A clinicopathological study of non-functioning pituitary neuroendocrine tumours using the World Health Organization 2022 classification.

Background: The 2022 World Health Organization (WHO) classification of pituitary neuroendocrine tumour (PitNET) supersedes the previous one in 2017 and further consolidates the role of transcription factors (TF) in the diagnosis of PitNET. Here, we investigated the clinical utility of the 2022 WHO classification, as compared to that of 2017, in a cohort of patients with non-functioning PitNET (NF-PitNET). Methods: A total of 113 NF-PitNET patients who underwent resection between 2010 and 2021, and had follow-up at Queen Mary Hospital, Hong Kong, were recruited. Surgical specimens were re-stained for the three TF: steroidogenic factor (SF-1), T-box family member TBX19 (TPIT) and POU class 1 homeobox 1 (Pit-1). The associations of different NF-PitNET subtypes with tumour-related outcomes were evaluated by logistic and Cox regression analyses. Results: Based on the 2022 WHO classification, the majority of NF-PitNET was SF-1-lineage tumours (58.4%), followed by TPIT-lineage tumours (18.6%), tumours with no distinct lineage (16.8%) and Pit-1-lineage tumours (6.2%). Despite fewer entities than the 2017 classification, significant differences in disease-free survival were present amongst these four subtypes (Log-rank test p=0.003), specifically between SF-1-lineage PitNET and PitNET without distinct lineage (Log-rank test p<0.001). In multivariable Cox regression analysis, the subtype of PitNET without distinct lineage (HR 3.02, 95% CI 1.28-7.16, p=0.012), together with tumour volume (HR 1.04, 95% CI 1.01-1.07, p=0.017), were independent predictors of a composite of residual or recurrent disease. Conclusion: The 2022 WHO classification of PitNET is a clinically useful TF and lineage-based system for subtyping NF-PitNET with different tumour behaviour and prognosis.

Harnessing the potential of large language models in medical education: promise and pitfalls.

OBJECTIVES: To provide balanced consideration of the opportunities and challenges associated with integrating Large Language Models (LLMs) throughout the medical school continuum. PROCESS: Narrative review of published literature contextualized by current reports of LLM application in medical education. CONCLUSIONS: LLMs like OpenAI's ChatGPT can potentially revolutionize traditional teaching methodologies. LLMs offer several potential advantages to students, including direct access to vast information, facilitation of personalized learning experiences, and enhancement of clinical skills development. For faculty and instructors, LLMs can facilitate innovative approaches to teaching complex medical concepts and fostering student engagement. Notable challenges of LLMs integration include the risk of fostering academic misconduct, inadvertent overreliance on AI, potential dilution of critical thinking skills, concerns regarding the accuracy and reliability of LLM-generated content, and the possible implications on teaching staff.

The duality of CXCR3 in glioblastoma: unveiling autocrine and paracrine mechanisms for novel therapeutic approaches.

Glioblastoma (GBM) is a highly aggressive brain tumor associated with limited therapeutic options and a poor prognosis. CXCR3, a chemokine receptor, serves dual autocrine-paracrine functions in cancer. Despite gaps in our understanding of the functional role of the CXCR3 receptor in GBM, it has been shown to hold promise as a therapeutic target for the treatment of GBM. Existing clinical therapeutics and vaccines targeting CXCR3 ligand expression associated with the CXCR3 axes have also shown anti-tumorigenic effects in GBM. This review summarizes existing evidence on the oncogenic function of CXCR3 and its ligands CXCL9, CXCL10, and CXCL11, in GBM, and examines the controversies concerning the immunomodulatory functions of the CXCR3 receptor, including immune T cell recruitment, polarization, and positioning. The mechanisms underlying monotherpies and combination therapies targeting the CXCR3 pathways are discussed. A better understanding of the CXCR3 axes may lead to the development of strategies for overcoming the limitations of existing immunotherapies for GBM.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

A Pilot Study of Short-Course Oral Vitamin A and Aerosolised Diffuser Olfactory Training for the Treatment of Smell Loss in Long COVID.

