Behavioral disorders in multiple sclerosis: a comprehensive review.

Multiple sclerosis (MS) is a heterogenous autoimmune-mediated disease of the central nervous system (CNS) characterized by inflammation, demyelination and chronic progressive neurodegeneration. Among its broad and unpredictable range of neuropsychiatric symptoms, behavioral changes are common, even from the early stages of the disease, while they are associated with cognitive deficits in advanced MS. According to DSM-5, behavioral disorders include attention deficits, oppositional, defiant and conduct disorders, anxiety, panic, obsessive-compulsive disorders (OCD), disruptive and emotional disorders, while others include also irritability, agitation, aggression and executive dysfunctions. Approximately 30 to 80% of individuals with MS demonstrate behavioral changes associated with disease progression. They are often combined with depression and other neuropsychiatric disorders, but usually not correlated with motor deficits, suggesting different pathomechanisms. These and other alterations contribute to disability in MS. While no specific neuropathological data for behavioral changes in MS are available, those in demyelination animal models share similarities with white matter and neuroinflammatory abnormalities in humans. Neuroimaging revealed prefrontal cortical atrophy, interhemispheric inhibition and disruption of fronto-striato-thalamic and frontoparietal networks. This indicates multi-regional patterns of cerebral disturbances within the MS pathology although their pathogenic mechanisms await further elucidation. Benefits of social, psychological, behavioral interventions and exercise were reported. Based on systematical analysis of PubMed, Google Scholar and Cochrane library, current epidemiological, clinical, neuroimaging and pathogenetic evidence are reviewed that may aid early identification of behavioral symptoms in MS, and promote new therapeutic targets and strategies.

The LTAR Cropland Common Experiment at Upper Mississippi River Basin-St. Paul.

The Soil and Water Management Research Unit of the USDA-Agricultural Research Service is located in St. Paul, MN, and conducts long-term research at the University of Minnesota Research and Outreach Center located at Rosemount, MN. As part of USDA's Long-Term Agroecosystem Research (LTAR) network, the croplands common experiment (CCE) at this location is focused on integration of a kura clover (Trifolium ambiguum M. Bieb.) living mulch (KCLM) system into the prevailing 2-year rotation of corn (Zea mays L.) and soybean (Glycine max L.) that is typical of the midwestern Corn Belt. The LTAR-CCE conducted at Rosemount, MN, aims to compare the long-term environmental and agronomic performance of KCLM while identifying challenges and developing management strategies for this alternative practice. The use of a living mulch for this region is advantageous because, once established, it does not require additional time for fall field operations typically associated with winter cover crops. Results from LTAR-CCE studies at this site show that KCLM results in a substantial increase in soil field-saturated hydraulic conductivity and decreases in leaching of nitrate-nitrogen (NO3 --N). Disadvantages of the KCLM system include potential for increased emissions of nitrous oxide (N2O) and reduced crop yields, particularly during drought. Also, the optimal approach for crop row establishment in the spring remains uncertain. Ongoing LTAR-CCE research with KCLM aims to better understand and quantify both benefits and risks across conditions of interannual weather variability and changing climate to develop guidance for suitable adoption and management of this alternative practice.

Behavioral disorders in dementia with Lewy bodies: old and new knowledge.

Dementia with Lewy bodies (DLB), the second most common primary degenerative neurocognitive disorder after Alzheimer disease, is frequently preceded by REM sleep behavior disorders (RBD) and other behavioral symptoms, like anxiety, irritability, agitation or apathy, as well as visual hallucinations and delusions, most of which occurring in 40-60% of DLB patients. Other frequent behavioral symptoms like attention deficits contribute to cognitive impairment, while attention-deficit/hyperactivity disorder (ADHD) is a risk factor for DLB. Behavioral problems in DLB are more frequent, more severe and appear earlier than in other neurodegenerative diseases and, together with other neuropsychiatric symptoms, contribute to impairment of quality of life of the patients, but their pathophysiology is poorly understood. Neuroimaging studies displayed deficits in cholinergic brainstem nuclei and decreased metabolism in frontal, superior parietal regions, cingulate gyrus and amygdala in DLB. Early RBD in autopsy-confirmed DLB is associated with lower Braak neuritic stages, whereas those without RBD has greater atrophy of hippocampus and increased tau burden. αSyn pathology in the amygdala, a central region in the fear circuitry, may contribute to the high prevalence of anxiety, while in attention dysfunctions the default mode and dorsal attention networks displayed diverging activity. These changes suggest that behavioral disorders in DLB are associated with marked impairment in large-scale brain structures and functional connectivity network disruptions. However, many pathobiological mechanisms involved in the development of behavioral disorders in DLB await further elucidation in order to allow an early diagnosis and adequate treatment to prevent progression of these debilitating disorders.

