California Institute Research Articles

COMPARISON OF VARIOUS METRICS FOR EVALUATING THE PERFORMANCE OF DEEP LEARNING BINARY CLASSIFICATION, PARTICULARLY WHEN UNDERLYING IMAGING DATA ARE IMBALANCED

Subchondral bone marrow lesions (BMLs) are associated with symptoms and structural progression of knee OA. Automated detection of BMLs using deep learning approaches may help in screening potential participants in clinical trials and enrich study samples for fast structural progressors or for a specific pain phenotype. The metric commonly used to evaluate the performance of deep learning binary classification (i.e., receiver operating characteristic (ROC)) might not be as informative as other metrics of performance, especially when the underlying data used to train and validate the deep learning models are imbalanced as in the case when the outcomes of interest are rare. To compare the evaluation of deep learning binary classification of BMLs based on imbalanced data from the OAI study using various performance metrics. We used the sagittal intermediate-weighted (IW) fat-suppressed (FS) MRI data of 2,467 participants from the OAI study in the data analysis. We dichotomized the MOAKS (MRI Osteoarthritis Knee Score) BML grades (scored from 0-3) into presence or absence classes. The split was done by categorizing grades > 0 as presence and grades = 0 as absence. After the deep learning models were trained, we obtained the status of BMLs from MRI images on each of 13 subregions in femur and tibia (e.g., Femur Central Medial (FemCentMed), Tibia Anterior Lateral (TibAntLat), Tibia Posterior Medial (TibPostMed)). We applied ROC, precision-recall (PR), precision-recall gain (PRG), F1, and the Matthews correlation coefficient (MCC) to summarize the prediction performance of the deep learning models using the test data. The available MOAKS data from the OAI are imbalanced. The class imbalance ratios (i.e., presence of BMLs vs absence of BMLs) are 569:2427, 49:2947, and 191:2805 in the FemCentMed, TibAntLat, and TibPostMed, respectively. When the data are this severely imbalanced, metrics such as the area under the ROC curve (ROC-AUC) and PR-AUC show conflicting performance results in TibAntLat and TibPostMed (see Table 1). In general, a binary classifier with a ROC-AUC value of 0.8 to 0.9 is considered excellent and has an outstanding performance with a value of more than 0.9. The ROC metric (ROC-AUC = 0.84) is too optimistic since the precision and sensitivity are nearly zero, indicating that almost all data are assigned to the absence of BMLs class. The PR curve (PR-AUC = 0.10) is more informative compared to the ROC as it is consistent with the values of precision and sensitivity. The MCC and F1 results are also consistent with those of the PR curve for high- (TibAntLat) or low-class (FemCentMed) imbalance ratios. The class imbalance ratio coupled with results of the ROC, PR, and MCC should be reported for deep learning models of binary classification, particularly in the circumstance where the underlying data are imbalanced. To properly interpret the prediction performance of deep learning models of binary classification, an expanded set of performance metrics should be reported. None. AG is consultant to Pfizer, Novartis, Regeneron, TissueGene, Merck Serono, and AstraZeneca. AG and FWR are shareholders of BICL, LLC. FWR is consultant to Calibr –California Institute of Biomedical Research and Grunenthal. KK is consultant to Regeneron, LG Chem, and Express Scripts. He is principal investigator for pharma sponsored clinical trials to Abbvie, Cumberland, and GSK and DSMB to Kolon TissueGene and Avalor Therapeutics.

INTRA-ARTICULAR KNEE INJECTION TECHNICAL SUCCESS RATE—COMPARISON BETWEEN ULTRASOUND- AND PALPATION-GUIDED INJECTION USING RADIOGRAPHIC DEPICTION OF INTRA-ARTICULAR AIR AS REFERENCE STANDARD

