Association Between Human Metabolomics and Rheumatoid Arthritis: A Systematic Review and Meta-analysis.

OBJECTIVE: The underdiagnosis and inadequate treatment of rheumatoid arthritis (RA) can be attributed to the various clinical manifestations presented by patients. To address this concern, we conducted an extensive review and meta-analysis, focusing on RA-related metabolites. METHODS: A comprehensive literature search was conducted in PubMed, the Cochrane Library, Web of Science, and Embase to identify relevant studies published up to October 5, 2022. The quality of the included articles was evaluated and, subsequently, a meta-analysis was conducted using Review Manager software to analyze the association between metabolites and RA. RESULTS: Forty nine studies met the inclusion criteria for the systematic review, and six of these studies were meta-analyzed to evaluate the association between 28 reproducible metabolites and RA. The results indicated that, compared to controls, the levels of histidine (RoM = 0.83, 95% CI = 0.79-0.88, I2 = 0%), asparagine (RoM = 0.83, 95% CI = 0.75-0.91, I2 = 0%), methionine (RoM = 0.82, 95% CI = 0.69-0.98, I2 = 85%), and glycine (RoM = 0.81, 95% CI = 0.67-0.97, I2 = 68%) were significantly lower in RA patients, while hypoxanthine levels (RoM = 1.14, 95% CI = 1.09-1.19, I2 = 0%) were significantly higher. CONCLUSION: This study identified histidine, methionine, asparagine, hypoxanthine, and glycine as significantly correlated with RA, thus offering the potential for the advancement of biomarker discovery and the elucidation of disease mechanisms in RA.

Polyoxazoline-Conjugated l-Asparaginase: An Antibody-Production-Free Therapeutic Agent for Acute Lymphoblastic Leukemia.

l-asparaginase (ASNase), an enzyme that catalyzes the hydrolysis of l-asparagine into l-aspartic acid, is frequently used as a medication for acute lymphoblastic leukemia (ALL). However, when derived from bacterial sources, this enzyme can elicit side effects, including allergic or hypersensitivity reactions, owing to immune responses. Here, we describe the synthesis of polyoxazoline-conjugated ASNase (POx-ASNase) and investigate its enzyme activity, anticancer efficacy, immunogenicity, and retention in the bloodstream. The water-soluble POx was coupled with surface lysine residues of ASNase using a bifunctional cross-linker. The average number of polymers bound to each enzyme was determined as 10. Although the enzymatic activity of POx-ASNase decreased to 56% of that of native ASNase, its temperature and pH dependencies remained unaltered. Remarkably, the lyophilized powder form of POx-ASNase retained its catalytic ability for 24 months. POx-ASNase demonstrated nearly identical anticancer efficacy compared to naked ASNase against leukemia and lymphoma cells (MOLT-4, CLBL-1, and K562) while displaying no cytotoxicity toward normal cells. Animal experiments conducted using rats revealed that the POx decoration suppressed the generation of anti-ASNase IgM and IgG antibodies with no detection of anti-POx antibodies. The half-life within the bloodstream extended to 34 h, representing a 17-fold increase compared to unmodified ASNase. These findings suggest that POx-ASNase serves as an anticancer therapeutic agent, characterized by the absence of antibody production and notably extended circulation persistence.

Utility of ASNS gene methylation evaluated with the HPLC method as a pharmacogenomic biomarker to predict asparaginase sensitivity in BCP-ALL.

Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for safer and more efficacious therapy, a clinical biomarker predicting asparaginase sensitivity is highly anticipated. Asparaginase depletes serum asparagine by deaminating asparagine into aspartic acid, and ALL cells are thought to be sensitive to asparaginase due to reduced asparagine synthetase (ASNS) activity. We have recently shown that allele-specific methylation of the ASNS gene is highly involved in asparaginase sensitivity in B-precursor ALL (BCP-ALL) by using next-generation sequence (NGS) analysis of bisulphite PCR products of the genomic DNA. Here, we sought to confirm the utility of methylation status of the ASNS gene evaluated with high-performance liquid chromatography (HPLC) analysis of bisulphite PCR products for future clinical applications. In the global methylation status of 23 CpG sites at the boundary region of promoter and exon 1 of the ASNS gene, a strong positive correlation was confirmed between the mean percent methylation evaluated with the HPLC method and that with the NGS method in 79 BCP-ALL cell lines (R2 = 0.85, p = 1.3 × 10-33) and in 63 BCP-ALL clinical samples (R2 = 0.84, p = 5.0 × 10-26). Moreover, methylation status of the ASNS gene evaluated with the HPLC method was significantly associated with in vitro asparaginase sensitivities as well as gene and protein expression levels of ASNS. These observations indicated that the ASNS gene methylation status evaluated with the HPLC method is a reliable biomarker for predicting the asparaginase sensitivity of BCP-ALL.

L-Asparaginase delivery systems targeted to minimize its side-effects.

L-asparaginase (L-ASP) is one of the key enzymes used in therapeutic applications, particularly to treat Acute Lymphocytic Leukemia (ALL). L-asparagine is a non-essential amino acid, which means that it can be synthesized by the body and is not required to be obtained through the diet. The synthesis of L-asparagine occurs primarily in the liver, but it also takes place in other tissues throughout the body. In contrast, leukemic cells cannot synthesize L-asparagine due the absence of L-asparagine synthetase and should obtain it from circulating sources for protein synthesis and cell division processes to ensure their vital functions. L-ASP catalyzes the deamination process of L-asparagine amino-acid into aspartic acid and ammonia, depriving leukemic cells of asparagine. This leads to decreased protein synthesis and cell division in tumor cells. However, using L-ASP has side effects, such as hypersensitivity or allergic reaction, antigenicity, short half-life, temporary blood clearance, and toxicity. L-ASP immobilization can minimize the side effects of L-ASP by stopping the immune system from attacking non-human enzymes and improving the enzyme's performance. The first strategy includes modification of enzyme structure, such as covalent binding (conjugation), adsorption to the support material and cross-linking of the enzyme. The chemical modification of residues, often nonspecific, changes the enzyme's hydrophobicity and surface charge, lowering the enzyme's activity. Also, the first strategy exposes the enzyme's surface to the environment. This eliminates its performance and does not allow targeted delivery of the enzyme. The second strategy is based on the entrapment of the enzyme inside the protecting structure or encapsulation. This strategy offers the same benefits as the first. Still, it also enables reducing toxicity, prolonging in vivo half-life, enhancing stability and activity, enables a targeted delivery and controlled release of the enzyme. Compared to the first strategy, encapsulation does not modify the chemical structure of the enzyme since L-ASP is only effective against leukemia in its native tetrameric form. This review aims to present state of the art in L-ASP formulations developed for reducing the side effects of L-ASP, focusing on describing improvements in their safety. The primary focus in the field remains to be improving the overall performance of the L-ASP formulations. Almost all encapsulation systems allow reducing immune response due to screening the enzyme from antibodies and prolonging its half-life. However, the enzyme's activity and stability depend on the encapsulation system type. Therefore, the selection of the right encapsulation system is crucial in therapy due to its effect on the performance parameters of the L-ASP. Biodegradable and biocompatible materials, such as chitosan, alginate and liposomes, mainly attract the researcher's interest in enzyme encapsulation. The research trends are also moving towards developing formulations with targeted delivery and increased selectivity.

