First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Impact-induced muscle damage and urinary pterins in professional rugby: 7,8-dihydroneopterin oxidation by myoglobin.

Muscle damage caused through impacts in rugby union is known to increase oxidative stress and inflammation. Pterins have been used clinically as markers of oxidative stress, inflammation, and neurotransmitter synthesis. This study investigates the release of myoglobin from muscle tissue due to force-related impacts and how it is related to the subsequent oxidation of 7,8-dihydroneopterin to specific pterins. Effects of iron and myoglobin on 7,8-dihydroneopterin oxidation were examined in vitro via strong cation-exchange high-performance liquid chromatography (SCX-HPLC) analysis of neopterin, xanthopterin, and 7,8-dihydroxanthopterin. Urine samples were collected from 25 professional rugby players pre and post four games and analyzed for myoglobin by enzyme-linked immunosorbent assay, and 7,8-dihydroneopterin oxidation products by HPLC. Iron and myoglobin oxidized 7,8-dihydroneopterin to neopterin, xanthopterin, and 7,8-dihydroxanthopterin at concentrations at or above 10 µM and 50 µg/mL, respectively. All four games showed significant increases in myoglobin, neopterin, total neopterin, biopterin, and total biopterin, which correlated between each variable (P < 0.05). Myoglobin and iron facilitate 7,8-dihydroneopterin oxidation to neopterin and xanthopterin. In vivo delocalization of myoglobin due to muscle damage may contribute to oxidative stress and inflammation after rugby. Increased concentrations of biopterin and total biopterin may indicate production of nitric oxide and monoamine neurotransmitters in response to the physical stress.

Building-related health symptoms and classroom indoor air quality: a survey of school teachers in New York State.

UNLABELLED: Most previous research on indoor environments and health has studied school children or occupants in non-school settings. This investigation assessed building-related health symptoms and classroom characteristics via telephone survey of New York State school teachers. Participants were asked about 14 building-related symptoms and 23 classroom characteristics potentially related to poor indoor air quality (IAQ). Poisson regression analysis was used to assess the relationship between these symptoms and each classroom characteristic, controlling for potential confounders. About 500 teachers completed the survey. The most frequently reported classroom characteristics included open shelving (70.7%), food eaten in class (65.5%), dust (59.1%), and carpeting (46.9%). The most commonly reported symptoms included sinus problems (16.8%), headache (15.0%), allergies/congestion (14.8%), and throat irritation (14.6%). Experiencing one or more symptoms was associated most strongly with reported dust (relative risk (RR) = 3.67; 95% confidence interval (CI): 2.62-5.13), dust reservoirs (RR = 2.13; 95% CI: 1.72-2.65), paint odors (RR = 1.73; 95% CI: 1.40-2.13), mold (RR = 1.71; 95% CI: 1.39-2.11), and moldy odors (RR = 1.65 95% CI: 1.30-2.10). Stronger associations were found with increasing numbers of reported IAQ-related classroom characteristics. Similar results were found with having any building-related allergic/respiratory symptom. This research adds to the body of evidence underscoring the importance to occupant health of school IAQ. PRACTICAL IMPLICATIONS: Teachers play an important role in educating children, and teacher well-being is important to this role. Health symptoms among New York teachers while at work are common and appear to be associated with numerous characteristics related to poor classroom IAQ. Improving school Indoor Air Quality may reduce sickness and absenteeism and improve teacher performance.

MRI findings in the lumbar spines of asymptomatic elite junior tennis players.