To date no study has investigated the actual technical success rate of IA injections into the joint space. Knowledge of technical success is relevant to determine potential efficacy confounders due to inappropriate injection. The aim of this study was to determine the success rate of intra-articular injection of an investigational treatment of knee osteoarthritis pain into the knee joint with and without ultrasound guidance, using radiographic documentation of intra-articular air injection as the reference. Between December 2020 and March 2022, 216 patients underwent intra-articular injection of an investigational treatment, a cryopreserved Amniotic Suspension Allograft (ASA, Organogenesis, Canton, MA) into the knee joint, either under ultrasound guidance or with palpation-based injection without imaging guidance. Injection of the study treatment was performed in a phase 3 prospective double-blind, multicenter, placebo-controlled, parallel group, randomized control trial (RCT) in subjects with moderate to severe symptomatic knee osteoarthritis. Injection was performed by physicians or physician-assistants in Orthopedics, Internal Medicine, Rheumatology, or Radiology. Inclusion criteria were the presence of radiographic knee OA (Kellgren and Lawrence grade 2 or above) and knee pain. About half of the recruited patients underwent ultrasound guided injection and the other half had palpation-guided injection without imaging guidance. 1 mL of 1% lidocaine was used to anesthetize the skin and periarticular tissues with a 27g needle prior to using a 21g 1.5-inch needle or 22g 3-inch needle for joint aspiration and injection of either ASA (2mL ASA + 2 mL saline) or 4 mL placebo (USP normal saline). After the injection of study treatment, and with the needle in the same exact location, 10 mL of air were injected, and a lateral X-ray of the knee was performed within 10 minutes to document the presence of intra-articular air. Radiographs were read by a musculoskeletal radiologist blinded to injection technique. Patients’ age, gender, body mass index (BMI), and radiographic knee OA grade were recorded. Collected data (success rate of intra-articular injection) were stratified according to guidance method (with or without ultrasound), approach of injection (medial, lateral suprapatellar, anterior), specialty of injector (Orthopedics, Rheumatology, Internal Medicine, or Radiology), experience of injector (<10 years, 10 years or more but <20 years, 20 years or more), sex, BMI, and Kellgren and Lawrence grade. One-sided Cochran-Armitage test for trend was used to evaluate if there was decreasing success rate with increasing BMI, and to evaluate if there was increasing success rate with increasing injector experience. Included were 216 patients whose mean age was 59.8 (SD ± 10.2) years, and mean BMI 30.6 (4.8). 134 patients were male (62.0%). 94 patients had US-guided injection and 117 patients had palpation-guided injection. Details of demographic characteristics are summarized in Table 1. Of these, 159 injections were intra-articular and 42 extra-articular. 3 injections were indeterminate since air was not visible on the X-ray and excluded from analysis. Although US-guided injection had higher success rate (80/94, 85.1%) than palpation-based injection (89/117, 76.1%), there was no statistically significant difference (p=0.10). There was no difference of success rate with respect of injection approach (medial or lateral, p=0.75). No statistically significant difference in success rate was seen regarding injector specialty, patient sex, BMI, or radiographic OA grade (Table 1). Table 2 also shows more experienced injectors had better success rate than less experienced injectors albeit not statistically significant (p=0.11). There was no trend for decreasing success rate of intra-articular injection with increasing BMI (3 categories), with p-value=0.43. Neither ultrasound-guided nor palpation-guided injection provides 100% success rate for intra-articular injection of the knee as demonstrated by intra-articular air visualization on radiography. The more experienced operators have a higher success rate, with a threshold of 10 years of experience, while specialty or training seems to be less relevant. While ultrasound-guided injection showed somewhat higher success rates compared to palpation-guided injection, documentation of intraarticular injection using air seems paramount to avoid subsequent extra-articular injection of investigational or disease modifying osteoarthritis drug (DMAOD) compound and thus, maximize efficacy. No funding was received for the analysis of this Study. AG has received consultancies from Pfizer, Novartis, Regeneron, AstraZeneca, Merck Serono, and TissueGene and is shareholder of Boston Imaging Core Lab (BICL), LLC. FWR is shareholder of BICL, LLC. and has received consultancies, speaking fees, and/or honoraria from Calibr –California Institute of Biomedical Research and Grünenthal, GmbH. MDC is shareholder of BICL, LLC. CORRESPONDENCE ADDRESS: [email protected]

PREVALENCE OF POTENTIAL MRI-BASED EXCLUSIONARY FINDINGS IN OSTEOARTHRITIS CLINICAL TRIALS: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI)

PREVALENCE OF POTENTIAL MRI-BASED EXCLUSIONARY FINDINGS IN OSTEOARTHRITIS CLINICAL TRIALS: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI)

Brief of Patent Law Professors as Amici Curiae in Support of Petitioners (Apple Inc. et al. v. California Institute of Technology)

Brief of Patent Law Professors as Amici Curiae in Support of Petitioners (Apple Inc. et al. v. California Institute of Technology)

PREVALCENCE OF MR‐DECTED CARTILAGE DAMAGE IN KNEES WITH KELLGREN-LAWRENCE 2 & 3 OSTEOARTHRITIS AND IMPLICATIONS FOR CLINICAL TRIALS