NMR-based metabolomic analysis for the effects of moxibustion on imiquimod-induced psoriatic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Moxibustion is a traditional medical intervention of traditional Chinese medicine. It refers to the direct or indirect application of ignited moxa wool made of mugwort leaves to acupuncture points or other specific parts of the body for either treating or preventing diseases. Moxibustion has been proven to be effective in treating skin lesions of psoriasis. AIM OF THE STUDY: This study was performed to elucidate molecular mechanisms underlying the effects of moxibustion treatment on imiquimod-induced psoriatic mice. MATERIALS AND METHODS: We established an imiquimod (IMQ)-induced psoriatic mice (Model) and assessed the effects of moxibustion (Moxi) treatment on skin lesions of psoriatic mice by the PASI scores and expressions of inflammation-related factors relative to normal control mice (NC). We then performed nuclear magnetic resonance (NMR)-based metabolomic analysis on the skin tissues of the NC, Model and Moxi-treated mice to address metabolic differences among the three groups. RESULTS: Moxi mice showed reduced PASI scores and decreased expressions of the pro-inflammatory cytokines IL-8, IL-17A and IL-23 relative to Model mice. Compared with the Model group, the NC and Moxi groups shared 9 characteristic metabolites and 4 significantly altered metabolic pathways except for taurine and hypotaurine metabolism uniquely identified in the NC group. To a certain extent, moxibustion treatment improved metabolic disorders of skin lesions of psoriatic mice by decreasing glucose, valine, asparagine, aspartate and alanine-mediated cell proliferation and synthesis of scaffold proteins, alleviating histidine-mediated hyperproliferation of blood vessels, and promoting triacylglycerol decomposition. CONCLUSIONS: This study reveals the molecular mechanisms underlying the effects of moxibustion treatment on the skin lesions of psoriasis, potentially improving the clinical efficacy of moxibustion.

Targeting amino acid metabolism in cancer.

Metabolic rewiring is a characteristic hallmark of cancer cells. This phenomenon sustains uncontrolled proliferation and resistance to apoptosis by increasing nutrients and energy supply. However, reprogramming comes together with vulnerabilities that can be used against tumor and can be applied in targeted therapy. In the last years, the genetic background of tumors has been identified thoroughly and new therapies targeting those mutations tested. Nevertheless, we propose that targeting the phenotype of cancer cells could be another way of treatment aiming to avoid drug resistance and non-responsiveness of cancer patients. Amino acid metabolism is part of the altered processes in cancer cells. Amino acids are building blocks and also sensors of signaling pathways regulating main biological processes. In this comprehensive review, we described four amino acids (asparagine, arginine, methionine, and cysteine) which have been actively investigated as potential targets for anti-tumor therapy. Asparagine depletion is successfully used for decades in the treatment of acute lymphoblastic leukemia and there is a strong implication to apply it to other types of tumors. Arginine auxotrophic tumors are great candidates for arginine-starvation therapy. Higher requirement for essential amino acids such as methionine and cysteine point out promising targetable weaknesses of cancer cells.

Evaluation of PEG-L-asparaginase in asparagine suppression and anti-drug antibody development in healthy Beagle dogs: A multi-phase preclinical study.

L-asparaginase is a frequently used drug in the treatment of canine malignant lymphoma. Since production and availability of native E. coli-derived L-asparaginase are limited, PEG-L-asparaginase (PEG-ASP) is an alternative. However, recommended doses and dosing intervals are mainly empirically determined. A multi-phase clinical dose-finding study with seven healthy Beagle dogs was conducted to find the minimum effective dose and, potentially, a dosing interval for PEG-ASP in dogs. Plasma concentrations of amino acids and PEG-ASP activity were measured at various time points after administration of different doses of PEG-ASP. Anti-PEG and anti-asparaginase antibody titres were measured. Administration of 10 IU/kg PEG-ASP resulted in asparagine depletion in all dogs, albeit for various durations: for 9 days in all dogs, 15 days in five dogs, 21 days in three dogs and 29 days in one dog. Asparagine suppression occurred at PEG-ASP plasma concentrations < 25 IU/L. Subsequent administrations of a second and third dose of 20 IU/kg and 40 IU/kg PEG-ASP resulted in asparagine suppression at < 9 days in five dogs, accompanied by the development of antibodies against PEG and L-asparaginase. Two dogs with prolonged asparagine suppression after the second and third administration did not develop antibodies. Marked individual variation in the mechanism and duration of response to PEG-ASP was noted. Antibody formation against PEG-ASP was frequently observed and sometimes occurred after one injection. This study suggests that PEG-ASP doses as high as the currently used dose of 40 IU/kg might not be needed in treatment of canine malignant lymphoma.

A Patent Review on the Use of L-Asparaginase in the Treatment of Acute Lymphocytic Leukemia.

