Effect of Chronic Steroid Use on Postoperative Wound Complications in Patients Undergoing Arterial Bypass Surgery for Lower Extremity Peripheral Arterial Disease.

BACKGROUND: While existing literature reports adverse effects of chronic steroid use on surgical wound outcomes, there remains lack of data exploring the effect of steroids on postoperative outcomes following lower extremity arterial bypass surgery. This study aims to explore the effect of chronic steroid use on surgical outcomes in patients undergoing open revascularization for lower extremity arterial occlusive disease. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) files between 2005 and 2020, all patients receiving aortoiliac or infrainguinal arterial bypass for peripheral arterial disease (PAD) were identified by Current Procedural Terminology (CPT) codes. Patient characteristics and 30-day outcomes were compared using χ2 test and independent t-test, and the association of chronic steroid use with wound complications was studied using multivariable logistic regression analysis. RESULTS: A total of 44,675 patients undergoing open lower extremity revascularization (LER) were identified, of which 1,807 patients were on chronic steroids, and 42,868 patients were not on chronic steroids. On multivariable logistic regression analysis, being on chronic steroids was associated with higher rates of deep surgical site infections (SSIs) (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.03-1.83), any SSI (OR 1.22, 95% CI 1.04-1.43), and wound dehiscence (OR 1.42, 95% CI 1.03-1.96). Chronic steroid users also had significantly increased odds of developing sepsis (OR 1.56, 95% CI 1.19-2.04), pneumonia (OR 1.44, 95% CI 1.08-1.91), urinary tract infection (UTI) (OR 1.54, 95% CI 11.13-2.09), deep vein thrombosis (DVT) (OR 1.60, 95% CI 1.01-2.53), 30-day readmission (OR 1.30, 95% CI 1.12-1.50), reoperation (OR 1.17, 95% CI 1.01-1.37), and mortality (OR 1.33, 95% CI 1.01-1.76) compared with nonchronic steroid users. CONCLUSIONS: This study confirms that chronic corticosteroid use is associated with higher risk of SSIs in patients undergoing lower extremity arterial bypass surgery. These patients typically have various underlying health issues, emphasizing the need for personalized treatment and management to reduce steroid-related postoperative complications and improve survival.

Intrinsic and Microenvironmental Drivers of Glioblastoma Invasion.

Gliomas are diffusely infiltrating brain tumors whose prognosis is strongly influenced by their extent of invasion into the surrounding brain tissue. While lower-grade gliomas present more circumscribed borders, high-grade gliomas are aggressive tumors with widespread brain infiltration and dissemination. Glioblastoma (GBM) is known for its high invasiveness and association with poor prognosis. Its low survival rate is due to the certainty of its recurrence, caused by microscopic brain infiltration which makes surgical eradication unattainable. New insights into GBM biology at the single-cell level have enabled the identification of mechanisms exploited by glioma cells for brain invasion. In this review, we explore the current understanding of several molecular pathways and mechanisms used by tumor cells to invade normal brain tissue. We address the intrinsic biological drivers of tumor cell invasion, by tackling how tumor cells interact with each other and with the tumor microenvironment (TME). We focus on the recently discovered neuronal niche in the TME, including local as well as distant neurons, contributing to glioma growth and invasion. We then address the mechanisms of invasion promoted by astrocytes and immune cells. Finally, we review the current literature on the therapeutic targeting of the molecular mechanisms of invasion.

Preclinical Models and Technologies in Glioblastoma Research: Evolution, Current State, and Future Avenues.

Glioblastoma is the most common malignant primary central nervous system tumor and one of the most debilitating cancers. The prognosis of patients with glioblastoma remains poor, and the management of this tumor, both in its primary and recurrent forms, remains suboptimal. Despite the tremendous efforts that are being put forward by the research community to discover novel efficacious therapeutic agents and modalities, no major paradigm shifts have been established in the field in the last decade. However, this does not mirror the abundance of relevant findings and discoveries made in preclinical glioblastoma research. Hence, developing and utilizing appropriate preclinical models that faithfully recapitulate the characteristics and behavior of human glioblastoma is of utmost importance. Herein, we offer a holistic picture of the evolution of preclinical models of glioblastoma. We further elaborate on the commonly used in vitro and vivo models, delving into their development, favorable characteristics, shortcomings, and areas of potential improvement, which aids researchers in designing future experiments and utilizing the most suitable models. Additionally, this review explores progress in the fields of humanized and immunotolerant mouse models, genetically engineered animal models, 3D in vitro models, and microfluidics and highlights promising avenues for the future of preclinical glioblastoma research.

The Role of Epac in Cancer Progression.