Many potential disease-modifying osteoarthritis drugs (DMOADs) have been investigated, but to date no DMOADs that slow or stop disease progression have been approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A potential reason for the lack of demonstrated efficacy may be reliance on radiographs for defining structural inclusion and exclusion criteria for clinical trials, such as use of joint space width and Kellgren-Lawrence (KL) grade as surrogates for cartilage damage. To estimate the distribution of cartilage damage seen on knee MRI in a sample of knees with radiographic KL 2 and 3 OA that would potentially qualify for a DMOAD trial. We selected knees from the Osteoarthritis Initiative (OAI) that met common structural inclusion criteria for DMOAD trial enrollment at OAI baseline: knees with radiographs centrally graded as KL 2 or 3 and medial minimum joint space width (mJSW) ≥ 1.5mm. A musculoskeletal radiologist with 10 years of experience in semi-quantitative MRI assessment scored knee cartilage damage in the medial and lateral tibiofemoral and patellofemoral compartments using WORMS (Whole-Organ Magnetic Resonance Imaging Score). Coronal intermediate weighted (IW) TSE and sagittal fat-suppressed IW TSE sequences on 3T MRI were used. The WORMS cartilage scores, which are based on both the extent and depth of cartilage damage, were collapsed into 4 categories: no cartilage damage (WORMS 0 and 1), focal partial or full-thickness (PT/FT) cartilage damage (WORMS 2 and 2.5), diffuse partial thickness (PT) cartilage damage (WORMS 3 and 4), and diffuse full-thickness (FT) cartilage damage (WORMS 5 and 6). We estimated the prevalence of each category of cartilage damage in KL2 and KL3 knees; 95% confidence intervals (CI) accounted for clustering at the participant-level since some participants contributed two knees to the analysis. We identified 2,372 participants contributing 3,446 knees with radiographic OA (KL 2 and 3) and medial mJSW ≥ 1.5mm. There were 2,318 KL2 knees and 1,128 KL3 knees. We found no cartilage damage in any compartments in 9.8% (95%CI: 8.5, 11.1) of KL2 knees and 2.0% (95%CI: 1.1, 2.9) of KL3 knees. Cartilage damage was absent in the medial tibiofemoral compartment in 52.4% (95%CI: 50.1, 54.6) of KL2 knees, and 14.4% (95%CI: 12.2, 16.6) of KL3 knees, versus 61% (95%CI: 58.8, 63.2) of KL2 knees and 53.6% (95%CI: 50.4, 56.7) of KL3 knees in the lateral compartment. When medial and lateral compartments were combined, cartilage damage was absent in 34.8% (95%CI: 32.7, 36.9) of the KL2 knees, and 4.3% (95%CI: 3.0, 5.5) of the KL3 knees. Diffuse FT cartilage lesions in the medial compartment were found in 6.1% (95%CI: 5.0, 7.1) of KL2 knees and 42.5% (95%CI: 39.4, 45.6) of KL3 knees. MRI screening prior to clinical trial enrollment may identify a substantial percentage of knees with normal cartilage, as well as knees with diffuse FT cartilage lesions that may not be responsive to DMOADs, depending on the mode of action of a given pharmacological compound. AG has received consultancies fees from Pfizer, Novartis, AstraZeneca, Merck Serono, Regeneron and TissueGene and is shareholder of Boston Imaging Core Lab (BICL), LLC a company providing image assessment services. FWR is shareholder of BICL, LLC and has received consultancies fees from Calibr–California Institute of Biomedical Research and Grünenthal, GmbH. DH receives publication royalties from Wolters-Kluwer. CKK has received consultancy fees from Thuasne, Regeneron, Novartis, Kolon Tissue Gene, Taiwan Liposome, Amzell AZ, LG Chem, Express Scripts, and has received grants from Lilly, Pfizer GSK, Cumberland CORRESPONDENCE ADDRESS: mjarraya@mgh.harvard.edu .

Hans Charles Freeman 1929–2008

Hans Freeman was born in Germany and arrived in Australia with his parents in 1938. A brilliant student at the University of Sydney, he spent a seminal year at the California Institute of Technology before joining the staff at Sydney and initiating research on bioinorganic chemistry, studying metal ion complexes of compounds of biological significance such as amino acids, peptides and proteins. In his use of X-ray crystallography he was a pioneer in Australia, constructing his first crystallographic apparatus and mastering the necessary computing, at first by hand but soon with electronic computers. The culmination of his work with a series of collaborators was the structure of the blue, copper-containing metalloprotein, plastocyanin. Freeman also employed another advanced technique—X-ray spectroscopy and the study of X-ray absorption fine structure. He was a leading figure in Australia and internationally, and played an important role in gaining access for Australian scientists to international facilities such as synchrotron radiation sources at the dawning of the era of ‘Big Science’.