L-asparaginase (L-asparagine amino hydrolase, E.C.3.5.1.1) is the most important chemotherapeutic drug used in treating Acute Lymphocytic Leukemia (ALL), decreasing blood asparagine rates causing apoptosis in tumor cells. However, pharmacological drugs cause several side effects making treatments difficult. Thus, searches for new sources of L-asparaginase or enzyme modifications focus on discovering new products to use in therapy. This article reviewed published patents from 2000 to 2020 related to the treatment of ALL using L-asparaginase. Many organisms have been shown as potential viable L-asparaginase producers for use in the treatment of ALL. However, this patent review shows that few of these organisms are gaining attention to becoming bioproducts for the market. It is expected that drugs in the testing phase and patents related to the treatment of ALL and other cancers will become real products. Besides, a treatment using an amino acid depletion approach, now referring to asparagine, altogether with a compound that directly interferes with the expression of the asparagine synthase gene, is more suitable for the treatment of ALL and possibly to other cancers.

Reacciones alérgicas por L-asparaginasa en niños con leucemia linfoide aguda / L-asparagibase allergic reactions in children with lymphoblastic acute leukemia

La L-asparaginasa es un medicamento utilizado en distintas fases de todos los protocolos de tratamiento actuales de la leucemia linfoide aguda (LLA). Se describen múltiples manifestaciones secundarias a la L asparaginasa entre las que las reacciones alérgicas son las más frecuente. Se estudiaron 144 niños con diagnóstico de LLA tratados en el Instituto de Hematología e Inmunología, entre 1998 y el 2013. En 30 pacientes (21 por ciento) se presentaron reacciones alérgicas, similar a lo descrito en la literatura. El 76,6 por ciento de ellos habían recibido una dosis acumulativa menor de 80 000 UI (media de 48 757) y el mayor número de las reacciones alérgicas (86,7 por ciento) se reportó entre las dosis 9 y 18 recibidas (media de 11 dosis). Se observó una mayor supervivencia en los enfermos que recibieron más dosis (19 - 26 dosis) (p = 0.003). La sobrevida libre de eventos fue también mayor en este grupo (p= 0.357)(AU)

ABSTRACT L-asparaginase is a medication used in different phases of all current treatment protocols for acute lymphoid leukemia. Multiple secondary manifestations to L- asparaginase are described, and allergic reactions are the most frequent. We studied 144 children with acute lymphoblastic leukemia treated at the Instituto de Hematología e Inmunología between 1998 and 2013. Thirty patients (21 percent) had allergic reactions, similar to what is described in literature; 76.6 percent of them had received a cumulative dose of less than 80 000 IU (average of 48 757); and the highest number of allergic reactions (86.7 percent) was reported between doses 9 and 18 received (mean of 11 doses). A greater global survival was observed in patients who received more doses (19 - 26 doses) (p=0.003). Event free survival was also higher in this group (p= 0.357)(AU)

Worsening of Seizures After Asparagine Supplementation in a Child with Asparagine Synthetase Deficiency.

OBJECTIVE: Asparagine synthetase deficiency is an autosomal recessive neurometabolic disorder characterized clinically by severe congenital microcephaly, global developmental delay, intractable epilepsy, and motor impairment in the form of spastic quadriparesis. Diagnosis is confirmed by findings of low cerebral spinal fluid or plasma asparagine in addition to a mutation of the subsequently in ASNS gene. There is no documented trial of asparagine as a treatment for this disorder. PATIENT DESCRIPTION: We present a child with asparagine synthetase deficiency whose mental status improved slightly from a vegetative state to a minimally conscious state after starting asparagine supplementation. He subsequently became irritable, developed sleep disturbance, and experienced worsening seizures, requiring discontinuation of the asparagine supplements. CONCLUSIONS: Asparagine supplementation may be not effective in controlling the seizures in asparagine synthetase deficiency, and it is likely to make them worse.

Asparagine attenuates intestinal injury, improves energy status and inhibits AMP-activated protein kinase signalling pathways in weaned piglets challenged with Escherichia coli lipopolysaccharide.

