The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients' symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety.

The effect of agitating buffy coats on platelet quality before soft spin.

BACKGROUND: Platelet plays a vital role in both physiological and pathological processes. However, the limited storage time of platelet in vitro poses an immense challenge for its applications because of the increased risk of bacterial contamination and platelet storage lesions. Agitation can inhibit lesions by facilitating continuous oxygenation of platelets and permitting excess carbon dioxide to be removed during storage. However, it is still not known whether agitating BCs gives a positive effect on platelet quality. OBJECTIVES: To evaluate the quality difference between platelet concentrates (PCs) from buffy coats (BCs) held rest and agitation. METHODS: Samples were withdrawn for cell count, blood gas analysis, free hemoglobin level, hypotonic shock response, maximum aggregation rate, activation marker expression (CD62P and CD42b) and coagulation function. RESULTS: We found the PCs prepared from the agitating BCs had fewer residual WBCs, exhibited a better gas exchange ability, slower metabolism (higher pH, higher content glucose, and lower lactic acid levels), better hypotonic shock response, and lower levels of CD62P. The TEG-PC assays showed no difference in coagulation function. CONCLUSION: Our findings showed that BC can be agitated overnight before a soft spin.

Modular arrangements of sequence motifs determine the functional diversity of KDM proteins.

Histone lysine demethylases (KDMs) play a vital role in regulating chromatin dynamics and transcription. KDM proteins are given modular activities by its sequence motifs with obvious roles division, which endow the complex and diverse functions. In our review, according to functional features, we classify sequence motifs into four classes: catalytic motifs, targeting motifs, regulatory motifs and potential motifs. JmjC, as the main catalytic motif, combines to Fe2+ and α-ketoglutarate by residues H-D/E-H and S-N-N/Y-K-N/Y-T/S. Targeting motifs make catalytic motifs recognize specific methylated lysines, such as PHD that helps KDM5 to demethylate H3K4me3. Regulatory motifs consist of a functional network. For example, NLS, Ser-rich, TPR and JmjN motifs regulate the nuclear localization. And interactions through the CW-type-C4H2C2-SWIRM are necessary to the demethylase activity of KDM1B. Additionally, many conservative domains that have potential functions but no deep exploration are reviewed for the first time. These conservative domains are usually amino acid-rich regions, which have great research value. The arrangements of four types of sequence motifs generate that KDM proteins diversify toward modular activities and biological functions. Finally, we draw a blueprint of functional mechanisms to discuss the modular activity of KDMs.

Two-Drug Combinations Therapy of Different Doses of Valsartan Existing Diverse Significance for Hypertensive Patients.

Background: The incidence of hypertension and clinical complications (e.g., heart, cerebrovascular and kidney injury) is increasing worldwide. It is widely known that a relatively large dose of valsartan (320 mg) could alleviate clinical complications. The current network meta-analysis assessed which drug could be combined with a relatively large dose of valsartan to control blood pressure (BP) more effectively. And which combination therapy with different dosages of valsartan did not induce excessive BP reduction with increasing dosages of valsartan. Methods: The PubMed, Embase, Medline, Cochrane Library, CNKI, Wanfang, and CSTJ databases were searched from inception to October 2022 for relevant randomized controlled trials (RCTs). The search strategies included concepts related to hypertension and two-drug combination therapy of different doses of valsartan, and there were no language or data restrictions. The outcomes included adverse effects and changes in systolic BP and diastolic BP. Permanent discontinuations related to treatment were the most accurate and objective measure of adverse effects. The common adverse effects of most studies (i.e., dizziness, headache, nasopharyngitis, asthenia and urticaria) were also included. A Bayesian network meta-analysis was performed, and mean differences with 95% confidence intervals were calculated. ADDIS and STATA were used for Bayesian model network meta-calculation. Results: Thirty-four RCTs were included involving 26,752 patients, and the interventions included different doses of valsartan combined with various types and doses of drugs. Among many combination therapies, the combination of valsartan 320 mg with amlodipine 10 mg (p < 0.01) had the best antihypertensive effect without significant adverse effects. Compared with valsartan 80 mg and 160 mg, valsartan 320 mg combined with hydrochlorothiazide 25 mg (p > 0.05) did not further reduce BP and was not shown to increase the incidence of adverse effects. Conclusions: Combination therapy with a relatively large dose of valsartan could control BP and improve clinical complications effectively. However, for hypertensive patients with different treatment requirements, specific choices should be made regarding whether to control BP, treat clinical complications, or both.

