Biomedical subjects
Publications and source records attributed to Jim Xiang.
This study assessed daily aspirate samples from an indwelling sinus catheter during high-dose, short-course levofloxacin (750 mg daily x 5 days) treatment of acute maxillary sinusitis. Pathogens were isolated from 4 of 18 recruited patients. Bacteriologic eradication occurred within 24 h for 3 patients and 72 h for the 4th.
STUDY OBJECTIVE: This randomized, multicenter study compares the analgesic efficacy and safety of tramadol/acetaminophen versus hydrocodone/acetaminophen versus placebo for the treatment of acute musculoskeletal pain caused by ankle sprain. METHODS: Adults were enrolled with ankle sprain with a diagnosis of partial ligament tear, pain visual analog scale score of 50 to 100 mm (0="no pain," 100="extreme pain"), and pain numeric rating scale score of 2 to 3 (0="none," 3="severe"). Patients reported pain intensity on these scales and pain relief (-1="pain worse," 4="complete relief") hourly for 4 hours after the first dose of tramadol/acetaminophen 75 mg/650 mg, hydrocodone/acetaminophen 7.5 mg/650 mg, or placebo, and daily for 5 days, with as-needed dosing. RESULTS: Tramadol/acetaminophen (n=192) and hydrocodone/acetaminophen (n=204) provided greater total pain relief than placebo (n=207; P<.001) during the first 4 hours (mean scores [95% confidence interval (CI)] 6.6 [95% CI 6.1 to 7.1], 6.8 [95% CI 6.3 to 7.3], and 5.4 [95% CI 4.9 to 5.9], respectively; possible range -4 to 16), decreased pain intensity during the first 4 hours, and increased average pain relief on days 1 to 5. No efficacy measure was significantly different between the tramadol/acetaminophen and hydrocodone/acetaminophen groups. Common adverse events included somnolence, nausea, dizziness, and vomiting. CONCLUSION: One or 2 capsules of 37.5 mg tramadol/325 mg acetaminophen and 1 capsule of 7.5 mg hydrocodone/650 mg acetaminophen were well tolerated, had comparable clinical utility, and were more effective than placebo in the management of acute musculoskeletal pain caused by ankle sprain.
Exosomes (EXO) derived from dendritic cells (DC), which express major histocompatibility complex (MHC) and costimulatory molecules, have been used for antitumour vaccines. However, they are still less effective by showing only prophylatic immunity in animal models or very limited immune responses in clinical trials. In this study, we showed that ovalbumin (OVA) protein-pulsed DC (DC(OVA))-derived EXO (EXO(OVA)) displayed MHC class I-OVA I peptide (pMHC I) complexes, CD11c, CD40, CD80, CCR7, DEC205, Toll-like receptor 4 (TLR4), TLR9, MyD88 and DC-SIGN molecules, but at a lower level than DC(OVA). EXO(OVA) can be taken up by DC through LFA-1/CD54 and C-type lectin/mannose (glucosamine)-rich C-type lectin receptor (CLR) interactions. Mature DC pulsed with EXO(OVA), which were referred to as mDC(EXO), expressed a higher level of pMHC I, MHC II, and costimulatory CD40, CD54 and CD80 than DC(OVA). The mDC(EXO) could more strongly stimulate OVA-specific CD8(+) T-cell proliferation in vitro and in vivo, and more efficiently induce OVA-specific cytotoxic T-lymphocyte responses, antitumour immunity and CD8(+) T-cell memory in vivo than EXO(OVA) and DC(OVA). In addition, mDC(EXO) could also more efficiently eradicate established tumours. Therefore, mature DC pulsed with EXO may represent a new, highly effective DC-based vaccine for the induction of antitumour immunity.
The rapid and efficient expansion of CD8(+) memory T cells after the second encounter with a pathogen constitutes a hallmark trait of adaptive immunity. Yet, the contribution of CD4(+) T cells to the expansion of memory CD8(+) T cells remains the subject of controversy. Here, we show that, antigen-specific CD4(+) T cells, once activated by dendritic cells (DC) in vitro, have the capacity to stimulate expansion of memory CD8(+) T cells in vivo. The memory CD8(+) T cell expansion triggered by active CD4(+) T cells are mediated through DC-derived MHC I/peptide complexes and CD80 molecules displayed on the active CD4(+) T cells, with the involvement of IL-2 secreted by the active CD4(+) T cells. These results highlight a previously undescribed role of active CD4(+) T cells in triggering expansion of memory CD8(+) T cells.
