BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

OBJECTIVES: To evaluate the efficacy of molecular targeted agents in children with progressive pediatric low-grade gliomas (pLGG). METHODS: A retrospective analysis was conducted on pLGG patients treated with oral targeted therapies at the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, from July 2021. Treatment responses and safety profiles were assessed. RESULTS: Among the 20 enrolled patients, the trametinib group (n=12, including 11 cases with BRAF fusions and 1 case with BRAF V600E mutation) demonstrated 4 partial responses (33%) and 2 minor responses (17%), with a median time to response of 3.0 months. In the vemurafenib group (n=6, all with BRAF V600E mutation), 5 patients achieved partial responses (83%), showing a median time to response of 1.0 month. Comparative analysis revealed no statistically significant difference in progression-free survival rates between the two treatment groups (P>0.05). The median duration of clinical benefit (defined as partial response + minor response + stable disease) was 11.0 months for vemurafenib and 18.0 months for trametinib. Two additional cases, one with ATM mutation treated with olaparib for 24 months and one with NF1 mutation receiving everolimus for 21 months, discontinued treatment due to sustained disease stability. No severe adverse events were observed in any treatment group. CONCLUSIONS Molecular targeted therapy demonstrates clinical efficacy with favorable tolerability in pLGG. Vemurafenib achieves high response rates and induces early tumor shrinkage in patients with BRAF V600E mutations, supporting its utility as a first-line therapy.
Humans ; Glioma/genetics* ; Male ; Female ; Child ; Child, Preschool ; Retrospective Studies ; Brain Neoplasms/genetics* ; Molecular Targeted Therapy/adverse effects* ; Adolescent ; Infant ; Proto-Oncogene Proteins B-raf/genetics* ; Pyrimidinones/therapeutic use* ; Mutation

OBJECTIVETo evaluate the efficacy and safety of telbivudine use during the second and third trimester of pregnancy for reducing hepatitis B virus (HBV) transmission from highly viremic hepatitis B e antigen-positive (HBeAg+) mothers to their fetuses.

METHODSPregnant women, between weeks 20 to 32 of gestation, who were HBeAg+ and had HBV DNA more than 1.0*10(7) copies/mL were enrolled in our study. The women were offered inclusion into one of two treatment arms, based upon their personal preference: telbivudine or no telbivudine. The patients in the telbivudine treatment arm were administered 600 mg/d telbivudine at least until postpartum week 4. All delivered infants in both treatment arms were administered hepatitis B immune globulin (HBIG; 200 IU) within 12 hours of delivery and recombinant HBV vaccine (20 mug) at 0, 1 and 6 months. The HBV perinatal transmission rate was determined by measuring HBsAg and HBV DNA in infants at postpartum week 28.

RESULTSA total of 220 pregnant women were enrolled in our study, 120 chose the telbivudine arm and 100 chose the control arm. All telbivudine treated subjects were registered in the Antiretroviral Pregnancy Registry. Telbivudine treatment was associated with a marked reduction in the mothers' serum HBV DNA, HBeAg and ALT levels before delivery. A striking decline of HBV DNA levels in treated mothers was observed at week 2 of treatment, which was followed by a gradual and steady decrease that continued until delivery. Thirty-seven (31%) of the telbivudine-treated mothers and none (0%) of the untreated controls had polymerase chain reaction-undetectable viremia at delivery. At week 28, 0% of the infants delivered from telbivudine-treated mothers were HBsAg+ or HBV DNA+, as compared to 8% HBsAg+ or HBV DNA+ in the untreated control arm (P = 0.002). No telbivudine discontinuations occurred from adverse events, and no congenital deformities were observed in the infants delivered to telbivudine-treated mothers. Eighty mothers discontinued telbivudine at week 4 postpartum, and there were no cases of severe hepatitis. There were no significant differences between the two treatment arms for postpartum hemorrhage, adverse events during pregnancy, cesarean section, gestational age, or infants' height/weight or Apgar scores.

CONCLUSIONSTelbivudine use during the second and third trimester of pregnancy in HBeAg+ highly viremic mothers can safely reduce perinatal HBV transmission rates. Telbivudine was well-tolerated by our patient group. Furthermore, no safety concerns were observed in either the telbivudine-treated mothers or their delivered infants in short term follow-up.