Multi-substrate selectivity based on key loops and non-homologous domains: new insight into ALKBH family.

AlkB homologs (ALKBH) are a family of specific demethylases that depend on Fe2+ and α-ketoglutarate to catalyze demethylation on different substrates, including ssDNA, dsDNA, mRNA, tRNA, and proteins. Previous studies have made great progress in determining the sequence, structure, and molecular mechanism of the ALKBH family. Here, we first review the multi-substrate selectivity of the ALKBH demethylase family from the perspective of sequence and structural evolution. The construction of the phylogenetic tree and the comparison of key loops and non-homologous domains indicate that the paralogs with close evolutionary relationship have similar domain compositions. The structures show that the lack and variations of four key loops change the shape of clefts to cause the differences in substrate affinity, and non-homologous domains may be related to the compatibility of multiple substrates. We anticipate that the new insights into selectivity determinants of the ALKBH family are useful for understanding the demethylation mechanisms.

Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor.

Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an IC(50) value of 7 nM.

Infection of Diabetes Foot Caused by Carbapenem-Resistant Proteus penneri Mediated by a Novel Plasmid Containing blaNDM.

Objective: A strain of Proteus penneri with carbapenem resistance was found in a patient with a diabetic foot infection. We studied drug resistance, genome, and homology of P. penneri to support clinical prevention and treatment of infection caused by carbapenem-resistant P. penneri (CR-PPE). Methods: The strains were obtained through bacterial culture from purulence. VITEK 2 compact (GN13) and Kirby-Bauer (K-B) disk diffusion methods were used for antimicrobial susceptibility testing. Ceftriaxone, amikacin, gentamicin, ampicillin, aztreonam, ceftazidime, ciprofloxacin, levofloxacin, cefepime, trimethoprim-sulfamethoxazole, tobramycin, cefotetan, piperacillin-tazobactam, ampicillin-sulbactam, ertapenem, piperacillin, meropenem, cefuroxime, cefazolin, cefoperazone/sulbactam, cefoxitin, and imipenem were used for antimicrobial susceptibility testing. After bacterial genome extraction, sequencing, and sequence assembly, whole-genome sequencing (WGS) was performed to explore the CR-PPE genotype. Results: CR-PPE was resistant to two carbapenems (imipenem and ertapenem), ceftriaxone, and cefazolin, and was sensitive to aztreonam, piperacillin-tazobactam, and cefotetan. WGS results depict that the resistant phenotype of CR-PPE is consistent with the genotype, without common virulence genes of Enterobacteriaceae bacteria detected (virulence factor database). The carbapenem resistance gene blaNMD-1 is contained in a new plasmid, pWF127-NDM. The transposon Tn125 in pWF127-NDM carrying blaNMD-1 has almost the same structure as Tn125 in the reference plasmid pHFK418-NDM (Accession: MH491967). In addition, through phylogenetic analysis, CR-PPE depicts the closest evolutionary relationship with GCF 024129515.1, which was found in Gallus gallus in the Czech Republic in 2019 (downloaded from National Center for Biotechnology Information database). According to the evolutionary tree, CR-PPE has high homology with the two P. penneri strains found in China. Conclusion: CR-PPE exhibits strong drug resistance owing to the presence of multiple resistance genes. CR-PPE infection should receive more attention, especially in patients with underlying diseases, such as diabetes and weak immunity.

Macrophage-mediated delivery of magnetic nanoparticles for enhanced magnetic resonance imaging and magnetothermal therapy of solid tumors.

Magnetothermal therapy (MHT) has attracted significant attention due to the advantages of non-/minimal invasiveness, high efficiency, and excellent tissue penetration. However, developing small MHT agents (<50 nm) with excellent magnetothermal conversion performance and high tumor enrichment is a great challenge. Herein, a macrophage-mediated delivery of small Fe@Fe3O4-DHCA nanoparticles (∼14 nm) was designed for enhanced magnetic resonance imaging (MRI) and MHT of solid tumors. Based on the "Trojan horse" loading properties of the macrophages (RAW267.4 cells), the aggregation of Fe@Fe3O4-DHCA nanoparticles in the cells results in an enhanced MRI and magnetothermal performance in vitro. In addition, the MHT effect of RAW267.4 loaded with Fe@Fe3O4-DHCA in vivo is better than that of Fe@Fe3O4-DHCA alone, due to the tumor-targeting performance of RAW267.4 cells. This macrophage-mediated delivery provides a new strategy for the enhanced treatment effect of MHT based on Fe@Fe3O4-DHCA nanoparticles, and has great application potential for clinic tumor therapy.

