A randomized trial of TLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer.

Background: Randomized controlled trial to evaluate synergy between taxane plus platinum chemotherapy and CADI-05, a Toll like receptor-2 agonist targeting desmocollin-3 as a first-line therapy in advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients with advanced NSCLC (stage IIIB or IV) were randomized to cisplatin-paclitaxel (chemotherapy group, N = 112) or cisplatin-paclitaxel plus CADI-05 (chemoimmunotherapy group, N = 109). CADI-05 was administered a week before chemotherapy and on days 8 and 15 of each cycle and every month subsequently for 12 months or disease progression. Overall survival was compared using a log-rank test. Computed tomography was carried out at baseline, end of two cycles and four cycles. Response rate was evaluated using Response Evaluation Criteria in Solid Tumors criteria by an independent radiologist. Results: As per intention-to-treat analysis, no survival benefit was observed between two groups [208 versus 196 days; hazard ratio, 0.86; 95% confidence interval (CI) 0.63-1.19; P = 0.3804]. In a subgroup analysis, improvement in median survival by 127 days was observed in squamous NSCC with chemoimmunotherapy (hazard ratio, 0.55; 95% CI 0.32-0.95; P = 0.046). In patients receiving planned four cycles of chemotherapy, there was improved median overall survival by 66 days (299 versus 233 days; hazard ratio, 0.64; 95% CI 0.41 to 0.98; P = 0.04) in the chemoimmunotherapy group compared with the chemotherapy group. This was associated with the improved survival by 17.48% at the end of 1 year, in the chemoimmunotherapy group. Systemic adverse events were identical in both the groups. Conclusion: There was no survival benefit with the addition of CADI-05 to the combination of cisplatin-paclitaxel in patients with advanced NSCLC; however, the squamous cell subset did demonstrate a survival advantage.

Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigen-negative chronic hepatitis B virus infection.

Hepatitis B e-antigen negative (e(-)) chronic HBV infection (CHI) encompasses a heterogeneous clinical spectrum ranging from inactive carrier (IC) state to e(-) chronic hepatitis B (CHB), cirrhosis and hepatic decompensation. In the backdrop of dysfunctional virus-specific T cells, natural killer (NK) cells are emerging as innate effectors in CHI. We characterized CD3(-) CD56(+) NK cells in clinically well-defined, treatment-naive e(-) patients in IC, e(-)CHB or decompensated liver cirrhosis (LC) phase to appraise their role in disease progression. The NK cell frequencies increased progressively with disease severity (IC 8.2%, e(-)CHB 13.2% and LC 14.4%). Higher proportion of NK cells from LC/e(-)CHB expressed CD69, NKp46, NKp44, TRAIL and perforin, the last two being prominent features of CD56(bright) and CD56(dim) NK subsets, respectively. The frequencies of CD3(-) CD56(+) NK cells together with TRAIL(+) CD56(bright) and Perforin(+) CD56(dim) NK cells correlated positively with serum alanine transaminase levels in e(-)CHB/LC. K562 cell-stimulated NK cells from e(-)CHB/LC exhibited significantly greater degranulation but diminished interferon-γ production than IC. Further, Perforin(+) NK cell frequency inversely correlated with autologous CD4(+) T-cell count in e(-) patients and ligands of NK receptors were over-expressed in CD4(+) T cells from e(-)CHB/LC relative to IC. Co-culture of sorted CD56(dim) NK cells and CD4(+) T cells from e(-)CHB showed enhanced CD4(+) T-cell apoptosis, which was reduced by perforin inhibitor, concanamycin A, suggesting a possible perforin-dependent NK cell-mediated CD4(+) T-cell depletion. Moreover, greater incidence of perforin-expressing NK cells and decline in CD4(+) T cells were noticed intrahepatically in e(-)CHB than IC. Collectively, NK cells contribute to the progression of e(-)CHI by enhanced TRAIL- and perforin-dependent cytolytic activity and by restraining anti-viral immunity through reduced interferon-γ secretion and perforin-mediated CD4(+) T-cell lysis.

Comparative effects of pyrolytic products of fiber reinforced plastic and wood shavings on the respiratory variables in mice.

Comparative inhalation toxicity studies of pyrolytic products (smoke) from synthetic polymer, fiberglass reinforced plastic (FRP) and teak wood shavings were carried out in male Swiss albino mice. The breathing pattern and the respiratory variables were monitored using a computer program that recognizes the modifications of the respiratory pattern. Exposure to the smoke from both the polymers caused a concentration dependent decrease in normal breathing and an increase in sensory irritation measure. The acute lethal concentration 50 values for a 15 min static inhalation exposure to the smoke from FRP and teak wood shavings were found to be > 200.00 and 62.99 g/m(3), respectively. Hence the inhalation toxicity of smoke from FRP sample on a mass basis is approximately one-third that of the smoke from teak wood. The concentration of smoke causing 50% respiratory depression of the exposed animals were found to be 6.877 and 0.106 g/m(3) for FRP and teak wood samples, respectively. Thus the sensory irritancy of the smoke from FRP sample is approximately 65 times lesser than the smoke from teak wood. The higher sensory irritancy potential of wood smoke as compared to FRP smoke may be caused by a greater number of submicron particles (size range of 2 micron and less) and greater percentage of gases present in wood smoke as compared to FRP smoke. Thus in case of accidental fires, synthetic polymers like FRP may be a safer choice for structural parts and interiors than the natural wood.

Role of Anopheles culicifacies during an outbreak of malaria in Gorubandha P.H.C., Assam.

Entomological investigation during an outbreak of malaria in Gorubandha PHC in Sonitpur district revealed unusually high density of Anopheles culicifacies followed by An.minimus. Parity rates of both the species were very high, 65% and 62.2% respectively. An. culicifacies was incriminated as malaria vector. Sporozoite rate recorded was 0.63%. Both the species were found susceptible to DDT. This substantiates the epidemiological observation which yielded 98% Plasmodium falciparum malaria out of 35.2% malaria positive cases. Incrimination of An. culicifacies means adding one more malaria vector to this region.