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Introduction Endovascular therapy (EVT) has revolutionized acute stroke treatment, but large vessel recanalization does not always result in tissue‐level reperfusion. Cerebral blood flow (CBF) is not routinely monitored during EVT. Here we aimed to leverage diffuse correlation spectroscopy (DCS), a novel transcranial optical imaging technique, to assess the relationship between microvascular CBF and post‐EVT outcomes. Methods Frontal lobe CBF was monitored by DCS in 40 patients undergoing EVT. Baseline CBF deficit was calculated as the percentage of CBF impairment on pre‐EVT CT perfusion. Microvascular reperfusion was calculated as the percentage increase in DCS‐derived CBF that occurred with recanalization. The adequacy of reperfusion was defined by persistent CBF deficit, calculated as: baseline CBF deficit ‐ microvascular reperfusion. Good functional outcome was defined as 90‐day modified Rankin Scale ≤2. Results 36 (of 40) patients achieved successful recanalization, in whom microvascular reperfusion in itself was not associated with infarct volume or functional outcome. However, patients with good functional outcomes had a smaller persistent CBF deficit (median: 1%; IQR: ‐11%–16%) than patients with poor outcomes (median: 28%; IQR: 2%–50%), p=0.02. Smaller persistent CBF deficit was also associated with smaller infarct volume (p=0.004). Multivariate models confirmed that persistent CBF deficit was independently associated with infarct volume and functional outcome. Conclusion CBF augmentation alone does not predict post‐EVT outcomes, but when microvascular reperfusion closely matches the baseline CBF deficit, patients experience favorable clinical and radiographic outcomes. By recognizing inadequate reperfusion, bedside CBF monitoring may provide opportunities to personalize post‐EVT care aimed at CBF optimization.

Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.

Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD‐1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death‐ligand 1 (PD‐L1) found on cancer cells. Blocking PD‐1/PD‐L1 binding improves T‐cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD‐1/PD‐L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti‐PD‐1/PD‐L1 treatment. Chemokine‐like factor (CKLF)–like MARVEL transmembrane domain–containing 6 (CMTM6) has been recently identified as a major regulator of PD‐L1. Another member in the CMTM family, CKLF‐like MARVEL transmembrane domain–containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD‐L1 in the context of liver cancer. Up‐regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD‐L1 expression, hence facilitating escape from T cell–mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD‐L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD‐L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8+ T‐cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti‐PD‐L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti‐PD‐L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti‐PD‐L1 immunotherapy in patients with liver cancer.

Background Endovascular therapy for acute ischemic stroke has revolutionized clinical care for patients with stroke and large vessel occlusion, but treatment remains time sensitive. At our stroke center, up to half of the door‐to‐groin time is accounted for after the patient arrives in the angio‐suite. Here, we apply the concept of a highly visible timer in the angio‐suite to quantify the impact on endovascular treatment time. Methods This was a single‐center prospective pseudorandomized study conducted over a 32‐week period. Pseudorandomization was achieved by turning the timer on and off in 2‐week intervals. The primary outcome was angio‐suite‐to‐groin time, and secondary outcomes were angio‐suite‐to‐intubation time, groin‐to‐recanalization time, and 90‐day modified Rankin scale. A stratified analysis was performed based on type of anesthesia (ie, endotracheal intubation versus not). Results During the 32‐week study period, 97 mechanical thrombectomies were performed. The timer was on and off for 38 and 59 cases, respectively. The timer resulted in faster angio‐suite‐to‐groin time (28 versus 33 minutes; P=0.02). The 5‐minute reduction in angio‐suite‐to‐groin was maintained after adjusting for intubation status in a multivariate regression (P=0.02). There was no difference in the 90‐day modified Rankin scale between groups. The timer impact was consistent across the 32‐week study period. Conclusions A highly visible timer in the angio‐suite achieved a meaningful, albeit modest, reduction in endovascular treatment time for patients with stroke. Given the lack of risk and low cost, it is reasonable for stroke centers to consider a highly visible timer in the angio‐suite to improve treatment times.

