signifinder enables the identification of tumor cell states and cancer expression signatures in bulk, single-cell and spatial transcriptomic data.

Over the last decade, many studies and some clinical trials have proposed gene expression signatures as a valuable tool for understanding cancer mechanisms, defining subtypes, monitoring patient prognosis, and therapy efficacy. However, technical and biological concerns about reproducibility have been raised. Technical reproducibility is a major concern: we currently lack a computational implementation of the proposed signatures, which would provide detailed signature definition and assure reproducibility, dissemination, and usability of the classifier. Another concern regards intratumor heterogeneity, which has never been addressed when studying these types of biomarkers using bulk transcriptomics. With the aim of providing a tool able to improve the reproducibility and usability of gene expression signatures, we propose signifinder, an R package that provides the infrastructure to collect, implement, and compare expression-based signatures from cancer literature. The included signatures cover a wide range of biological processes from metabolism and programmed cell death, to morphological changes, such as quantification of epithelial or mesenchymal-like status. Collected signatures can score tumor cell characteristics, such as the predicted response to therapy or the survival association, and can quantify microenvironmental information, including hypoxia and immune response activity. signifinder has been used to characterize tumor samples and to investigate intra-tumor heterogeneity, extending its application to single-cell and spatial transcriptomic data. Through these higher-resolution technologies, it has become increasingly apparent that the single-sample score assessment obtained by transcriptional signatures is conditioned by the phenotypic and genetic intratumor heterogeneity of tumor masses. Since the characteristics of the most abundant cell type or clone might not necessarily predict the properties of mixed populations, signature prediction efficacy is lowered, thus impeding effective clinical diagnostics. Through signifinder, we offer general principles for interpreting and comparing transcriptional signatures, as well as suggestions for additional signatures that would allow for more complete and robust data inferences. We consider signifinder a useful tool to pave the way for reproducibility and comparison of transcriptional signatures in oncology.

Efficacy and safety of everolimus and zotarolimus-eluting stents versus first-generation drug-eluting stents in patients with diabetes: A meta-analysis of randomized trials.

INTRODUCTION: Patients with diabetes and coronary artery disease remain at high risk for adverse cardiovascular events after percutaneous coronary intervention. The efficacy and safety of the various drug-eluting stents (DES) in patients with diabetes is unclear. METHODS: Randomized controlled trials comparing first-generation DES [paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES)] with everolimus-eluting stents (EES) and zotarolimus-eluting stents (ZES) in diabetic patients were systematically searched. Efficacy [target vessel revascularization (TVR) and target lesion revascularization (TLR)] and safety [major adverse cardiac events (MACE), all-cause and cardiac mortality, myocardial infarction, stent thrombosis] outcomes were evaluated. RESULTS: Eighteen randomized controlled trials comprising of 8095 patients (17,000 patient-years of follow-up) were included. Compared to first-generation DES, EES significantly decreased MACE by 18% (relative risk [RR]: 0.82, 95% confidence interval [CI]: 0.70-0.96), myocardial infarction by 43% (RR: 0.57, 95% CI: 0.39-0.84) and stent thrombosis by 46% (RR: 0.54, 95% CI: 0.35-0.82) in patients with diabetes. Moreover EES showed a trend towards reduction in rates of TLR and TVR (p=0.05). ZES was associated with 89% increased risk for TLR (RR: 1.89, 95% CI: 1.10-3.22) compared to first-generation DES. Furthermore, meta-regression analysis showed a greater magnitude of benefit of EES over first-generation DES for MACE (p=0.037) and stent thrombosis (p=0.036) in diabetic patients requiring Insulin. CONCLUSIONS: In patients with diabetes and coronary artery disease undergoing stenting, EES is the most efficacious and safe DES. The outcomes data for ZES in diabetes patients were limited and further trials are needed.

Parkinsonian gait ameliorated with a moving handrail, not with a banister.

OBJECTIVE: To determine whether haptic (touch and proprioception) cues from touching a moving handrail while walking can ameliorate the gait symptoms of Parkinson disease (PD), such as slowness and small stride length. DESIGN: Nonrandomized, controlled before-after trial. SETTING: Physical therapy clinic. PARTICIPANTS: People with PD (n=16) and healthy age-matched control subjects (n=16) with no neurologic disorders volunteered. No participants withdrew. INTERVENTIONS: We compared gait using a moving handrail as a novel assistive aid (speed self-selected) versus a banister and unassisted walking. Participants with PD were tested on and off dopaminergic medication. MAIN OUTCOME MEASURES: Mean gait speed, stride length, stride duration, double-support duration, and medial-lateral excursion. RESULTS: With the moving handrail, participants with PD increased gait speed relative to unassisted gait by 16% (.166m/s, P=.009, d=.76; 95% confidence interval [CI], .054-.278m/s) and increased stride length by 10% (.053m, P=.022, d=.37; 95% CI, .009-.097m) without significantly changing stride or double-support duration. The banister reduced speed versus unassisted gait by 11% (-.097m/s, P=.040, d=.40; 95% CI, .002-.193m/s) and reduced stride length by 8% (.32m, P=.004, d=.26; 95% CI, .010-.054m), whereas it increased stride duration by 3% (.023s, P=.022, d=.21; 95% CI, .004-.041s) and double-support duration by 35% (.044s, P=.031, d=.58; 95% CI, .005-.083s). All medication × condition interactions were P>.05. CONCLUSIONS: Using haptic speed cues from the moving handrail, people with PD walked faster by spontaneously (ie, without specific instruction) increasing stride length without altering cadence; banisters slowed gait. Haptic cues from the moving handrail can be used by people with PD to engage biomechanical and neural mechanisms for interpreting tactile and proprioception changes related to gait speed to control gait better than static cues afforded by banisters.