Cancer continues to be a prime contributor to global mortality. Despite tremendous research efforts and major advances in cancer therapy, much remains to be learned about the underlying molecular mechanisms of this debilitating disease. A better understanding of the key signaling events driving the malignant phenotype of cancer cells may help identify new pharmaco-targets. Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a plethora of biological processes, including those that are characteristic of malignant cells. Over the years, most cAMP-mediated actions were attributed to the activity of its effector protein kinase A (PKA). However, studies have revealed an important role for the exchange protein activated by cAMP (Epac) as another effector mediating the actions of cAMP. In cancer, Epac appears to have a dual role in regulating cellular processes that are essential for carcinogenesis. In addition, the development of Epac modulators offered new routes to further explore the role of this cAMP effector and its downstream pathways in cancer. In this review, the potentials of Epac as an attractive target in the fight against cancer are depicted. Additionally, the role of Epac in cancer progression, namely its effect on cancer cell proliferation, migration/metastasis, and apoptosis, with the possible interaction of reactive oxygen species (ROS) in these phenomena, is discussed with emphasis on the underlying mechanisms and pathways.

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies.

Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma's response to therapeutic modalities.

Pediatric Hemispheric High-Grade Gliomas and H3.3-G34 Mutation: A Review of the Literature on Biological Features and New Therapeutic Strategies.

Pediatric high-grade glioma (pHGG) encompasses a wide range of gliomas with different genomic, epigenomic, and transcriptomic features. Almost 50% of pHGGs present a mutation in genes coding for histone 3, including the subtype harboring the H3.3-G34 mutation. In this context, histone mutations are frequently associated with mutations in TP53 and ATRX, along with PDGFRA and NOTCH2NL amplifications. Moreover, the H3.3-G34 histone mutation induces epigenetic changes in immune-related genes and exerts modulatory functions on the microenvironment. Also, the functionality of the blood-brain barrier (BBB) has an impact on treatment response. The prognosis remains poor with conventional treatments, thus eliciting the investigation of additional and alternative therapies. Promising molecular targets include PDGFRA amplification, BRAF mutation, EGFR amplification, NF1 loss, and IDH mutation. Considering that pHGGs harboring the H3.3-G34R mutation appear to be more susceptible to immunotherapies (ITs), different options have been recently explored, including immune checkpoint inhibitors, antibody mediated IT, and Car-T cells. This review aims to summarize the knowledge concerning cancer biology and cancer-immune cell interaction in this set of pediatric gliomas, with a focus on possible therapeutic options.

Brain Nucleic Acid Delivery and Genome Editing via Focused Ultrasound-Mediated Blood-Brain Barrier Opening and Long-Circulating Nanoparticles.

We introduce a two-pronged strategy comprising focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening and long-circulating biodegradable nanoparticles (NPs) for systemic delivery of nucleic acids to the brain. Biodegradable poly(ß-amino ester) polymer-based NPs were engineered to stably package various types of nucleic acid payloads and enable prolonged systemic circulation while retaining excellent serum stability. FUS was applied to a predetermined coordinate within the brain to transiently open the BBB, thereby allowing the systemically administered long-circulating NPs to traverse the BBB and accumulate in the FUS-treated brain region, where plasmid DNA or mRNA payloads produced reporter proteins in astrocytes and neurons. In contrast, poorly circulating and/or serum-unstable NPs, including the lipid NP analogous to a platform used in clinic, were unable to provide efficient nucleic acid delivery to the brain regardless of the BBB-opening FUS. The marriage of FUS-mediated BBB opening and the long-circulating NPs engineered to copackage mRNA encoding CRISPR-associated protein 9 and single-guide RNA resulted in genome editing in astrocytes and neurons precisely in the FUS-treated brain region. The combined delivery strategy provides a versatile means to achieve efficient and site-specific therapeutic nucleic acid delivery to and genome editing in the brain via a systemic route.

The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies.

Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population. Despite the use of multiple therapeutic approaches consisting of surgical resection, craniospinal irradiation, and multiagent chemotherapy, the prognosis of many patients with medulloblastoma remains dismal. Additionally, the high doses of radiation and the chemotherapeutic agents used are associated with significant short- and long-term complications and adverse effects, most notably neurocognitive delay. Hence, there is an urgent need for the development and clinical integration of targeted treatment regimens with greater efficacy and superior safety profiles. Since the adoption of the molecular-based classification of medulloblastoma into wingless (WNT) activated, sonic hedgehog (SHH) activated, group 3, and group 4, research efforts have been directed towards unraveling the genetic, epigenetic, transcriptomic, and proteomic profiles of each subtype. This review aims to delineate the progress that has been made in characterizing the neurodevelopmental and molecular features of each medulloblastoma subtype. It further delves into the implications that these characteristics have on the development of subgroup-specific targeted therapeutic agents. Furthermore, it highlights potential future avenues for combining multiple agents or strategies in order to obtain augmented effects and evade the development of treatment resistance in tumors.

Smoking Is Not an Independent Risk Factor for Surgery in Patients with Crohn's Disease on Biologic Therapy.

