Clinical features and prognosis of chronic natural killer cell lymphoproliferative disorders.

OBJECTIVE: To analyze the current treatment status and prognostic regression of the chronic NK cell lymphoproliferative disorder (CLPD-NK). METHODS: We retrospectively analyzed the clinical features, treatment and prognosis of 18 patients with CLPD-NK who were treated at our Hospital between September 2016 and September 2022. RESULTS: Eighteen patients were included: three patients were treated with chemotherapy, five patients underwent immune-related therapy, one patient was treated with glucocorticoids alone, five patients were administered granulocyte colony-stimulating factor, blood transfusion therapy, or anti-infection therapy, followed by observation and follow-up, and four patients were observed without treatment. Fifteen patients survived, including two patients who achieved complete remission (CR) and seven patients who achieved partial remission (PR), of whom one patient progressed to Aggressive NK-cell leukemia (ANKL) and sustained remission after multiple lines of treatment; three patients were not reviewed, of which one patient was still in active disease, three patients developed hemophagocytic syndrome during treatment and eventually died, one of them had positive Epstein-Barr virus (EBV) expression. The 5-years overall survival rate was 83%. CONCLUSION: Most patients with CLPD-NK have inert progression and a good prognosis, whereas some patients have a poor prognosis after progressing to ANKL and combined with hemophagocytic syndrome. Abnormal NK cells invading the center suggest a high possibility of ANKL development, and immunosuppressants and hormones are effective treatments for this disease.

Immunogenicity and safety of an Escherichia coli-produced human papillomavirus (types 6/11/16/18/31/33/45/52/58) L1 virus-like-particle vaccine: a phase 2 double-blind, randomized, controlled trial.

The Escherichia coli-produced human papillomavirus (HPV) 16/18 bivalent vaccine (Cecolin) has received prequalification by the World Health Organization based on its high efficacy and good safety profile. We aimed to evaluate the immunogenicity and safety of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine (Cecolin 9) through the randomized, blinded phase 2 clinical trial. Eligible healthy women aged 18-45 years were randomly (1:1) allocated to receive three doses of 1.0 mL (270 µg) of Cecolin 9 or placebo with a 0-1-6-month schedule. The primary endpoint was the seroconversion rate and geometric mean titer of neutralizing antibodies (nAbs) one month after the full vaccination course (month 7). The secondary endpoint was the safety profile including solicited adverse reactions occurring within 7 d, adverse events (AEs) occurring within 30 d after each dose, and serious adverse events (SAEs) occurring during the 7-month follow-up period. In total, 627 volunteers were enrolled and randomly assigned to Cecolin 9 (n = 313) or placebo (n = 314) group in Jiangsu Province, China. Almost all participants in the per-protocol set for immunogenicity (PPS-I) seroconverted for nAbs against all the nine HPV types at month 7, while two failed to seroconvert for HPV 11 and one did not seroconvert for HPV 52. The incidence rates of total AEs in the Cecolin 9 and placebo groups were 80.8% and 72.9%, respectively, with the majority of them being mild and recovering shortly. None of the SAEs were considered related to vaccination. In conclusion, the E. coli-produced 9-valent HPV (9vHPV) vaccine candidate was well tolerated and immunogenic, which warrants further efficacy studies in larger populations.

Safety and immunogenicity of an Escherichia coli-produced 9-valent human papillomavirus L1 virus-like particle vaccine (types 6/11/16/18/31/33/45/52/58) in healthy adults: an open-label, dose-escalation phase 1 clinical trial.

