In preclinical studies of young mice, nanoparticles showed excellent anti-tumor therapeutic effects by harnessing Peripheral Blood Monocytes (PBMs) and evading the immune system. However, the changes ...of age will inevitably affect PBMs and the immune system, and there is a serious lack of relevant research. Sialic acid (SA)-octadecylamine (ODA) was synthesized, and SA- or polyethylene glycol (PEG)-modified epirubicin (EPI) liposomes (EPI-SL and EPI-PL, respectively) were prepared to explore differences in antitumor treatment using 8-month-old and 8-week-old Kunming mice. Based on presented data, 8-month-old mice had more PBMs in peripheral blood than 8-week-old mice, and age differences resulted in different anti-tumor treatment effects following EPI-SL and EPI-PL treatment. Following EPI-PL administration, the tumor volume was significantly smaller in 8-week-old mice than in 8-month-old mice (* p < 0.05). Eight-month-old mice treated with EPI-SL (8M-SL) presented no damage to healthy tissue, with a 100% survival rate, and 50% mice in 8M-SL showed ‘shedding’ of tumor tissues from the growth site. Accordingly, 8-month-old mice treated with EPI-SL achieved the best therapeutic effect at different ages and with different liposomes. EPI-SL could improve the antitumor effect of 8-week-old and 8-month-old mice.
The relative age of galaxies at different redshifts can be used to infer the Hubble parameter and put constraints on cosmological models. We select luminous red galaxies (LRGs) from the Sloan Digital ...Sky Survey Data Release 7 and then cross match it with the MPA/JHU catalog of galaxies to obtain a large sample of quiescent LRGs at redshift z ~ 0.03-0.39. The total number of quiescent LRGs, 23,883, is divided into four sub-samples according to their velocity dispersions and each sub-sample is further divided into 12 redshift bins. With upcoming surveys, such as the Baryon Oscillation Spectroscopic Survey, even larger samples of quiescent massive LRGs may be obtained, and thus the Hubble parameter can be measured with high accuracy using the age-redshift relation.
Background
Chronic inflammation contributes to approximately 20% of cancers; the underlying mechanisms are still elusive. Here, using an animal model of colitis to colon-cancerous transformation, we ...demonstrated that endoplasmic reticulum (ER) stress couples with metabolic reprogramming to promote a malignant transformation of chronic inflammation.
Methods
The animal model for chronic colitis to colon-cancerous transformation was established in C57BL/6N mice by azoxymethane (AOM) and dextran sodium sulfate (DSS) treatments. The differential proteins in control and AOM/DSS-treated colon mucosa were determined using proteomic analysis; the kinetics of metabolic modifications were monitored by mitochondrial oxygen flux, extracellular acidification, and targeted metabolomics; the molecule linker between ER stress and metabolic modifications were identified by coimmunoprecipitation, KEGG pathway analysis, and the subcutaneous tumor model using gene-specific knockdown colon cancer cells. Tissue array analysis were used to evaluate the differential protein in cancer and cancer-adjacent tissues.
Results
AOM/DSS treatment induced 38 tumors in 10 mice at the 14th week with the mean tumor size 9.35 ± 3.87 mm
2
, which was significantly decreased to 5.85 ± 0.95 mm
2
by the ER stress inhibitor 4-phenylbutyric acid (4PBA). Seven differential proteins were determined from control (1,067 ± 48) and AOM/DSS-treated mucosa (1,077 ± 59); the level of ER protein PDIA2 (protein disulfide isomerase-associated 2) was increased over 7-fold in response to AOM/DSS treatment. PDIA2 interacted with 420 proteins that were involved in 8 signaling pathways, in particular with 53 proteins in metabolic pathways. PDIA2 translocated from ER to mitochondria and interacted with the components of complexes I and II to inhibit oxophosphorylation but increase glycolysis. Knockdown PDIA2 in colon cancer cells restored the metabolic imbalance and significantly repressed tumor growth in the xenograft animal model. 4PBA therapy inhibited the AOM/DSS-mediated overexpression of PDIA2 and metabolic modifications and suppressed colon cancer growth. In clinic, PDIA2 was overexpressed in colon cancer tissues rather than cancer-adjacent tissues and was related with the late stages and lymph node metastasis of colon cancer.
