Cross-Sectional Melt Pool Geometry of Laser Scanned Tracks and Pads on Nickel Alloy 718 for the 2022 Additive Manufacturing Benchmark Challenges.

The Additive Manufacturing Benchmark Series (AM Bench) is a NIST-led organization that provides a continuing series of additive manufacturing benchmark measurements, challenge problems, and conferences with the primary goal of enabling modelers to test their simulations against rigorous, highly controlled additive manufacturing benchmark measurement data. To this end, single-track (1D) and pad (2D) scans on bare plate nickel alloy 718 were completed with thermography, cross-sectional grain orientation and local chemical composition maps, and cross-sectional melt pool size measurements. The laser power, scan speed, and laser spot size were varied for single tracks, and the scan direction was varied for pads. This article focuses on the cross-sectional melt pool size measurements and presents the predictions from challenge problems. Single-track depth correlated with volumetric energy density while width did not (within the studied parameters). The melt pool size for pad scans was greater than single tracks due to heat buildup. Pad scan melt pool depth was reduced when the laser scan direction and gas flow direction were parallel. The melt pool size in pad scans showed little to no trend against position within the pads. Uncertainty budgets for cross-sectional melt pool size from optical micrographs are provided for the purpose of model validation.

Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure.

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

Subarachnoid haemorrhage associated with pituitary apoplexy and radiographically occult supraclinoid internal carotid artery aneurysms.

In patients with pituitary adenomas, incidental intracranial aneurysms have been documented. Previous studies have highlighted the importance of preoperative imaging in these patients. However, imaging may be limited and fail to show the presence of vascular abnormalities. In this report, we discuss a case of a man in his 30s presenting with a newly diagnosed pituitary adenoma. CT and MRI, on admission, showed a pituitary mass with extension into the right cavernous sinus. After a sudden neurological deterioration, emergent CT/CT angiography revealed pituitary apoplexy with subarachnoid extension without vascular abnormalities. Successful emergency transsphenoidal hypophysectomy was followed by digital subtraction angiography which revealed the presence of two right supraclinoid internal carotid artery aneurysms. With this case, we aim to highlight the need for further vascular imaging in patients with pituitary apoplexy and subarachnoid haemorrhage, as preoperative imaging may be negative for vascular abnormalities especially in the setting of cavernous sinus invasion.

Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge.

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.

Management and outcomes of surgical site tuberculosis infection due to infected bone graft in spine surgery: a single-institution experience and 1-year postoperative follow-up.

OBJECTIVE: In 2021, several patients across the United States received bone allograft contaminated with Mycobacterium tuberculosis (TB). TB is typically a pulmonary infection with many possible extrapulmonary manifestations, including skeletal tuberculosis. However, TB is a rare causative organism of postoperative surgical site infection. Iatrogenic skeletal TB infections are not widely reported in the medical literature; therefore, treatment and associated outcomes are relatively unknown. In this series, the authors report 6 cases of patients who received a mesenchymal stem cell-enhanced bone graft infected with TB at their institution, including the clinical courses, imaging findings, management plans, and outcomes at 1 year postoperatively. METHODS: A retrospective review was performed of 6 consecutive patients who underwent spinal fusion surgery at the authors' institution and received bone graft from a lot contaminated with TB. Collected data included patient demographic characteristics, indications for surgery, surgical procedures performed, timing of contamination discovery, medical treatment, and follow-up information including reoperation, healing progress, and imaging findings. RESULTS: Five of 6 patients (83.3%) eventually tested positive for TB via interferon-gamma release assay or wound culture. They experienced significant complications, including surgical site infections with neck swelling, pain, dysphagia, and wound dehiscence. Extensive soft-tissue infection was common; however, significant bony involvement was not observed. Surgical wound debridement was required in 4 patients, and all patients received medical management with standard RIPE (rifampin, isoniazid pyrazinamide, pyridoxine, and ethambutol) therapy for 8 weeks with extension of rifampin and isoniazid for scheduled 12 months. All patients (excluding 1 patient who died of COVID-19) showed signs of improvement with adequately healing wounds at the most recent follow-up at a median (range) of 12 (6-13) months postoperatively. To date, no patients have developed pulmonary TB. CONCLUSIONS: Direct inoculation with TB via contaminated bone grafts resulted in a high rate of severe soft-tissue infection, although extensive skeletal and pulmonary involvement has not been observed at 1 year postoperatively; this review includes the longest reported follow-up period for this TB outbreak. Medical management remains the mainstay of therapy for these patients, with most patients showing recovery with oral antibiotic therapy. The severity of these infections arising from mesenchymal stem cell-containing bone allografts that undergo an alternative sterilization process than standard allografts raises concerns regarding the added risks of infection, which should be weighed against the expected benefits of these grafts.

