Highlights d INCR1 is expressed from the PD-L1 locus in interferonstimulated tumor cells d INCR1 regulates tumor interferon signaling d Silencing INCR1 sensitizes tumor cells to T cell-mediated killing d INCR1 binds HNRNPH1 to promote PD-L1 and JAK2 expression

Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum­(IV) prodrugs of cisplatin and perfluoroaryl peptide macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem-like cells. We investigate the pharmacokinetics of this conjugate in mice and show that the amount of platinum in the brain after treatment with the conjugate is 15-fold greater than with cisplatin after 5 h.

OBJECTIVETimely aneurysm occlusion and neurointensive care treatment are key principles in the management of aneurysmal subarachnoid hemorrhage (aSAH) to prevent secondary brain injury. Patients with early (EHA) and delayed hospital admission (DHA) were compared in terms of clinical presentation, treatment strategies, aSAH-related complications, and outcome.METHODSIn this retrospective study, consecutive aSAH patients were treated at a single neurovascular center between 2009 and 2019. Propensity score matching was performed to account for divergent baseline characteristics.RESULTSAmong 509 included patients, 55 were admitted more than 48 hours after ictus (DHA group). DHA patients were significantly younger (52 ± 11 vs 56 ± 14 years, p = 0.03) and had lower World Federation of Neurosurgical Societies scores (p < 0.01) than EHA patients. In 54.5% of the cases, DHA patients presented with neurological deterioration or aggravated symptoms. Propensity score matching revealed a higher vasospastic infarction rate in the DHA group (41.5%) than in the EHA group (22.6%) (p = 0.04). A similar portion of patients in both groups achieved favorable outcome at midterm follow-up (77.3% vs 73.6%, p = 0.87). DHA patients (62.3%) received conventional coiling more often than EHA patients (41.5%) (p = 0.03).CONCLUSIONSDHA patients are at an increased risk of cerebral infarction. Nevertheless, state-of-the-art neurointensive care treatment can result in a good clinical outcome.

Glioblastoma (GBM) is the most common and deadliest form of brain tumor and remains amongst the most difficult cancers to treat. Brevican (Bcan), a central nervous system (CNS)‐specific extracellular matrix protein, is upregulated in high‐grade glioma cells, including GBM. A Bcan isoform lacking most glycosylation, dg‐Bcan, is found only in GBM tissues. Here, dg‐Bcan is explored as a molecular target for GBM. In this study, a d‐peptide library is screened to identify a small 8‐amino acid dg‐Bcan‐Targeting Peptide (BTP) candidate, called BTP‐7 that binds dg‐Bcan with high affinity and specificity. BTP‐7 is preferentially internalized by dg‐Bcan‐expressing patient‐derived GBM cells. To demonstrate GBM targeting, BTP‐7 is radiolabeled with 18F, a radioisotope of fluorine, and increased radiotracer accumulation is found in intracranial GBM established in mice using positron emission tomography (PET) imaging. dg‐Bcan is an attractive molecular target for GBM, and BTP‐7 represents a promising lead candidate for further development into novel imaging agents and targeted therapeutics.

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Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4 K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

ObjectiveTo evaluate the effectiveness of early (<3 months) cranioplasty (CP) and late CP (>3 months) on post-operative complications in patients receiving decompressive craniotomy (DC) for traumatic brain injury (TBI).MethodsThe Cochrane Library, PubMed and EMBASE databases were systematically searched for studies published prior to May 21, 2017. A meta-analysis examined post-operative overall complication rates, infection rates, subdural fluid collection and operating times according to early and late CP.ResultsOf the initial 1675 references, five studies, all cohort, involving a total of 413 patients, were selected for the review. There was no difference between early and late CP in post-operative overall complication rate (RR=0.68, 95%CI [0.36, 1.29]) and the post-operative infection rate (RR=0.50, 95%CI [0.20, 1.24]) in patients receiving DC for TBI. However, there was a significant difference in post-operative subdural effusion (RR=0.24, 95%CI [0.07, 0.78]) and mean operative time (mean difference = −33.02 min, 95%CI [−48.19, −17.84]) both in favour of early CP.ConclusionsNo differences were found between early and late CP in post-operative overall complications and procedural related infections in patients receiving DC for TBI, but early CP reduced the complication of subdural effusion and the mean operating time. These findings need to be confirmed by large, randomised controlled trials.

BackgroundInfection is a common complication in acute stroke. Whether or not preventive antibiotics reduce the risk of infection or even lead to a favorable outcome and reduction of mortality after a stroke still remains equivocal. This review was performed to update the current knowledge on the effect and possible benefits of prophylactic antibiotic therapy in patients with stroke.MethodsA systematic review and meta-analysis of preventive antibiotics`effect on the incidence of infection, favorable outcome (mRS≤2) and mortality in patients with acute stroke is performed with relevant randomized controlled trials.ResultsSix studies were identified, involving 4125 participants. Compared with the control group, the treated groups were significantly less prone to suffer from early overall infections [RR = 0.52, 95%CI (0.39, 0.70), p<0.0001], early pneumonia [RR = 0.64, 95%CI (0.42, 0.96), p = 0.03] and early urinary tract infections [RR = 0.35, 95%CI (0.25, 0.48), p<0.00001]. However, there was no significant difference in overall mortality [RR = 1.07, 95%CI (0.90, 1.27), p = 0.44], early mortality [RR = 0.99, 95%CI (0.78, 1.26), p = 0.92], late mortality [RR = 1.12, 95%CI (0.94, 1.35), p = 0.21] or favorable outcome [RR = 1.00, 95%CI (0.92, 1.08), p = 0.98].ConclusionAlthough preventive antibiotic treatment did reduce the occurrence of early overall infections, early pneumonia and early urinary tract infection in patients with acute stroke, this advantage was not eventually translated to a favorable outcome and reduction in mortality. Future studies are warranted to identify any subgroup of stroke patients who might benefit from preventive antibiotic treatment.