Background: A safe and highly efficacious Escherichia coli (E. coli)-produced HPV 16/18 bivalent vaccine has been prequalified by the World Health Organization. Here, we conducted a single-center, open-label, dose-escalation phase 1 clinical trial to evaluate the safety and immunogenicity of the second-generation nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine. Method: Twenty-four eligible volunteers aged 18-45 years were enrolled in January 2019 in Dongtai, China and received 0.5 mL (135 µg) or 1.0 mL (270 µg) of the candidate vaccine with a 0/1/6-month dose-escalation schedule. Local and systemic adverse events (AEs) occurring within 30 days after each vaccination and serious adverse events (SAEs) occurring within 7 months were recorded. Blood samples from each participant were collected before and 2 days after the first and third vaccinations to determine changes in laboratory parameters. Serum IgG and neutralizing antibody (nAb) levels against each HPV type at month 7 were analyzed (ClinicalTrials.gov: NCT03813940). Findings: The incidences of total AEs in the 135 µg and 270 µg groups were 66.7% and 83.3%, respectively. All AEs were mild or moderate, and no SAEs were reported. No clinically significant changes were found in paired blood indices before or after any of the vaccinations. All the participants in the per-protocol set except for two who failed to seroconvert for HPV 11 or 58 in the 135 µg group seroconverted at month 7 for both IgG and nAbs. Interpretation: The candidate E. coli-produced 9vHPV vaccine has been preliminarily proven to be well tolerated and immunogenic, which encourages further studies in large cohorts with a wider age range. Funding: This study was supported by the National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Fujian Province Health and Education Joint Research Program, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax Biotechnology Co., Ltd.

[Review of pharmacological effects and toxicological information of Arecae Semen].

The main chemical composition of Arecae Semen has been summarized, which can bring the pharmacological action and toxicological action to the nervous system, digestive system, cardiovascular system, urinary and reproductive system. Arecae Semen has inhibition and killing effect to most parasite. It can also activate the cholinergic receptor, promote gastrointestinal propulsive motility in mice and inhibit helicobacter pylori, Xu Lang schoenleinii, influenza virus. Arecae Semen chewing results in oral mucositis fibrosis, which has not only carcinogenic mutagenic effect but also eproductive and nervous system toxicity. And Chinese medicine Yinpian use Arecae Semen of compatibility has no adverse reaction reports.

Reduction- and thermo-sensitive star polypeptide micelles and hydrogels for on-demand drug delivery.

Dual stimuli-sensitive star polypeptide was for the first time synthesized and self-assembled into reduction- and thermo-sensitive micelles and hydrogels, demonstrating tunable size, mechanical and triggered drug-release properties useful for on-demand drug delivery.

Imbalance between tissue inhibitor of metalloproteinase 1 and matrix metalloproteinase 9 after cardiopulmonary resuscitation.

AIMS: This study aimed to determine whether (a) there was an imbalance between matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) after cardiopulmonary resuscitation (CPR) in a canine model of prolonged ventricular fibrillation (VF); (b) with the duration of VF, the degree of the imbalance would be greater; and (c) there was a relationship between the level of MMP-9 or TIMP-1 and the cardiac function. METHODS AND RESULTS: Ventricular fibrillation was electrically induced in 24 dogs. The animals were randomly divided into 3 groups (sham control, n = 8; 8-minute VF, n = 8; 12-minute VF, n = 8). Echocardiographic measurement and hemodynamic variables were recorded before VF and after return of spontaneous circulation. Tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-9 were analyzed by Western blot and immunohistochemistry. Compared with sham controls, dogs under VF and CPR showed significantly decreased level of TIMP-1 (P < .001), and with the duration of VF, the level of TIMP-1 declined (P < .01). The level of MMP-9 did not achieve statistical significance in the 3 groups (P > .05); however, they were higher in VF and longer duration VF groups. The ratios of TIMP-1/MMP-9 were lower in VF groups (P < .05). There was a negative correlation between TIMP-1 and left atrium dimension and left ventricular diastolic dimensions (r = -0.83 and r = -0.96, respectively; P < .01) and a positive correlation between TIMP-1 and left ventricular ejection fraction (r = 0.85; P < .01). CONCLUSIONS: There was an imbalance between TIMP-1 and MMP-9 after CPR. It may partly contribute to the postresuscitation cardiac dysfunction.

[Effect of atorvastatin on carotid intima-medial of thickness of primary hypertension patients of Han nationality in China].