We previously showed that naive CD4+ Th cells acquire peptide-MHC class I (pMHC I) and costimulatory molecules from OVA-pulsed dendritic cells (DC(OVA)), and act as Th-APCs in stimulation of CD8+ CTL responses. In this study, we further demonstrated that naive CD8+ cytotoxic T (Tc) cells also acquire pMHC I and costimulatory CD54 and CD80 molecules by DC(OVA) stimulation, and act as Tc-APC. These Tc-APC can play both negative and positive modulations in antitumor immune responses by eliminating DC(OVA) and neighboring Tc-APC, and stimulating OVA-specific CD8+ central memory T responses and antitumor immunity. Interestingly, the stimulatory effect of Tc-APC is mediated via its IL-2 secretion and acquired CD80 costimulation, and is specifically targeted to OVA-specific CD8+ T cells in vivo via its acquired pMHC I complexes. These principles could be applied to not only antitumor immunity, but also other immune disorders (e.g., autoimmunity).
CD4+ T cells are essential for the maintenance of CD8+ memory T (Tm) cells following acute infection, but the importance of CD4+ T cells for the maintenance and expansion of CD8+ Tm cells to non-infectious antigens remains mostly unknown. Here, we showed that ovalbumin (OVA)-specific CD8+ Tm cell precursors derived from in vitro stimulation of TCR transgenic OT I CD8+ T cells with OVA protein-pulsed bone marrow-derived dendritic cells (DCOVA) can give rise to functional CD8+ Tm cells after adoptively transferred into mice. These CD8+ Tm cells can be maintained and remain fully functional in CD4+ T cell-absent environments in vivo. Furthermore, CD4+ T cells are not essential for the expansion of these CD8+ Tm cells. Finally, these in vitro DCOVA-activated CD8+ Tm cells maintained in CD4-deficient mice are also able to confer fully protective immunity against a later challenge of OVA-expressing tumor cells. Collectively, these findings demonstrate that in contrast to acute infections, maintenance and expansion of CD8+ Tm cells after priming with OVA protein-pulsed dendritic cells are independent of CD4+ T cells.
In a previous study, we demonstrated that immunization with the uveitogenic peptide interphotoreceptor retinoid-binding protein (IRBP) 1-20 induces both CD4 and CD8 uveitogenic T cells in the B6 mouse. In the current study, we determined the role of the CD8 IRBP-specific T cells in the pathogenesis of experimental autoimmune uveitis. We also determined the conditions that facilitated the activation of CD8 autoreactive T cells. Our results showed that the beta2-microglobulin(-/-) mouse had a greatly decreased susceptibility to induction of experimental autoimmune uveitis by adoptive transfer of IRBP-specific T cells from B6 mice. We also showed that unlike CD4 autoreactive T cells, activated CD8 autoreactive T cells produced only a limited number and amounts of growth factors. As a result, in the absence of exogenously supplied growth factor(s), CD8 T cell activation and expansion were aborted. However, the growth and expansion of triggered CD8 autoreactive T cells could be supported by various cytokines. In addition to factors produced by activated CD4 autoreactive T cells, factors produced by nonlymphoid cells, such as IL-7 and IL-15, and unidentified factors in the culture supernatants of astrocytes and retinal pigment epithelial cells support the CD8 autoreactive T cells as well. Finally, we showed that, although several cytokines augmented the CD8 T cell response in vitro, different cytokines appeared to act on different CD8 subsets or on different activation/differentiation phases of CD8 autoreactive T cells. As a result, cytokines, such as IL-7, supported the proliferation and survival of CD8 IRBP-specific T cells, while others had only a growth-promoting effect.
OBJECTIVE: Compare two dosage strengths of levofloxacin in the treatment of acute bacterial sinusitis. STUDY DESIGN AND SETTING: Multicenter clinical trial comparing levofloxacin 750 mg for 5 days vs levofloxacin 500 mg for 10 days. RESULTS: Sinus fluid samples were obtained by antral puncture (59.2%) or by sinus endoscopy (40.8%). Among microbiologically evaluable patients, 91.4% (139/152) of patients receiving levofloxacin 750 mg achieved clinical success vs 88.6% (132/149) of patients receiving levofloxacin 500 mg (95% CI -10.0, 4.2). Clinical success rates by pathogen were above 90% in both treatment groups for the 3 typical pathogens of acute sinusitis: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The safety profile of the 2 dosage strengths was similar. CONCLUSION: Levofloxacin 750 mg for 5 days is noninferior to levofloxacin 500 mg for 10 days. SIGNIFICANCE: Levofloxacin 750 mg for 5 days represents a safe and effective treatment regimen for acute bacterial sinusitis. EBM RATING: A-1b.