Positive effects of selenium supplementation on selenoprotein S expression and cytokine status in a murine model of acute liver injury.

BACKGROUND: It is a consensus that selenomethionine (SeMet) can protect liver from damage, but the immune mechanism of SeMet in acute liver injury (ALI) is still unclear. This study aims to investigate the protective effects of SeMet against ALI and to elucidate the possible immune mechanism. METHODS: Firstly, the role of SeMet in CCl4-induced ALI mice was investigated through survival rate, serum ALT and AST, liver necrosis and apoptosis analysis. The expression and secretion of inflammatory cytokines and chemokines in the liver and serum of CCl4-induced ALI mice were analyzed by qRT-PCR and ELISA. Then the immune cell phenotypes were analyzed by flow cytometry and confocal imaging. In addition, MDSCs depletion, CXCL12/CXCR4 axis blocking and selenoprotein S (SELENOS) knockdown assays were used to reveal the immune mechanism of SeMet. RESULTS: We found that SeMet prolonged survival rate, decreased the serum ALT and AST, alleviated liver necrosis and inhibited hepatocytes apoptosis. Prospective, SeMet decreased the expression of IL-6 and TNF-α, and increased the expression of IL-10. Interestingly, SeMet decreased the expression of MCP-1, while increased the expression of CXCL12. The immune analysis showed that SeMet decreased the activation of T cells through promoting MDSCs accumulation mediated by CXCL12/CXCR4 axis. Furthermore, SeMet increased SELENOS expression in vivo, and knockdown of SELENOS effectively abolished the protective effect of SeMet during ALI. CONCLUSION: This study demonstrates that SeMet alleviates CCl4-induced ALI by promoting MDSCs accumulation through SELENOS mediated CXCL12/CXCR4 axis. Therefore, our study infers that selenium intake may be as a new therapeutic option for management of inflammation-mediated liver injury.

Genomic insights of the WRKY genes in kenaf (Hibiscus cannabinus L.) reveal that HcWRKY44 improves the plant's tolerance to the salinity stress.

The WRKY transcription factors (TFs) are among the most diverse TF families of plants. They are implicated in various processes related to plant growth and stress response. Kenaf (Hibiscus cannabinus L.), an important fiber crop, has many applications, including the phytoremediation of saline-alkaline soil. However, the roles of WRKY TFs in kenaf are rarely studied. In the present study, 46 kenaf WRKY genes were genome-widely identified and characterized by gene structure, phylogeny and expression pattern analysis. Furthermore, the HcWRKY44 gene was functionally characterized in Arabidopsis under salinity and drought stresses. HcWRKY44 is a nuclear-localized protein that is positively induced by salinity and drought, with roots showing maximum accumulation of its transcripts. Under NaCl and abscisic acid (ABA) stress conditions, plants overexpressing HcWRKY44 had higher germination rates, better root growth and increased survival than control plants; however, it did not improve the ability to withstand drought stress. Moreover, ABA signaling genes (ABI1, ABI2, and ABI5), ABA-responsive genes (ABF4, RD29B, COR15A, COR47, and RD22), stress-related genes (STZ, P5CS, and KIN1), and ionic homeostasis-related genes (SOS1, AHA1, AHA2, and HKT1) were positively induced in HcWRKY44 transgenic plants under NaCl treatment. These results suggest that HcWRKY44 improved plant's tolerance to salt stress but not osmotic stress through an ABA-mediated pathway. In summary, this study provides provided comprehensive information about HcWRKY genes and revealed that HcWRKY44 is involved in salinity tolerance and ABA signaling.

To Analyze the Application Value of Perioperative Nursing Care in Patients with Resected Brain Tumor Accompanied with Epileptic Symptoms under Cortical Electrocorticography Monitoring.