OBJECTIVE: To evaluate the MRI findings in the lumbar spines of asymptomatic elite junior tennis players. MATERIALS AND METHODS: The lumbar spine MRI studies of 98 asymptomatic junior elite tennis players (51 male, 47 female) with a mean age of 18 years (age range 11.2-26.3 years; standard deviation 3.1) was reviewed by two consultant musculoskeletal radiologists using consensus opinion. Images were assessed using accepted classification systems. RESULTS: Four players (4%) had no abnormality. Facet joint arthropathy occurred in 89.7% of the players, being mild in 84.5% of cases. There were 41 synovial cysts in 22.4% of the cohort all occurring in the presence of facet arthropathy. Disc degeneration was noted in 62.2 % of players, being mild in 76.2% of those affected. Disc herniation was noted in 30.6% of players, with 86.1% of these being broad based and 13.9% being focal. There was nerve root compression in 2%. There were 41 pars interarticularis abnormalities in 29.6% of patients, 63.4% of these being grades 1-3. There was grade 1 spondylolisthesis in 5.1% of players. The prevalence of facet joint arthropathy, disc degeneration, disc herniation and pars interarticularis fracture was lower in female players than in male and lower in the under 16-year-olds compared with the over 20-year-olds. CONCLUSION: There is a significant amount of underlying pathology that would normally go undetected in this group of asymptomatic elite athletes. Whilst these findings cannot be detected clinically, their relevance is in facilitating appropriate prehabilitation to prevent loss of playing time and potentially career-ending injuries.

Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia.

Central core disease (CCD) of muscle is an inherited myopathy which is closely associated with malignant hyperthermia (MH) in humans. CCD has recently been shown to be tightly linked to the ryanodine receptor gene (RYR1) and mutations in this gene are known to be present in MH. Mutation screening of RYR1 has led to the identification of two previously undescribed mutations in different CCD pedigrees. One of these mutations was also detected in an unrelated MH pedigree whose members are asymptomatic of CCD. The data suggest a model to explain how a single mutation may result in two apparently distinct clinical phenotypes.

Diagnostic validation of vertebral heart score machine learning algorithm for canine lateral chest radiographs.

OBJECTIVES: The vertebral heart score is a measurement used to index heart size relative to thoracic vertebra. Vertebral heart score can be a useful tool for identifying and staging heart disease and providing prognostic information. The purpose of this study is to validate the use of a vertebral heart score algorithm compared to manual vertebral heart scoring by three board-certified veterinary cardiologists. MATERIALS AND METHODS: A convolutional neural network centred around semantic segmentation of relevant anatomical features was developed to predict heart size and vertebral bodies. These predictions were used to calculate the vertebral heart score. An external validation study consisting of 1200 canine lateral radiographs was randomly selected to match the underlying distribution of vertebral heart scores. Three American College of Veterinary Internal Medicine board-certified cardiologists were enrolled to manually score 400 images each using the traditional Buchanan method. Post-scoring, the cardiologists evaluated the algorithm for misaligned anatomic landmarks and overall image quality. RESULTS: The 95th percentile absolute difference between the cardiologist vertebral heart score and the algorithm vertebral heart score was 1.05 vertebrae (95% confidence interval: 0.97 to 1.20 vertebrae) with a mean bias of -0.09 vertebrae (95% confidence interval: -0.12 to -0.05 vertebrae). In addition, the model was observed to be well calibrated across the predictive range. CLINICAL SIGNIFICANCE: We have found the performance of the vertebral heart score algorithm comparable to three board-certified cardiologists. While validation of this vertebral heart score algorithm has shown strong performance compared to veterinarians, further external validation in other clinical settings is warranted before use in those settings.

A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

BACKGROUND: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. PATIENTS AND METHODS: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. CONCLUSIONS: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.

Suppression of T and B lymphocyte activation by a Yersinia pseudotuberculosis virulence factor, yopH.

The acquired immune responses are crucial to the survival of Yersinia-infected animals. Mice lacking T cells are sensitive to Yersinia infection, and a humoral response to Yersinia can be protective. Diverse mechanisms for Yersinia to impair and evade the host innate immune defense have been suggested, but the effects of Yersinia on lymphocytes are not known. Here, we demonstrate that after a transient exposure to Y. pseudotuberculosis, T and B cells are impaired in their ability to be activated through their antigen receptors. T cells are inhibited in their ability to produce cytokines, and B cells are unable to upregulate surface expression of the costimulatory molecule, B7.2, in response to antigenic stimulation. The block of lymphocyte activation results from the inhibition of early phosphorylation events of the antigen receptor signaling complex. Through the use of Y. pseudotuberculosis mutants, we show that the inhibitory effect in both T cells and B cells is dependent on the production of Yersinia outermembrane protein (Yop) H, a tyrosine phosphatase. Our results suggest a mechanism by which the pathogenic bacteria may modulate a wide range of T and B cell-mediated immune responses.

