A Novel Neoadjuvant Therapy for Operable Locally Invasive Non–Small-Cell Lung Cancer. Phase I Study of Neoadjuvant Stereotactic Body Radiotherapy. LINNEARRE I (NCT02433574)

Background

Despite improved staging and surgical techniques, the rate of incomplete resection (R1) of non–small-cell lung cancer (NSCLC) has not significantly decreased. Patients with R1 resection have worse survival compared with those with complete resection (R0). Stereotactic body radiotherapy (SBRT) is a rapid and convenient radiotherapy treatment that delivers high-dose radiotherapy to tumors with high precision while sparing normal organs. Although its efficacy in treating small lung tumors is documented, its use as neoadjuvant therapy for locally advanced (LA) NSCLC has not been examined. We hypothesized that a short course of preoperative SBRT is feasible and can be delivered safely as a neoadjuvant therapy in patients at risk for incomplete resection.

Cysteine proteinase type III is protective against Leishmania infantum infection in BALB/c mice and highly antigenic in visceral leishmaniasis individuals

Visceral leishmaniasis is the most acute form of leishmaniasis and vaccination is the best approach to control it. One of the major groups of virulence factors in Leishmania belongs to cysteine proteinase family. In this study, for the first time, the protective potential of Leishmania infantum cysteine proteinase type III (CPC) by using a prime-boost strategy is evaluated in BALB/c mice. The experiment was carried out in three groups of mice. Vaccinated group was primed with pcDNA-cpc and boosted with rCPC-DHFR in combination with CpG motif and Montanide 720 as adjuvant. Control groups received pcDNA and rDHFR or PBS. The ratio of IgG2a/IgG1, nitric oxide concentration and IFN-gamma induction in vaccinated group is significantly higher than controls. Furthermore, the parasite load of vaccinated group is significantly lower than controls. In addition, sera reactivity of visceral leishmaniasis individuals was examined and showed considerable reactivities toward rCPC in comparison with cutaneous leishmaniasis. The achieved result is highly encouraging the use of cysteine proteinases types I, II and III as vaccine candidate against visceral leishmaniasis.     

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial

This study aimed to investigate the role of baseline levels of peripheral inflammation when testing the efficacy of antidepressant augmentation with minocycline in patients with treatment-resistant depression. We conducted a 4-week, placebo-controlled, randomised clinical trial of minocycline (200 mg/day) added to antidepressant treatment in 39 patients selected for elevated levels of serum C-reactive protein (CRP ≥ 1 mg/L), n = 18 randomised to minocycline (M) and n = 21 to placebo (P). The main outcome was the change in Hamilton Depression Rating Scale (HAM-D-17) score from baseline to week 4, expressed both as mean and as full or partial response, in the overall sample and after further stratification for baseline CRP≥3 mg/L. Secondary outcomes included changes in other clinical and inflammatory measures. Changes in HAM-D-17 scores and the proportion of partial responders did not differ between study arms. After stratification for CRP levels <3 mg/L (CRP⁻) or ≥3 mg/L (CRP⁺), CRP⁺/M patients showed the largest changes in HAM-D-17 scores (mean ± SD = 12.00 ± 6.45) compared with CRP^-/M (2.42 ± 3.20, p < 0.001), CRP⁺/P (3.50 ± 4.34, p = 0.003) and CRP⁻/P (2.11 ± 3.26, p = 0.006) patients, and the largest proportion (83.3%, p = 0.04) of partial treatment response at week 4. The threshold point for baseline CRP to distinguish responders from non-responders to minocycline was 2.8 mg/L. Responders to minocycline had higher baseline IL-6 concentrations than non-responders (p = 0.03); IFNγ was significantly reduced after treatment with minocycline compared with placebo (p = 0.03). Our data show some evidence of efficacy of add-on treatment with minocycline in MDD patients but only in those with low-grade inflammation defined as CRP ≥3 mg/L.Subject terms: Depression, Predictive markers, Translational research     

Affinity of anticancer drug, daunomycin, to core histones in solution： comparison of free and cross-linked proteins

