskeleton as well as oxidative stress provides an attractive way for ND therapy.

In silico repurposing the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing clear cell renal carcinoma.

The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.

Effects of Preoperative Iodine Administration on Thyroidectomy for Hyperthyroidism: A Systematic Review and Meta-analysis.

OBJECTIVE: The current guidelines recommend that potassium iodide be given in the immediate preoperative period for patients with Graves' disease who are undergoing thyroidectomy. Nonetheless, the evidence behind this recommendation is tenuous. The purpose of this study is to clarify the benefits of preoperative iodine administration from published comparative studies. DATA SOURCES: We searched PubMed, Embase, Cochrane, and CINAHL from 1980 to June 2018. REVIEW METHODS: Studies were included that compared preoperative iodine administration and no premedication before thyroidectomy. For the meta-analysis, studies were pooled with the random-effects model. RESULTS: A total of 510 patients were divided into the iodine (n = 223) and control (n = 287) groups from 9 selected studies. Preoperative iodine administration was significantly associated with decreased thyroid vascularity and intraoperative blood loss. Significant heterogeneity was present among studies. We found no significant difference in thyroid volume or operative time. Furthermore, the meta-analysis showed no difference in the risk of postoperative complications, including vocal cord palsy, hypoparathyroidism/hypocalcemia, and hemorrhage or hematoma after thyroidectomy. CONCLUSION: Preoperative iodine administration decreases thyroid vascularity and intraoperative blood loss. Nonetheless, it does not translate to more clinically meaningful differences in terms of operative time and postoperative complications.

Systematic polypharmacology and drug repurposing via an integrated L1000-based Connectivity Map database mining.

Drug repurposing aims to find novel indications of clinically used or experimental drugs. Because drug data already exist, drug repurposing may save time and cost, and bypass safety concerns. Polypharmacology, one drug with multiple targets, serves as a basis for drug repurposing. Large-scale databases have been accumulated in recent years, and utilization and integration of these databases would be highly helpful for polypharmacology and drug repurposing. The Connectivity Map (CMap) is a database collecting gene-expression profiles of drug-treated human cancer cells, which has been widely used for investigation of polypharmacology and drug repurposing. In this study, we integrated the next-generation L1000-based CMap and an analytic Web tool, the L1000FWD, for systematic analyses of polypharmacology and drug repurposing. Two different types of anti-cancer drugs were used as proof-of-concept examples, including histone deacetylase (HDAC) inhibitors and topoisomerase inhibitors. We identified KM-00927 and BRD-K75081836 as novel HDAC inhibitors and mitomycin C as a topoisomerase IIB inhibitor. Our study provides a prime example of utilization and integration of the freely available public resources for systematic polypharmacology analysis and drug repurposing.

Transcriptome analysis of papillary thyroid cancer harboring telomerase reverse transcriptase promoter mutation.

BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations have recently been identified as an important prognostic factor in thyroid cancer. Studies suggest that TERT may have noncanonical functions beyond telomere maintenance. METHODS: Clinicopathological information and transcriptome data for papillary thyroid carcinoma (PTC) samples were obtained from The Cancer Genome Atlas (TCGA). Propensity score matching was performed to adjust for potential confounding variables between the TERT promoter wild-type group and the mutant group. Gene expression data of 36 patients in the mutant group were systemically compared to those of 72 patients in the wild-type group. RESULTS: Tumors with TERT promoter mutations had a higher TERT expression. Pathways central to DNA damage responses and cell cycle regulation were significantly enriched among 888 upregulated genes. Transporter and metabolic activities were overrepresented among 799 downregulated genes. There was no difference in the expression of most of the thyroid differentiation genes. CONCLUSION: The TERT promoter mutations were associated with proliferative and metabolic alterations in PTC.

Parathyroidectomy decreases neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios.

BACKGROUND: Systemic inflammation has been implicated in complications and heightened mortality of patients with secondary hyperparathyroidism. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are widely available surrogate markers of inflammation. This study sought to delineate the changes in NLR and PLR after parathyroidectomy. METHODS: A total of 213 patients undergoing initial parathyroidectomy from 2010 to 2015 for secondary hyperparathyroidism were identified from a prospectively maintained clinical database. Among 183 patients free of persistent or recurrent disease, follow-up NLR and PLR were available for analysis in 85 patients. RESULTS: In the whole study population, the baseline NLR was positively correlated with male sex, total white blood cell count, height, serum phosphorus, and calcium-phosphorus product levels. The baseline PLR was positively correlated with platelet count, serum phosphorus, and calcium-phosphorus product levels and negatively associated with patient age. Postoperative parathyroid hormone levels were positively correlated with NLR and PLR at follow-up. For patients who had successful parathyroidectomy, there was a decrease in NLR (P = 0.0006), PLR (P = 0.0003), and platelet count (P = 0.033), whereas hemoglobin significantly increased (P = 0.0002) after surgery. Those with persistent or recurrent hyperparathyroidism had no change in NLR, PLR, hemoglobin, total white blood cell, or platelet count. CONCLUSIONS: Successful parathyroidectomy is associated with a decrease in NLR and PLR. The modulatory effects of parathyroidectomy on systemic inflammation may partially explain the benefits of surgery in secondary hyperparathyroidism.