Exploring the Impact of Astaxanthin Supplementation in Conjunction with a 12-Week CrossFit Training Regimen on Selected Adipo-Myokines Levels in Obese Males.

OBJECTIVE: Obesity is associated with an exacerbated metabolic condition that is mediated through impairing balance in the secretion of some adipo-myokines. Therefore, the objective of the present study was to explore the impact of astaxanthin supplementation in conjunction with a 12-week CrossFit training regimen on some selected adipo-myokines, insulin insensitivity, and serum lipid levels in obese males. MATERIAL AND METHODS: This study is a randomized control trial design; 60 obese males were randomly divided into four groups of 15, including the control group (CG), supplement group (SG), training group (TG), and combined training and supplement group (TSG). The participants were subjected to 12 weeks of astaxanthin (AST) supplementation [20 mg/d capsule, once/d] or CrossFit training or a combination of both interventions. The training regimen comprised 36 sessions of CrossFit, each lasting 60 min, conducted three times per week. The metabolic indices, body composition, anthropometrical, cardio-respiratory, and also some plasma adipo-myokine factors, including decorin (DCN), activin A, myostatin (MST), transforming growth factor (TGF)-ß1, and follistatin (FST), were examined 12 and 72 h before the initiation of the main interventional protocols, and then 72 h after the final session of the training protocol. RESULTS: There was no significant difference in the baseline data between the groups (p > 0.05). There were significant interactions between group x time for DCN (η2 = 0.82), activin A (η2 = 0.50), FST (η2 = 0.92), MST (η2 = 0.75), and TGFB-1 (η2 = 0.67) (p < 0.001 for all the variables). Significantly changes showed for DCN in TSG compared to TG and SG and also TG compared to SG (p = 0.0001); for activin A in SG compared to TG (p = 0.01) and TSG (p = 0.002); for FST in SG compared to TG and TSG (p = 0.0001), also in TSG compared to TG (p = 0.0001); for MST in SG, TG, and TSG compared to CG (p = 0.0001) and also in TSG compared to SG (p = 0.0001) and TG (p = 0.001); for TGFB-1 in SG, TG, and TSG compared to CG (p = 0.0001) and also TSG compared to SG (p = 0.0001) and TG (p = 0.001). CONCLUSIONS: The 12-week CrossFit training concurrent with AST supplementation reduced anthropometric and metabolic factors and also serum lipid levels while producing positive changes in body composition and cardiovascular factors. Increased FST and DCN and reduced activin A, MST, and TGF-ß1 were other affirmative responses to both interventions.

Osteopontin deletion attenuates cyst growth but exacerbates fibrosis in mice with cystic kidney disease.

Osteopontin (OPN) is a multi-functional glycoprotein that coordinates the innate immune response, prevents nanocrystal formation in renal tubule fluid, and is a biomarker for kidney injury. OPN expression is markedly increased in cystic epithelial cells of polycystic kidney disease (PKD) kidneys; however, its role in PKD progression remains unclear. We investigated the in vitro effects of recombinant OPN on the proliferation of tubular epithelial cells from PKD and normal human kidneys and in vivo effects of OPN deletion on kidney cyst formation, fibrosis, and mineral metabolism in pcy/pcy mice, a non-orthologous model of autosomal-dominant PKD. In vitro studies revealed that OPN enhanced the proliferation of PKD cells but had no effect on normal kidney cells. Deletion of OPN in pcy/pcy mice significantly reduced kidney cyst burden; however, this was accompanied by increased fibrosis and no change in kidney function. The loss of OPN had no effect on kidney macrophage numbers, cyst epithelial cell proliferation, or apoptosis. Furthermore, there was no difference in kidney mineral deposition or mineral metabolism parameters between pcy/pcy mice with and without OPN expression. Global deletion of OPN reduced kidney cyst burden, while paradoxically exacerbating kidney fibrosis in mice with cystic kidney disease.

Thematic analysis of patient perspectives in a randomized controlled trial for a remote perioperative telemonitoring program.