Musculoskeletal sonography of the normal foot.

Traumatic, degenerative and rheumatological injuries of the foot are common and can be managed by an ever increasing number of treatments and surgical interventions. High-frequency sonography is inexpensive, portable and is unique in allowing true dynamic assessment of the ligamentous, muscular and tendinous structures. The ultrasound technique demonstrates a steep learning curve and requires detailed knowledge of the foot anatomy. Ultrasound assessment plays an important role in the diagnosis and management of injuries of these structures by guiding rehabilitation and surgical intervention without delay. However, intimate knowledge of the ultrasound appearances of the foot anatomy and normal variants is paramount to correctly identify pathological conditions. We describe the normal sonographic appearances of the foot musculoskeletal structures with MR correlation including joints and their ligaments, dorsal and plantar surfaces of the foot, and the arches of the foot and their supporting structures.

Controlled local release of PPARγ agonists from biomaterials to treat peripheral nerve injury.

OBJECTIVE: Poor clinical outcomes following peripheral nerve injury (PNI) are partly attributable to the limited rate of neuronal regeneration. Despite numerous potential drug candidates demonstrating positive effects on nerve regeneration rate in preclinical models, no drugs are routinely used to improve restoration of function in clinical practice. A key challenge associated with clinical adoption of drug treatments in nerve injured patients is the requirement for sustained administration of doses associated with undesirable systemic sideeffects. Local controlled-release drug delivery systems could potentially address this challenge, particularly through the use of biomaterials that can be implanted at the repair site during the microsurgical repair procedure. APPROACH: In order to test this concept, this study used various biomaterials to deliver ibuprofen sodium or sulindac sulfide locally in a controlled manner in a rat sciatic nerve injury model. Following characterisation of release parameters in vitro, ethylene vinyl acetate tubes or polylactic-co-glycolic acid wraps, loaded with ibuprofen sodium or sulindac sulfide, were placed around directly-repaired nerve transection or nerve crush injuries in rats. MAIN RESULTS: Ibuprofen sodium, but not sulindac sulfide caused an increase in neurites in distal nerve segments and improvements in functional recovery in comparison to controls with no drug treatment. SIGNIFICANCE: This study showed for the first time that local delivery of ibuprofen sodium using biomaterials improves neurite growth and functional recovery following PNI and provides the basis for future development of drug-loaded biomaterials suitable for clinical translation.

Early expression of the gene for interphotoreceptor retinol-binding protein during photoreceptor differentiation suggests a critical role for the interphotoreceptor matrix in retinal development.