OBJECTIVES: To investigate the efficacy of 10 mg or 20 mg atorvastatin + long acting antihypertensive in carotid intima-medial thickness (IMT). METHODS: 151 patients of Han nationality in South China with mild hypertensive were randomly divided into 3 groups: atorvastatin 10 mg group (n = 50) receive 10 mg atorvastatin and amlodipine + benazepril; atorvastatin 20 mg group (n = 61) receive 20 mg atorvastatin and amlodipine + benazepril; the control group (n = 40) receive amlodipine + benazepril. The patients were detected IMT, vascular function, lipids and inflammatory factor in pretherapy and every 3 months. RESULTS: atorvastatin 10 mg or 20 mg groups have significantly change contrast to control group: (1) IMT was decreased (P < 0.01). (2) Deltadia-P% and Deltadia-N% were increased (P < 0.01). (3) LDL-C level was decreased by 30% in a atorvastatin 10 mg group and 40.48% in 20 mg group respectively (P < 0.01). CONCLUSION: Atorvastatin delays the development of atherosclerosis in hypertensive patients, improves endothelial function, and strengthens the effect of lipid-lowering.

Involvement of ERK1/2 pathway in TGF-beta1-induced VEGF secretion in normal human cytotrophoblast cells.

Transforming growth factor-beta1 (TGF-beta1) plays a pivotal role in the angiogenesis during the development of placenta, but the intracellular signaling mechanism by which TGF-beta1 stimulates this process remains poorly understood. In this article, we demonstrated that exposure of normal human cytotrophoblast cells to TGF-beta1 stimulated the secretion of the VEGF gene encoding vascular endothelial growth factor, which is a key factor in angiogenesis. Meanwhile, treatment of normal human cytotrophoblast cells with TGF-beta1-induced expression of HIF-1a, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. Our data indicated that TGF-beta1 induced extracellular signal- regulated kinase (ERK) 1/2 phosphorylation in normal human cytotrophoblast cells. Moreover, treating cells with PD98059, an inhibitor of ERK1/2 signaling, inhibited TGF-beta1 stimulation of VEGF secretion and HIF-1a protein expression. These data indicated that in normal human cytotrophoblast cells, TGF-beta1 induced HIF-1a-mediated VEGF secretion, and TGF-beta1-stimulated-ERK1/2 activation may be involved in this process.

Expression of Smad2 and Smad4, transforming growth factor-beta signal transducers in rat endometrium during the estrous cycle, pre-, and peri-implantation.

SMADs are intracellular signaling molecules that transmit signals elicited by members of transforming growth factor-beta (TGF-beta) superfamily. To decipher the mechanism of TGF-beta signaling during the estrous cycle and implantation, we performed in situ hybridization to investigate the expression patterns of mRNAs for Smad2 and Smad4 in rat endometrium during the estrous cycle and on Days 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, and 6.5 of pregnancy. Intense epithelial expression of Smad2 mRNA at diestrus and proestrus was reduced at estrus and metaestrus, while Smad4 maintained its constitutive expression during the estrous cycle. During pre-implantation, both Smads were accumulated in the luminal epithelium and the glandular epithelium. Contrary to the dramatic Smad4 expression, Smad2 was highly down-regulated on Day 2.5 and was increased on Day 3.5. During peri-implantation, both Smads were expressed in the luminal epithelium, subepithelial stroma, and the primary decidual zone. Smad4 was down-modulated on Day 5.5. These results suggest that (a) both Smads are involved in the tissue remodeling of cycling and pregnant rat uteri; (b) TGF-beta signaling functions mainly in the epithelium during pre-implantation and Smad2 is involved in the endometrial switch from the neutral phase to the receptive phase; (c) TGF-beta signaling is down-regulated at the time when trophoblast invasion begins and both Smads are involved in the formation of the primary decidual zone.

Normoxic induction of the hypoxic-inducible factor-1 alpha by interleukin-1 beta involves the extracellular signal-regulated kinase 1/2 pathway in normal human cytotrophoblast cells.

