Publications by authors named "Kevin Carlin"

Article Synopsis
  • DLL3 is found in over 70% of small cell lung cancers (SCLC), which are aggressive and have few treatment options, leading to poor patient outcomes.
  • HPN328 is a new trispecific T cell-activating therapy that targets DLL3, enhances T-cell activation, and prolongs its presence in the body, showing strong tumor-killing abilities in lab and animal studies.
  • Initial tests indicate HPN328 is effective and safe, with plans for a clinical trial to further evaluate its effectiveness in patients with DLL3-expressing cancers.*
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Resistance represents a major challenge for antibody-based therapy for COVID-19. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2.

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The physiological demands of pregnancy inevitably result in changes of both biochemical and hematological parameters as the fetus develops. Alterations in blood parameters have been observed to shift according to both trimester and species, to support fetal physiological needs and maternal basal requirements. Establishing normal reference ranges for each stage in gestation is important to facilitate diagnosis of underlying health concerns and prevent over-diagnosing abnormalities.

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Pulmonary disease has been well documented in wild and managed dolphin populations. The marginal lymph nodes of the dolphin thorax provide lymphatic drainage to the lungs and can indicate pulmonary disease. This study standardized a technique for rapid, efficient, and thorough ultrasonographic evaluation of the marginal lymph nodes in bottlenose dolphins ( Tursiops truncatus).

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We compared mature dolphins with 4 other groupings of mature cetaceans. With a large data set, we found great brain diversity among 5 different taxonomic groupings. The dolphins in our data set ranged in body mass from about 40 to 6,750 kg and in brain mass from 0.

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While nonspecific adsorption is widely used for immobilizing proteins on solid surfaces, the random nature of protein adsorption may reduce the activity of immobilized proteins due to occlusion of the active site. We hypothesized that the orientation a protein assumes on a given surface can be controlled by systematically introducing mutations into a region distant from its active site, thereby retaining activity of the immobilized protein. To test this hypothesis, we generated a combinatorial protein library by randomizing six targeted residues in a binding protein derived from highly stable, nonimmunoglobulin Sso7d scaffold; mutations were targeted in a region that is distant from the binding site.

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We show that a combinatorial library constructed by random pairwise assembly of low affinity binders can efficiently generate binders with increased affinity. Such a library based on the Sso7d scaffold, from a pool of low affinity binders subjected to random mutagenesis, contained putative high affinity clones for a model target (lysozyme) at higher frequency than a library of monovalent mutants generated by random mutagenesis alone. Increased binding affinity was due to intramolecular avidity generated by linking binders targeting nonoverlapping epitopes; individual binders of K ∼ 1.

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Marine mammals play crucial ecological roles in the oceans, but little is known about their microbiotas. Here we study the bacterial communities in 337 samples from 5 body sites in 48 healthy dolphins and 18 healthy sea lions, as well as those of adjacent seawater and other hosts. The bacterial taxonomic compositions are distinct from those of other mammals, dietary fish and seawater, are highly diverse and vary according to body site and host species.

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Similar to humans, bottlenose dolphins (Tursiops truncatus) can develop metabolic syndrome and associated high ferritin. While fish and fish-based fatty acids may protect against metabolic syndrome in humans, findings have been inconsistent. To assess potential protective factors against metabolic syndrome related to fish diets, fatty acids were compared between two dolphin populations with higher (n = 30, Group A) and lower (n = 19, Group B) mean insulin (11 ± 12 and 2 ± 5 μIU/ml, respectively; P < 0.

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We have identified two related series of dibenzazepine and dibenzoxazepine sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays.

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We have identified a new series of N-aryl azacycles as sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays. Analogs from this series possessed selectivity over hERG, reasonable oral exposure in rat PK studies and are predicted to have limited CNS penetration.

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Transient receptor potential vanilloid type 1 (TRPV1) channels are capable of detecting and integrating noxious stimuli and play an important role in nociceptor activation and sensitization. It has been demonstrated that oxidizing agents are capable of positively modulating (sensitizing) the TRPV1 channel. The present study investigates the ability of the thiol-oxidizing agent phenylarsine oxide (PAO) to modulate TRPV1 currents under voltage-clamp conditions.