Technology Maturation Efforts for the Next Generation of Grating Spectrometer Hyperspectral Infrared Sounders

As we look forward to the next generation of hyperspectral infrared (IR) atmospheric sounders, grating spectrometers hold promise for improved performance (e.g., horizontal and spectral resolutions) and more rapid revisit while reducing the size and complexity of the instrument. We briefly revisit the technology used in the Atmospheric Infrared Sounder (AIRS), recognizing that it was developed in the 1990’s and has matured key technologies in the areas of IR detectors, optical coatings, gratings, and cryocoolers. AIRS has been an unqualified success not only as a science and operational mission but also as a technology demonstration of the reliability and simplicity of grating spectrometer IR sounding instruments. Advancements in focal plane arrays (FPAs) have enabled a new class of grating spectrometer IR sounders that offer more spectral channels on a single FPA, mitigating some of the issues seen in AIRS that used linear arrays. These improvements have been manifested in the CubeSat Infrared Atmospheric Sounder (CIRAS) brassboard instrument, developed at the California Institute of Technology Jet Propulsion Laboratory with industry partner Ball Aerospace. Further enhancements beyond those used in CIRAS enable the development of a new class of instruments with a very long-wavelength infrared response and a very high spatial resolution (<2 km) that can be used for the next generation of IR sounders. Grating spectrometers provide advantages over other methods, including smaller apertures due to the ability to use larger FPAs, having no moving parts or laser metrology systems to produce spectra, lower internal FPA readout rates, and lower overall system data rates.

SIZE OF KNEE OSTEOPHYTES is under‐estimated as Assessed by MRI USING CT AS A REFERENCE STANDARD

The radiographic diagnosis of knee osteoarthritis (OA) is based on the presence of a definite osteophyte (OP). Epidemiologic studies and clinical trials commonly employ MRI using standard clinical sequences and OP assessment is one of the features included. Commonly used sequence protocols in such studies are based on triplanar fat suppressed T2- or proton density-weighted sequences with bony features as well as fibrous and lipomatous tissues appearing hypointense. This may potentially result in underestimation of such features including osteophyte assessment. Computed tomography (CT) is considered as the modality of choice for the analysis of OPs and may therefore be considered a reference standard. To explore the diagnostic performance of routine MRI as used in observational studies and clinical trials of knee OA for the assessment of OPs in all three knee compartments and the femoral notch using CT as a reference standard. The Strontium Ranelate Efficacy in Knee Osteoarthritis Trial (SEKOIA) clinical trial explored the effect of 3 years of treatment with strontium ranelate in patients with primary knee OA. All patients included in the current study participated in the CT sub-study of SEKOIA. In the current investigation, baseline data from three different centers were used. OPs were scored using a modified MOAKS scoring system in the patellofemoral (PFJ), the medial tibio-femoral (TFJ) and the lateral TFJ. Size was assessed from 0 to 3 in 18 locations. Descriptive statistics were used to describe differences in ordinal grading between CT and MRI. In addition, weighted-kappa statistics were employed to assess agreement between scoring using the two methods. Finally, sensitivity, specificity, positive predictive value and negative predictive value as well as AUC measures of diagnostic performance were employed using CT as the reference standard. Mean age of the randomized patients was 62.9 ±7.5 years with a majority of women (70%). Body mass index was 29.9±5.0 kg/m 2 . The target knee JSW was 3.50±0.84 mm at baseline, patients were Kellgren and Lawrence grade 2 (62%) or 3 (38%). Included were 74 patients with available MRI and CT data. Altogether 1332 locations were evaluated. For the PFJ MRI detected 141 (72%) of 197 CT-defined OPs with a w-kappa of 0.58 (95% CI [0.52-0.65]). In the medial TFJ, MRI detected 178 (81%) of 219 CT-OPs with a w-kappa of 0.58 (95% CI [0.51-0.64]). For the lateral compartment these numbers were 84 (70%) of 120 CT-OPs with a w-kappa of 0.58 (95% CI [0.50-0.66]). Regarding disagreement, for the PFJ MRI underestimated OP size in 94 cases (21%) and over-estimated in 27 cases (6%). For the medial TFJ these numbers were 90 (20%) and 29 (7%), and for the lateral TFJ 67 (15%) and 15 (3%). Details of the diagnostic performance analysis are presented in Table 1 . MRI underestimates presence and size of osteophytes in all 3 knee compartments. However, the sensitivity of >0.9 for OP detection in the medial compartment, which is commonly the compartment of relevance in clinical DMOAD trials, reflects that MRI is adequately able to detect osteophytes that commonly define structural disease. CT may be helpful particularly reading assessment of small osteophytes particularly in early disease. No funding was received for this sub-analysis of the SEKOIA Study AG has received consultancies, speaking fees, and/or honoraria from Pfizer, Novartis, AstraZeneca, Merck Serono, and TissueGene and is President and shareholder of Boston Imaging Core Lab (BICL), LLC a company providing image assessment services. FWR is Chief Medical Officer and shareholder of BICL, LLC. and has received consultancies, speaking fees, and/or honoraria from Calibr –California Institute of Biomedical Research and Grünenthal, GmbH CORRESPONDENCE ADDRESS: frank.roemer@uk-erlangen.de .