BACKGROUND: Remote patient telemonitoring programs offer the potential to enhance access and communication with medical providers. This study assessed the patient-reported experience during perioperative telemonitoring for gastrointestinal (GI) oncologic surgery. METHODS: Between October 2021 and July 2023, patients with GI cancer were enrolled in the remote telemonitoring trial and randomized into the intervention or enhanced usual care arm. Although the enhanced usual care arm adhered to standard protocols for problem reporting, the intervention arm received active nursing support for monitoring data deviations from predetermined thresholds. The program culminated in a 15-minute exit interview comprised 9 total questions to gather insights into the patient experiences with device usage, symptom reporting, and communication with the healthcare team. Thematic analysis was conducted on all responses to present a patient-centric summary. RESULTS: Of the 114 patients completing the study, 100 patients (88%) participated in the exit interview. Most enrolled patients (n = 68) were diagnosed as having colorectal cancer. The intervention arm reported greater ease and accessibility in electronic data reporting and communication with healthcare team compared to the enhanced usual care arm (94% vs 69%). Qualitative analysis identified 3 themes used to describe the program: "instilling an affirmative and proactive mindset toward recovery," "receiving timely attention from healthcare team," and "benefits of device usage and electronic health surveys." The subthemes highlighted an appreciative and empowering mindset among most patients. CONCLUSION: Most enrolled patients expressed satisfaction with the program to facilitate their postoperative recovery. These positive testimonials present a promising outlook for future implementation from the patient perspective.

Impact of spinach thylakoid extract-induced 12-week high-intensity functional training on specific adipokines in obese males.

BACKGROUND: Obesity presents multifarious etiopathologies with its management being a global challenge. This article presents the first ever report on the impact of spinach thylakoid extract-induced high-intensity functional training (HIFT) on obesity management via regulating the levels of novel adipokine, C1q/TNF-related Protein-12 (CTRP-12), furin, and Krüppel-like factor 15 (KLF-15). METHODS: Sixty-eight obese male subjects were randomly divided into four groups: control group (CG), supplement group (SG), training group (TG), and the combined training and supplement group (TSG). After initial assessments of all groups, the training group commenced a twelve-week HIFT using the CrossFit program (comprising of three training sessions per week, each lasting 30 min). Eligible candidates were randomly assigned to either receive thylakoid-rich spinach extract (5 g per day) or a matching placebo (5 g per day of corn starch, 30 min before lunch) for a total duration of 12 weeks. All required data and investigations were collected at 48 h pre- and post-training. RESULTS: The results indicated a substantial correlation between exercise and the time of KLF-15, furin, and CTRP-12 demonstrating effect sizes of 0.3, 0.7, and 0.6, respectively. Additionally, the training and supplementation group (TSG) exhibited a substantial decrease in low-density lipoprotein (LDL), total cholesterol (TC), and triglyceride (TG) levels (p < 0.0001). Concurrently, there was a significant increase in high-density lipoprotein-cholesterol (HDL-C) levels (p = 0.0001). Furthermore, a notable difference between the groups emerged in HDL, LDL, TC, and TG levels, supported by effect sizes of 0.73, 0.86, 0.96, and 0.89, respectively (p < 0.05). CONCLUSION: The study offered novel insights into the management of obesity using supplements induced by spinach-derived thylakoid extract during a 12-week HIFT program. The proposed combination intervention may reverse obesity-induced insulin resistance and metabolic dysfunctions by positive regulation of CTRP-12/adipolin and KLF15 and simultaneous suppression of furin levels.

Higher intracranial positioning of an 8 Fr guide catheter improves efficacy of aspiration thrombectomy in large vessel occlusion stroke.

BACKGROUND: Higher positioning of a large bore guide catheter during endovascular thrombectomy (EVT) is hypothesized to potentially improve thrombectomy success. OBJECTIVE: To evaluate the safety and efficacy of intracranial guide catheter placement during EVT using a multicenter database. METHODS: We reviewed data on consecutive patients undergoing EVT for anterior circulation large vessel occlusion (LVO) at three comprehensive stroke centers between October 2019 and December 2022. Participants were allocated to one of two cohorts: intracranial (n=141)-guide catheter tip positioned in the petrous carotid or further distal; and control (n=285)-guide catheter tip below the petrous carotid. Primary outcome was excellent reperfusion (Thrombolysis in Cerebral Ischemia (TICI) 2c or better), first pass effect (TICI 2c or better after one pass), and arterial access to final reperfusion time. The unpaired t-test, Mann-Whitney U test, and Fisher's exact test were used to compare themeans, medians and proportions of the two groups, respectively. P values & lt;0.05 were considered statistically significant two cohorts. RESULTS: A total of 426 patients were included in the analysis. Patients with guide catheter location in the petrous segment or further distal had a significantly higher first-pass effect (111/284, 39.1% vs 37/141, 26.2%, P=0.009). There was no significant difference in final excellent recanalization rates between groups (202/285, 70.9% vs 92/141, 65.2%, P=0.266). Furthermore, intracranial positioning of the guide catheter was associated with significantly shorter time to final recanalization (median 21.0 (13.0-38.0) min vs 30.0 (17.0-48.0) min, P<0.001). CONCLUSION: Positioning a large bore guide catheter in the petrous segment or further distal resulted in a significantly higher rate of first pass effect, faster procedural times, and equivalent final excellent reperfusion rates compared with more proximal guide catheter placement for patients with anterior circulation LVO.

