Enhancing cancer therapy: The role of drug delivery systems in STAT3 inhibitor efficacy and safety.

The signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, resides in the nucleus to regulate genes essential for vital cellular functions, including survival, proliferation, self-renewal, angiogenesis, and immune response. However, continuous STAT3 activation in tumor cells promotes their initiation, progression, and metastasis, rendering STAT3 pathway inhibitors a promising avenue for cancer therapy. Nonetheless, these inhibitors frequently encounter challenges such as cytotoxicity and suboptimal biocompatibility in clinical trials. A viable strategy to mitigate these issues involves delivering STAT3 inhibitors via drug delivery systems (DDSs). This review delineates the regulatory mechanisms of the STAT3 signaling pathway and its association with cancer. It offers a comprehensive overview of the current application of DDSs for anti-STAT3 inhibitors and investigates the role of DDSs in cancer treatment. The conclusion posits that DDSs for anti-STAT3 inhibitors exhibit enhanced efficacy and reduced adverse effects in tumor therapy compared to anti-STAT3 inhibitors alone. This paper aims to provide an outline of the ongoing research and future prospects of DDSs for STAT3 inhibitors. Additionally, it presents our insights on the merits and future outlook of DDSs in cancer treatment.

Structural and Energetic Origin of Different Product Specificities and Activities for SETD3 and Its Mutants on the Methylation of the ß-Actin H73K Peptide: Insights from a QM/MM Study.

The methylation of the lysine residue can affect some fundamental biological processes, and specific biological effects of the methylations are often related to product specificity of methyltransferases. The question remains concerning how active-site structural features and dynamics control the activity as well as the number (1, 2, or 3) of methyl groups on methyl lysine products. SET domain containing protein 3 (SETD3) has been identified recently as the ß-actin histidine73-N3 methyltransferase, and also, it has a weak methylation activity on the H73K ß-actin peptide for which the target H73 residue is mutated into K73. Interestingly, the K73 methylation activity of SETD3 increases significantly as a result of the N255 → A or N255 → F/W273 → A mutation, and the N255A product specificity also differs from that of wild-type. Here, we performed QM/MM molecular dynamics and potential of mean force (PMF) simulations for SETD3 and its mutants (N255A and N255F/W273A) to study how SETD3 and its mutants could have different product specificities and activities for the K73 methylation. The PMF simulations show that the barrier for the first methylation of K73 is higher compared to the barrier of the H73 methylation in SETD3. Moreover, the second methylation of K73 has been found to have a barrier from the free energy simulation that is higher by 2.2 kcal/mol compared to the barrier of the first methyl transfer to K73, agreeing with the suggestion that SETD3 is a monomethylase. For the first, second, and third methylations of K73 in the N255A mutant, the barriers obtained from the PMF simulations for transferring the second and third methyl groups are found to be lower relative to the barrier for the first methyl transfer. Thus, N255A can be considered as a trimethyl lysine methyltransferase. In addition, for the first K73 methylation, the activities from the PMF simulations follow the order of N255F/W273A > N255A > WT, in agreement with experiments. The examination of the structural and dynamic results at the active sites provides better understanding of different product specificities and activities for the K73 methylations in SETD3 and its mutants. It is demonstrated that the existence of well-balanced interactions at the active site leading to the near attack conformation is of crucial importance for the efficient methyl transfers. Moreover, the presence of potential interactions (e.g., the C-H···O and cation-π interactions) that are strengthening at the transition state can also be important. Furthermore, the activity as well as product specificity of the K73 methylation also seems to be controlled by certain active-site water molecules which may be released to provide extra space for the addition of more methyl groups on K73.

Expression of Selenoprotein Genes Is Affected by Obesity of Pigs Fed a High-Fat Diet.

BACKGROUND: Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. OBJECTIVE: This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. METHODS: Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. RESULTS: The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29-42% and affected (P < 0.05-0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. CONCLUSIONS: The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue thyroid hormone activity, endoplasmic reticulum protein degradation, and phosphorylation of lipids. This porcine model may be used to study interactive mechanisms between excess fat intake and selenoprotein function.

Porcine serum can be biofortified with selenium to inhibit proliferation of three types of human cancer cells.

Our objectives were to determine if porcine serum could be enriched with selenium (Se) by feeding pigs with high concentrations of dietary Se and if the Se-biofortified serum inhibited proliferation of 3 types of human cancer cells. In Expt. 1, growing pigs (8 wk old, n = 3) were fed 0.02 or 3.0 mg Se/kg (as sodium selenite) for 16 wk and produced serum with 0.5 and 5.4 µmol/L Se, respectively. In Expt. 2, growing pigs (5 wk old, n = 6) were fed 0.3 or 1.0 mg Se/kg (as Se-enriched yeast) for 6 wk and produced serum with 2.6 and 6.2 µmol/L Se, respectively. After the Se-biofortified porcine sera were added at 16% in RPMI 1640 to treat NCI-H446, DU145, and HTC116 cells for 144 h, they decreased (P < 0.05) the viability of the 3 types of human cancer cells by promoting apoptosis, compared with their controls. This effect was replicated only by adding the appropriate amount of methylseleninic acid to the control serum and was mediated by a downregulation of 8 cell cycle arrest genes and an upregulation of 7 apoptotic genes. Along with 6 previously reported selenoprotein genes, selenoprotein T (Selt), selenoprotein M (Selm), selenoprotein H (Selh), selenoprotein K (Selk), and selenoprotein N (Sepn1) were revealed to be strongly associated with the cell death-related signaling induced by the Se-enriched porcine serum. In conclusion, porcine serum could be biofortified with Se to effectively inhibit the proliferation of 3 types of human cancer cells and the action synchronized with a matrix of coordinated functional expression of multiple selenoprotein genes.