Recent developments in tumor immunology and biotechnology have made cancer gene therapy and immunotherapy feasible. The current efforts for cancer gene therapy mainly focus on using immunogenes, chemogenes and tumor suppressor genes. Central to all these therapies is the development of efficient vectors for gene therapy. By far, adenovirus (AdV)-mediated gene therapy is one of the most promising approaches, as has confirmed by studies relating to animal tumor models and clinical trials. Dendritic cells (DCs) are highly efficient, specialized antigen-presenting cells, and DC-based tumor vaccines are regarded as having much potential in cancer immunotherapy. Vaccination with DCs pulsed with tumor peptides, lysates, or RNA, or loaded with apoptotic/necrotic tumor cells, or engineered to express certain cytokines or chemokines could induce significant antitumor cytotoxic T lymphocyte (CTL) responses and antitumor immunity. Although both AdV-mediated gene therapy and DC vaccine can both stimulate antitumor immune responses, their therapeutic efficiency has been limited to generation of prophylactic antitumor immunity against re-challenge with the parental tumor cells or to growth inhibition of small tumors. However, this approach has been unsuccessful in combating well-established tumors in animal models. Therefore, a major strategic goal of current cancer immunotherapy has become the development of novel therapeutic strategies that can combat well-established tumors, thus resembling real clinical practice since a good proportion of cancer patients generally present with significant disease. In this paper, we review the recent progress in AdV-mediated cancer gene therapy and DC-based cancer vaccines, and discuss combined immunotherapy including gene therapy and DC vaccines. We underscore the fact that combined therapy may have some advantages in combating well-established tumors vis-a-vis either modality administered as a monotherapy.
Because dendritic cell (DC)-derived exosomes (EXO) harbor many important DC molecules involved in inducing immune responses, EXO-based vaccines have been extensively used to induce antitumor immunity in different animal tumor models. However, it is not clear which route of EXO administration can induce more efficient antitumor immune responses. In this study, we compared the antitumor immunity derived from EXO vaccine by way of the two common administration routes, the subcutaneous (s.c.) and the intradermal (i.d.) administrations. Our data showed that the i.d. EXO administration resulted in more EXO-absorbed DC migrating into the T-cell areas of draining lymph nodes than the s.c. administration. Interestingly, the i.d. EXO administration also resulted in an enhanced ovalbumin (OVA)-specific CD8(+) T-cell proliferation and CD8(+) CTL effector responses in vivo, compared to the s.c. administration. Similarly, compared to the s.c. vaccination, the i.d. vaccination induced stronger antitumor immunity in the animal tumor model. Therefore, the i.d. EXO vaccination is superior to the s.c. one and should be considered when EXO-based vaccine is designed.
Oncolytic adenovirus (rAd)-mediated E1A gene therapy of cancer has become a novel therapeutic modality. In this study, we constructed a recombinant oncolytic adenovirus (rAd-E1A) expressing the tumor suppressor E1A gene. We demonstrated that the rAd-E1A replicated in HepG2 and SMMC-7721 human hepatocellular carcinoma (HCC) cells but attenuated in the normal liver cell line HL-7702. It induced HCC cell apoptosis through upregulation of apoptosis-associated Bax, caspase-3, and Fas and downregulation of survivin and Bcl-2 in a p53-dependent pathway. It also downregulated the expression of angiogenesis- associated vascular endothelial growth factor (VEGF) and CD34 genes and reduced tumor vessel formation and angiogenesis. In mice bearing SMMC-7721 tumors, intratumoral injections of rAd- E1A significantly inhibited HCC growth. Therefore, the oncolytic adenovirus-mediated E1A gene therapy may be a useful therapeutic approach for HCC treatment.