Adult ; DNA, Viral ; Female ; Hepatitis B ; transmission ; virology ; Hepatitis B virus ; Humans ; Infectious Disease Transmission, Vertical ; prevention & control ; Nucleosides ; adverse effects ; therapeutic use ; Pregnancy ; Pregnancy Complications, Infectious ; prevention & control ; virology ; Pregnancy Trimester, Second ; Pregnancy Trimester, Third ; Pyrimidinones ; adverse effects ; therapeutic use ; Thymidine ; analogs & derivatives ; Viral Load ; Young Adult

To study the influences of warming kidney prescription on antiviral therapeutic efficacy and creatine kinase (CK) level in telbivudine-treated HBeAg-positive chronic hepatitis B patients with kidney yang deficiency syndrome. Ninety-six cases were enrolled and randomly divided into two groups (n=48 each): warming kidney prescription treatment or control. Both groups were treated for 52 weeks with telbivudine monotherapy, but the treatment group received additional treatment with the warming kidney prescription. Traditional Chinese medicine (TCM) syndrome score, biochemical response, virological response, serological response, CK level, and adverse reactions were recorded for each group in order to perform comparative analysis of the warming kidney prescription's effects. A total of 84 patients, including 43 cases in the treatment group, completed the study. The warming kidney prescription led to significantly improved total clinical syndrome efficacy, TCM syndrome score, biochemical response, virological response, and HBeAg serological responses, as evidenced by changes for each parameter observed in the treatment group versus the control group (respectively, 88.37% vs. 63.41%, 4.97+/-1.88 vs. 10.13+/-3.72, 95.35% vs. 75.61%, 81.40% vs. 56.10%, 48.84% vs. 26.83% (all, P less than 0.05)). No patient in either group experienced primary treatment failure. Seven cases, all from the control group, experienced virological breakthrough. Elevated CK was observed in both the treatment and control groups, but significantly more patients in the control group experienced this adverse reaction (respectively, 73.17% vs. 44.19%; P less than 0.01). The warming kidney prescription can increase telbivudine antiviral therapeutic efficacy and decrease the telbivudine-induced increase in creatine kinase in HbeAg-positive chronic hepatitis B patients with kidney yang deficiency syndrome.
Adult ; Antiviral Agents ; therapeutic use ; Creatine Kinase ; blood ; Female ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Male ; Middle Aged ; Nucleosides ; therapeutic use ; Phytotherapy ; Pyrimidinones ; therapeutic use ; Thymidine ; analogs & derivatives

OBJECTIVETo investigate the efficacy of Telbivudine and Entecavir for therapy of HBeAg positive chronic hepatitis B for 52 weeks.

METHODSIn this random and control study, the efficacy of Telbivudine and Entecavir treatments were compared in 180 patients with HBeAg positive chronic hepatitis B.The patients were randomly assigned to a daily 600 mg Telbivudine treatment group or daily 0.5 mg Entecavir group for 52 weeks.

RESULTSAt week 52, HBV DNA undetectable rate was better in the Entecavir-treated group than in the Telbivudine-treated group, but didn't reach statistical significance. The viral breakthrough rates were significantly lower in the Entecavir-treated group than in the Telbivudine-treated group (x2 = 4.09, P <0.05). The clearance and seroconversion of HBeAg and the mean reductions of HBeAg from baseline at week 52 were significantly greater in the telbivudine-treated group than in the entecavir-treated group (x(2) clearance = 4.63, x(2) seroconversion = 4.80, (t-mean) reductions = 2.02; P < 0.05). The HBeAg seroconversion rates were not associated with both baseline ALT and baseline HBV DNA in both groups (P more than 0.05). In Telbivudine-treated group, the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 1 log at week 12 and the HBeAg baseline were independent factors correlated to HBeAg seroconversion rates at week 52 by Binary Logistic analysis, and also in entecavir-treated group the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 2 log at week 36 and the HBeAg decline is more than 2 log at week 12 were independent factors correlated to HBeAg seroconversion rates at week 52.

CONCLUSIONSignificant difference of HBeAg seroconversion rates at week 52 existed between Telbivudine-treated group and Entecavir-treated group. Entecavir is significantly superior to Telbivudine with less resistance to nucleosides. HBeAg decline is more than 2 log at week 24 is the best predicting factor for HBeAg seroconversion at week 52.