A prospective randomized controlled trial of semi-mechanical versus hand-sewn or circular stapled esophagogastrostomy for prevention of anastomotic stricture.

BACKGROUND: Successful anastomosis is essential in esophagogastrectomy, and the application of the circular stapler effectively reduces the anastomotic leakage, although stricture formation has become more frequent. The present study, a randomized controlled trial, compared the recently developed semi-mechanical anastomosis with a hand-sewn or circular stapled esophagogastrostomy in prevention of anastomotic stricture. METHODS: Between November 2007 and September 2008, 160 consecutive patients with esophageal carcinoma underwent surgical treatment our department. Five patients were excluded from this study, and the remaining 155 patients were completely randomized to receive either an everted plus side extension esophagogastrostomy (semi-mechanical [SM] group) or a conventional hand-sewn esophagogastric anastomosis ([HS] group) or a circular stapled ([CS] group) esophagogastric anastomosis, after dissection of the esophageal tumor and construction of a tubular stomach. The primary outcome was the incidence of an anastomotic stricture at 3 months after the operation (defined as the diameter of the anastomotic orifice ≤ 0.8 cm on esophagogram). Secondary outcomes were the dysphagia score and reflux score, as well as the anastomotic diameter. RESULTS: The anastomotic stricture rate was 0 % (0/45) in the SM group, 9.6 % (5/52) in the HS group, and 19.1 % (9/47) in the CS group (p < 0.001). The mean diameter of the anastomotic orifice was 18.2 ± 4.7 mm in the SM group, 11.5 ± 2.4 mm in the HS group, and 9.5 ± 3.0 mm in the CS group (p < 0.001). The reflux/regurgitation score among the three groups was similar. CONCLUSIONS: Semi-mechanical esophagogastric anastomosis could prevent stricture formation more effectively than hand-sewn or circular stapler esophagogastrostomy, without increasing gastroesophageal reflux.

[Association between number of lymphadenectomy and postoperative complication in surgery for esophageal carcinoma].

OBJECTIVE: To investigate the association between the number of lymph nodes retrieval and the incidence of postoperative complications in patients with esophageal carcinoma. METHOD: From January 2008 to December 2009, 794 patients with esophageal carcinoma underwent esophagectomy and lymphadenectomy in the Department of Thoracic Surgery at the West China Hospital of Sichuan University. The clinical data, surgeons, the extent of lymphadenectomy and its association with operative morbidity were retrospectively analyzed. RESULTS: There was no operative death. A total of 84 patients with complication(10.6%) were documented. There were 11,770 lymph nodes harvested in total with an average of 14.8. Multivariate logistic regression showed that gender, number of metastatic lymph nodes, level of anastomosis, and surgeons' experience were risk factors associated with postoperative complications (all P<0.05), while the number and group of lymph node resection were not(all P>0.05). CONCLUSION: Within a rational range of lymphadenectomy(<50) following esophagectomy, the postoperative complications are significantly associated with the gender, extent of regional lymph nodes metastasis, site of anastomosis and the expertise of the surgeons, but not associated with the number and group of lymph nodes resection.

A high-selenium diet induces insulin resistance in gestating rats and their offspring.

Although supranutrition of selenium (Se) is considered a promising anti-cancer strategy, recent human studies have shown an intriguing association between high body Se status and diabetic risk. This study was done to determine if a prolonged high intake of dietary Se actually induced gestational diabetes in rat dams and insulin resistance in their offspring. Forty-five 67-day-old female Wistar rats (n=15/diet) were fed a Se-deficient (0.01 mg/kg) corn-soy basal diet (BD) or BD+Se (as Se-yeast) at 0.3 or 3.0mg/kg from 5 weeks before breeding to day 14 postpartum. Offspring (n=8/diet) of the 0.3 and 3.0mg Se/kg dams were fed with the same respective diet until age 112 days. Compared with the 0.3mg Se/kg diet, the 3.0mg/kg diet induced hyperinsulinemia (P<0.01), insulin resistance (P<0.01), and glucose intolerance (P<0.01) in the dams at late gestation and/or day 14 postpartum and in the offspring at age 112 days. These impairments concurred with decreased (P<0.05) mRNA and/or protein levels of six insulin signal proteins in liver and muscle of dams and/or pups. Dietary Se produced dose-dependent increases in Gpx1 mRNA or GPX1 activity in pancreas, liver, and erythrocytes of dams. The 3.0mg Se/kg diet decreased Selh (P<0.01), Sepp1 (P=0.06), and Sepw1 (P<0.01), but increased Sels (P<0.05) mRNA levels in the liver of the offspring, compared with the 0.3mg Se/kg diet. In conclusion, supranutrition of Se as a Se-enriched yeast in rats induced gestational diabetes and insulin resistance. Expression of six selenoprotein genes, in particular Gpx1, was linked to this metabolic disorder.