Background Acute endovascular revascularization for isolated internal carotid occlusion without tandem intracranial occlusion has been proposed to prevent early neurologic deterioration (END) and improve outcome, but has not been shown to be more effective than medical therapy. We aimed to evaluate prognosis with initial medical therapy alone, and also performed a systematic review to put these results in a broader context. Methods We performed a retrospective cohort study of patients admitted over a 2‐year period with acute stroke/transient ischemic attack due to isolated internal carotid artery occlusion. Subjects with tandem intracranial occlusion or Alberta Stroke Program Early CT Score (ASPECTS) ≤5 were excluded. The primary outcome was END within 48 hours (National Institute of Health Stroke Scale [NIHSS] increase ≥4 persisting for ≥24 hours). Secondary outcomes included discharge NIHSS and disposition. We also performed a systematic review and meta‐analysis of published studies along with the data from our cohort. Results Twenty‐three patients met our inclusion criteria. Median age was 69 years, initial Alberta Stroke Program Early CT Score 10, and NIHSS score 3. END attributed to recurrent ischemia occurred in 5/23 patients (22%, 95% CI: 7%–44%). At discharge, 78% had a favorable outcome with a median NIHSS of 2 (interquartile range 1–3). END appeared more frequent in those with higher baseline NIHSS. In our systematic review, 7 prior studies met our inclusion criteria. END occurred in 17% (95% CI: 12%–23%) of patients, 18% with medical therapy versus 13% with endovascular therapy, with substantial heterogeneity among studies. Conclusion In patients with acute stroke or transient ischemic attack due to isolated internal carotid occlusion, END is relatively common (occurring in about 1 out of 6 patients). Further research is needed to evaluate the roles of maximal medical management or acute endovascular thrombectomy in these patients.

Summary: Vascular development is a complex multistep process involving the coordination of cellular functions such as migration, proliferation, and differentiation. How mechanical forces generated by cells and transmission of these physical forces control vascular development is poorly understood. Using an endothelial-specific genetic model in mice, we show that deletion of the scaffold protein Angiomotin (Amot) inhibits migration and expansion of the physiological and pathological vascular network. We further show that Amot is required for tip cell migration and the extension of cellular filopodia. Exploiting in vivo and in vitro molecular approaches, we show that Amot binds Talin and is essential for relaying forces between fibronectin and the cytoskeleton. Finally, we provide evidence that Amot is an important component of the endothelial integrin adhesome and propose that Amot integrates spatial cues from the extracellular matrix to form a functional vascular network.

Abstract COVID‐19 infection can be a possible trigger for peripartum cardiomyopathy. Multidisciplinary teamwork was crucial for the favorable outcome in our patient. Small bowel strangulation is a rare complication post‐cesarean section.

Objective: Transcranial Doppler is commonly used to calculate cerebral autoregulation, but measurements are typically restricted to a single cerebral artery. In exploring topographic heterogeneity, this study reports the first thorough comparison of autoregulation in all major cerebral vessels.Methods: In forty healthy adults, flow velocity was monitored in the anterior, middle, and posterior cerebral arteries, and synchronized with arterial blood pressure. A transfer function analysis provided characteristics of autoregulation by quantifying the relationship between blood pressure and cerebral blood flow velocity.Results: Phase, which quantifies the time course of autoregulation, was similar in all vessels. Gain, which quantifies the magnitude of hemodynamic regulation, was lower in posterior cerebral artery, indicative of tighter regulation. However, after adjusting for baseline flow differences in each vascular territory, normalized gain was similar in all vessels.Conclusions: Discriminating dynamic cerebral autoregulation between cerebrovascular territories is feasible with a transcranial doppler based approach. In the posterior cerebral artery of healthy volunteers, absolute flow is more tightly regulated, but relative flow regulation is consistent across cerebrovascular territories.Significance: The methodology can be applied to focal disease states such as stroke or posterior reversible encephalopathy syndrome, in which the topographic distribution of autoregulation may be particularly critical.

Cervical carotid artery dissections (CAD) usually produce ischemic symptoms as a result of thromboembolic phenomena, but hemodynamic insufficiency from flow-limiting stenosis can cause symptoms in a few patients [1]. CAD of the distal cervical and petrous ICA can be challenging to treat, particularly in the presence of vessel kinking or marked tortuosity of the distal cervical ICAs. The carotid stent systems used for atherosclerotic disease at the proximal ICA or carotid bulb are typically too stiff and large to safely track into a tortuous distal carotid artery, and the low radial force of the Pipeline flow diverter may occasionally result in inadequate flow restoration and even stent collapse in flow-limiting carotid dissections with large intramural thrombus burden [2,3]. In this paper, via 2 illustrative cases, we detail our experience with the latest iteration of the Neuroform stent system, the Neuroform Atlas (Stryker Neurovascular, Freemont, CA), for treatment of symptomatic flow-limiting distal cervical ICA dissections, with an emphasis on the advantages of the updated stent design.

Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. Here, the authors show that in hepatocellular carcinoma, hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5′-AMP, which in turn promote the maintenance of MDSCs by preventing their differentiation.