ExxonMobil buys resin firm Materia

ExxonMobil Chemical has acquired Materia, a company formed by California Institute of Technology professor Robert Grubbs to make thermoset resins using the science for which he won the 2005 Nobel Prize in Chemistry. Materia uses ruthenium catalysts to carry out olefin metathesis, a customizable reaction that breaks carbon-carbon double bonds and forms new ones. The firms say Materia’s materials are lighter, stronger, and more durable than epoxies, vinyl esters, and polyesters.

The dominant features of the internet linguistics

This research aims at the modern Internet linguistics features by carrying out linguistic analysis using descriptive statistics of students in distance learning. A linguistic analysis found that most students used lexical, orthographic, paralinguistic, and graphic features when communicating in an online classroom. A total of 452 messages, containing a corpus of 6,340 words, were analyzed and found that only 23.72% of the total corpus was found with lexical, spelling, paralinguistic and graphical features at the Massachusetts Institute of Technology, 22.63% at Stanford University, 21.78% at Harvard University, 24.58% at the California Institute of Technology and 22.76% at Oxford University.

Baltimore Wins Lasker-Koshland Award.

The Albert and Mary Lasker Foundation has bestowed its prestigious Lasker-Koshland Award for Special Achievement in Medical Science upon David Baltimore, PhD, president emeritus and distinguished professor of biology at the California Institute of Technology (Caltech) in Pasadena, and 1975 Nobel Laureate in Physiology or Medicine, calling him "one of the premier biomedical scientists of the last five decades."

In the Struggle: Scholars and the Fight Against Industrial Agribusiness in California

In the Struggle: Scholars and the Fight Against Industrial Agribusiness in California

Monoacylglycerol Lipase Inhibition: A Strategy to Treat Chronic Pain in a Humanized Sickle Cell Mouse Model

Introduction: Sickle Cell Disease (SCD) is a major cause of morbidity and mortality worldwide, and affects more than 100,000 people in the US. Acute, vaso-occlusive pain crises are the hallmark of the disease and the primary cause of hospitalization. Recurrent, acute pain episodes compound and result in chronic pain for many patients, though the mechanisms of this transition are poorly understood. Although opioids remain the standard of care to treat SCD chronic pain, their myriad adverse side effects (e.g., constipation, respiratory depression, abuse liability, dependence) as well as the fact that SCD chronic pain requires prolonged opioid treatment that results in tolerance, severely limit their therapeutic utility. Thus, a pressing need exists to identify effective non-opioid analgesic strategies to reduce SCD chronic pain. Humanized mouse models of SCD, such as the Berkeley (BERK) model, provide a useful tool to investigate disease pathophysiology and evaluate novel therapeutic strategies. Dorsal Root Ganglion neurons are peripheral sensory neurons essential for pain preclinical investigations. DRG neurons from rodents in neuropathic pain models show hyperexcitability. Inhibitors of the major degradative enzyme of 2-arachidonoylglycerol, monoacylglycerol lipase (MAGL), reduce nociceptive behavior in neuropathic and inflammatory preclinical models of pain through cannabinoid receptor-dependent and -independent mechanisms. MAGL inhibitors have yet to be tested in BERK mice and we hypothesize that they will ameliorate pain-like behavior and neuronal hyperexcitability. Here we evaluate the effects of MJN110 in a series of pain-related behaviors in BERK mice.Methods: Male and female HbSS-BERK (sickle) and HbAA-BERK (control) mice were used as subjects for these experiments. Pain-like behaviors were assessed using the Von Frey, Hot Plate, and Grip Strength tests. Neuronal hyperexcitability was assessed using whole cell patch clamp electrophysiology of L4-S1 dorsal root ganglia (DRG) neurons. For the dose-response experiments, MJN-110 (1.25, 2.5, 5, and 10 mg/kg, i.p.) was administered one hour prior to testing. Data were analyzed as Student's t-test, one- and two-way ANOVAs followed by Tukey or Sidak post-hoc analysis when appropriate (p < 0.05 considered significant).Results: HbSS-BERK mice displayed profound mechanical allodynia, as well as thermal and deep tissues/musculoskeletal hyperalgesia. HbSS-BERK mice possess extremely hyperexcitable DRG neurons. MJN-110 dose-dependently reduced mechanical allodynia and thermal hyperalgesia in HbSS-BERK mice. Importantly, BERK mice given seven days of daily injections of MJN-110 (5 mg/kg) displayed sustained antinociception that did not undergo tolerance. Ongoing studies are aimed to determine whether MJN110 ameliorates the hyperexcitability of DRG neurons.Conclusion: These initial findings, not only validate that BERK mice show hypersensitive responses to mechanical and heat stimuli, but also demonstrate that neurons innervating the distal parts of BERK mice are hyperexcitable. Additionally, MJN110 reduces these hyper-nociceptive behaviors suggesting that MAGL inhibition represents a viable strategy to reduce chronic pain behaviors in the BERK mouse model. DisclosuresGupta: Tautona Group: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 1910 Genetics: Other: Grantee; Grifols: Other: Grantee; SCDAA: Membership on an entity's Board of Directors or advisory committees; CSL Behring LLC: Honoraria; NIH: Other: Grantee; University of Minnestoa Foundation: Other: Philanthropic Funding; Southern California Institute for Research and Education Foundation: Other: Philanthropic Funding; Cyclerion: Research Funding; UCI Foundation: Other: Philanthropic Funding. Smith: Emmaus Pharmaceuticals: Consultancy; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceuticsl: Consultancy, Honoraria; Novo-Nordisk: Other: DSMB; Pfizer: Consultancy, Research Funding; Imara: Research Funding; Forma Therapeutics: Consultancy, Research Funding; Agios: Research Funding.