During early pregnancy, an environment of relative low oxygen tension is essential for normal embryonic and placental vasculature. In low-oxygen conditions, the hypoxic-inducible factor-1 (HIF-1), composed of alpha and beta subunits, controls the expression of a number of genes such as vascular endothelial growth factor (VEGF), a key angiogenic factor. The recent studies in some tumor cells have found that the labile component, HIF-1 alpha, is not only activated by hypoxia but also by peptides such as interleukin-1 (IL-1) in normoxia. In this article, we demonstrated that exposure of normal human cytotrophoblast cells to IL-1 beta stimulated the expression of HIF-1 alpha protein. Meanwhile, IL-1 beta also induced the secretion of VEGF in normal human cytotrophoblast cells. Our data indicated that IL-1 beta induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Moreover, treatment of cells with PD98059, an inhibitor of ERK1/2 signaling, inhibited the stimulation of HIF-1 alpha protein expression and VEGF secretion by IL-1 beta. These data indicate that, in normal human cytotrophoblast cells, IL-1 beta induces HIF- 1 alpha-mediated VEGF secretion and that IL-1 beta-stimulated ERK1/2 activation may be involved in this process.

Effect of ubiquitin-proteasome pathway on mouse blastocyst implantation and expression of matrix metalloproteinases-2 and -9.

Previous studies have documented that ubiquitin-related proteins are present in human, baboon, rhesus monkey, cow, sheep, and mouse pregnant uteri, indicating that the ubiquitin-proteasome pathway (UPP) may be involved in the extensive uterine remodeling during mammalian early pregnancy, but there is still no direct evidence. A mouse intrauterine injection model was employed to study the direct effect of the UPP on mouse embryo implantation and its possible mechanisms. On Day 3 of pregnancy in each mouse, one of the uterine horns in each mouse was injected with different concentrations of lactacystin, a specific proteasome inhibitor, or anti-ubiquitin antibody, and the other side was used as a control. On days 5, 6, and 7, the number of implanted embryos was counted and the expression and gelatinolytic activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 were studied. Results presented here illustrate that injection of lactacystin and anti-ubiquitin antibody significantly inhibited mouse embryo implantation. Further investigations by reverse transcription-polymerase chain reaction and gelatin zymography showed that MMP-2 and MMP-9 mRNA expression, as well as the gelatinolytic activity of MMP-9 in the lactacystin-treated uterine horn, significantly decreased, whereas the activity of MMP-2 was not significantly affected. The results obtained from this study, together with previous reports, suggest that the UPP is involved in mouse embryo implantation, and UPP's effect on embryo implantation is achieved at least in part by regulating MMP-2 and MMP-9 mRNA expression and the gelatinolytic activity of MMP-9.

Expression and functional analysis of liver receptor homologue 1 as a potential steroidogenic factor in rat ovary.

Liver receptor homologue 1 (LRH-1) is a member of the nuclear receptor superfamily originally found in liver cells. LRH-1 participates in regulation of cholesterol metabolism and bile acid synthesis. Recent studies have shown that LRH-1 is even more highly expressed in the ovary, and LRH-1 has been implicated as a key transcriptional regulator of cytochrome P450 aromatase (P450arom) in vitro. In the present study, we investigated the spatiotemporal expression patterns of LRH-1 using in situ hybridization and immunohistochemistry in ovaries from rats with a 4-day estrous cycle, from pregnant rats, from immature rats treated with eCG to stimulate follicular development, and from eCG-treated rats that were subsequently given hCG to stimulate ovulation and luteinization. To establish a potential connection between the expression of LRH-1 and that of the steroidogenic genes in vivo, we directly compared the localization patterns of LRH-1 and P450arom transcripts in consecutive ovarian sections from these animals. LRH-1 mRNA and protein were primarily localized to granulosa cells and luteinized follicles or newly formed corpora lutea (CLs) of immature and adult rats, and the levels of expression increased during eCG-hCG-induced follicular development and ovulation. In the functional CLs of pregnant rats, a biphasic change in LRH-1 mRNA content occurred throughout the gestation process, whereas LRH-1 protein was persistently detected during the entire pregnancy. In the consecutive ovarian sections, expression of LRH-1 was approximately colocalized with that of P450arom in both tertiary and Graafian follicles and the functional CLs of pregnant rats. LRH-1 mRNA and protein expression preceded those of P450arom during early follicular development. Stage-specific expression of LRH-1 in rat granulosa and luteal cells suggests a role for LRH-1 in the regulation of ovarian function. The overlapping but distinct expression patterns of LRH-1 and P450arom circumstantially support the recent finding that LRH-1 serves as a critical upstream regulator of P450arom gene expression in ovarian cells, but LRH-1 also may be a multifunctional steroidogenic factor in ovarian physiology.