Translating Outcomes from the Clinical Setting to Preclinical Models: Chronic Pain and Functionality in Chronic Musculoskeletal Pain.

Fibromyalgia (FM) is a chronic pain disorder characterized by chronic widespread musculoskeletal pain (CWP), resting pain, movement-evoked pain (MEP), and other somatic symptoms that interfere with daily functioning and quality of life. In clinical studies, this symptomology is assessed, while preclinical models of CWP are limited to nociceptive assays. The aim of the study was to investigate the human-to-model translatability of clinical behavioral assessments for spontaneous (or resting) pain and MEP in a preclinical model of CWP. For preclinical measures, the acidic saline model of FM was used to induce widespread muscle pain in adult female mice. Two intramuscular injections of acidic or neutral pH saline were administered following baseline measures, 5 days apart. An array of adapted evoked and spontaneous pain measures and functional assays were assessed for 3 weeks. A novel paradigm for MEP assessment showed increased spontaneous pain following activity. For clinical measures, resting and movement-evoked pain and function were assessed in adult women with FM. Moreover, we assessed correlations between the preclinical model of CWP and in women with fibromyalgia to examine whether similar relationships between pain assays that comprise resting and MEP existed in both settings. For both preclinical and clinical outcomes, MEP was significantly associated with mechanical pain sensitivity. Preclinically, it is imperative to expand how the field assesses spontaneous pain and MEP when studying multi-symptom disorders like FM. Targeted pain assessments to match those performed clinically is an important aspect of improving preclinical to clinical translatability of animal models.

Case Report: Unusual Aggregation of Different Glomerulopathies in a Family Resolved by Genetic Testing and Reverse Phenotyping.

Glomerular diseases (GDs) are a major cause of chronic kidney disease in children. The conventional approach to diagnosis of GDs includes clinical evaluation and, in most cases, kidney biopsy to make a definitive diagnosis. However, in many cases, clinical presentations of different GDs can overlap, leading to uncertainty in diagnosis and management even after renal biopsy. In this report, we identify a family with clinical diagnoses of postinfectious glomerulonephritis and IgA nephropathy in a parent and two children. Renal biopsies were initially inconclusive; however, genetic testing showed that the two individuals diagnosed at different points with IgA nephropathy carried novel segregating pathogenic variants in COL4A5 gene. We were only able to make the final diagnoses in each of the family members after genetic testing and reverse phenotyping. This case highlights the utility of genetic testing and reverse phenotyping in resolving clinical diagnosis in families with unusual constellations of different glomerulopathies. We propose that clustering of different glomerular disease phenotypes in a family should be an indication for genetic testing followed by reverse phenotyping.

The RGS-RhoGEFs control the amplitude of YAP1 activation by serum.

