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 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.

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.