Culturing conditions may affect dendritic cell (DC) maturation status and functional effects. We have previously demonstrated that different DC subsets play distinct roles in immune responses. The splenic CD4-8- DC subset that secretes transforming growth factor (TGF)-beta stimulates CD4+ regulatory T type 1 (Tr1) cell responses, and this leads to antitumor immune tolerance. In this study, we investigated the potential effect of culturing conditions, namely: (1) duration of culturing and (2) the dose of antigen ovalbumin (OVA) for DC pulsing, respectively, in the conversion of tolerogenic CD4-8- DC into immunogenic DCs. Our data showed that isolated CD4-8- DCs cultured for an additional 18 hours in medium containing 15-20 ng/mL granulocyte macrophage colony-stimulating factor (GM-CSF) became more mature compared to the freshly isolated CD4-8- DCs. When pulsed with OVA at the relatively high concentration of 1 mg/mL, but not at 0.1 mg/mL, the CD4-8- DCs could be converted into immunogenic CD4-8- DCs, which stimulated CD4+ T-cell differentiation into type 1 helper T (Th1) cells. Vaccination of mice with converted CD4-8- DCs induced strong OVA-specific cytotoxic T-lymphocyte (CTL) responses and protective immunity against OVA-expressing BL6-10OVA B16 melanoma. Taken together, our findings indicate that the conversion of DCs from a tolerogenic to an immunogenic state can be achieved by the elongation of DC culturing time in combination with a high-dose antigen for DC pulsing. Therefore, our results may have a significant impact in designing DC-based antitumor vaccines.
Infections with Hepatitis C virus (HCV) pose a serious health problem worldwide. In this study, the hypothesis that adoptive transfer of dendritic cells (DCs) pulsed with HCV NS3 protein and matured with an oligodeoxynucleotide (ODN) containing CpG motifs (CpG) ex vivo would initiate potent HCV-specific protective immune responses in vivo was tested. NS3 protein was efficiently transduced into DCs and treatment of DCs with CpG ODN induced phenotypic maturation and specifically increased the expression of CD40. DCs matured with CpG ODN produced higher interleukin 12 levels and a stronger allogeneic T-cell response compared with untreated DCs. Notably, there were no differences between NS3-pulsed DCs and DCs pulsed with a control protein with respect to phenotype, cytokine production or mixed lymphocyte reaction, indicating that transduction with NS3 protein did not impair DC functions. Compared with the untreated NS3-pulsed DCs, the NS3-pulsed DCs matured with CpG ODN induced stronger cellular immune responses including enhanced cytotoxicity, higher interferon-gamma production and stronger lymphocyte proliferation. Upon challenge with a recombinant vaccinia virus expressing NS3, all mice immunized with NS3-pulsed DCs showed a significant reduction in vaccinia virus titres when compared with mock-immunized mice. However, the NS3-pulsed DCs matured with CpG ODN induced higher levels of protection compared with the untreated NS3-pulsed DCs. These data are the first to show that NS3-pulsed DCs induce specific immune responses and provide protection from viral challenge, and also demonstrate that CpG ODNs, which have a proven safety profile, would be useful in the development of DC vaccines.
OBJECTIVE: This study evaluated the efficacy and safety of tramadol extended-release (tramadol ER) tablets once daily in subjects with osteoarthritis pain. METHODS: This 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial included 1020 adults with osteoarthritis of the knee or hip and baseline pain intensity >or= 40 on a 100-mm pain visual analog scale (0 = no pain, 100 = extreme pain). Subjects took placebo or were titrated to a target dose of tramadol ER 100, 200, 300, or 400 mg once daily. MAIN OUTCOME MEASURES: The co-primary efficacy variables were pain and physical function subscales of the WOMAC Osteoarthritis Index and subject global assessment of disease activity. RESULTS: Mean changes in WOMAC Osteoarthritis Index pain and physical function subscales were significantly different between tramadol ER and placebo, overall (p <or= 0.021) and for each dose (p <or= 0.050). However, the protocol-specified decision rule for the 3 co-primary endpoints was not satisfied because the overall comparison of subject global assessment of disease activity was not statistically significant (p = 0.079). All doses of tramadol ER once daily were more effective than placebo (p <or= 0.050) for WOMAC Osteoarthritis Index joint stiffness subscale, WOMAC Osteoarthritis Index composite score, pain intensity of the index joint, and daily pain intensity scores. Tramadol ER 200 and 300 mg were significantly more effective than placebo (p <or= 0.050) for subject global assessment of disease activity and pain intensity of non-index joints. Adverse events (e.g., constipation, dizziness, nausea, somnolence, headache) occurred most often with tramadol ER 400 mg. CONCLUSIONS: Tramadol ER 100-300 mg once daily was associated with significant improvement in pain intensity and physical function, and was well tolerated, despite the use of a fixed-dose study design not reflective of usual clinical practice. Tramadol ER is a useful treatment option for patients with osteoarthritis pain.