Nogo-a Pathway Contributes to Neural Injury and Pain in Sickle Cell Disease

Sickle cell disease (SCD) is characterized by chronic pain and bouts of extreme acute pain from vasoocclusive crises (VOC). Sickle pain has both neuropathic and inflammatory features (Tran et al., Blood 2017). Mechanisms underlying neural injury remain unknown in SCD. Neurite outgrowth inhibitor (NOGO-A/reticulon-4) and its receptor NGR1 contribute to pain, neuronal damage, and inhibition of neurite outgrowth (Hu et al., FASEB J 2019). We examined if NOGO-A pathway is activated in a sickle microenvironment and if its inhibition will ameliorate hyperalgesia in BERK sickle mice. We used Rho kinase activity (ROCK) downstream of NGR1 as a readout of activation of NOGO-A/NGR1 pathway. We observed increased expression of NOGO-A (~260%, p<0.05) and NGR1 (~180%, p<0.05) in the dorsal root ganglia, and increased NOGO-A and ROCK activity in spinal cords of sickle mice compared to control mice expressing normal human hemoglobin A. Earlier, we found that an endogenous cannabinoid, palmitoylethanolamide (PEA) inhibits spinal NOGO-A expression and ROCK activity in sickle mice (Argueta et al., ASH 2020 #225). We hypothesized that sickle microenvironment with cell-free heme and inflammation activates NOGO-A/NGR1-ROCK pathway leading to nerve injury and pain, and inhibition of this pathway will ameliorate hyperalgesia in sickle mice.Using terminally differentiated rat pheochromocytoma (PC12) cells, we simulated a sickle microenvironment with hemin (40 µM) and TNFα (1 ng/ml) (H+T). H+T elevated ROCK activity compared to vehicle (~40%, p<0.05). PEA (30 uM) and 2 µM NEP (1-40), a competitive antagonist of NGR1, attenuated H+T-induced ROCK activity (both p<0.01); co-treatment had no additive effect, indicating a common pathway. As well, siRNA (10 nM) knockdown of NGR1 reversed H+T-induced ROCK activity (p<0.001), which was equally effective with 30 µM PEA co-treatment. Functionally, treatment with 30 µM PEA or 2 µM NEP (1-40) enhanced neurite outgrowth in H+T-treated PC-12 cells (~120%, p<0.001). NEP (1-40) at 5 mg/kg reduced mechanical and cold (both ~50%, p<0.001) hyperalgesia in sickle mice compared to baseline (BL) and/or vehicle treatment. Together, these data demonstrate that NOGO-A/NGR1 pathway activation may underlie nerve injury, and inhibition of this pathway with a NGR1 antagonist or PEA promotes neurite outgrowth and reduces hyperalgesia in a sickle microenvironment.We next examined the contribution of exogenously administered and endogenously produced PEA in ameliorating hyperalgesia. Mass spectrometry revealed that spinal PEA is reduced in female (p<0.05) and male (p<0.001) sickle mice compared to age/sex-matched control mice. Exogenous PEA (i.p. 20 mg/kg/d) reduced cold avoidance over a 3-day treatment period, showing significantly more time in the cold chamber compared to BL or vehicle at 1 h, 24 h, and 72 h (p<0.05). The analgesic effect of PEA was maintained for 9 days of treatment without developing tolerance. We next increased endogenous PEA by inhibiting its degradative enzyme, N-acylethanolamine acid amidase, with ARN19702 (i.p. 3, 10, & 30 mg/kg/d), which reduced mechanical (~50%, p<0.001) and cold hyperalgesia (~40%, p<0.001) over 72 hours in a dose-dependent manner. Since hypoxia and ischemia reperfusion injury contribute to acute VOC pain, we incited hypoxia-reoxygenation (HR; 3 h @ 8% O 2, 92% N 2, followed by 1 h @ normoxia) to simulate acute VOC pain. We observed that 5-day pretreatment with PEA (i.p. 20 mg/kg/d) before HR prevented mechanical and cold hyperalgesia following HR in sickle mice. Moreover, treatment with PEA after HR incitement significantly reduced hyperalgesia for 24 h after HR compared to BL (~30%, p<0.001) and vehicle treated (~66%, p<0.001) sickle mice.NGR1 antagonism reduces spinal microglial injury/activation. Heme and TNFα have been shown to cause microglial injury in vitro, while spinal microglial activation has been demonstrated in sickle mice (Lei et al., Antioxid Redox Signal 2021). Thus, NGR1/ROCK cascade may contribute to both neuronal injury and inflammation in the central nervous system leading to neuropathic pain. Our data suggest that PEA and targeting NOGO-A pathway may prevent/reduce chronic and acute hyperalgesia in sickle mice. We speculate that interventions targeting NOGO-A pathway may prevent/reduce neuropathic pain and that PEA has the translational potential for the treatment of chronic and acute pain in SCD. DisclosuresGupta: Tautona Group: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 1910 Genetics: Other: Grantee; Grifols: Other: Grantee; SCDAA: Membership on an entity's Board of Directors or advisory committees; CSL Behring LLC: Honoraria; NIH: Other: Grantee; University of Minnestoa Foundation: Other: Philanthropic Funding; Southern California Institute for Research and Education Foundation: Other: Philanthropic Funding; Cyclerion: Research Funding; UCI Foundation: Other: Philanthropic Funding.