Self-thrombosing intracranial aneurysms are relatively uncommon and the conditions that lead to their formation are unknown, although they can be seen following subarachnoid hemorrhage and in autopsy specimens. We seek to raise awareness of the unintended iatrogenic thrombosis of intracranial aneurysms, its ischemic consequences, and the use of mechanical thrombectomy in its treatment. A 50-year-old hypertensive woman presented with a sudden onset of severe headache concerning for a ruptured cerebral aneurysm (Hunt-Hess 2). HCT showed diffuse subarachnoid hemorrhage (modified Fisher grade 3), and CTA showed two aneurysms arising from an anterior communicating (ACOM) complex fenestration and one aneurysm arising from the proximal left anterior cerebral artery (ACA) A1 segment. Successful coil embolization of the distal ACOM aneurysm was followed by an attempted balloon-assisted coil embolization of a left ACA A1 aneurysm that led to self-thrombosis and partial occlusion of the A1 segment. After mechanical thrombectomy, there was significant reduction in left A1 thrombus burden. The patient developed an asymptomatic small infarct of the left caudate, likely by occlusion of an anatomic variant of the recurrent artery of Heubner arising from the A1 segment. To our knowledge, this is the first reported case of a self-thrombosing aneurysm during attempted balloon-assisted embolization. Propagation of the thrombus can lead to parent vessel occlusion and ischemia, and, in this case, an anatomic variant of the recurrent artery of Heubner from A1 made this more likely. Intra-arterial mechanical thrombectomy may be used in the treatment of an iatrogenic vessel thrombosis. Keywords: Self-thrombosing, Heubner artery, Aneurysm, Caudate, Anatomic variant

Hepatocellular carcinoma (HCC) is an aggressive tumor, with a high mortality rate due to late symptom presentation and frequent tumor recurrences and metastasis. It is also a rapidly growing tumor supported by different metabolic mechanisms; nevertheless, the biological and molecular mechanisms involved in the metabolic reprogramming in HCC are unclear. In this study, we found that pyruvate kinase M2 (PKM2) was frequently over-expressed in human HCCs and its over-expression was associated with aggressive clinicopathological features and poor prognosis of HCC patients. Furthermore, knockdown of PKM2 suppressed aerobic glycolysis and cell proliferation in HCC cell lines in vitro. Importantly, knockdown of PKM2 hampered HCC growth in both subcutaneous injection and orthotopic liver implantation models, and reduced lung metastasis in vivo. Of significance, PKM2 over-expression in human HCCs was associated with a down-regulation of a liver-specific microRNA, miR-122. We further showed that miR-122 interacted with the 3UTR of the PKM2 gene. Re-expression of miR-122 in HCC cell lines reduced PKM2 expression, decreased glucose uptake in vitro, and suppressed HCC tumor growth in vivo. Our clinical data and functional studies have revealed a novel biological mechanism involved in HCC metabolic reprogramming.

Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell–derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target. Editor's summary: Obesity is a risk factor for the development of several types of cancer, but how obesity contributes to tumorigenesis remains incompletely understood. Using a mouse model of colon cancer, Bagchi et al. found that tumor-associated macrophages (TAMs) accumulate and drive tumor growth in obese mice. Obesity-associated accumulation of oleic acid enhanced tumor acidity and suppressed TAM inflammatory responses. During obesity, TAMs up-regulated the acid-sensing receptor GPR65, which promoted growth of both colon and liver tumors. Together, these findings identify tumor acidity and GPR65-mediated TAM adaptations as drivers of tumor growth in obesity-associated cancers. —Claire Olingy [ABSTRACT FROM AUTHOR]

Cancer cells preferentially utilize glucose and glutamine, which provide macromolecules and antioxidants that sustain rapid cell division. Metabolic reprogramming in cancer drives an increased glycolytic rate that supports maximal production of these nutrients. The folate cycle, through transfer of a carbon unit between tetrahydrofolate and its derivatives in the cytoplasmic and mitochondrial compartments, produces other metabolites that are essential for cell growth, including nucleotides, methionine, and the antioxidant NADPH. Here, using hepatocellular carcinoma (HCC) as a cancer model, we have observed a reduction in growth rate upon withdrawal of folate. We found that an enzyme in the folate cycle, methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L), plays an essential role in support of cancer growth. We determined that MTHFD1L is transcriptionally activated by NRF2, a master regulator of redox homeostasis. Our observations further suggest that MTHFD1L contributes to the production and accumulation of NADPH to levels that are sufficient to combat oxidative stress in cancer cells. The elevation of oxidative stress through MTHFD1L knockdown or the use of methotrexate, an antifolate drug, sensitizes cancer cells to sorafenib, a targeted therapy for HCC. Taken together, our study identifies MTHFD1L in the folate cycle as an important metabolic pathway in cancer cells with the potential for therapeutic targeting., Introduction Cancer cells exhibit at least 2 distinctive metabolic traits: increased glycolytic rate, and increased capacity against oxidative stress. Cancer cells, even in the presence of [O.sub.2], preferentially utilize glycolytic [...]