Background: Olfactory dysfunction (OD) is a common neurosensory manifestation in long COVID. An effective and safe treatment against COVID-19-related OD is needed. Methods: This pilot trial recruited long COVID patients with persistent OD. Participants were randomly assigned to receive short-course (14 days) oral vitamin A (VitA; 25,000 IU per day) and aerosolised diffuser olfactory training (OT) thrice daily (combination), OT alone (standard care), or observation (control) for 4 weeks. The primary outcome was differences in olfactory function by butanol threshold tests (BTT) between baseline and end-of-treatment. Secondary outcomes included smell identification tests (SIT), structural MRI brain, and serial seed-based functional connectivity (FC) analyses in the olfactory cortical network by resting-state functional MRI (rs-fMRI). Results: A total of 24 participants were randomly assigned to receive either combination treatment (n = 10), standard care (n = 9), or control (n = 5). Median OD duration was 157 days (IQR 127-175). Mean baseline BTT score was 2.3 (SD 1.1). At end-of-treatment, mean BTT scores were significantly higher for the combination group than control (p < 0.001, MD = 4.4, 95% CI 1.7 to 7.2) and standard care (p = 0.009) groups. Interval SIT scores increased significantly (p = 0.009) in the combination group. rs-fMRI showed significantly higher FC in the combination group when compared to other groups. At end-of-treatment, positive correlations were found in the increased FC at left inferior frontal gyrus and clinically significant improvements in measured BTT (r = 0.858, p < 0.001) and SIT (r = 0.548, p = 0.042) scores for the combination group. Conclusions: Short-course oral VitA and aerosolised diffuser OT was effective as a combination treatment for persistent OD in long COVID.

Targeting unfolded protein response using albumin-encapsulated nanoparticles attenuates temozolomide resistance in glioblastoma.

BACKGROUND: Chemoresistant cancer cells frequently exhibit a state of chronically activated endoplasmic reticulum (ER) stress. Engaged with ER stress, the unfolded protein response (UPR) is an adaptive reaction initiated by the accumulation of misfolded proteins. Protein disulfide isomerase (PDI) is a molecular chaperone known to be highly expressed in glioblastomas with acquired resistance to temozolomide (TMZ). We investigate whether therapeutic targeting of PDI provides a rationale to overcome chemoresistance. METHODS: The activity of PDI was suppressed in glioblastoma cells using a small molecule inhibitor CCF642. Either single or combination treatment with TMZ was used. We prepared nanoformulation of CCF642 loaded in albumin as a drug carrier for orthotopic tumour model. RESULTS: Inhibition of PDI significantly enhances the cytotoxic effect of TMZ on glioblastoma cells. More importantly, inhibition of PDI is able to sensitise glioblastoma cells that are initially resistant to TMZ treatment. Nanoformulation of CCF642 is well-tolerated and effective in suppressing tumour growth. It activates cell death-triggering UPR beyond repair and induces ER perturbations through the downregulation of PERK signalling. Combination treatment of TMZ with CCF642 significantly reduces tumour growth compared with either modality alone. CONCLUSION: Our study demonstrates modulation of ER stress by targeting PDI as a promising therapeutic rationale to overcome chemoresistance.

Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms.

Declining global DNA methylation and cognitive impairment are reported to occur in the normal aging process. It is not known if DNA methylation plays a role in the efficacy of memory-enhancing therapies. In this study, aged animals were administered prelimbic cortical deep brain stimulation (PrL DBS) and/or L-methionine (MET) treatment. We found that PrL DBS and MET (MET-PrL DBS) co-administration resulted in hippocampal-dependent spatial memory enhancements in aged animals. Molecular data suggested MET-PrL DBS induced DNA methyltransferase DNMT3a-dependent methylation, robust synergistic upregulation of neuroplasticity-related genes, and simultaneous inhibition of the memory-suppressing gene calcineurin in the hippocampus. We further found that MET-PrL DBS also activated the PKA-CaMKIIα-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. We next inhibited the activity of DNA methyltransferase (DNMT) by RG108 infusion in the hippocampus of young animals to establish a causal relationship between DNMT activity and the effects of PrL DBS. Hippocampal DNMT inhibition in young animals was sufficient to recapitulate the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS. Our findings implicate hippocampal DNMT as a therapeutic target for PrL DBS and pave way for the potential use of non-invasive neuromodulation modalities against dementia.

Immune related biomarkers for cancer metastasis to the brain.