The Neoliberalization of Higher Education: Paradoxing Students' Basic Needs at a Hispanic-Serving Institution

Millions of college students in the United States lack access to adequate food, housing, and other basic human needs. These insecurities have only been exacerbated in recent decades by the country's neoliberal approach to higher education, with disproportionately negative consequences for historically underserved populations (e.g., racial/ethnic minorities, low-income students, and first-generation college students). For each of these reasons, this study explores the organizational paradoxes faced by students attending a public, 4-year Hispanic-Serving Institution (HSI) in southern California. Drawing upon 30 semi-structured interviews with undergraduates who self-identified as historically underserved, our three-stage conceptualization of data analysis revealed three specific paradoxes: (1) provision vs. dependence, (2) sympathy vs. distancing, and (3) bootstrapping vs. unattainability. We conclude with practical and theoretical implications for alleviating the repercussions of neoliberal policies on today's college students.

Chemists pull asymmetric C–N compounds from engineered enzyme

Chemists have coaxed a common enzyme into catalyzing the formation of an enantioselective carbon-nitrogen bond. The approach can generate the preferred enantiomer of amines and anilines within molecules of interest ( Nat. Chem. 2021, DOI: 10.1038/s41557-021-00794-z ). Such chiral C–N bonds are practically ubiquitous in pharmaceuticals, from antibiotics to anticancer compounds. Frances Arnold and other scientists from the California Institute of Technology and the University of Girona used directed evolution to engineer a dual-function enzyme that performs a two-step, asymmetric N–H insertion into a carbene intermediate. The enzyme can produce over 90% of the preferred enantiomer. Such selectivity is difficult using traditional organic synthesis methods. Zhen Liu , a postdoctoral researcher in Arnold’s lab and the paper’s first author, says nonenzymatic carbene N–H insertion requires two different catalysts: one to form the carbene intermediate and a second to donate a proton and produce the final aniline product. The team’s enzyme

Leptomeningeal Disease in Breast Cancer: Pre-Treatment Prognostic Factors and Outcomes

