Fieldsklitgaard5153
Coxiella burnetii, the causative agent of Q fever, is an intracellular bacterial pathogen. Studies on Coxiella have shown that a type IVB secretion system (T4BSS) contributes to the establishment of the infection by transferring protein molecules. In this report, we focus on two core proteins of the Coxiella T4BSS, namely the IcmG/DotF protein (CBU_1626) and the IcmK/DotH protein (CBU_1628). Here we present a method for the recombinant expression of IcmG and IcmK in E. coli. IcmG was purified by Strep-Tactin affinity chromatography and size exclusion chromatography, while for the purification of IcmK an additional anion exchange chromatography step was introduced. The yields of the purified IcmG and IcmK proteins were 1.2 mg/L and 3 mg/L, respectively. The purified proteins showed predominant band on SDS-PAGE gel of 37 kDa for the IcmG and 40 kDa for the IcmK. CB-839 mouse Protein folding is confirmed by circular dichroism spectroscopy. The dynamic light scattering experiment indicated that IcmG and IcmK existed in a homogenous form. Further Blue native PAGE indicates the presences of a monomeric form for the IcmK and IcmG. Our work lays the basis for functional exploration and structural determination of IcmG and IcmK proteins of Coxiella's secretion system.
The introduction in clinical practice of the immune checkpoint inhibitors (ICIs) radically changed the treatment algorithm of lung cancers. To characterize the toxicity of ICIs (atezolizumab, durvalumab, nivolumab, pembrolizumab) is important for personalizing treatment.
We performed a systematic review and meta-analysis of phase III randomized controlled trials assessing ICIs, from inception until April 23
, 2020. We extracted the data from the ICI arm of each trial for indirect comparisons to estimate relative risk for immune-related adverse events (irAEs), severe (grade ≥3) irAEs, drug discontinuation due to irAEs or toxic death.
Sixteen trials included a total of 6226 subjects randomized to the experimental immunotherapy arm. Immunotherapy was administered in monotherapy (8 trials), in combination with chemotherapy (6 trials) or other ICI (2 trials). Any grade irAEs and severe irAEs for ICI were 37.1% and 18.5%, respectively. Discontinuations due to any grade irAEs and severe irAEs were 13.8% and 9.2%, respectively; toxic deaths were 2.9% in the immunotherapy arm. Pooled data on any, severe and organ-specific irAEs showed that immunotherapy has a significantly lower risk of irAEs compared to immuno-chemotherapy, especially when analysis was restricted to monoimmunotherapy, like drug discontinuation and toxic death (all p < 0.05). Detailed comparisons between different ICIs provided treatment-related risk profiles for organ-specific irAEs.
Our findings contribute to clarifying frequency and features of immune-related toxicities between different ICIs in lung cancer patients, including any grade irAEs, severe irAEs, drug discontinuation and toxic deaths, and may be useful to inform the selection of treatment.
Our findings contribute to clarifying frequency and features of immune-related toxicities between different ICIs in lung cancer patients, including any grade irAEs, severe irAEs, drug discontinuation and toxic deaths, and may be useful to inform the selection of treatment.
To evaluate the effectiveness of photobiomodulation therapy (PBMT) in the prevention and treatment of radiation dermatitis (RD).
A systematic review was conducted using seven databases and the gray literature. We performed a meta-analysis to summarize the effect sizes of response rates (RRs).
We included seven clinical trials. Breast cancer patients receiving PBMT developed more grade 1 RD than the control group (RR 1.55, 95 % CI 1.14-2.10, I
= 51 %). PBMT appears to prevent RD grade 2 (RR 0.33, 95 % CI 0.09-1.23, I
= 85 %) and RD grade 3 (RR 0.21, 95 % CI 0.05-0.94, I
= 0%) with very low certainty of evidence.
There is very low certainty of evidence that PBMT was effective in the prevention of RD. However, PBMT showed a significant effect to prevent grade 3 RD in breast cancer patients. Thus, further randomized clinical trials are required to confirm the promising effect of PBMT in RD.
There is very low certainty of evidence that PBMT was effective in the prevention of RD. However, PBMT showed a significant effect to prevent grade 3 RD in breast cancer patients. Thus, further randomized clinical trials are required to confirm the promising effect of PBMT in RD.In trials of novel immuno-oncology drugs, the proportional hazards (PH) assumption often does not hold for the primary time-to-event (TTE) efficacy endpoint, likely due to the unique mechanism of action of these drugs. In practice, when it is anticipated that PH may not hold for the TTE endpoint with respect to treatment, the sample size is often still calculated under the PH assumption, and the hazard ratio (HR) from the Cox model is still reported as the primary measure of the treatment effect. Sensitivity analyses of the TTE data using methods that are suitable under non-proportional hazards (non-PH) are commonly pre-planned. In cases where a substantial deviation from the PH assumption is likely, we suggest designing the trial, calculating the sample size and analyzing the data, using a suitable method that accounts for non-PH, after gaining alignment with regulatory authorities. In this comprehensive review article, we describe methods to design a randomized oncology trial, calculate the sample size, analyze the trial data and obtain summary measures of the treatment effect in the presence of non-PH. For each method, we provide examples of its use from the recent oncology trials literature. We also summarize in the Appendix some methods to conduct sensitivity analyses for overall survival (OS) when patients in a randomized trial switch or cross-over to the other treatment arm after disease progression on the initial treatment arm, and obtain an adjusted or weighted HR for OS in the presence of cross-over. This is an example of the treatment itself changing at a specific point in time - this cross-over may lead to a non-PH pattern of diminishing treatment effect.