OBJECTIVE: To explore the application value of perioperative nursing for patients with brain tumors with epilepsy symptoms under the cortical electrocorticography (EEG) monitoring. METHODS: A total of 86 patients with brain tumor complicated with epilepsy admitted to the department of brain surgery of our hospital from January 2018 to December 2019 were selected as the research objects, and all underwent resection under cortical EEG monitoring. According to different nursing methods, they were divided into the control group and observation group, each with 43 cases. The control group was given perioperative basic nursing, and the observation group was given perioperative comprehensive nursing. The EEG image of the patient during the operation was observed by a portable EEG monitor. Anxiety and depression were assessed by self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores. The self-made satisfaction questionnaire was used to investigate the nursing satisfaction. A visual analogue (VAS) score is used to assess pain degree. A multiparameter monitor was used to detect the patient's heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). The quality of life was assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-30). The complication rate and recurrence rate were also counted. RESULTS: Eighty-six patients with epileptic brain tumor developed spikes in 35 cases, including 7 meningiomas, 22 gliomas, and 6 cholesteatomas; 27 cases of sharp waves, including 14 meningiomas, 12 gliomas, and 1 case of cholesteatomas; and 24 cases of complex wave, including 9 cases of meningioma, 13 cases of glioma, and 2 cases of cholesteatoma. There was no significant difference in the scores of SAS, SDS, VAS, HR, SBP, DBP, and quality of life between the two groups at T0. The VAS score increased at T1 and T2, and the increase in the control group was greater than that in the observation group. At T3 and T4, the SAS, SDS, and VAS scores of the two groups decreased, and the observation group decreased more than the control group. HR, SBP, and DBP of the two groups showed an upward trend at T1 and T2, and the increase in the control group was more significant than that in the observation group. At T3, the three indicators of the two groups decreased, and the observation group decreased more significantly than the control group. At T4, the scores of all indicators of the quality of life of the two groups increased, and the observation group increased more significantly than the control group. The nursing satisfaction of the observation group was higher than that of the control group. The complication rate and recurrence rate in the observation group were decreased compared with the control group. CONCLUSION: Perioperative comprehensive nursing intervention for patients with epileptic brain tumor undergoing resection under cortical EEG monitoring can reduce or even eliminate the recurrence rate of epilepsy, reduce the patient's pain and stress response, and improve the patient's quality of life. It can also reduce the occurrence of complications, improve nursing satisfaction, thereby improving patient compliance, and has a high clinical application value.

Discovery of novel fatty acid synthase (FAS) inhibitors based on the structure of ketoaceyl synthase (KS) domain.

Development of fatty acid synthase (FAS) inhibitors has increasingly attracted much attention in recent years due to their potential therapeutic use in obesity and cancers. In this investigation, pharmacophore modeling based on the first crystal structure of human KS domain of FAS was carried out. The established pharmacophore model was taken as a 3D query for retrieving potent FAS inhibitors from the chemical database Specs. Docking study was further carried out to refine the obtained hit compounds. Finally, a total of 28 compounds were selected based on the ranking order and visual examination, which were first evaluated by a cell line-based assay. Seven compounds that have good inhibition activity against two FAS overexpressing cancer cell lines were further evaluated by an enzyme-based assay. One compound with a new chemical scaffold was found to have low micromolar inhibition potency against FAS, which has been subjected to further chemical structural modification.

Melamine-tainted milk product-associated urinary stones in children.

BACKGROUND: An outbreak of urinary stones related to consumption of melamine-tainted milk products (MTMP) occurred in China in 2008. The aim of the present study was to evaluate such children to identify their clinical features and risk factors. METHODS: Renal ultrasound was performed for 7328 children who presented to a Sichuan teaching hospital between 13 September and 15 October 2008 due to concern of such stones. Clinical data, family information, feeding history and urinary stones were analyzed. RESULTS: Of the 7328 children, 189 (2.58%) had ultrasound findings of urinary stones, and 51 were admitted. Age (mean ± SD) was 27.4 ± 25.5 months, and 101 were male and 88, female. The odds ratio (OR) for urinary stones for infants and young children (1-3 years) as compared to older children (>3 years), was 2.42 (95% confidence interval [CI], 1.64-3.56; P < 0.0001) and 1.95 (95%CI, 1.31-2.89; P < 0.0011), respectively. Independent risk factors associated with urinary stones included consumption of MTMP with melamine at > 5500 mg/kg (OR, 13.3; 95%CI, 6.8-26.1, P < 0.0001) as compared to that with melamine at < 200 mg/kg, and younger father (P = 0.0006). On logistic regression, the only risk factor associated with inpatient care was lower family income per person (OR, 4.4; 95%CI, 1.2-15.9, P = 0.02). Repeat ultrasound for 51 children at mean follow up of 15.3 ± 8.9 days found that 33 passed out all stones, which was associated with a larger number of smaller stones (P = 0.003). Urinary stones contained melamine and uric acid, but no cyanuric acid. CONCLUSIONS: MTMP-associated urinary stones were more frequent in young children and more severe in children from poorer families.