Leptomeningeal disease (LMD) is a devastating diagnosis with limited treatment options and poor prognosis. With recent advances in treatment, women with breast cancer (BC) are living longer and the incidence of LMD in this population is increasing. There remains little data regarding the prognosis and optimal treatment of these patients. As such, we conducted a multi-institutional retrospective review of women with BC LMD and analyzed outcomes based on prognostic factors and treatments.We analyzed the records of women diagnosed with BC LMD via MRIs of their brain and/or spine between 2000 and 2020 at two academic medical centers. Demographic and clinical characteristics were abstracted from electronic medical records and an in-depth radiographic review was performed by a neuro-radiologist for each case. Univariate and multivariate Cox proportional-hazards models were generated to identify factors associated with prolonged survival. Collection and analysis of the data was approved by institutional IRB.We identified 227 women with BC LMD. Prior to developing LMD, most women initially presented with Stage I-III BC (62.1%) with ductal histology (67.0%) and biological subtypes including ER-positive/HER2-negative (56.8%), HER2-positive (17.6%), and triple-negative (22.0%). LMD was first diagnosed a median of 4.6 years (range: 0 to 34.1 years) after the initial diagnosis of BC, and the median age at LMD diagnosis was 54.6 years (range: 29.4 to 84.5 years). At time of LMD diagnosis, 146 (64.3%) women presented with a Karnofsky Performance Status (KPS) ≥ 70, 90 (39.6%) had a preceding parenchymal brain metastasis, and 23 (10.1%) had LMD as their only site of metastatic disease. Radiographically, classical LMD (61.7%) was observed more frequently than nodular-only LMD (13.2%). Brain-only LMD was present in 55.1% of patients, spine-only in 6.1% of patients, and both brain and spine in 38.8% of patients. Median survival from the time of LMD diagnosis was 4.5 months (95% CI: 3.4-7.8). Pre-treatment clinical factors associated with improved survival on univariate analysis included ER-positive/HER2-negative subtype (P = 0.010), KPS ≥ 70 (P < 0.001), LMD as the only site of metastasis (P = 0.004), stable or controlled extracranial metastases (P = 0.042), absence of leukopenia (P = 0.040) and the presence of nodular LMD (P < 0.001). After adjusting for these clinical factors, the receipt of radiation therapy (adjusted hazard ratio [AHR] 0.50, 95% CI: 0.37 - 0.68), systemic therapy (AHR 0.27, 95% CI: 0.19 - 0.38) and intrathecal chemotherapy (AHR 0.49, 95% CI: 0.33 - 0.75) were all associated with improved survival.In one of the largest multi-institutional reviews to date, we found that several pre-treatment clinical factors were significantly associated with improved survival among women with breast cancer LMD. However, despite treatment overall survival remains poor, and there is a need for new, effective therapies.M.G. Milligan: None. A. Aitelli: None. W.A. Mehan: Consultant; Kura Oncology. D.D. Shi: None. D.N. Cagney: Research Grant; Viewray, NhTheraguix. K.S. Oh: None. N. Wang: None. P. Brastianos: Research Grant; Merck, Eli Lily, BMS. Honoraria; Merck, Genentech. Consultant; Angiochem, Dantari Pharmaceuticals, Elevatebio, Eli Lily, Genentech, Pfizer, SK Life Sciences, Tesaro. B. Moy: Research Grant; PUMA biotechnology. N.U. Lin: Research Grant; Genentech, Merck, Pfizer, Seattle Genetics. Consultant; PUMA Biotechnology, Seattle Genetics, Daiichi Sankyo, Astra Zeneca, Denali Therapeutics, California Institute for Regenerative Medicine, Prelude Therapeutics. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital.

Biden chooses science advisers

US president Joe Biden announced Sept. 22 the new members of his scientific advisory committee, including several leaders in the chemistry enterprise. The President’s Council of Advisors on Science and Technology (PCAST) will consist of 30 members from a variety of disciplines, including agriculture, engineering, neuroscience, and cybersecurity. Biden had announced the three cochairs for PCAST in January. They are Biden’s science adviser and Broad Institute mathematician and geneticist Eric Lander ; Chemistry Nobel Laureate and California Institute of Technology chemical engineer Frances Arnold; and Massachusetts Institute of Technology geophysicist and vice president for research Maria Zuber. The full council is the most diverse ever, the administration says. More than half the members are women and more than a third are people of color or immigrants. This is also the first time women have served as PCAST cochairs. “We are thrilled that some of our most accomplished Americans are willing

Automated Noise Calibration System (VT-1000)

This paper details an automated Noise Source calibration system in development at Jet Propulsion Laboratory, California Institute of Technology (JPL). The paper begins with a discussion on noise figure and excess-noise-ratio (ENR) theory, fundamentals and governing equations. As part of the fundamentals there is a discussion of the system’s use of the Y-factor method to obtain accurate measurements of the unit under test (UUT), and how these measurements are compared against a known ENR standard to obtain the UUT’s ENR values. There is also an in-depth discussion on uncertainty quantification for noise source system calibrations. The architecture of the automated calibration system is provided, which includes both the system’s hardware and software configuration. The software is written in Python 3, and provides the user detailed instruction on how to proceed, including step-by-step connection requirements. This system automates much of the measurement process, including real-time uncertainty quantification and report generation, as well as real-time feedback to the user to allow intervention. The system takes advantage of a database of results from previous measurements to compare calibration history of the ENR measurements. The automated system presented here operates over a frequency range from 10 MHz to 50 GHz, and has shown substantial time savings over traditional manual methods of performing this calibration

The Borders of Black Power

The Borders of Black Power