Interphotoreceptor retinol-binding protein (IRBP), the major protein component of the subretinal space, is in a strategic position to mediate cellular interactions between the retinal pigmented epithelium (RPE) and the neural retina. While IRBP appears to be involved in vitamin A transport during the visual cycle in the adult, the role of this protein during eye development has not been determined. As a first step to understanding the role of IRBP during retinal development, we have studied the expression of the mRNA for this glycolipoprotein during photoreceptor differentiation in the rat. A rat neural retina cDNA library was prepared from which an IRBP clone was isolated. The clone contains an open reading frame followed by a 3' noncoding sequence ending in 10 adenosine residues. The coding region has an identity of 83.9 and 82.5% with the nucleotide sequence of human and bovine IRBP, respectively. Rats (Sprague-Dawley, Wistar, and Royal College of Surgeon pink-eyed controls) have a 6.4 and a 5.2-kb mRNA for IRBP which are present in a 1:4 ratio and thus are the only vertebrate known to definitely have more than one major form of the IRBP message. Genomic Southern blots are consistent with the hypothesis that there is only one allele of the IRBP gene, suggesting that the two forms are produced by alternative processing of the mRNA. To generate an antisense RNA probe for use in molecular titration assays and Northern blots, an Eco RI-Bam HI fragment from the coding region was subcloned in between flanking Sp6 and T7 promoters. Total RNA was prepared from undissected rat globes from postnatal days p0-p22. The expression of the mRNA for IRBP was studied by Northern blots and the level of the transcripts determined by solution hybridization assays. Approximately 10(5) IRBP mRNA transcripts/micrograms total eye RNA are present at birth. This increases to a final level of 3.1 X 10(6) transcripts/micrograms total RNA by p9. The one-half maximal level of the mRNA occurs at p4.2 which is 2 wk before the one-half maximal level of IRBP is reached in the subretinal space (Gonzalez-Fernandez, F., R. A. Landers, P. A. Glazebrook, S.-L. Fong, G. I. Liou, D. M. K. Lam, and C. D. B. Bridges. 1984. J. Cell Biol. 99:2092-2098). The expression of the mRNA for IRBP reflects the developmental emergence of the interphotoreceptor matrix as an important structure within the retina.(ABSTRACT TRUNCATED AT 400 WORDS)

Nuclear explosions and distant earthquakes: a search for correlations.

An apparent correlation between nuclear explosions and earthquakes has been reported for the events between September 1961 and September 1966. When data from the events between September 1966 and December 1968 are examined, this correlation disappears. No relationship between the size of the nuclear explosions and the number of distant earthquakes is apparent in the data.

An experiment in earthquake control at rangely, colorado.

An experiment in an oil field at Rangely, Colorado, has demonstrated the feasibility of earthquake control. Variations in seismicity were produced by controlled variations in the fluid pressure in a seismically active zone. Precise earthquake locations revealed that the earthquakes clustered about a fault trending through a zone of high pore pressure produced by secondary recovery operations. Laboratory measurements of the frictional properties of the reservoir rocks and an in situ stress measurement made near the earthquake zone were used to predict the fluid pressure required to trigger earthquakes on preexisting fractures. Fluid pressure was controlled by alternately injecting and recovering water from wells that penetrated the seismic zone. Fluid pressure was monitored in observation wells, and a computer model of the reservoir was used to infer the fluid pressure distributions in the vicinity of the injection wells. The results of this experiment confirm the predicted effect of fluid pressure on earthquake activity and indicate that earthquakes can be controlled wherever we can control the fluid pressure in a fault zone.

Seismic activity and faulting associated with a large underground nuclear explosion.

The 1.1-megaton nuclear test Benham caused movement on previously mapped faults and was followed by a sequence of small earthquakes. These effects were confined to a zone extending not more than 13 kilometers from ground zero; they are apparently related to the release of natural tectonic strain.

New evidence on the state of stress of the san andreas fault system.

Contemporary in situ tectonic stress indicators along the San Andreas fault system in central California show northeast-directed horizontal compression that is nearly perpendicular to the strike of the fault. Such compression explains recent uplift of the Coast Ranges and the numerous active reverse faults and folds that trend nearly parallel to the San Andreas and that are otherwise unexplainable in terms of strike-slip deformation. Fault-normal crustal compression in central California is proposed to result from the extremely low shear strength of the San Andreas and the slightly convergent relative motion between the Pacific and North American plates. Preliminary in situ stress data from the Cajon Pass scientific drill hole (located 3.6 kilometers northeast of the San Andreas in southern California near San Bernardino, California) are also consistent with a weak fault, as they show no right-lateral shear stress at approximately 2-kilometer depth on planes parallel to the San Andreas fault.

Recombinant DNA-produced alpha 1-antitrypsin administered by aerosol augments lower respiratory tract antineutrophil elastase defenses in individuals with alpha 1-antitrypsin deficiency.