Actin-dependent mechanisms drive the nuclear translocation of Yap1 to enable its co-activation of transcription factors that induce pro-growth and survival programs. While Rho GTPases are necessary for the nuclear import of YAP1, the relevant Guanine Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs) that connect this process to upstream signaling are not well defined. To this end, we measured the impact of expressing sixty-seven RhoGEFs and RhoGAPs on the YAP1 dependent activity of a TEAD element transcriptional reporter. Robust effects by all three members of the regulator of G-protein signaling (RGS) domain containing RhoGEFs (ArhGEF1, ArhGEF11 and ArhGEF12) prompted studies relating their known roles in serum signaling onto the regulation of Yap1. Under all conditions examined, ArhGEF12 preferentially mediated the activation of YAP1/TEAD by serum versus ArhGEF1 or ArhGEF11. Conversely, ArhGEF1 in multiple contexts inhibited both basal and serum elevated YAP1 activity through its GAP activity for Gα13. The sensitivity of such inhibition to cellular density and to low states of serum signaling supports that ArhGEF1 is a context dependent regulator of YAP1. Taken together, the relative activities of the RGS-RhoGEFs were found to dictate the degree to which serum signaling promotes YAP1 activity.

Risk of Brain Herniation After Craniotomy With Preoperative Lumbar Spinal Drainage: A Single-Surgeon Experience of 365 Patients Among 3000 Major Cranial Cases.

BACKGROUND: Lumbar spinal drainage (LSD) can significantly facilitate brain relaxation and improve ease of surgical goals for a variety of neurosurgical indications. Although rapid drainage of large volumes of spinal fluid can theoretically produce shifts in brain compartments and herniation syndromes, the clinical significance of this phenomenon when LSD is used immediately before craniotomy is unclear. OBJECTIVE: To report a large single-surgeon consecutive experience with symptomatic brain herniation after lumbar drainage before craniotomy. METHODS: Included were 365 patients who underwent LSD with either lumbar drain or lumbar puncture for a variety of different neurosurgical pathologies between 2008 and 2018 immediately before craniotomy. We reviewed the surgical indications, craniotomy location, approach, type of LSD, presence of postoperative brain herniation on imaging, type of herniation, clinical symptoms, lesion pathology, and 30-d modified Rankin Scale score for each patient. RESULTS: There was no patient who suffered from the development of new or worsening symptomatic or radiological brain herniation directly related to use of immediate preoperative LSD. This included 204 supratentorial and 161 infratentorial procedures. Surgical indications included 188 tumors, 5 aneurysms, 37 arteriovenous malformations, 2 revascularization procedures, 97 microvascular decompressions, 10 optic nerve decompressions requiring extradural clinoidectomy for tumor removal, and 26 "other" pathologies. CONCLUSION: Brain herniation did not occur postoperatively with the use of immediate preoperative LSD in our series, regardless of craniotomy location, pathology, extent of mass effect, or approach. Our experience suggests that LSD is a potentially safe preoperative adjunct that can be used to facilitate surgical objectives.

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population.

Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice. Methods: Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes. Causative mutations were defined as missense, truncating, and obligatory splice site variants with a minor allele frequency <1% in controls. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico models. We further evaluated for differences in age at disease onset, family history of SRNS or chronic kidney disease, race, sex, renal biopsy findings, and extra-renal manifestations in subgroups with and without disease causing variants. Results: We identified causative variants in 40 of 181 families (22.1%) with SRNS. Variants in INF2, COL4A3, and WT1 were the most common, accounting for over half of all causative variants. Causative variants were identified in 34 of 86 families (39.5%) with familial disease and 6 of 95 individuals (6.3%) with sporadic disease (χ2 p < 0.00001). Family history was the only significant clinical predictor of genetic SRNS. Conclusion: We identified causative mutations in almost 40% of all families with hereditary SRNS and 6% of individuals with sporadic disease, making family history the single most important clinical predictors of monogenic SRNS. We recommend genetic testing in all patients with SRNS and a positive family history, but only selective testing in those with sporadic disease.

The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes.

BACKGROUND: We previously reported that mutations in the anillin (ANLN) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP. METHODS: We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLNR431C and ANLNG618C during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN (ANLNWT ) or ANLNR431C . RESULTS: Experiments in anln-deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLNR431C increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLNR431C -expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLNR431C -expressing podocytes. Inhibition of mTOR, GSK-3ß, Rac1, or calcineurin ameliorated the effects of ANLNR431C . Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR. CONCLUSIONS: The ANLNR431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes.