A simple preparation of 2,3,4,6-tetra-o-acyl-gluco-, galacto- and mannopyranoses and relevant theoretical study.

The deacylation of glucose, galactose and mannose pentaacetates, galactose and mannose penta(3-bromo)benzoates, as well as the dealkylation of 2,3,4,6-tetra-O-acetyl and 2,3,4,6-tetra-O-(3-bromo)benzoyl methyl alpha-D-glucopyranosides have been studied. In addition, a computational study on the deacylation of beta-D-glucose pentaacetate has been carried out with density functional theory (B3LYP/6-31G*). The anomeric effect during deacetylation and dealkylation has been clearly demonstrated in both experimental and computational results.

Implications of soluble E-cadherin level of antiviral treatment in patients with chronic hepatitis C virus infection.

BACKGROUND AND AIMS: Soluble E-cadherin (sE-cadherin) has been observed elevated in patients with various diseases, and implicated in the occurrence and development of those diseases. The implications of sE-cadherin in chronic hepatitis C virus (HCV) infection are still unclear. The purpose of this study is to explore the significance of sE-cadherin in chronic hepatitis C infection and the correlation with treatment response. METHODS: 87 chronic HCV infected patients and 60 healthy subjects were enrolled in this study. Blood samples from patients receiving the combined treatment of pegylated interferon-a (Peg-IFN-α) with ribavirin (RBV) were collected before treatment, during 4th, 12th therapy weeks, end of the treatment, and 24 weeks post-therapy. Plasma sE-cadherin level was detected by enzyme-linked immunosorbent assay (ELISA) and the relationship between sE-cadherin and antiviral treatment outcome was analyzed. RESULTS: Plasma sE-cadherin concentrations of Chronic HCV infected patients were significantly higher than that of healthy controls. A strong correlation between sE-cadherin level and the HCV viral load, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and also glutamyl transpeptidase (GGT) level was detected. Chronic HCV infected patients achieving rapid virological response (RVR) and sustained virological response (SVR) had lower baseline sE-cadherin concentrations compared with the non-RVR and non-SVR groups respectively. Univariate and multivariate regression analyses suggested that baseline plasma sE-cadherin level was predictive of therapeutic effect in patients with chronic HCV infection. CONCLUSION: Baseline sE-cadherin level could be considered as an independent predictor of SVR with Peg-IFN-α plus ribavirin therapy in the Chinese Han population chronic HCV infection patients. Effective antiviral therapy might restore sE-cadherin at physiological levels.

Effects of fat distribution on lung function in young adults.

AIMS: To study the associations between fat distribution and lung functions in healthy subjects of young adults and to explore potential gender difference in these correlations. METHODS: A total of 2101 adult participants were recruited. Height, weight, and vital capacity index (VCI) were measured and recorded according to the national physical fitness test standard. Body compositions, including body mass index (BMI), body fat percentage (BFP), waist-to-hip ratio (WHR), fat-free mass (FFM), trunk muscle mass (TMM), fat mass (FM), visceral fat area (VFA), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT), were conducted using body composition analyzer. Data were analyzed by SPSS 20.0 software. RESULTS: We found that male participants showed significantly higher BMI, WHR, FFM, TMM, VFA, and VCI, but lower FM, BFP, and SAT in comparison with women. However, there was no significant difference in VAT between the male and female. Lung functions represented by VCI were negatively correlated with FM, VAT, SAT, and VFA for both men and women (r < 0; P < 0.05). Among these negative correlations, VCI was more inversely correlated with VFA for men but with SAT for women, respectively. After dividing the whole populations by BMI, BFP, and WHR, further correlation analysis showed VCI was still more negatively correlated with VFA for all male subgroups (r < 0; P < 0.05). On the contrary, VCI was more negatively correlated with SAT in BMI-underweight, BMI-normal, BFP-low fat, BFP-normal fat, WHR-normal, and WHR-obese subgroups (r < 0; P < 0.05), while VFA and VAT was more inversely correlated with VCI in BMI- and BFP-overweight+obese subgroups (r < 0; P < 0.05). CONCLUSIONS: Fat accumulation is highly associated with the vital capacity index in young adults. In general, VCI was more negatively correlated with VFA for men but with SAT for women, respectively, in comparison with other tested indices.

c-Jun-dependent ß3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns.

