Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade.

There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability.

CXCL9 recombinant adeno-associated virus (AAV) virotherapy sensitizes glioblastoma (GBM) to anti-PD-1 immune checkpoint blockade.

The promise of immunotherapy to induce long-term durable responses in conventionally treatment resistant tumors like glioblastoma (GBM) has given hope for patients with a dismal prognosis. Yet, few patients have demonstrated a significant survival benefit despite multiple clinical trials designed to invigorate immune recognition and tumor eradication. Insights gathered over the last two decades have revealed numerous mechanisms by which glioma cells resist conventional therapy and evade immunological detection, underscoring the need for strategic combinatorial treatments as necessary to achieve appreciable therapeutic effects. However, new combination therapies are inherently difficult to develop as a result of dose-limiting toxicities, the constraints of the blood-brain barrier, and the suppressive nature of the GBM tumor microenvironment (TME). GBM is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment, infiltration, and activation. We have developed a novel recombinant adeno-associated virus (AAV) gene therapy strategy that enables focal and stable reconstitution of the GBM TME with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for cytotoxic T lymphocytes (CTLs). By precisely manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by CD8-postive cytotoxic lymphocytes, sensitizing GBM to anti-PD-1 immune checkpoint blockade (ICB). These effects are accompanied by immunologic signatures evocative of an inflamed and responsive TME. These findings support targeted AAV gene therapy as a promising adjuvant strategy for reconditioning GBM immunogenicity given its excellent safety profile, TME-tropism, modularity, and off-the-shelf capability, where focal delivery bypasses the constrains of the blood-brain barrier, further mitigating risks observed with high-dose systemic therapy.

Perioperative Management of the Acute Stroke Patient: From Door to Needle to NeuroICU.

Acute ischemic stroke is a neurologic emergency that requires precise care due to high likelihood of morbidity and mortality. Current guidelines recommend thrombolytic therapy with alteplase within the first 3 to 4.5 hours of initial stroke symptoms and endovascular mechanical thrombectomy within the first 16 to 24 hours. Anesthesiologists may be involved in the care of these patients perioperatively and in the intensive care unit. Although the optimal anesthetic for these procedures remains under investigation, this article will review how to best optimize and treat these patients to achieve the best outcomes.

Syndromic obesity with neurodevelopmental delay: Opportunities for targeted interventions.

Obesity is a growing public health problem in many developed countries, although similar trends are increasingly being described in some developing nations. The genetic underpinnings of obesity continue to arouse increasing research interests, investigations, and discussions. The recent advances in next generation sequencing technologies have shed some more light on the diverse monogenic and polygenic causes of obesity. Syndromic obesity due to chromosomal or monogenic defects has attendant co-morbidities, which may include neurodevelopmental delays, dysmorphism as well as organ-specific developmental anomalies. An improved understanding of the nature of neurodevelopmental challenges in syndromic obesity may pave the way for personalized dietary and physical activity management approaches. This review article describes the clinical and molecular genetic aspects of obesity-related syndromes and the associated neurodevelopmental disabilities. The potential opportunities for individualized nutrigenomic managements of syndromic obesity are also highlighted.

Anesthesia and postoperative pain control-multimodal anesthesia protocol.

Multimodal analgesia (MMA) involves the use of additive or synergistic combinations of analgesics to achieve clinically required analgesia while minimizing significant side effects associated with higher dose of a single equianalgesic medication such as an opioid analgesic. MMA generally involves optimizing non-opioid pharmacologic and non-pharmacologic interventions and reserving opioid use to treat breakthrough pain. Patients receiving medications via MMA protocols are likely to have lower opioid consumption compared to those managed using primarily IV opioid patient-controlled analgesia. MMA pain management strategies have become important components of enhanced recovery after surgery (ERAS) protocols in an effort to optimize care by standardizing analgesic medications in the perioperative setting while minimizing adverse effects and improving quality and patient outcomes. Successful implementation of a MMA requires the input and cooperation of all of the stakeholders including the caregivers as well as the patients. Health system benefits can also be realized from the implementation of an effective MMA, as fewer opioid related side effects can improve patient recovery and lead to faster discharge and improved utilization of resources.