Alpha 1-Antitrypsin (alpha 1AT) deficiency is characterized by insufficient amounts of alpha 1AT to protect the lower respiratory tract from neutrophil elastase, resulting in emphysema. Yeast-produced recombinant alpha 1AT (rAAT) has normal antielastase function but is associated with high renal clearance, thus obviating chronic intravenous administration. As an alternative, we evaluated aerosol administration of rAAT to alpha 1AT-deficient individuals. After aerosol administration of single doses of 10-200 mg of rAAT, epithelial lining fluid (ELF) alpha 1AT antineutrophil elastase defenses were augmented in proportion to the dose of rAAT administered. ELF alpha 1AT levels and antineutrophil elastase capacity 4 h after 200 mg rAAT aerosol were increased 40-fold over preaerosol levels, and were fivefold increased over baseline at 24 h after aerosol administration. rAAT was detectable in serum after aerosol, indicating that the lower respiratory tract epithelium may be permeable to rAAT, and that aerosolized rAAT is capable of gaining access to lung interstitium. No adverse clinical effects were noted. These observations demonstrate that aerosol administration of rAAT is safe and results in significant augmentation of lung antineutrophil elastase defenses, suggesting this method is a feasible approach to therapy. Because this approach is clinically unproven, further studies will be necessary to establish the long-term clinical efficacy of aerosol therapy in alpha 1AT deficiency.

Cerebral aneurysmal arteriopathy in an adult patient with acquired immunodeficiency syndrome.

In adult patients with acquired immunodeficiency syndrome (AIDS), cerebral arteritis usually takes the form of arterial wall thickening, stenosis, and occlusion, leading to cerebral ischemia and infarction. Aneurysms and intracranial hemorrhage are much less commonly associated with cerebral vasculitis. For reasons not entirely clear, this form is seen more often in pediatric patients infected with human immunodeficiency virus. We report an adult patient with cerebral aneurysmal arteriopathy who presented shortly after his AIDS-defining illness in a setting of severe immune suppression and high viral load.

Sugar control of the plant cell cycle: differential regulation of Arabidopsis D-type cyclin gene expression.

In most plants, sucrose is the major transported carbon source. Carbon source availability in the form of sucrose is likely to be a major determinant of cell division, and mechanisms must exist for sensing sugar levels and mediating appropriate control of the cell cycle. We show that sugar availability plays a major role during the G(1) phase by controlling the expression of CycD cyclins in Arabidopsis. CycD2 mRNA levels increase within 30 min of the addition of sucrose; CycD3 is induced after 4 h. This corresponds to induction of CycD2 expression early in G(1) and CycD3 expression in late G(1) near the S-phase boundary. CycD2 and CycD3 induction is independent both of progression to a specific point in the cell cycle and of protein synthesis. Protein kinase activity of CycD2- and CycD3-containing cyclin-dependent kinases is consistent with the observed regulation of their mRNA levels. CycD2 and CycD3 therefore act as direct mediators of the presence of sugar in cell cycle commitment. CycD3, but not CycD2, expression responds to hormones, for which we show that the presence of sugars is required. Finally, protein phosphatases are shown to be involved in regulating CycD2 and CycD3 induction. We propose that control of CycD2 and CycD3 by sucrose forms part of cell cycle control in response to cellular carbohydrate status.

The value of MRI undertaken immediately after reduction of the hip as a predictor of long-term acetabular dysplasia.

Our aim was to determine whether abnormalities noted on MRI immediately after reduction for developmental dysplasia of the hip could predict the persistance of dysplasia and aid surgical planning. Scans of 13 hips in which acetabular dysplasia had resolved by the age of four years were compared with those of five which had required pelvic osteotomy for persisting dysplasia. The scans were analysed by two consultant musculoskeletal radiologists who were blinded to the outcome in each child. The postreduction scans highlighted a number of anatomical abnormalities secondary to developmental dysplasia of the hip, but statistical analysis showed that none were predictive of persisting acetabular dysplasia in the older child, suggesting that the factors which determine the long-term outcome were not visible on these images.