Lack of EGFR mutations benefiting gefitinib treatment in adenocarcinoma of esophagogastric junction.

BACKGROUND: The epidermal growth factor receptor (EGFR) inhibitor, gefitinib, has been reported to successfully treat advanced non-small cell lung cancer patients with genetic mutations in EGFR. The aim of this study was to investigate the existence of EGFR mutations in carcinoma of esophagogastric junction, and also to explore the possibility of treating carcinoma of esophagogastric junction using gefitinib. METHODS: From Aug. 2009 to Jun. 2010, 65 patients with carcinoma of esophagogastric junction underwent surgical resection. The tumor tissue and corresponding blood specimens were collected from all cases. The DNA was extracted and PCR amplification was accomplished based on designed primers for exons 18, 19, 20, and 21. EGFR exons 18, 19, 20 and 21 of both cancer cell and white blood cell were finally successfully sequenced. RESULTS: In exon 20, a variant from CAG to CAA at codon 787 (2361G-> A) was identified in 19 patients, which was a genomic variation of EGFR since it was found in both cancer tissue and white blood cells. This EGFR alteration was a synonymous single nucleotide polymorphism (SNP) since CAA and CAG were encoding the same amino-acid of Glutamine (Q787Q, NCBI database 162093G > A, SNP ID: rs10251977). No genetic alteration was found in exons 18, 19 or 21. CONCLUSIONS: Adenocarcinoma of esophagogastric junction rarely presents EGFR mutation, especially gefitinib-associated mutations such as L858R, or delE746-A750. This means that the gefitinib-based gene target therapy should not be recommended for treating carcinoma of esophagogastric junction.

[Subcarinal lymph node metastasis and strategy of lymphadenectomy in thoracic esophageal carcinoma].

OBJECTIVE: To assess the metastatic frequency of subcarinal lymph nodes of thoracic esophageal carcinoma and its influencing factors, in order to determine the adequate range of lymph node dissection during esophagectomy. METHODS: The clinical data from a cohort of 782 patients with thoracic esophageal carcinoma who underwent esophagectomy with lymphadenectomy were analyzed retrospectively with respect to the impact of subcarinal lymph nodes dissection or no dissection on the incidence of postoperative complications. RESULTS: The metastasis rate of subcarinal lymph nodes was 17.5%. The metastasis rates in the upper, middle and lower esophageal carcinomas were 8.3%, 19.1% and 16.2%, respectively (P > 0.05). For T1, T2, T3 and T4, they were 0, 4%, 22.2% and 34%, respectively (P < 0.05). The overall incidence of postoperative complications with and without subcarinal lymph nodes dissection was 19.0% versus 14.6% (P > 0.05), and the incidence of pulmonary complications was 10.3% versus 7.3% (P > 0.05). CONCLUSIONS: Thoracic esophageal carcinomas have a high metastasis rate of subcrinal lymph nodes, and subcarinal lymph nodes dissection is not associated with increasing perioperative complications. Therefore, for the thoracic esophageal carcinoma, no matter the tumor site, esophageal cancer length or size, once the tumor invades the outer membrane, routine subcarinal lymph node dissection should be done.

Linear stapled esophagogastrostomy is more effective than hand-sewn or circular stapler in prevention of anastomotic stricture: a comparative clinical study.

OBJECTIVE: The aim of this study was to retrospectively compare the operative effects of linear stapled intrathoracic esophagogastrostomy with hand-sewn or circular stapled anastomosis in prevention of anastomotic stricture. METHOD: Between October 2007 and October 2009, 293 patients with esophageal or gastric cardia cancer underwent a curative intent resection. Patients received either a linear stapled (LS group, n = 166), conventional hand-sewn (HS group, n = 59), or circular stapled intrathoracic esophagogastric anastomosis (CS group, n = 68). The patients were followed-up and compared at 3 months after the operation. RESULT: Three groups of patients were comparable on clinical baseline characteristics. There was one operative death in the HS group. The operative complications were documented in 15 patients (5.1%), with no difference among three groups (χ(2) = 2.215, P = 0.330). The follow-up rate was 96.9%. The anastomotic diameter was 1.6 ± 0.4 cm in the LS group, 1.2 ± 0.3 cm in the HS group, and 1.0 ± 0.4 cm in the CS group, respectively (F = 58.110, P < 0.001). The anastomotic stricture rates were 1.9% (3/162) in the LS group, 9.3% (5/54) in the HS group, and 20.9% (14/67) in the CS group, respectively (χ(2) = 24.095, P < 0.001). The reflux score in LS group was lower than other two groups (H = 6.995, P = 0.030). CONCLUSION: The linear stapled esophagogastrostomy could decrease anastomotic stricture without increasing gastroesophageal reflux.