Adolescent ; Adult ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; Female ; Guanine ; analogs & derivatives ; therapeutic use ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Male ; Middle Aged ; Nucleosides ; therapeutic use ; Pyrimidinones ; therapeutic use ; Thymidine ; analogs & derivatives ; Treatment Outcome ; Young Adult

BACKGROUND/AIMS: Revaprazan (Revanex(R)) is a novel proton pump inhibitor (PPI) that has a somewhat different effect on proton pump compared with the other PPI's, also (called as 'acid pump antagonist'). We aimed to examine the false negative rate of 13C-urea breath test (UBT) in the patients with Helicobacter pylori (H. pylori) associated peptic ulcer disease who were treated with revaprazan and evaluate the anti-urease activity of revaprazan. METHODS: Total 55 patients were enrolled in this study. They received EGD examination between January 2009 and December 2009 and diagnosed histologically as H. pylori associated peptic ulcer disease. All patients took revaprazan only. Three patients were excluded because of underlying chronic disease and inappropriate breath sampling. The remaining 52 patients had UBT at 0, 2 and 4 weeks of revaprazan use. After 2 weeks of the cessation of revaprazan, they had the fourth UBT. RESULTS: At 2 and 4 weeks, the false negative rates of UBT were 5.8% and 23.1%, respectively (p=0.05). After 2 weeks of the cessation, the cases of the false negative result were five. Four out of five patients had prolonged negative results on two or three successive tests, and baseline 13C difference value did not predict the false negative results. CONCLUSIONS: False negative results of UBT were common and increased with prolonged use of acid pump antagonist. As PPI, it had also anti-urease activity and most patients (47/52, 90.4%) reverted to positive results by 2 weeks after the cessation of taking the medication.
*Breath Tests ; Carbon Isotopes ; False Negative Reactions ; Female ; Helicobacter Infections/complications/*diagnosis ; *Helicobacter pylori ; Humans ; Male ; Middle Aged ; Peptic Ulcer/*drug therapy/microbiology ; Proton Pump Inhibitors/*therapeutic use ; Pyrimidinones/*therapeutic use ; Tetrahydroisoquinolines/*therapeutic use ; Urea/*diagnostic use

No abstract available.
*Breath Tests ; Carbon Isotopes ; False Negative Reactions ; Helicobacter Infections/complications/*diagnosis ; *Helicobacter pylori ; Humans ; Peptic Ulcer/*drug therapy/microbiology ; Proton Pump Inhibitors/*therapeutic use ; Pyrimidinones/*therapeutic use ; Tetrahydroisoquinolines/*therapeutic use ; Urea/*diagnostic use

Over the past decade, advances in the antiviral therapy in patients with chronic hepatitis B have enabled the sustained suppression of hepatitis B viral replication and the prevention of progressive liver disease. Hepatitis B surface antigen (HBsAg) has been used to diagnose patients with hepatitis B virus infection. Recently, test for quantitative HBsAg titers are available and on-treatment HBsAg quantitations are used to predict treatment outcome. Serum HBV DNA levels have been shown to predict natural course of chronic hepatitis B infection. The HBV DNA levels have been reported to be positively correlated with the development of cirrhosis, hepatocellular carcinoma and related death. The baseline and on-treatment levels of HBV DNA are important factors for predicting treatment outcomes. In this article, we will discuss the role of HBV DNA and HBsAg quantitation during antiviral therapy.
Antiviral Agents/*therapeutic use ; Carcinoma, Hepatocellular/etiology ; DNA, Viral/*blood ; Hepatitis B Surface Antigens/*blood ; Hepatitis B virus/*genetics ; Hepatitis B, Chronic/complications/*drug therapy ; Humans ; Lamivudine/therapeutic use ; Liver Cirrhosis/etiology ; Liver Neoplasms/etiology ; Nucleosides/therapeutic use ; Pyrimidinones/therapeutic use

Adult ; Antiviral Agents ; adverse effects ; therapeutic use ; Female ; Hepatitis B, Chronic ; drug therapy ; Humans ; Nucleosides ; adverse effects ; therapeutic use ; Pregnancy ; Pregnancy Complications, Infectious ; drug therapy ; Pyrimidinones ; adverse effects ; therapeutic use ; Thymidine ; analogs & derivatives ; Treatment Outcome ; Young Adult

Adolescent ; Adult ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; Female ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Male ; Middle Aged ; Nucleosides ; therapeutic use ; Pyrimidinones ; therapeutic use ; Thymidine ; analogs & derivatives ; Young Adult