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The aqueous solution structure of protoxin II (ProTx II) indicated that the toxin comprises a well-defined inhibitor cystine knot (ICK) backbone region and a flexible C-terminal tail region, similar to previously described NaSpTx III tarantula toxins. In the present study we sought to explore the structure-activity relationship of the two regions of the ProTx II molecule. As a first step, chimeric toxins of ProTx II and PaTx I were synthesized and their biological activities on Nav1.

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High molecular weight (HMW) adiponectin levels are reduced in humans with type 2 diabetes and insulin resistance. Similar to humans with insulin resistance, managed bottlenose dolphins (Tursiops truncatus) diagnosed with hemochromatosis (iron overload) have higher levels of 2 h post-prandial plasma insulin than healthy controls. A parallel reaction monitoring assay for dolphin serum adiponectin was developed based on tryptic peptides identified by mass spectrometry.

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Lung disease is common among wild and managed populations of bottlenose dolphins Tursiops truncatus. The purpose of the study was to apply standardized techniques to the ultrasound evaluation of dolphin lungs, and to identify normal and abnormal sonographic findings associated with pleuropulmonary diseases. During a 5 yr period (2005 to 2010), 498 non-cardiac thoracic ultrasound exams were performed on bottlenose dolphins at the Navy Marine Mammal Program in San Diego, California, USA.

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Unlabelled: Hemochromatosis in bottlenose dolphins (Tursiops truncatus) is associated with high postprandial plasma insulin levels, suggestive of insulin resistance. In humans, insulin resistance is associated with liver pathologies, including excessive iron deposition and nonalcoholic fatty liver disease. Dolphin liver tissues, in addition to excessive iron storage, were evaluated for other pathologies supportive of underlying insulin resistance.

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Protoxin II is biologically active peptide containing the inhibitory cystine knot motif. A synthetic version of the toxin was generated with standard Fmoc solid phase peptide synthesis. If N-methylmorpholine was used as a base during synthesis of the linear protoxin II, it was found that a significant amount of racemization (approximately 50%) was observed during the process of cysteine residue coupling.

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Background: There are currently no reliable markers of acute domoic acid toxicosis (DAT) for California sea lions. We investigated whether patterns of serum peptides could diagnose acute DAT. Serum peptides were analyzed by MALDI-TOF mass spectrometry from 107 sea lions (acute DAT n = 34; non-DAT n = 73).

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Previous work has shown that motoneurone excitability is enhanced by a hyperpolarization of the membrane potential at which an action potential is initiated (V(th)) at the onset, and throughout brainstem-evoked fictive locomotion in the adult decerebrate cat and neonatal rat. Modeling work has suggested the modulation of Na(+) conductance as a putative mechanism underlying this state-dependent change in excitability. This study sought to determine whether modulation of voltage-gated sodium channels could induce V(th) hyperpolarization.

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Bottlenose dolphins can have iron overload (that is, hemochromatosis), and managed populations of dolphins may be more susceptible to this disease than are wild dolphins. Serum iron, total iron-binding capacity (TIBC), transferrin saturation, and ferritin were measured in 181 samples from 141 dolphins in 2 managed collections and 2 free-ranging populations. Although no iron indices increased with age among free-ranging dolphins, ferritin increased with age in managed collections.

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There is currently no known natural animal model that fully complements type 2 diabetes in humans. Criteria for a true natural animal model include the presence of a fasting hyperglycemia, evidence of insulin resistance, and pathologies matching that reported in humans. To investigate the bottlenose dolphin (Tursiops truncatus) as a comparative model for type 2 diabetes in humans, hourly plasma and urine chemistry changes, including glucose, were analyzed among five healthy, adult dolphins for 24 h following ingestion of 2.

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Although locomotion is known to be generated by networks of spinal neurons, knowledge of the properties of these neurons is limited. Using neonatal transgenic mice that express enhanced green fluorescent protein (EGFP) driven by the c-fos promoter, we visualized EGFP-positive neurons in spinal cord slices from animals that were subjected to a locomotor task or drug cocktail [N-methyl-D-aspartate, serotonin (5-HT), dopamine, and acetylcholine (ACh)]. The activity-dependent expression of EGFP was also induced in dorsal root ganglion neurons with electrical stimulation of the neurons.

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In spinal motoneurons, activation of dendritically located depolarizing conductances can lead to amplification of synaptic inputs and the production of plateau potentials. Immunohistochemical and computational studies have implicated dendritic CaV1.3 channels in this amplification and suggest that CaV1.

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