The Effects of PVP(Fe(III)) Catalyst on Polymer Molecular Weight and Gene Delivery via Biodegradable Cross-Linked Polyethylenimine

The original publication is available at www.springerlink.comPurpose Crosslinked, degradable derivatives of low-molecular-weight polyethylenimine (PEI) are relatively efficient and non-cytotoxic gene delivery agents. To further investigate these promising materials, a new synthetic approach was developed using a poly(4-vinylpyridine)-supported Fe(III) catalyst (PVP(Fe(III))) that provides more facile synthesis and enhanced control of polymer molecular weight. Methods Biodegradable polymers (D.PEI) comprising 800-Da PEI crosslinked with 1,6-hexanediol diacrylate and exhibiting molecular weights of 1.2, 6.2, and 48 kDa were synthesized utilizing the PVP(Fe(III)) catalyst. D.PEI/DNA polyplexes were characterized using gel retardation, ethidium bromide exclusion, heparan sulfate displacement, and dynamic light scattering. In vitro transfection, cellular uptake, and cytotoxicity of the polyplexes were tested in human cervical cancer cells (HeLa) and human breast cancer cells (MDA-MB-231). Results D.PEIs tightly complexed plasmid DNA and formed 320- to 440-nm diameter polyplexes, similar to those comprising non-degradable, 25-kDa, branched PEI. D.PEI polyplexes mediated 2- to 5-fold increased gene delivery efficacy compared to 25-kDa PEI and exhibited 20% lower cytotoxicity in HeLa and no toxicity in MDA-MB-231. In addition, 2- to 7-fold improved cellular uptake of DNA was achieved with D.PEI polyplexes. Conclusions PVP(Fe(III)) catalyst provided a more controlled synthesis of D.PEIs, and these materials demonstrated improved in vitro transfection efficacy and reduced cytotoxicity

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Should prior FIT results be incorporated as an additional variable to estimate risk of colorectal neoplasia? A prospective study of 5,813 screening colonoscopies.

Recent studies showed that previous negative results from faecal immunochemical tests (FITs) for colorectal cancer (CRC) screening was associated with lower risk of advanced neoplasia (AN). We evaluated whether prior FIT results should be included to estimate the risk of AN in 2008-2012.A community-based screening practice recruited 5,813 asymptomatic residents aged 50 to 70 years in Hong Kong for CRC screening. We included study participants who had (1). positive FIT with subsequent colonoscopy workup (FIT+ group; n = 356); (2). negative FIT in three consecutive years and received a colonoscopy (FIT- group; n = 857); (3). received colonoscopy without FIT (colonoscopy group; n = 473); and (4). received both colonoscopy and FIT at the same time (combined group; n = 4,127). One binary logistic regression model evaluated whether prior FIT results were associated with colonoscopy findings of AN.The proportion of participants having AN/CRC was 18.0% (FIT+), 5.5% (FIT-), 8.0% (colonoscopy group), and 4.3% (combined group), respectively. When compared with the colonoscopy group, those in the FIT- group were not significantly more or less likely to have AN/CRC (AOR = 0.77, 95% C.I. = 0.51 to 1.18, p = 0.230). Having one (AOR = 0.73, 95% C.I. 0.48-1.12, p = 0.151) or three consecutive negative FIT result (AOR = 0.98, 95% C.I. 0.60-1.62, p = 0.944) were not associated with lower risks of AN/CRC. Subjects in the FIT+ group was 3.32-fold (95% C.I. 2.07 to 5.32, p < 0.001) more likely to have AN/CRC.These findings indicated that subjects with negative FIT findings could be risk stratified similarly as those who had not previously received FIT

The association between prior FIT findings and colonoscopic findings of advanced neoplasia/CRC.

<p>*The n number and % represent the number and proportion (across rows) of subjects found to have advanced neoplasia or colorectal cancer on colonoscopy. Advanced Neoplasia is defined as any colorectal adenoma which has a size of ≥ 10 mm in diameter, high grade dysplasia, villous or tubulovillous histologic characteristics, or any combination thereof. BMI: Body Mass Index; CRC: colorectal cancer; FIT: Faecal Immunochemical Tests; IHD: Ischemic Heart Disease; NSAIDs: Non-steroidal Anti-Inflammatory Disease.</p><p>The association between prior FIT findings and colonoscopic findings of advanced neoplasia/CRC.</p

The association between CRC screening groups and the colonoscopic findings of advanced neoplasia/CRC.

<p>The adjusted model controlled for age, gender, BMI, smoking, alcohol intake, family history of CRC and self-reported hypertension. n (%) represents the number and proportion of patients having advanced neoplasia or CRC for each row.</p><p>The association between CRC screening groups and the colonoscopic findings of advanced neoplasia/CRC.</p

Proceedings of The HKIE Geotechnical Division 43rd Annual Seminar: Towards a Smart-Green-Resilient Geo-Future for World-class City

This seminar proceedings contain articles on the various research ideas of the academic community and practitioners presented at The HKIE Geotechnical Division 43rd Annual Seminar (GDAS2023). This seminarprovides a platform for policymakers, practitioners, and academia to share their insights and brainstorm ideas with a view to seizing future opportunities and shaping the new future of Hong Kong. GDAS2023 was organized by the Geotechnical Division, The Hong Kong Institution of Engineers on 19th May 2023. Seminar Title: The HKIE Geotechnical Division 43rd Annual SeminarSeminar Acronym: GDAS2023Seminar Date: 19 May 2023Seminar Location:  Hong KongSeminar Organizers: Geotechnical Division, The Hong Kong Institution of Engineers Link to the GDAS2021 Proceedings: Proceedings of The HKIE Geotechnical Division 41st Annual Seminar Link to the GDAS2022 Proceedings: Proceedings of The HKIE Geotechnical Division 42nd Annual Semina

Proceedings of The HKIE Geotechnical Division 42nd Annual Seminar: A New Era of Metropolis and Infrastructure Developments in Hong Kong, Challenges and Opportunities to Geotechnical Engineering

This seminar proceedings contain articles on the various research ideas of the academic community and practitioners presented at The HKIE Geotechnical Division 42nd Annual Seminar (GDAS2022). GDAS2022 was organized by the Geotechnical Division, The Hong Kong Institution of Engineers on 13th May 2022. Seminar Title: The HKIE Geotechnical Division 42nd Annual SeminarSeminar Acronym: GDAS2022Seminar Date: 13 May 2022Seminar Location:  Hong KongSeminar Organizers: Geotechnical Division, The Hong Kong Institution of Engineers Link to the GDAS2021 Proceedings: Proceedings of The HKIE Geotechnical Division 41st Annual Semina