303 Background: ICIs are a common therapeutic option for many solid tumors. While prior studies have shown that ATB exposure may negatively impact ICI outcomes through gut microbiome changes, many were small studies with heterogeneity in ATB classes and exposure windows. Here, we performed a population level retrospective cohort study to evaluate the impact of ATB exposure prior to ICI on OS. Methods: We used administrative data to identify a cohort of cancer patients > 65 years of age receiving ICIs from June 2012 to October 2018 in Ontario, Canada and deterministically linked with databases to obtain socio-demographic and clinical co-variates and ATB prescription claims. Multivariable cox-proportional hazard models evaluated the impact of ATB exposure both within 1 year and 60 days prior to starting ICI on OS, adjusted for age, gender, body mass index, comorbidities, autoimmune history, hospitalization in the past year and treatment facility level at start of ICI therapy. Results: Among 2737 patients, median age 73; 43% received Nivolumab, 41% Pembrolizumab and 13% Ipilimumab; 53% were lung cancer, 34% melanoma. Median ATB treatment duration for patients receiving ATB within 1 year (59%) and 60 days (19%) prior to ICI were 14 days (SD = 32) and 9 days (SD = 13) respectively. Median OS estimate was 306 days. Any ATB exposure within 1 year prior to ICI was associated with worse OS (aHR = 1.12 95% CI [1.12-1.23] p = 0.03). A non significant dose effect was seen based on weeks of ATB exposure 1 year prior to ICI (aHR = 1.01 per week [1.00-1.02] p = 0.10). ATB class analysis identified fluoroquinolone exposure within 1 year (aHR = 1.26 [1.13-1.40] p < 0.001) and 60 days before ICI (aHR = 1.20 [0.99-1.45] p = 0.06) were associated with worse OS; with a dose effect based on total weeks of exposure over 1 year (aHR = 1.07 per week [1.03-1.11] p < 0.001) and 60 days (aHR = 1.12 per week [1.03-1.23] p = 0.01). Subgroup analysis showed similar results for patients receiving anti-PD1 ICIs, where patients exposed to fluoroquinolone both 1 year (aHR = 1.28 [1.15-1.44] p < 0.001) and 60 days (aHR = 1.19 [0.98-1.44] p = 0.08) before ICIs had poorer OS with dose effects observed based on weeks of fluoroquinolone exposure. Similarly, subgroup analyses based on disease site identified that lung cancer patients exposed to fluoroquinolones 1 year before starting ICIs (aHR = 1.22 [1.06-1.39] p = 0.005) and melanoma patients exposed to fluoroquinolones 60 days before starting ICIs (aHR = 1.66 [1.12-2.47] p = 0.01) had poorer OS. Conclusions: Exposure to ATBs and specifically fluoroquinolones prior to ICI therapy is associated with worse OS. Interventions aimed at altering the gut microbiome may be required to help improve outcomes for patients on ICIs with prior ATB exposure.
The in situ generation of siRNAs in living cells can greatly enhance the specificity and efficiency of gene therapy. Inspired by the natural molecular machines that organize different compartments sequentially in a limited space to facilitate cellular process, this work constructs a DNA nanomachine (DNM) by alternately hybridizing two pairs of DNA/RNA hybrids to a DNA scaffold generated by rolling circle amplification for highly efficient in situ siRNA assembly in living cells. After target cell-specific delivery of DNM, intracellular specific microRNA can work as a trigger to operate the DNM by initiating DNA cascade displacement reaction between DNA/RNA hybrids along the scaffold for continuous generation of siRNAs. Using miR-21 as a model, efficient siRNAs generation is achieved via DNA templated cascade reaction, which demonstrated impressive suppressions to VEGF mRNA and protein expressions in cells and in vivo tumor growth and indicated promising application of the designed strategy in gene therapy.
This project deals with odd-parity superconductor Sr2RuO4 and related material systems, aiming at understanding the unconventional nature of superconductivity in this material. An odd-parity superconductor is expected to feature a novel topological object, the half-flux-quantum vortex that hosts a Majorana anyons. Majorana anyons carry non-Abelian statistics that can be used as the building block for constructing a fault-tolerated topological quantum computer. Half-flux-quantum vortices form in an odd-parity superconductor because of the availability of charge neutral spin supercurrent in addition to the normal supercurrent. Half-height magnetization steps were found in a cantilever magnetometry measurement of doubly connected mesoscopic samples of Sr2RuO4 in the presence of an in-plane magnetic field (J. Jang, D. G. Ferguson, V. Vakaryuk, R. Budakian, S. B. Chung, P. M. Goldbart, and Y. Maeno, Science 331, 186 (2011)), which suggests the presence of a half-flux-quantum (Φ0/2 = h/4e) state. Evidence for half flux quantum states, which can be viewed as coreless half vortices, was obtained in mesoscopic samples of Sr2RuO4 in the torque magnetomitry measurements. However, the existence of such an important property has not been confirmed by any other independent measurement.
