Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy.

DNA damage and cytoplasmic DNA induce type-1 interferon (IFN-1) and potentiate responses to immune checkpoint inhibitors. Our prior work found that inhibitors of the DNA damage response kinase ATR (ATRi) induce IFN-1 and deoxyuridine (dU) incorporation by DNA polymerases, akin to antimetabolites. Whether and how dU incorporation is required for ATRi-induced IFN-1 signaling is not known. Here, we show that ATRi-dependent IFN-1 responses require uracil DNA glycosylase (UNG)-initiated base excision repair and STING. Quantitative analyses of nine distinct nucleosides reveals that ATRi induce dU incorporation more rapidly in UNG wild-type than knockout cells, and that induction of IFN-1 is associated with futile cycles of repair. While ATRi induce similar numbers of micronuclei in UNG wild-type and knockout cells, dU containing micronuclei and cytoplasmic DNA are increased in knockout cells. Surprisingly, DNA fragments containing dU block STING-dependent induction of IFN-1, MHC-1, and PD-L1. Furthermore, UNG knockout sensitizes cells to IFN-γ in vitro , and potentiates responses to anti-PD-L1 in resistant tumors in vivo . These data demonstrate an unexpected and specific role for dU-rich DNA in suppressing STING-dependent IFN-1 responses, and show that UNG-deficient tumors have a heightened response to immune checkpoint inhibitors. STATEMENT OF SIGNIFICANCE: Antimetabolites disrupt nucleotide pools and increase dU incorporation by DNA polymerases. We show that unrepaired dU potentiates responses to checkpoint inhibitors in mouse models of cancer. Patients with low tumor UNG may respond to antimetabolites combined with checkpoint inhibitors, and patients with high tumor UNG may respond to UNG inhibitors combined with checkpoint inhibitors.

Preoperative predictors of prolonged length of stay in radical cystectomy: a retrospective study using the American College of Surgeons-National Surgical Quality Improvement Program Dataset.

Background: Radical cystectomy (RC) is considered a complex procedure that entails significant morbidity and mortality. Objectives: We aimed to determine pre-operative patient characteristics that help predict a prolonged length of hospital stay (PLOS) following RC. Design and Methods: The American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database was used to select patients who underwent RC between the years 2011 and 2020. Prolonged length of stay was defined as a hospital stay ⩾9 days. We compared patient demographics, pre-operative labs, surgical characteristics, and medical history between patients with or without PLOS. Multivariable logistic regression models controlling for pre-operative characteristics and propensity score matching for post-operative complications were conducted to control for possible confounders. Results: The analysis yielded details of 19,158 RC patients of which 6007 (31%) patients had a PLOS. Patients with PLOS were more likely to have post-operative complications that could serve as predictors for the PLOS rather than their pre-operative characteristics. Hence, we matched our cohort for these complications. After matching, patient pre-operative characteristics that predict PLOS included female gender (Odds Ratio (OR) = 5.91), 10-year increase in age (OR = 1.15), non-White race (OR = 1.98), partially or totally dependent functional health status (OR = 2.86), bleeding disorders (OR = 4.67), congestive heart failure (OR = 1.59), pre-operative transfusion (OR = 3.03), and a 20-min increase in operative time (OR = 1.01) (p < 0.046). Conclusion: Patient demographics and pre-operative factors can help predict PLOS in RC patients. These predictors could serve as tools for patient counseling and risk stratification.

Nanoparticles: Attractive tools to treat colorectal cancer.

Colorectal Cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite the notable advances achieved over the last few decades, CRC remains a hard-to-treat deadly disease in many patients. This is attributed mainly to chemo- and immuno-resistance, which frequently emerge soon after treatment with conventional therapeutics. Systemic treatments are also constrained by their many undesired and serious side effects. More recently, nanomedicine has emerged as an attractive modality that can overcome issues of therapeutic resistance, improper delivery, or suboptimal targeting of tumor cells. Many nanomaterials, having already been examined in pre-clinical and clinical studies, are now considered biocompatible and relatively safe. Indeed, around 50 nano-formulations have so far been approved as diagnostic and therapeutic agents in humans. Here, in this review, we describe a set of imperative nanoparticles (NPs) involved in diagnosing and treating CRC. In particular, we discuss the theragnostic roles of quantum dots, iron oxide NPs, Polylactide-co-glycolic acid (PLGA) NPs, dendrimer NPs, carbon nanotubes, liposomes, and gold NPs. We dissect the molecular and clinical evidence supporting the use of these NPs in CRC. We also highlight their implications in targeted drug delivery as well as their anti-tumorigenic properties and effects on the cardinal hallmarks of CRC. We conclude by highlighting the notion that nanomedicine is emerging as an attractive approach to address the unmet needs in managing several diseases, including CRC.

Road traffic injury in Lebanon: A prospective study to assess injury characteristics and risk factors.

BACKGROUND: Road traffic injury (RTI) is a significant yet poorly characterized cause of morbidity and mortality in the Middle East. This hospital-based-study examined RTI in Lebanon and provided an understanding of their characteristics. METHODS: We collected prospective RTI data from three participating hospitals over 3 months using a designed tool based on Canadian CHIRPP and WHO tools. We performed logistic regression analysis to examine the relationship between contributing risk factors (age, sex) and injury types as well as the association of safety measures used (seatbelts or helmets) and body parts injured. RESULTS: A total of 153 patients were collected. Male preponderance with 72%, with mean age 32.6 (SD = 14.9) years. RTI was highest among passengers aged 15 to 29 (48%). Motorcyclists comprised the greatest injury proportion (38%), followed by vehicle-occupants (35%), and pedestrians (25%) (P = .04). Hip injuries represented the most affected body part (48.7%), followed by head/neck (38.2%). Only 31% (n = 47) of victims applied safety measures (seatbelts or helmets). Six drivers (7%) reported cell phone use at collision. The use of safety measures was associated with a substantial reduction in head/neck injuries (P = .03), spine injuries (P = .049), and lower risk of traumatic brain injury (TBI) (P = .02). CONCLUSIONS: RTI is a major health problem in Lebanon. Safety measures, though poorly adhered to, were associated with less severe injuries, and should be further promoted via awareness campaigns and enforcement. Trauma registries are needed to assess the RTI burden and inform safety interventions and quality-of-care improvement programs.

Metal-based nanoparticles: Promising tools for the management of cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide. A search for more effective treatments of CVD is increasingly needed. Major advances in nanotechnology opened new avenues in CVD therapeutics. Owing to their special properties, iron oxide, gold and silver nanoparticles (NPs) could exert various effects in the management and treatment of CVD. The role of iron oxide NPs in the detection and identification of atherosclerotic plaques is receiving increased attention. Moreover, these NPs enhance targeted stem cell delivery, thereby potentiating the regenerative capacity at the injured sites. In addition to their antioxidative and antihypertrophic capacities, gold NPs have also been shown to be useful in the identification of plaques and recognition of inflammatory markers. Contrary to first reports suggestive of their cardio-vasculoprotective role, silver NPs now appear to exert negative effects on the cardiovascular system. Indeed, these NPs appear to negatively modulate inflammation and cholesterol uptake, both of which exacerbate atherosclerosis. Moreover, silver NPs may precipitate bradycardia, conduction block and sudden cardiac death. In this review, we dissect the cellular responses and toxicity profiles of these NPs from various perspectives including cellular and molecular ones.