Brain metastasis accounts for a large number of cancer-related deaths. The host immune system, involved at each step of the metastatic cascade, plays an important role in both the initiation of the brain metastasis and their treatment responses to various modalities, through either local and or systemic effect. However, few reliable immune biomarkers have been identified in predicting the development and the treatment outcome in patients with cancer brain metastasis. Here, we provide a focused perspective of immune related biomarkers for cancer metastasis to the brain and a thorough discussion of the potential utilization of specific biomarkers such as tumor mutation burden (TMB), genetic markers, circulating and tumor-infiltrating immune cells, cytokines, in predicting the brain disease progression and regression after therapeutic intervention. We hope to inspire the field to extend the research and establish practical guidelines for developing and validating immune related biomarkers to provide personalized treatment and improve treatment outcomes in patients with metastatic brain cancers.

Vitamin D Promotes Remyelination by Suppressing c-Myc and Inducing Oligodendrocyte Precursor Cell Differentiation after Traumatic Spinal Cord Injury.

Demyelination due to oligodendrocytes loss occurs after traumatic spinal cord injury (TSCI). Several studies have suggested the therapeutic potential of vitamin D (VitD) in demyelinating diseases. However, experimental evidence in the context of TSCI is limited, particularly in the presence of prior VitD-deficiency. In the present study, a contusion and a transection TSCI rat model were used, representing mild and severe injury, respectively. Motor recovery was assessed in rats with normal VitD level or with VitD-deficiency after 8 weeks' treatment post-TSCI (Cholecalciferol, 500 IU/kg/day). The impact on myelin integrity was examined by transmission electron microscopy and studied in vitro using primary culture of oligodendrocytes. We found that VitD treatment post-TSCI effectively improved hindlimb movement in rats with normal VitD level irrespective of injury severity. However, cord-transected rats with prior deficiency did not seem to benefit from VitD supplementation. Our data further suggested that having sufficient VitD was essential for persevering myelin integrity after injury. VitD rescued oligodendrocytes from apoptotic cell death in vitro and enhanced their myelinating ability towards dorsal root axons. Enhanced myelination was mediated by increased oligodendrocyte precursor cells (OPCs) differentiation into oligodendrocytes in concert with c-Myc downregulation and suppressed OPCs proliferation. Our study provides novel insights into the functioning of VitD as a regulator of OPCs differentiation as well as strong preclinical evidence supporting future clinical testing of VitD for TSCI.

Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.

The mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) has shown oncogenic roles in various cancers and may have non-metabolic functions. This study investigated the role of MTHFD2 in glioblastoma pathogenesis. We find that MTHFD2 expression is enriched in gliomas by analysing public databases and clinical specimens. RNA interference (RNAi) and inhibitor of MTHFD2 hamper the proliferation of glioblastoma and induce apoptosis in cell lines, glioma stem-like cells (GSCs) and patient-derived xenografts (PDX). Metabolomic analyses show that MTHFD2 depletion suppresses the central carbon metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle. GSEA reveals a novel non-metabolic function of MTHFD2 in association with the unfolded protein response (UPR). MTHFD2 depletion activates the PERK/eIF2α axis which contributes to translation inhibition and apoptosis; these effects are attenuated by a PERK inhibitor. Mechanistically, MTHFD2 may be linked to UPR via the post-transcriptionally regulation of chaperone protein GRP78. In conclusion, MTHFD2 could be a promising therapeutic target for glioblastoma. Besides its canonical role, MTHFD2 may contribute to glioblastoma pathogenesis via UPR, highlighting a newly identified functional link between one-carbon metabolism and cell stress response.

Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. However, extant investigations have mainly focused on gray matter injury within the primary injury site after ICH rather than on white matter (WM) injury in the brain and spinal cord. This focus partly accounts for the diminished therapeutic discovery. Recent evidence suggests that chondroitin sulphate proteoglycans (CSPG), which can bind to the neural transmembrane protein tyrosine phosphatase-sigma (PTPσ), may facilitate axonal regrowth and remyelination by ameliorating neuroinflammation. METHODS: A clinically relevant ICH model was established using adult C57BL/6 mice. The mice were then treated systemically with intracellular sigma peptide (ISP), which specifically targets PTPσ. Sensorimotor function was assessed by various behavioral tests and electrophysiological assessment. Western blot was used to verify the expression levels of Iba-1 and different inflammatory cytokines. The morphology of white matter tracts of brain and spinal cord was evaluated by immunofluorescence staining and transmission electron microscopy (TEM). Adeno-associated virus (AAV) 2/9 injection was used to assess the ipsilateral axonal compensation after injury. Parallel in vitro studies on the effects of CSPG interference on oligodendrocyte-DRG neuron co-culture explored the molecular mechanism through which ISP treatment promoted myelination capability. RESULTS: ISP, by targeting PTPσ, improved WM integrity and sensorimotor recovery via immunomodulation. In addition, ISP administration significantly decreased WM injury in the peri-hematomal region as well as cervical spinal cord, enhanced axonal myelination and facilitated neurological restoration, including electrophysiologically assessed sensorimotor functions. Parallel in vitro studies showed that inhibition of PTPσ by ISP fosters myelination by modulating the Erk/CREB signaling pathway. CONCLUSIONS: Our findings revealed for the first time that manipulation of PTPσ signaling by ISP can promote prolonged neurological recovery by restoration of the integrity of neural circuits in the CNS through modulation of Erk/CREB signaling pathway.

Predictive value of Bispectral Index (BIS) in emergency neurosurgical patients: Loss of BIS reactivity to propofol predicts poor functional outcomes.

AIM: In emergency neurosurgical patients, evaluation with Glasgow Coma Scale (GCS) alone immediately after stopping sedation post-operatively might not differentiate those with good recovery from those with poor outcomes at 3 months. This study aimed to evaluate the prognostic value of measuring the Bispectral Index (BIS) and the correlation to propofol dosage during the use of sedation in the early post-operative period. METHODS: This is a prospective study on consecutive post-operative neurosurgical patients admitted to the neurosurgical ICU on propofol sedation. The primary outcome was the correlation between early post-operative BIS and the Propofol dosage with the modified Rankin scale (mRS) at 3 months. Secondary outcomes included the post-operative propofol requirement in patients with good functional outcomes (mRS 0-3) versus poor functional outcomes (mRS 4-6) at 3 months. RESULTS: In total, 728 BIS readings were collected from twenty-four patients for analysis. The BIS readings were significantly correlated to the propofol dosage in patients with good function outcomes at 3 months (p < 0.0001). BIS readings in patients with no associations to changes in propofol dosage during their ICU stay had poor outcomes (mRS 4-6) at 3 months (r = -0.0407). For patients with good functional outcomes at 3 months, a significantly higher propofol dosage was used for deep sedation (BIS 40 - 60) during the post-operative period (p < 0.001). CONCLUSION: For emergency neurosurgical patients whose BIS readings had lost correlation to the propofol dosage upon recovery, their functional outcomes at 3 months were poor. For those with good functional outcomes at 3 months, a significantly higher propofol dosage was required for deep sedation during their ICU stay. Patients with preserved correlation of BIS readings to changes in propofol dosages during the early post-operative period were associated with good functional outcomes at 3 months.

A previous hemorrhagic stroke protects against a subsequent stroke via microglia alternative polarization.

Microglia in hemorrhagic stroke contribute to both acute-phase exacerbation and late-phase attenuation of injury. Here, by using the mouse model, we reported that the shift in polarization of microglia from M1 to M2 phenotype could be altered by a past 'mini' stroke, resulting in better neurological function recovery, faster attenuation of lesion volume, and better survival. In mice with a previous stroke, M2 predominance appeared markedly in advance compared to mice without a previous stroke. Mechanistically, the RBC-mediated M2 polarization of microglia was synergistically enhanced by T cells: microglia cocultured with RBCs alone resulted in mild alterations to M2 markers, whereas in the presence of T cells, they expressed an early and sustained M2 response. These results suggest that by harnessing the microglia-mediated M2 polarization response, we could help mitigate devastating sequelae before a prospective hemorrhagic stroke even happens.

Chaperone protein P4HB predicts temozolomide response and prognosis in malignant glioma.