ß3GnT8, a key polylactosamine synthase, plays a vital role in progression of various types of human cancer. The role of ß3GnT8 in hepatocellular carcinoma (HCC) and the underlying mechanisms, however, remain largely unknown. In this study, we found that ß3GnT8 and polylactosamine were highly expressed in HCC tissues compared with those in adjacent paracancer tissues. Overexpression of ß3GnT8 promoted while knockdown of ß3GnT8 inhibited HCC cell invasion and migration in vitro. Importantly, enhanced tumorigenesis was observed in nude mice inoculated with ß3GnT8-overexpressing HCC cells, suggesting that ß3GnT8 is important for HCC development in vitro and in vivo. Mechanistically, ß3GnT8 modulated the N-glycosylation patterns of CD147 and altered the polylactosamine structures in HCC cells by physically interacting with CD147. In addition, our data showed the c-Jun could directly bind to the promoter of ß3GnT8 gene and regulate ß3GnT8 expression. ß3GnT8 regulated HCC cell invasion and migration in a C-Jun-dependent manner. Collectively, our study identified ß3GnT8 as a novel regulator for HCC invasion and tumorigenesis. Targeting ß3GnT8 may be a potential therapeutic strategy against HCC.

The combined therapeutic effects of 131iodine-labeled multifunctional copper sulfide-loaded microspheres in treating breast cancer.

Compared to conventional cancer treatment, combination therapy based on well-designed nanoscale platforms may offer an opportunity to eliminate tumors and reduce recurrence and metastasis. In this study, we prepared multifunctional microspheres loading 131I-labeled hollow copper sulfide nanoparticles and paclitaxel (131I-HCuSNPs-MS-PTX) for imaging and therapeutics of W256/B breast tumors in rats. 18F-fluordeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging detected that the expansion of the tumor volume was delayed (P<0.05) following intra-tumoral (i.t.) injection with 131I-HCuSNPs-MS-PTX plus near-infrared (NIR) irradiation. The immunohistochemical analysis further confirmed the anti-tumor effect. The single photon emission computed tomography (SPECT)/photoacoustic imaging mediated by 131I-HCuSNPs-MS-PTX demonstrated that microspheres were mainly distributed in the tumors with a relatively low distribution in other organs. Our results revealed that 131I-HCuSNPs-MS-PTX offered combined photothermal, chemo- and radio-therapies, eliminating tumors at a relatively low dose, as well as allowing SPECT/CT and photoacoustic imaging monitoring of distribution of the injected agents non-invasively. The copper sulfide-loaded microspheres, 131I-HCuSNPs-MS-PTX, can serve as a versatile theranostic agent in an orthotopic breast cancer model.

RNA interference-mediated silencing of ppGalNAc-T1 and ppGalNAc-T2 inhibits invasion and increases chemosensitivity potentially by reducing terminal α2,3 sialylation and MMP14 expression in triple­negative breast cancer cells.

Glycopeptide-preferring polypeptide N-acetylgalactosamine transferase (ppGalNAc­T) is a key enzyme that initiates the formation of the first GalNAc monosaccharide to polypeptides at Thr/Ser residues by O­linked glycosylation. In order to investigate the effects of ppGalNAc­T1 and ppGalNAc­T2 on the initiation of O­glycosylation, siRNA­ppGalNAc­T1 (si­T1) and siRNA­ppGalNAc­T2 (si­T2) were transfected into highly­invasive estrogen receptor­negative MDA­MB­231 cells to inhibit O­glycosylation. Downregulation of ppGalNAc­T1 demonstrated a significant reduction in the number of terminal α2,3 sialic acids, when compared to cells transfected with si­T2 or si­T1/T2. This downregulation led to a decrease in the invasion capabilities of the breast carcinoma cells, as well as enhanced chemosensitivity, which was the result antineoplastic drug effects. In addition, immunoprecipitation assays demonstrated that downregulation of ppGalNAc­T1 led to a reduction in the number of terminal α2,3 sialic acids on O­linked glycans of the matrix metalloproteinase­14 (MMP14) glycoprotein. Furthermore, MMP14 and vascular endothelial growth factor were downregulated in the si­T1 groups when compared with the si­T2 and si­T1/T2 groups. In conclusion, the results of the present study suggest that ppGalNAc­T1 may serve a pivotal role in the initiation of O­glycosylation, which may lead to a low density of α2,3 sialic acids on O­linked glycans of MMP14 when downregulated. Glycosylation serves a significant role in regulating the sensitivity of MMP14 to self­proteolysis, which ultimately decreases the invasion capabilities of breast cancer cells. The results of the present study may be useful in establishing the function of ppGalNAc­T1 during breast cancer invasion and metastasis.