Conclusions
Persistent ER stress reprograms the metabolism to promote the malignant transformation of chronic colitis; PDIA2 serves as a molecule linker between ER stress and metabolic reprogramming. The inhibition of ER stress restores metabolic homeostasis and attenuates the cancerous transformation of chronic inflammation.
Immunoscenescence plays a key role in the initiation and development of tumors. Furthermore, immunoscenescence also impacts drug delivery and cancer therapeutic efficacy. To reduce the impact of ...immunosenescence on anti-tumor therapy, this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid (SA)-modified liposomes into the tumor, kill tumor cells via SA-mediated photochemotherapy, enhance infiltration of neutrophils into the tumor, induce immunogenic death of tumor cells with chemotherapy, enhance infiltration of CD8+ T cells into the tumor-draining lymph nodes and tumors of immunosenescent mice, and achieve SA-mediated photochemotherapy. We found that CD8+ T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2- and 8-month-old mice; 16-month-old mice exhibited immunosenescence. The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice, and tumors recurred after scabbing. SA-mediated photochemotherapy enhanced tumor infiltration by CD8+ T cells and neutrophils, induced crusting and regression of tumors in 8-month-old mice, inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.
Immunosenescence decreased the antitumor therapeutic efficacy in 16-month-old mice. Sialic acid-mediated photochemotherapy enhanced infiltration of CD8+ T cells and neutrophils into tumors and eliminated the immunosenescence-mediated decline in antitumor therapeutic efficacy. Display omitted
The main aim of this study was to investigate the effect of CYP2B6 gene polymorphisms on efavirenz (EFV) plasma concentrations in Han Chinese patients with human immunodeficiency virus (HIV) ...infection.
In total, 322 patients were recruited for study. EFV plasma concentrations at steady-state were determined using high-performance liquid chromatography. Genotyping for seven single nucleotide polymorphisms (SNPs), including 171+967C>A, 171+3212C>T, 171+4335T>C, 516G>T, 785A>G, 1295-913G>A, and *1355A>G of CYP2B6, was performed using ligase detection reaction (LDR). SPSS 18.0 and Haploview 4.2 were applied for statistical analyses.
The average EFV concentration of patients was 2.35±2.09 μg/mL. Overall, 22% patients displayed EFV concentrations out of the therapeutic range of 1-4 μg/mL (13.1% < 1 μg/mL, 9.3% > 4 μg/mL). We observed significant association of 171+967C>A, 171+4335T>C, 516G>T, 785A>G and *1355A>G with high plasma EFV levels (p<.01). The predictive accuracy values of 171+4335CC, 516TT and 785GG for EFV concentrations > 4 μg/mL were 56.7%, 56.7% and 60%, respectively. We observed strong linkage disequilibrium for 171+967C>A, 171+4335T>C, 516G>T and 785A>G, resulting in five haplotypes. The frequencies of the five haplotypes (high to low) were as follows: CCTG (0.328), ACTG (0.280), ACCT (0.189), ATTG (0.186) and ACCG (0.017). The frequency of CCTG (0.524) in patients with EFV plasma concentrations < 1 μg/mL was significantly higher than that in other patient groups, while that of ACCT (0.733) was significantly higher in patients with EFV concentrations > 4 μg/mL, relative to other patient groups. Average EFV concentrations of patients carrying ACTG (1.78 μg/mL), ACCT (7.50 μg/mL), and ATTG (1.92 μg/mL) haplotypes were markedly higher than those of patients carrying the CCTG haplotype. The predictive accuracy of ACCT for EFV > 4 μg/mL was 81%.
Chinese patients administered standard doses of EFV require therapeutic drug monitoring or personalized medication management. Based on the current findings, we propose that 171+4335T>C, 516G>T, 785A>G and haplotype ACCT may be effectively used as genomic markers for EFV, which should aid in improving the efficacy of EFV-containing treatments and reduce the incidence of adverse reactions.