The intestine requires a high amount of energy to maintain its health and function; thus, energy deficits in intestinal mucosa may lead to intestinal damage. Asparagine (Asn) is a precursor for many other amino acids such as aspartate, glutamine and glutamate, which can be used to supply energy to enterocytes. In the present study, we hypothesise that dietary supplementation of Asn could alleviate bacterial lipopolysaccharide (LPS)-induced intestinal injury via improvement of intestinal energy status. A total of twenty-four weaned piglets were assigned to one of four treatments: (1) non-challenged control; (2) LPS+0 % Asn; (3) LPS+0·5 % Asn; (4) LPS+1·0 % Asn. On day 19, piglets were injected with LPS or saline. At 24 h post-injection, piglets were slaughtered and intestinal samples were collected. Asn supplementation improved intestinal morphology, indicated by higher villus height and villus height:crypt depth ratio, and lower crypt depth. Asn supplementation also increased the ratios of RNA:DNA and protein:DNA as well as disaccharidase activities in intestinal mucosa. In addition, Asn supplementation attenuated bacterial LPS-induced intestinal energy deficits, indicated by increased ATP and adenylate energy charge levels, and decreased AMP:ATP ratio. Moreover, Asn administration increased the activities of key enzymes involved in the tricarboxylic acid cycle, including citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase complex. Finally, Asn administration decreased the mRNA abundance of intestinal AMP-activated protein kinase-α1 (AMPKα1), AMPKα2, silent information regulator 1 (SIRT1) and PPARγ coactivator-1α (PGC1α), and reduced intestinal AMPKα phosphorylation. Collectively, these results indicate that Asn supplementation alleviates bacterial LPS-induced intestinal injury by modulating the AMPK signalling pathway and improving energy status.

Insight into HIV of IFN-induced myxovirus resistance 2 (MX2) expressed by traditional Chinese medicine.

Recently, an important topic of the acquired immunodeficiency syndrome (AIDS) had been published in 2013. In this report, the expression of the IFN-induced myxovirus resistance 2 (MX2) had been defined the function to kill the human immunodeficiency virus (HIV). The screening from the Traditional Chinese Medicine (TCM) database by simulating molecular docking and molecular dynamics could select candidate compounds, which may express MX2 against HIV. Saussureamine C, Crotalaburnine, and Precatorine are selected based on the highest docking score and other TCM compounds. The data from molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. According to the docking poses, hydrophobic interactions, and hydrogen bond with structure variations, this research could assess the interaction between protein and ligand interaction. In addition to the detection of TCM compound efficacy, we suggest that Saussureamine C is better than the others in protein-ligand interaction and the structural variation to express MX2.

Severe pulmonary arterial hypertension induced by SU5416 and ovalbumin immunization.

The combination of chronic hypoxia and treatment of rats with the vascular endothelial growth factor (VEGF) receptor blocker, SU5416, induces pulmonary angio-obliteration, resulting in severe pulmonary arterial hypertension (PAH). Inflammation is thought to contribute to the pathology of PAH. Allergic inflammation caused by ovalbumin (OVA) immunization causes muscularization of pulmonary arteries, but not severe PAH. Whether disturbance of the immune system and allergic inflammation in the setting of lung endothelial cell apoptosis causes PAH is unknown. We investigated the effects of OVA-allergic inflammation on the development of PAH initiated by VEGF blockade-induced lung endothelial cell apoptosis. OVA-immunized rats were treated with SU5416 to induce pulmonary vascular endothelial cell apoptosis. The combination of OVA and SU5416 treatment resulted in severe angio-obilterative PAH, accompanied by increased IL-6 expression in the lungs. c-Kit(+) and Sca-1(+) cells were found in and around the lung vascular lesions. Pan-caspase inhibiton, dexamethasone treatment, and depletion of B-lymphocytes using an anti-CD20 antibody suppressed this remodeling. OVA immunization also increased lung tissue hypoxia-induced factor-1α and VEGF expression. Our results also suggest that the increased expression of hypoxia-induced factor-1α and IL-6 induced by the allergic lung inflammation may be a component of the pathogenesis of PAH.