Introduction: The development and course of inflammatory bowel disease appear to be influenced by environmental factors. Particularly, smoking has been shown to assume a harmful role in Crohn's disease (CD) and a protective role in ulcerative colitis. This study aims to examine the effect of smoking on need for surgery in patients with moderate to severe CD receiving biologic therapy. Methods: This was a retrospective study of adult patients with CD at a University Medical Center over a 20-year period. Results: A total of 251 patients were included (mean age 36.0 ± 15.0; 70.1% males; current, former, and nonsmokers: 44.2%, 11.6%, and 43.8%, respectively). Mean duration on biologics was 5.0 ± 3.1 years (>2/3 received anti-TNFs, followed by ustekinumab in 25.9%) and a third of patients (29.5%) received more than one biologic. Disease-related surgeries (abdominal, perianal, or both) occurred in 97 patients (38.6%): 50 patients had surgeries prior to starting biologics only, 41 had some surgeries after, and 6 had insufficient information. There was no significant difference in surgeries between ever-smokers (current or previous) versus nonsmokers in the overall study group. On logistic regression, the odds of having any CD surgery were higher in patients with longer disease duration (OR = 1.05, 95% CI = 1.01, 1.09) and in those receiving more than one biologic (OR = 2.31, 95% CI = 1.16, 4.59). However, among patients who had surgery prior to biologic therapy, smokers were more likely to have perianal surgery compared to nonsmokers (OR = 10.6, 95% CI = 2.0, 57.4; p = 0.006). Conclusion: In biologic-naive CD patients requiring surgery, smoking is an independent predictor of perianal surgery. Smoking, however, is not an independent risk factor for surgery in this cohort after starting biologics. The risk of surgery in those patients is primarily associated with disease duration and the use of more than one biologic.

Epac as a tractable therapeutic target.

In 1957, cyclic adenosine monophosphate (cAMP) was identified as the first secondary messenger, and the first signaling cascade discovered was the cAMP-protein kinase A (PKA) pathway. Since then, cAMP has received increasing attention given its multitude of actions. Not long ago, a new cAMP effector named exchange protein directly activated by cAMP (Epac) emerged as a critical mediator of cAMP's actions. Epac mediates a plethora of pathophysiologic processes and contributes to the pathogenesis of several diseases such as cancer, cardiovascular disease, diabetes, lung fibrosis, neurological disorders, and others. These findings strongly underscore the potential of Epac as a tractable therapeutic target. In this context, Epac modulators seem to possess unique characteristics and advantages and hold the promise of providing more efficacious treatments for a wide array of diseases. This paper provides an in-depth dissection and analysis of Epac structure, distribution, subcellular compartmentalization, and signaling mechanisms. We elaborate on how these characteristics can be utilized to design specific, efficient, and safe Epac agonists and antagonists that can be incorporated into future pharmacotherapeutics. In addition, we provide a detailed portfolio for specific Epac modulators highlighting their discovery, advantages, potential concerns, and utilization in the context of clinical disease entities.

Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms.

Cancer is a leading cause of morbidity and mortality around the globe. Reactive oxygen species (ROS) play contradicting roles in cancer incidence and progression. Antioxidants have attracted attention as emerging therapeutic agents. Among these are flavonoids, which are natural polyphenols with established anticancer and antioxidant capacities. Increasing evidence shows that flavonoids can inhibit carcinogenesis via suppressing ROS levels. Surprisingly, flavonoids can also trigger excessive oxidative stress, but this can also induce death of malignant cells. In this review, we explore the inherent characteristics that contribute to the antioxidant capacity of flavonoids, and we dissect the scenarios in which they play the contrasting role as pro-oxidants. Furthermore, we elaborate on the pathways that link flavonoid-mediated modulation of ROS to the prevention and treatment of cancer. Special attention is given to the ROS-mediated anticancer functions that (-)-epigallocatechin gallate (EGCG), hesperetin, naringenin, quercetin, luteolin, and apigenin evoke in various cancers. We also delve into the structure-function relations that make flavonoids potent antioxidants. This review provides a detailed perspective that can be utilized in future experiments or trials that aim at utilizing flavonoids or verifying their efficacy for developing new pharmacologic agents. We support the argument that flavonoids are attractive candidates for cancer therapy.

Repurposing Cilostazol for Raynaud's Phenomenon.

Raynaud 's Phenomenon (RP) results from exaggerated cold-induced vasoconstriction. RP patients suffer from vasospastic attacks and compromised digital blood perfusion leading to a triple color change at the level the fingers. Severe RP may cause ulcers and threaten tissue viability. Many drugs have been used to alleviate the symptoms of RP. These include calcium-channel blockers, cGMP-specific phosphodiesterase type 5 inhibitors, prostacyclin analogs, and angiotensin receptor blockers. Despite their variety, these drugs do not treat RP but rather alleviate its symptoms. To date, no drug for RP has been yet approved by the U.S Food and Drugs Administration. Cilostazol is a selective inhibitor of phosphodiesterase-III, originally prescribed to treat intermittent claudication. Owing to its antiplatelet and vasodilating properties, cilostazol is being repurposed as a potential drug for RP. This review focuses on the different lines of action of cilostazol serving to enhance blood perfusion in RP patients.