MW33 is a fully humanized IgG1κ monoclonal neutralizing antibody, and may be used for the prevention and treatment of coronavirus disease 2019 (COVID-19). We conducted a randomized, double-blind, ...placebo-controlled, single-dose, dose-escalation Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of MW33. Healthy adults aged 18-45 years were sequentially enrolled into the 4, 10, 20, 40, and 60 mg/kg dose groups and infused with MW33 over 60 ± 15 min and followed for 85 days. All 42 enrolled participants completed the MW33 infusion, and 40 participants completed the 85-day follow-up period. 34 participants received a single infusion of 4 (n = 2), 10 (n = 8), 20 (n = 8), 40 (n = 8), and 60 mg/kg (n = 8) of MW33. 27 subjects in the test groups experienced 78 adverse events (AEs) post-dose, with an incidence of 79.4% (27/34). The most common AEs included abnormal laboratory test results, vascular and lymphatic disorders, and infectious diseases. The severity of AEs was mainly Grade 1 (92 AEs), and three Grade 2 and one Grade 4. The main PK parameters, maximum concentration (C
max
), and area under the concentration-time curve (AUC
0-t
, and AUC
0-∞
) in 34 subjects showed a linear kinetic relationship in the range of 10-60 mg/kg. The plasma half-life was approximately 25 days. The positive rates of serum ADAs and antibody titres were low with no evidence of an impact on safety or PK. In conclusion, MW33 was well-tolerated, demonstrated linear PK, with a lower positive rate of serum ADAs and antibody titres in healthy subjects.
Trial registration:
ClinicalTrials.gov identifier: NCT04427501
.
Trial registration:
ClinicalTrials.gov identifier: NCT04533048
.
Trial registration:
ClinicalTrials.gov identifier: NCT04627584
.
Recent studies have demonstrated that myocardial calpain triggers caspase-3 activation and myocardial apoptosis in models of sepsis, whereas the inhibition of calpain activity down-regulates ...myocardial caspase-3 activation and apoptosis. However, the mechanism underlying this pathological process is unclear. Therefore, in this study, our aim was to explore whether the Hsp90/Akt signaling pathway plays a role in the induction of myocardial calpain activity, caspase-3 activation and apoptosis in the septic mice.
Adult male C57 mice were injected with lipopolysaccharide (LPS, 4 mg/kg, i.p.) to induce sepsis. Next, myocardial caspase-3 activity and the levels of Hsp90/p-Akt (phospho-Akt) proteins were detected, and apoptotic cells were assessed by performing the TUNEL assay.
In the septic mice, there was an increase in myocardial calpain and caspase-3 activity in addition to an increase in the number of apoptotic cells; however, there was a time-dependent decrease in myocardial Hsp90/p-Akt protein levels. The administration of calpain inhibitors (calpain inhibitor-Ш or PD150606) prevented the LPS-induced degradation of myocardial Hsp90/p-Akt protein and its expression in cardiomyocytes in addition to inhibiting myocardial caspase-3 activation and apoptosis. The inhibition of Hsp90 by pretreatment with 17-AAG induced p-Akt degradation, and the inhibition of Akt activity by pretreatment with wortmannin resulted in caspase-3 activation in wildtype C57 murine heart tissues.
Myocardial calpain induces myocardial caspase-3 activation and apoptosis in septic mice via the activation of the Hsp90/Akt pathway.