Efficacy of natural L-asparagine in the complex therapy for malignant tumors in experimental studies.

AIM: To study the influence of natural L-asparagine on the efficacy of cytostatic therapy for malignant tumors in experimental investigations. MATERIALS AND METHODS: Female C57B1/6 mice weighing 18-20 g were selected for the experiments. Lewis' lung carcinoma (LLC) and melanoma B16 cells were used in the study. Animals were inoculated with tumor cells intramuscularly. Solution of L-asparagine in a volume of 0.2 ml per mouse (in appropriate doses) was administered to the animals using gastric probe, daily, for 14 days. Cyclophosphane was administered intraperitoneally in total doses of 180 mg/kg and 90 mg/kg on days 3 and 7 after tumor implantation. The percentage of tumor growth inhibition was calculated and inhibition index and frequency of metastasis were assessed. RESULTS: It has been shown that despite low activity of L-asparagine with regard to primary tumor, the level of metastasis inhibition is rather high (up to 91% depending on experimental model, therapy regimen and follow-up period). The analysis of previously obtained data and our studies indicate that L-asparagine derived from burdock (Arctium lappa) root has not only its own antimetastatic activity but it is also able to increase antimetastatic activity of cyclophosphane partially reducing toxic effect of cyclophosphane on the organism without decreasing its antitumor and antimetastatic activities. CONCLUSION: L-asparagine derived from burdock (Arctium lappa) root can be effective in the complex anticancer therapy with the use of appropriate chemotherapy doses and regimens.

Comparison between L-CHOP and an L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) for lymphoma in dogs.

An L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) was evaluated in 66 dogs with stages III-V lymphoma. Results were compared with a historical group of 71 dogs treated with an L-CHOP protocol. Complete remission (CR) rates (85 and 80%, respectively) did not differ significantly between protocols (P = 0.48). First CR duration for dogs treated with L-CHOP-CCNU-MOPP was significantly longer: median, 317 days; 2-year CR rate, 35% versus median, 298 days; 2-year CR rate, 13%, P = 0.05). For the L-CHOP-CCNU-MOPP protocol, dogs in substage-b had a 4.3 times greater hazard of having a relapse than dogs in substage-a (P = 0.002). Frequency of adverse chemotherapy-associated gastrointestinal effects did not differ between protocols (P = 0.77). Neutropenia (primarily after CCNU) occurred more frequently in dogs treated with L-CHOP-CCNU-MOPP (P < 0.001). In summary, the L-CHOP-CCNU-MOPP protocol showed an improved duration of first CR as compared with an L-CHOP protocol, but the relevance of this finding might be subject to clinical judgement.

[Therapeutic alternatives to native L-asparaginase in the treatment of adult acute lymphoblastic leukemia]. / Alternatives thérapeutiques à la L-asparaginase native dans le traitement de la leucémie aiguë lymphoblastique de l'adulte.

L-asparaginase is an effective antineoplastic agent, which is an integral part of combination chemotherapy protocols for adult acute lymphoblastic leukemia. Its antitumor effect results from the depletion of asparagine, an amino acid essential to leukemia cells, and subsequent inhibition of protein synthesis leading to cytotoxicity. However, its use has been limited by a high rate of hypersensitivity reactions and development of neutrolizing anti-asparaginase antibodies, and by the need of frequent administration. To overcome these limitations modified versions of L-asparaginase (such as asparaginase from other sources, pegylated formulations, and asparaginase loaded into erythrocytes) have been recently proposed. Advantages of these therapeutic alternatives to native L-asparaginase and their results as part of preliminary clinical trials in adults have been outlined in this review.

Clinicopathological study on peripheral T-cell non-Hodgkin lymphoma with bone marrow involvement: a retrospective analysis from China.