OBJECTIVE: To compare safety data with levofloxacin 500 mg and 750 mg from clinical trials for the treatment of respiratory infections. METHODS: We compared adverse event data for levofloxacin 500 mg and 750 mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy. RESULTS: Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500 mg and in 45.5% (519/1141) of those treated with 750 mg (p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) (p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in > or = 2% of patients. CONCLUSIONS: Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750 mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.
OBJECTIVE: To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder. METHOD: In this 12-week, randomized, double-blind, placebo-controlled trial, adults with bipolar I disorder (DSM-IV criteria) experiencing a manic or mixed episode with a Young Mania Rating Scale (YMRS) score of >or= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo. Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks. The study was conducted from October 2001 through October 2003. The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase. RESULTS: The mean +/- SD change in YMRS score from baseline was -10.1 +/- 8.7 (-40.1%) in the topiramate group (N = 143) and -9.6 +/- 8.2 (-40.2%) in the placebo group (N = 144, p = .797). Greater than 50% reduction in YMRS was achieved by 39% of the topiramate group and 38% of the placebo group (p = .914). No significant treatment differences were observed for secondary efficacy measures. Compared with adjunctive placebo, adjunctive topiramate did not worsen mania or induce depression. Paresthesia, diarrhea, and anorexia were more common in the topiramate group. The topiramate group achieved greater reductions than the placebo group in body weight (-2.5 vs. 0.2 kg, p < .001) and body mass index (-0.84 vs. 0.07 kg/m(2), p < .001). CONCLUSION: In patients treated with lithium or valproate, there was no difference in the reduction of YMRS score in the topiramate and placebo groups. Both groups showed declines of 40%. Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms.
Exosomes (EXO) derived from dendritic cells (DC) and tumor cells have been used to stimulate antitumor immune responses in animal models and in clinical trials. However, there has been no side-by-side comparison of the stimulatory efficiency of the antitumor immune responses induced by these two commonly used EXO vaccines. In this study, we selected to study the phenotype characteristics of EXO derived from a transfected EG7 tumor cells expressing ovalbumin (OVA) and OVA-pulsed DC by flow cytometry. We compared the stimulatory effect in induction of OVA-specific immune responses between these two types of EXO. We found that OVA protein-pulsed DCOVA-derived EXO (EXODC) can more efficiently stimulate naïve OVA-specific CD8+ T cell proliferation and differentiation into cytotoxic T lymphocytes in vivo, and induce more efficient antitumor immunity than EG7 tumor cell-derived EXO (EXOEG7). In addition, we elucidated the important role of the host DC in EXO vaccines that the stimulatory effect of EXO is delivered to T cell responses by the host DC. Therefore, DC-derived EXO may represent a more effective EXO-based vaccine in induction of antitumor immunity.
It is clear that dendritic cells (DCs) are essential for priming of T cell responses against tumors. However, the distinct roles DC subsets play in regulation of T cell responses in vivo are largely undefined. In this study, we investigated the capacity of OVA-presenting CD4-8-, CD4+8-, or CD4-8+ DCs (OVA-pulsed DC (DC(OVA))) in stimulation of OVA-specific T cell responses. Our data show that each DC subset stimulated proliferation of allogeneic and autologous OVA-specific CD4+ and CD8+ T cells in vitro, but that the CD4-8- DCs did so only weakly. Both CD4+8- and CD4-8+ DC(OVA) induced strong tumor-specific CD4+ Th1 responses and fully protective CD8+ CTL-mediated antitumor immunity, whereas CD4-8- DC(OVA), which were less mature and secreted substantial TGF-beta upon coculture with TCR-transgenic OT II CD4+ T cells, induced the development of IL-10-secreting CD4+ T regulatory 1 (Tr1) cells. Transfer of these Tr1 cells, but not T cells from cocultures of CD4-8- DC(OVA) and IL-10-/- OT II CD4+ T cells, into CD4-8+ DC(OVA)-immunized animals abrogated otherwise inevitable development of antitumor immunity. Taken together, CD4-8- DCs stimulate development of IL-10-secreting CD4+ Tr1 cells that mediated immune suppression, whereas both CD4+8- and CD4-8+ DCs effectively primed animals for protective CD8+ CTL-mediated antitumor immunity.