Prolyl 4-hydroxylase beta polypeptide (P4HB) is a chaperone protein associated with temozolomide (TMZ) resistance through the unfolded protein response. Cancer cells with constitutive activation of endoplasmic reticulum stress and upregulation of P4HB have been observed to show resistance against chemotherapies. The present study focused on the evaluation of the prognostic value of P4HB in subtypes of glioma with or without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. P4HB expression was assessed by immunohistochemical staining in 73 grade I-IV gliomas and its association with the clinicopathological data was determined. It was indicated that P4HB expression was significantly associated with several parameters, including age, tumour grade and the number of TMZ treatment cycles received. In the Kaplan-Meier analysis, P4HB expression was positively associated with risk of mortality and disease progression. In patients treated with TMZ, high P4HB expression was significantly associated with poor overall survival (OS) and progression-free survival (PFS). The association between MGMT promoter methylation and P4HB expression was also assessed. Patients with MGMTMethP4HBLow tumours had the most favourable PFS (48 months) among cases with various combinations of MGMT methylation status and P4HB expression. Multivariate analysis revealed that P4HB may be used as an independent prognostic indicator of OS, particularly in high-grade gliomas. The present study uncovered the potential role of P4HB in a nuanced pathological stratification during clinical decision-making with respect to MGMT promoter methylation status and TMZ treatment.

Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage.

BACKGROUND: Erythrophagocytosis by reparative monocyte-derived macrophage contributes to hematoma clearance and neurological recovery after intracerebral hemorrhage (ICH). Vitamin D (VitD) is a neuroprotective hormone and regulates the differentiation of monocyte-derived macrophage from monocytes. In this study, we examined the effects of VitD supplementation on monocyte-derived macrophage and hematoma clearance in rodent with ICH. METHODS: Neurobehavioral functions and hematoma volume were assessed using a collagenase injection model in both young- and middle-aged mice with or without VitD treatment given 2 hours post-ICH induction. We used flow cytometry to analyze CD36 expression and macrophage and undifferentiated monocyte cell numbers during in vivo erythrophagocytosis in collagenase and autologous blood injection models. Western blot analysis and immunofluorescence were used to assess the expression levels of the PPAR-γ (peroxisome proliferator-activated receptor γ)-CD36 axis and CD206. A macrophage differentiation study was conducted on murine bone marrow-derived monocytes. RESULTS: VitD promoted neurological recovery and facilitated hematoma clearance in both young- and middle-aged mice after ICH. Within the perihematomal region, mature macrophages, rather than undifferentiated monocytes, expressed higher levels of CD36 in driving erythrocyte clearance. VitD increased the macrophage number but decreased the monocyte number and elevated the levels of CD36 and PPAR-γ in the brain. In vitro, VitD accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. CONCLUSIONS: VitD promotes reparative macrophage differentiation, facilitates hematoma clearance, and improves neurobehavioral performance in mice with ICH, suggesting that VitD should be further examined as a potentially promising treatment for ICH.

Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities.

Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

Erythrophagocytosis by Microglia/Macrophage in Intracerebral Hemorrhage: From Mechanisms to Translation.

Intracerebral hemorrhage (ICH) is a devastating condition characterized by hematoma related mass effect. Microglia/macrophage (M φ) are rapidly recruited in order to remove the red blood cells through erythrophagocytosis. Efficient erythrophagocytosis can detoxify hemolytic products and facilitate neurological recovery after ICH. The underlying mechanisms include modulation of inflammatory response and oxidative stress, among others. It is a dynamic process mediated by a cascade of signal transduction, including "find-me" signals, "eat-me" signals and a set of phagocytotic receptors-ligand pairs that may be exploited as therapeutic targets. This review summarizes mechanistic signaling pathways of erythrophagocytosis and highlights the potential of harnessing M φ-mediated phagocytosis for ICH treatment.

Surgical revascularization for moyamoya angiopathy: Clinical and radiological outcomes of direct and indirect bypasses in 86 affected hemispheres.

Moyamoya is a progressive cerebral angiopathy that entails a formidable natural history of repeated ischemic or haemorrhagic insults if not intervened. The potential advantages of direct/combined bypass can be harvested only if they are not outweighed by perioperative morbidity. Direct bypasses for the paediatric group have been less utilized because of small vessel calibres and an inherently more robust angioplasticity. This study was undertaken to examine the clinical and perfusion imaging outcomes of operated moyamoya disease or syndrome patients in Hong Kong's Southeast Asian population. Comparison was made between direct/combined and indirect bypass cohorts. Subgroup analysis of the paediatric cohort was conducted to determine outcomes of a direct-bypass-first strategy. From November 2000 to September 2020, 86 hemispheres underwent revascularization at a tertiary neurosurgical unit with a mean clinical follow-up time of 70.0 months. 70.9% of the procedures involved direct bypasses. Direct/combined revascularization demonstrated superiority in restoring adequate cerebrovascular reserve capacity (CVRC) (63.2% vs 27.3%, p = 0.015), and freedom from transient ischemic attacks in the first 5 years post-operation by Kaplan-Meier plot with log-rank test (p = 0.038). Follow-up imaging revealed 96.5% of the bypass grafts remained patent. Direct/combined procedures significantly predicted restoration of adequate CVRC on follow-up perfusions scans by binary logistic regression (OR 4.57, p = 0.009). Compared to the adult cohort, direct bypasses in children carried no excessive perioperative morbidity. These results support a liberal bypass-first paradigm in both adult and paediatric cohorts.