AIM: The interaction of anthracycline anticancer drugs with chromatin, nucleosomes and histone H1 has been extensively studied. In the present study, for the first time, we have investigated the binding of anthracycline antibiotic, daunomycin, to free and cross-linked thymus core histones (CL-core) in solution and in the absence of DNA. METHODS: Fluorescence, UV/Vis spectroscopy and equilibrium dialysis techniques were used. RESULTS: The UV spectroscopy results show that daunomycin induces hypochromicity in the absorption spectra of the core histones. Fluorescence emission intensity is decreased upon daunomycin binding and the process is concentration dependent. The equilibrium dialysis shows that the binding is positive cooperative with the binding sites as Scatchard plot and Hill Coefficient confirm it. CONCLUSION: The results suggest that daunomycin shows much higher affinity to core histones free in solution than to CL-core, implying that the binding is most likely due to the accessibility of these proteins to the environment. It is suggested that daunomycin binds strongly to open state of histones, such as in tumor cells, rather than to their compact structure seen in normal chromatin.     

Management of ocular manifestations of Behcet's disease: outcome with cytotoxic drugs

Background and aim: Cytotoxic drugs, combined with steroids, are the first line of treatment for serious ocular manifestations in Behcet's disease (BD) such as uveitis and retinal vasculitis. If used judiciously, they are effective and safe, even in the long‐term. In our unit, the following cytotoxic drugs have been used for this purpose – oral or pulse cyclophosphamide, weekly methotrexate, chlorambucil, cyclosporin, azathioprine, or a combination of these. In our experience, these cytotoxic drugs had a similar range of efficacy regarding improvement in visual acuity. Having obtained the same treatment response, we pooled all our data together to evaluate the overall outcome of the eye complications in our cohort of BD patients. Methods: The treatment protocol was the same regardless of which cytotoxic drug was used. Prednisolone was given to all patients at an initial dose of 0.5 mg per kilogram of body weight per day. The dose was later tapered as necessary. If a patient was resistant to a given cytotoxic drug, the drug was changed to another. In pooled data, the results before the first treatment were compared with those after the last treatment. Visual acuity (VA) was measured using a Snellen chart (on a scale of 10). The Disease Activity Index (DAI) for anterior uveitis (AU), posterior uveitis (PU), and retinal vasculitis (RV) was measured according to the criteria of Ben Ezra. The Total Inflammatory Activity Index (TIAI) and the Total Adjusted Disease Activity Index (TADAI) were also calculated. Statistical analysis was performed using a Student's t‐test for paired samples comparing the data obtained before and after treatment. Results: At the last evaluation of our database (March 2004) on patients who had an active posterior uveitis and/or retinal vasculitis, 1104 were treated with cytotoxic drugs, of whom 290 patients received more than one treatment protocol. The mean duration of eye lesions was 32.8 months (SD 37.6). The mean treatment time was 20.1 months (SD 20.3). Overall, the VA of 70% of patients improved or maintained after treatment. The mean VA improved from 3.8 to 4.7 (t = 10.099, P < 0.000001). The mean DAI of AU improved from 2.5 to 0.8 (t = 19.575, P < 0.000001). The mean DAI of posterior uveitis improved from 2.1 to 0.9 (t = 28.616, P < 0.000001). The mean DAI of retinal vasculitis improved from 2.5 to 1.5 (t = 12.070, P < 0.000001). The mean TIAI improved from 16.5 to 7.9 (t = 20.13, P < 0.000001). The mean TADAI improved from 37.1 to 25.6 (t = 20.24, P < 0.000001). Further analysis showed methotrexate at a dose of 15 mg/week, and azathioprine at 2 mg/kg/day were preferred for posterior uveitis, while low dose pulsed cyclophosphamide (0.5 g/m²/month) – azathioprine combination therapy for retinal vasculitis. Conclusion: Cytotoxic drugs are efficacious in the treatment of serious ocular manifestations of BD.     

Introduction of protocols for mass production of Toxoplasma gondii tachyzoites of the genotype Ⅱ PRU strain

Background: Few investigations of genotype Ⅱ of Toxoplasma gondii, the most preva-lent form of the Toxoplasma parasite in humans, have been carried out on due t...