Abstract Background: As the high risk prostate cancer can be benefited from the combination of hypo-fractionated radiotherapy and pelvic conventional fraction radiotherapy, the comparison between fixed field dynamic IMRT and VMAT techniques can provide suggestion for clinical treatment. Methods: We selected 10 patients with high risk prostate cancer who received radiotherapy at Sun Yat-sen University Cancer Center from 2013 January to 2013 December. The target including the prostate, seminal vesicle and pelvic lymph nodes. With the same prescription and optimized parameters, 9 field IMRT, single arc and double arc VMAT treatment plans were designed, which are expressed by 9F, 1ARC and 2ARC respectively. The dose distribution of the targets, organs at risk (OAR), monitor units (MUs), treatment time and gamma pass ratios of dose verification were compared. Results: The D 2% (69.37±0.89)Gy,D 50% (66.92±0.63)Gy, HI(0.09±0.02) and CI(0.83±0.05) of PTV1 in 9F were slightly better than those of 1ARC which were (71.13±1.21) Gy, (68.50±0.76)Gy, (0.12±0.02), (0.74±0.07), except D 98% , the difference were significant(p<0.05). All dosimetric indices of PTV1 in 9F and 2ARC were close and has no significant differences (p>0.05). The V 95 % (99.45±0.78)% of PTV2 in 9F was slightly better than that in 1ARC (99.35±1.28)%, the difference was significant (p<0.05). All dosimetric indices of PTV2in 9F and 2ARC were close and the difference were no significant (p>0.05). The D mean of bladder and the V 67.5Gy of rectum between all three plans were similarity The D mean of left and right femoral in 1ARC and 2ARC were lower than that in 9F, and the difference was significant (p<0.05). Other dosimetric indices of OARs in 9F were lower than those in 1ARC and 2ARC, and much lower than 1ARC, the difference were significant (p<0.05). The mean monitor units in 1ARC and 2ARC were fewer by 70.0% and 67.2% in comparison with 9F. The treatment mean time in 1ARC and 2ARC were shorter by 81.7% and 61% in comparison with 9F. The verification pass ratios of γ(3%/3mm)were 97.8% (9F), 98.9% (1ARC) and 99.4% (2ARC) respectively, the difference were significant(p<0.05). Conclusion: Compared with IMRT, VMAT improved delivery efficiency noticeably. Two arcs provided comparable tumor dosimetric coverage, but performed worse in dose sparing for bladder, rectum and small bowel. IMRT plan was better than VMAT in prostate cancer simultaneous integrated boost radiotherapy.
A NIR-II light driven hydrogel nanomotor is reported for enhanced intravesical instillation of bladder cancer, by active motion of nanomotors facilitated their distribution in bladder and deep penetration into the mucosa layer of the bladder wall.
The 2019 novel coronavirus infectious disease (COVID-19) pandemic resulted in a surge of assays aimed at detecting severe acute respiratory syndrome (SARS) - coronavirus (CoV) - 2 infection and prior exposure. Although both molecular and antigen testing have clearly defined uses, the utility of serology remains uncertain and is presently not recommended for assessing immunity.We conducted a pragmatic, observational study evaluating four commercially available emergency use authorized laboratory-based COVID-19 serology assays (Assays A-D). Remnant samples from hospitalized, and non-hospitalized SARS-CoV-2 PCR positive patients, as well as vaccinated and unvaccinated individuals were collected and tested. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated. Antibody concentrations were compared across the platforms and populations.A total of 588 remnant samples derived from 500 patients were tested. PPA at 5-12 weeks post-PCR positive results for Assays A-D was 98.3, 97.4, 99.2, and 95.8% respectively. NPA was 100% across all platforms. Mean antibody concentrations at 2-4 weeks post-PCR positive result were significantly higher in hospitalized versus non-hospitalized patients, respectively, for Assay A (131.8 [101.7] vs. 95.6 [100.3] AU/mL, P < 0.001), B (61.7 [62.4] vs. 38.1 [40.5] AU/mL, P < 0.001), and C (157.6 [105.3] vs. 133.3 [100.7] AU/mL, P < 0.001). For individuals receiving two vaccine doses mean antibody concentrations were respectively 169.6 (104.4), 27.3 (50.8), 189.6 (120.9), 21.19 (13.1) AU/mL for Assays A-D.Overall, PPA and NPA differed across the four assays. Assays A and C produced higher PPA and NPA and detected larger concentrations of antibodies following vaccination.
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