Global Survey of Demand-Side Factors and Incentives that Influence Advanced Trauma Life Support (ATLS) Promulgation.

BACKGROUND: We aimed to identify and describe demand-side factors that have been used to support ATLS global promulgation, as well as current gaps in demand-side incentives. METHODS: We performed a cross-sectional survey about demand-side factors that influence the uptake and promulgation of ATLS and other trauma-related CME courses. The survey was sent to each of the four global ATLS region chiefs and 80 ATLS country directors. Responses were described and qualitative data were analyzed using a content analysis framework. RESULTS: Representatives from 30 countries and each region chief responded to the survey (40% response rate). Twenty of 30 country directors (66%) reported that there were some form of ATLS verification requirements. ATLS completion, not current verification, was often the benchmark. Individual healthcare systems were the most common agency to require ATLS verification (37% of countries) followed by medical/surgical accreditation boards (33%), governments (23%), training programs (27%), and professional societies (17%). Multiple credentialing frameworks were reported including making ATLS verification a requirement for: emergency unit or trauma center designation (40%), contract renewal or promotion (37%); professional licensing (37%); training program graduation (37%); and increases in remuneration (3%). Unique demand-side incentives were reported including expansion of ATLS to non-physician cadre credentialing and use of subsidies. CONCLUSION: ATLS region chiefs and country directors reported a variety of demand-side incentives that may facilitate the promulgation of ATLS. Actionable steps include: (i) shift incentivization from ATLS course completion to maintenance of verification; (ii) develop an incentive toolkit of best practices to support implementation; and (iii) engage leadership stakeholders to use demand-side incentives to improve the training and capabilities of the providers they oversee to care for the injured.

Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O6-methylguanine DNA methyltransferase (MGMT) expression and reactive oxygen species (ROS)-mediated DNA damage in glioblastoma.

Glioblastoma (GBM) is the most malignant primary tumor in the central nervous system of adults. Temozolomide (TMZ), an alkylating agent, is the first-line chemotherapeutic agent for GBM patients. However, its efficacy is often limited by innate or acquired chemoresistance. Cancer cells can rewire their metabolic programming to support rapid growth and sustain cell survival against chemotherapies. An example is the de novo serine synthesis pathway (SSP), one of the main branches from glycolysis that is highly activated in multiple cancers in promoting cancer progression and inducing chemotherapy resistance. However, the roles of SSP in TMZ therapy for GBM patients remain unexplored. In this study, we employed NCT503, a highly selective inhibitor of phosphoglycerate dehydrogenase (PHGDH, the first rate-limiting enzyme of SSP), to study whether inhibition of SSP may enhance TMZ efficacy in MGMT-positive GBMs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flowcytometry and colony formation assays demonstrated that NCT503 worked synergistically with TMZ in suppressing GBM cell growth and inducing apoptosis in T98G and U118 cells in vitro. U118 and patient-derived GBM subcutaneous xenograft models showed that combined NCT503 and TMZ treatment inhibited GBM growth and promoted apoptosis more significantly than would each treatment alone in vivo. Mechanistically, we found that NCT503 treatment decreased MGMT expression possibly by modulating the Wnt/ß-catenin pathway. Moreover, intracellular levels of reactive oxygen species were elevated especially when NCT503 and TMZ treatments were combined, and the synergistic effects could be partially negated by NAC, a classic scavenger of reactive oxygen species. Taken together, these results suggest that NCT503 may be a promising agent for augmenting TMZ efficacy in the treatment of GBM, especially in TMZ-resistant GBMs with high expression of MGMT.