The aim of this study was to evaluate the relationship between polymorphisms in CYP2C19 and the single‐dose pharmacokinetics (PKs) of omeprazole in healthy Chinese volunteers. A 20 mg single dose of ...omeprazole (Losec) enteric‐coated capsules or tablets was orally administered to 656 healthy subjects from eight subcenters. The polymorphic alleles of CYP2C19*2, *3, and *17 were determined by Sanger sequencing and Agena mass array. Plasma concentrations of omeprazole were determined by high‐performance liquid‐chromatography tandem mass spectrometry. PK parameters of area under the concentration versus time curve (AUC)0‐t, AUC from zero to infinity (AUC0‐∞), maximum plasma concentration (Cmax), and terminal half‐life (t1/2) were significantly influenced by CYP2C19 phenotype (all p < 0.001) and diplotype (all p < 0.001), and the same results were obtained in the subgroup analysis of the effects of diet and dosage form. The polymorphisms of CYP2C19*2(rs4244285; all PK parameters p < 0.001) and *3(rs4986893; pCmax = 0.020, and the p values of other PK parameters were less than 0.001) were significantly associated with the PKs of omeprazole. For CYP2C19*17 (rs12248560), only t1/2 showed a significant correlation (p = 0.032), whereas other PK parameters did not. The present study demonstrated that the Pks of omeprazole is greatly influenced by CYP2C19.
Autosomal-dominant congenital stromal corneal dystrophy (CSCD) is a human genetic disease characterized by corneal opacities beginning shortly after birth. It is linked to a frameshift mutation in ...decorin, resulting in a C-terminal truncation lacking 33 amino acids that includes the "ear" repeat, a feature specific for small leucine-rich proteoglycans. Our goals are to elucidate the roles of the mutant decorin in CSCD pathophysiology and to decipher the mechanism whereby mutant decorin affects matrix assembly. A novel animal model that recapitulates human CSCD was generated. This transgenic mouse model targets expression of truncated decorin to keratocytes, thereby mimicking the human frameshift mutation. Mutant mice expressed both wild-type and mutant decorin. Corneal opacities were found throughout, with increased severity toward the posterior stroma. The architecture of the lamellae was disrupted with relatively normal lamellae separated by regions of abnormal fibril organization. Within abnormal zones, the interfibrillar spacing and the fibril diameters were increased. Truncated decorin negatively affected the expression of endogenous decorin, biglycan, lumican, and keratocan and positively affected fibromodulin. Our results provide a mechanistic explanation for the generation of corneal opacities in CSCD. Thus, truncated decorin acts in a dominant-negative manner to interfere dually with matrix assembly and binding to receptor tyrosine kinases, thereby causing abnormal expression of endogenous small leucine-rich proteoglycans leading to structural abnormalities within the cornea and vision loss.
Abstract Vitiligo is a cutaneous pigmentary disorder characterized by the loss of epidermal melanocytes. Strong evidence supports the theory that autoimmune mechanisms, namely B cell auto-antibody ...production and auto-reactive T cell cytotoxicity, are involved in this affliction. It is well known that autoimmunity results from a breakdown of self-tolerance. However, the mechanism which leads to the break-down of self-tolerance and subsequently causes the development of autoimmunity in vitiligo remains obscure. B lymphocyte activating factor of the tumour necrosis factor family is a recently identified ligand that is required for peripheral B-cell survival and homeostasis, the excessive production of which may lead to autoimmunity. Based on a collection of indirect evidences, we postulate that in individuals predisposed through inheritance, over-expression of the B lymphocyte activating factor may cause a breakdown of self-tolerance and subsequently cause autoimmune vitiligo via several possible mechanisms: B lymphocyte activating factor activates self-reactive B cells to produce auto-antibodies against melanocytes; these B cells may function as cellular adjuvants for the activation of the CD4+ T cells, enhancing their helper effect on the activation of the CD8+ T cells; CD4+ T cells assist CD8+ T cells to respond to melanocytes antigen, leading to the autoreactive reaction; B lymphocyte activating factor activated B cells capture antigen and present it directly to the CD8+ T cells; and, B lymphocyte activating factor delivers a complete costimulation signal to the T cells (both CD4+ and CD8+ subset), playing an additional role in the autoimmune response in vitiligo. Future challenges remain to test these propositions. Advancement in the treatment of vitiligo is still unsatisfactory, and thus novel modalities of therapy need to be developed. Recently, B lymphocyte activating factor has been evaluated as an attractive target for immune therapy. Once the hypothesis of B lymphocyte activating factor mediating the breakdown of self-tolerance in vitiligo is corroborated, it can become a novel target for treatment of vitiligo.
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