Matrix metalloproteinase-28 transcript and protein are expressed in rhesus monkey placenta during early pregnancy.

The role of matrix metalloproteinases (MMP), especially newly described MMP, in trophoblast invasion during human embryo implantation is poorly understood. In this report, using a model of early pregnancy in the rhesus monkey, we have examined the expression and localization of the most recently identified MMP, MMP-28/epilysin, transcript and protein in macaque uterine samples on days 12, 18 and 26 of pregnancy. MMP-28 mRNA expression was shown by in-situ hybridization after day 12 of pregnancy, and both the syncytial and the cytotrophoblastic cell layers of placental villi, the cytotrophoblast cells of the trophoblastic column, and the extravillous trophoblast cells of trophoblastic shell were primary producers of MMP-28 transcript. Expression of MMP-28 mRNA was undetectable in the endovascular trophoblast cells, decidual cells, luminal and glandular epithelium, arterioles, and myometrium. RT-PCR analysis amplified a fragment of 258 nucleotides from rhesus monkey uterine samples containing implantation sites on days 18 and 26. The cDNA fragment, following sequencing, was confirmed to be part of the haemopexin-like domain of MMP-28. It has 95% identity with the corresponding region of human MMP-28 gene. Immunohistochemical analysis further demonstrated that the localization of MMP-28 protein was similar to that of its mRNA. The restricted distribution pattern of this novel MMP in the villous and extravillous trophoblasts during rhesus monkey early pregnancy suggests a potential role in trophoblast invasion associated with embryo implantation.

Expression and localization of RAP250 mRNA in rat ovary: possible implications in follicular development and ovulation.

The expression levels of nuclear receptor coregulators in specific tissue compartments and cells are thought to influence the expression of hormone-responsive genes involved in metabolism, development, and reproduction. RAP250 is a novel nuclear receptor coactivator highly expressed in brain and reproductive organs. To investigate the possible involvement of RAP250 in tissue-specific regulation of ovarian function, untreated immature, pregnant mare's serum gonadotropin luteinizing hormone (PMSG-LH)-primed, cycling, and pregnant rat models were used to study the localization and expression of RAP250 mRNA in rat ovary by in situ hybridization (ISH) and reverse transcriptase polymerase chain reaction (RT-PCR). The results showed that RAP250 mRNA was primarily localized to granulosa cells of healthy follicles in immature, cycling, and pregnant rats and increased during PMSG-induced follicular development. In the preovulatory and ovulatory follicles from the LH-primed rats of 48-h post-PMSG administration, the signals for RAP250 mRNA increased further and remained high until early luteal formation. Only a subset of corpora lutea during diestrus 1, diestrus 2, and initiation of pregnancy was weakly positive, and atretic follicles were largely negative. The RT-PCR results confirmed the presence of RAP250 mRNA in the rat ovary and strengthen the data from ISH. These findings suggest that RAP250 may play potential roles in follicular development and ovulation.

Expression of gelatinases and their tissue inhibitors in rat corpus luteum during pregnancy and postpartum.

Extensive tissue remodeling occurs in the corpus luteum (CL) during both formation and luteolysis. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are believed to play pivotal roles in these processes. In the present study, to evaluate the potential roles of matrix degrading proteases in luteal development and regression, we examined gelatinases and TIMP-1, -2, -3 mRNA expressions, as well as gelatinase activity in rat CL during pregnancy and postpartum using Northern blot, in situ hybridization, and gelatin zymography, respectively. The results showed that MMP-2 mRNA was only expressed at the early stages of pregnancy; TIMP-2 mRNA was highly expressed at the early and late pregnancy and day 1 postpartum, but could not be detected during the mid-phase of pregnancy; TIMP-3 mRNA expression was abundant during early pregnancy and peaked at day 7, but was absent from other time points examined. MMP-9 and TIMP-1 mRNAs in rat CL were below detectable level in the current study. Furthermore, the active MMP-2 was only present during the early stages of pregnancy, and no MMP-9 activity was observed in the zymogram. Taken together, our results suggest that MMP-2 and TIMP-3 may have functional roles in rat luteal formation, while TIMP-2 may be implicated in both formation and regression of the pregnant CL.