We reviewed 173 patients with an initial diagnosis of peripheral T-cell non-Hodgkin lymphoma (PTCL) and compared the patients with bone marrow involvement (BMI) to those without to have a better understanding of the clinical characteristics, treatments, survival and prognosis of PTCLs with BMI. We found that 40% (70/173) of the patients had BMI, and its frequency was 64% in angioimmunoblastic T-cell lymphoma (TCL), 46% in PTCL unspecified, 29% in anaplastic large T-cell lymphoma, 23% in extranodal NK/T-cell lymphoma and 13% in enteropathy-type TCL. In the BMI group, 36% of patients had lymphoma-associated hemophagocytic syndrome (LAHS), compared with 8% of the patients without BMI (8/103, P < 0.001). The estimated 1-year overall survival (OS) rates of patients with LAHS in the BMI and non-BMI groups were 5 and 49%, respectively. The increased levels of lactate dehydrogenase, fasting triglycerides and beta(2)-microglobulin between the BMI and non-BMI groups were not significantly different, but ferritin increased significantly and liver dysfunction-related diseases were seen more in the BMI group. As much as 51% of patients of the BMI group had anemia, compared with 27% of the patients without BMI (P = 0.001). The estimated 2-year OS rates in the two groups were 10 and 34%. The estimated 2-year OS rate of the 67 patients with BMI, who did not lose to follow-up, was 22%, compared with 38% in the non-BMI group. The median survival times of the 2 groups were 120 and 356 days. The estimated 2-year OS rate of patients treated by CHOP regimen was 9%, compared with 51% of those with intensive chemotherapy, with a significant difference (log rank P = 0.0008). The median survival time of the 14 patients subjected to chemotherapy combined with L: -asparaginase was 365 days and that of the 7 patients undergoing hemopoietic stem cell transplantation (HSCT) was 575 days. A total of 3 patients in a critical condition underwent plasmapheresis as initial therapy and achieved stable condition. We conclude that patients with PTCLs with BMI on initial diagnosis usually have hemaphagocytic syndrome and poor prognosis. BMI without lymphadenopathy is a patent clinical feature in most PTCLs. Patients with anemia on initial diagnosis in the BMI group usually have poor prognosis than those without. Intense chemotherapy, addition of L: -asparaginase in chemotherapy and HSCT are comparatively efficient treatments of PTCLs. For patients in critical conditions, plasmapheresis before chemotherapy would lower the risk and improve the tolerance to chemotherapy.

Efficacy and safety of ritonavir-boosted dual protease inhibitor therapy in antiretroviral-naive HIV-1-infected patients: the 2IP ANRS 127 study.

OBJECTIVES: We evaluate the efficacy and tolerability of ritonavir-boosted dual protease inhibitor as a nucleoside reverse transcriptase inhibitor-sparing regimen in a prospective open-label randomized pilot trial in antiretroviral-naive patients. METHODS: Thirty patients received fosamprenavir/atazanavir/ritonavir (Group 1) and 31 patients received saquinavir/atazanavir/ritonavir (Group 2). The primary endpoint for efficacy was the rate of early virological success, defined as plasma viral load <50 copies/mL at week 16. The study is registered with ClinicalTrials.gov (NCT00122603). RESULTS: At baseline, median (range) viral load was 4.8 log(10) copies/mL (4.0-5.7) and the median CD4 cell count was 271/mm(3) (197-740). Viral load was <50 copies/mL in 12/30 patients [40%, 95% confidence interval (CI) 23%-58%] and 13/31 patients (42%, 95% CI 25%-59%) at week 16 in Groups 1 and 2, respectively. Patients with failing regimens (viral load >or=400 copies/mL at week 16 or >or=50 copies/mL at week 24) were switched to a standard antiretroviral regimen. At week 48, by an intention-to-treat analysis, 23/30 patients (77%) and 26/31 patients (84%) had plasma HIV-1 RNA <50 copies/mL in Groups 1 and 2, respectively. Four patients discontinued treatment for adverse events, all before week 4. No major changes in the protease gene were detected at treatment failure relative to baseline. Baseline viral load <50 000 copies/mL was the only predictor of virological success at week 16. CONCLUSIONS: Ritonavir-boosted dual protease inhibitor regimens targeting only one step of viral replication were insufficient to rapidly suppress plasma HIV RNA to <50 copies/mL in antiretroviral-naive patients with high viral load at baseline.