Influence of scan strategy and process parameters on microstructure and its optimization in additively manufactured nickel alloy 625 via laser powder bed fusion.

Laser powder bed fusion (L-PBF) as an additive manufacturing process produces nearly fully dense nickel alloy 625 (IN625) parts with complex features. L-PBF generates surfaces and microstructure through directional solidification that can be controlled by scan strategies and selection of process parameters. This study provides experimental investigations on microstructure formation including sizes of cellular grains and growth directions of columnar grains on the nickel alloy 625 test coupons. The effects of process parameters including laser power, scan velocity, hatch distance, and scan strategy that produce various solidification cooling rates and thermal gradients during the process, which also contribute to resultant microstructure, have been analyzed. Optimization studies are conducted on several objectives to improve the productivity while controlling the process effects on the resultant microstructure using response surface regression, desirability functions, and multi-objective genetic algorithm optimization.

Predictive modeling and optimization of multi-track processing for laser powder bed fusion of nickel alloy 625.

This paper presents an integrated physics-based and statistical modeling approach to predict temperature field and meltpool geometry in multi-track processing of laser powder bed fusion (L-PBF) of nickel 625 alloy. Multi-track laser processing of powder material using L-PBF process has been studied using 2-D finite element simulations to calculate temperature fields along the scan and hatch directions for three consecutive tracks for a moving laser heat source to understand the heating and melting process. Based on the predicted temperature fields, width, depth and shape of the meltpool is determined. Designed experiments on L-PBF of nickel alloy 625 powder material are conducted to measure the relative density and meltpool geometry. Experimental work is reported on the measured density of built coupons and meltpool size. Statistically-based predictive models using response surface regression for relative density, meltpool geometry, peak temperature, and time above melting point are developed and multi-objective optimization studies are conducted by using genetic algorithm and swarm intelligence.

Multicenter retrospective evaluation of the validity of the Thoracolumbar Injury Classification and Severity Score system in children.

OBJECTIVE The Thoracolumbar Injury Classification and Severity Score (TLICS) system was developed to streamline injury assessment and guide surgical decision making. To the best of the authors' knowledge, external validation in the pediatric age group has not been undertaken prior to this report. METHODS This study evaluated the use of the TLICS in a large retrospective series of children and adolescents treated at 4 pediatric medical centers (Texas Children's Hospital, Children's Healthcare of Atlanta, Riley Children's Hospital, and Doernbecher Children's Hospital). A total of 147 patients treated for traumatic thoracic or lumbar spine trauma between February 1, 2002, and September 1, 2015, were included in this study. Clinical and radiographic data were evaluated. Injuries were classified using American Spinal Injury Association (ASIA) status, Denis classification, and TLICS. RESULTS A total of 102 patients (69%) were treated conservatively, and 45 patients (31%) were treated surgically. All patients but one in the conservative group were classified as ASIA E. In this group, 86/102 patients (84%) had Denis type compression injuries. The TLICS in the conservative group ranged from 1 to 10 (mean 1.6). Overall, 93% of patients matched TLICS conservative treatment recommendations (score ≤ 3). No patients crossed over to the surgical group in delayed fashion. In the surgical group, 26/45 (58%) were ASIA E, whereas 19/45 (42%) had neurological deficits (ASIA A, B, C, or D). One of 45 (2%) patients was classified with Denis type compression injuries; 25/45 (56%) were classified with Denis type burst injuries; 14/45 (31%) were classified with Denis type seat belt injuries; and 5/45 (11%) were classified with Denis type fracture-dislocation injuries. The TLICS ranged from 2 to 10 (mean 6.4). Eighty-two percent of patients matched TLICS surgical treatment recommendations (score ≥ 5). No patients crossed over to the conservative management group. Eight patients (8/147, 5%) had a calculated TLICS of 4, which meant they were candidates for surgery or conservative therapy by TLICS criteria. Excluding these patients, the degree of agreement between TLICS and surgeon decision was deemed to be very good (κ = 0.878). CONCLUSIONS The TLICS results and recommendations matched treatment in 96% of conservative group cases. In the surgical group, TLICS recommendations matched treatment in 93% of cases. The TLICS recommendations and surgeon decision making displayed very good concordance. The TLICS appears to be effective in the classification of thoracic and lumbar spine injuries and in guiding treatment in the pediatric age group.

Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors.

Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs.

Therapeutic potential of targeting the oncogenic SHP2 phosphatase.

The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the ß5-ß6 loop contribute to 11a-1's binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines.

A prospective study of microscope-integrated intraoperative fluorescein videoangiography during arteriovenous malformation surgery: preliminary results.

OBJECT: The authors report on the use of a recently developed microscope-integrated fluorescent module using low-dose intravenous fluorescein for videoangiography during arteriovenous malformation (AVM) surgery. METHODS: The authors analyzed the application of a low-dose intraoperative fluorescein in 4 consecutive patients undergoing AVM surgery. The ability to distinguish the associated vessels of the AVM from normal vessels and to assess the degree of AVM obliteration based on videoangiography of venous drainage was specifically analyzed. RESULTS: All 4 patients underwent fluorescein angiography without complication. In each case, videoangiography confirmed recognition of feeding arteries and draining veins through the operating oculars under the fluorescent mode. In one case involving a large frontal AVM, videoangiography demonstrated mainly cortical veins on the surface of the AVM and alerted the senior author to first tackle the feeding arteries in the interhemispheric space. While evaluating the flow within the different draining veins after most of the AVM was disconnected, videoangiography also prioritized the order for disconnection of large draining veins to allow mobilization the AVM and exposure of the remaining deep arterial feeders. In the other 3 cases, videoangiography allowed easy recognition of the angioarchitecture of the AVMs, estimated its cortical boundaries, and most importantly, assessed the flow within the draining veins before their disconnection. CONCLUSIONS: The authors found fluorescein videoangiography to be a useful adjunct in resection of AVMs. This technology offers the unique ability to visualize fluorescent vessels and nonfluorescent tissues in near-natural colors simultaneously and permits microsurgical manipulation of relevant structures under the fluorescent mode. Larger-scale studies are needed to establish its efficacy and wider applicability.

Fluorescein fluorescence use in the management of intracranial neoplastic and vascular lesions: a review and report of a new technique.

The use of fluorescent technologies in neurosurgery has a substantial history with applications to vascular and tumor surgery dating back to the 1940s. This review focuses on the applications of fluorescence imaging to intracranial vascular and neoplastic lesions using sodium fluorescein. The authors performed a literature search for articles about the use of sodium fluorescein in neurosurgery. Fifty-five articles were initially retrieved, and 37 of these were appropriate for this review. The subcategorization of these articles revealed 2 describing the properties of fluorescein, 19 articles relating to applications of fluorescein to tumor, 11 relating to vascular applications, and 5 reporting side effects associated with fluorescein use. Articles related to use of this agent in evaluation of CSF leak were excluded. Sodium fluorescein has been reported to be a useful surgical adjunct in resection of neoplastic lesions based on differential fluorescence between normal and neoplastic tissue. There are many reports on the utility of fluorescein in vascular imaging relating to arteriovenous malformations, aneurysms, and vessel anastomosis; however, these reports do not examine primary outcomes. Sodium fluorescein has been judged as generally safe with few reports of severe complications. Sodium fluorescein has demonstrated promise as a useful surgical adjunct in neurosurgery for vascular and neoplastic lesions. It is well tolerated, but further study is required to determine its full utility. Finally, we will introduce a new practical technology that could potentially improve intraoperative application of sodium fluorescein by improving its fluorescence visualization while using substantially lower doses of this dye.

Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.1³,7.19,¹³]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles.

A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC(50) = 0.5 nM) and cellular (IC(50) = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.