BCAM (basal cell adhesion molecule) protein expression in different tumor populations.

Basal Cell Adhesion Molecule (BCAM), a receptor for laminin subunit α5, plays a crucial role in the pathogenesis of various malignancies. Notably, evidence of hypermethylation at multiple immune checkpoints in patients with low BCAM expression suggests these individuals may respond favorably to immunotherapy using ICIs (immune checkpoint inhibitors). This finding lays the foundation for the hypothesis that BCAM may serve as an important biomarker in cancer patients. To investigate this potential, we evaluated BCAM expression patterns in 3114 patients from both discovery and validation cohorts, spanning seven cancer types, using quantitative immunofluorescence (QIF). We also explored the correlation between BCAM and PD-L1 expressions within these cohorts, aiming to establish its potential predictive value for immunotherapy response. Our findings indicate that BCAM was highly expressed in ovarian (79.2%) and lung (78.5%) tumors, with lower yet significant expression in breast (37.7%), head and neck (31.3%), and bladder-urothelial tumors (27.6%). Notably, high BCAM expression was associated with better OS in NSCLC. More importantly, BCAM expression did not correlate with PD-L1 protein expression in any of these tumors, highlighting its independent predictive potential. The widespread expression of BCAM across multiple tumor types, coupled with its lack of correlation with PD-L1 expression, highlights its potential as a predictive novel biomarker across various cancer types.

Swimming in cold water increases the browning process by diminishing the Myostatin pathway.

BACKGROUND: Brown adipose tissue (BAT) is a thermogenic tissue that uncouples oxidative phosphorylation from ATP synthesis and increases energy expenditure via non-shivering thermogenesis in mammals. Cold exposure and exercise have been shown to increase BAT and browning of white adipose tissue (WAT) in mice. This study aimed to determine whether there is an additive effect of exercise during cold exposure on markers related to browning of adipose tissue. in Wistar rats. METHODS: Twenty-four male Wistar rats were randomly divided into three groups: Control (C, 25˚C), Swimming in Neutral (SN, 30˚C) water, and Swimming in Cold (SC, 15˚C) water. Swimming included intervals of 2-3 min, 1 min rest, until exhausted, three days a week for six weeks, with a training load of 3-6% body weight. After the experimental protocol, interscapular BAT and inguinal subcutaneous white adipose tissue (WAT) were excised, weighed, and processed for beiging marker gene expression. RESULTS: SN and SC resulted in lower body weight gain, associated with reduced WAT and BAT volume and increased BAT number with greater effects observed in SC. Myostatin protein expression was lower in BAT, WAT, soleus muscle, and serum NC and SC compared to the C group. Expression of the interferon regulatory factor-4 (IRF4) gene in both BAT and WAT tissues was significantly greater in the SC than in the C. Expression of the PGC-1α in BAT was significantly increased in the SC compared to C and increased in WAT in NC and SC. Expression of the UCP1 in BAT and WAT increased in the SC group compared to other groups. CONCLUSION: The findings demonstrate that six weeks of swimming training in cold water promotes additive effects of the expression of genes and proteins involved in the browning process of adipose tissue in Wistar rats. Myostatin inhibition may possess a regulator effect on the PGC-1α - UCP1 pathway that mediates adipose tissue browning.

A growth-differentiation factor 15 receptor agonist in randomized placebo-controlled trials in healthy or obese persons.

BACKGROUND: Growth Differentiation Factor 15 (GDF15), a divergent member of the TGF-ß superfamily, signals via the hindbrain glial-derived neurotrophic factor receptor alpha-like and rearranged during transfection receptor co-receptor (GFRAL-RET) complex. In nonclinical species, GDF15 is a potent anorexigen leading to substantial weight loss. MBL949 is a half-life extended recombinant human GDF15 dimer. METHODS: MBL949 was evaluated in multiple nonclinical species and then in humans in two randomized and placebo-controlled clinical trials. In the Phase 1 first-in-human, single ascending dose trial MBL949 or placebo was injected subcutaneously to overweight and obese healthy volunteers (n=65) at doses ranging from 0.03 to 20 mg. In Phase 2, MBL949 or placebo was administered subcutaneously every other week for a total of 8 doses to obese participants (n=126) in five different dose regimens predicted to be efficacious based on data from the Phase 1 trial. RESULTS: In nonclinical species, MBL949 was generally safe and effective with reduced food intake and body weight in mice, rats, dogs, and monkeys. Weight loss was primarily from reduced fat, and metabolic endpoints improved. A single ascending dose study in overweight or obese healthy adults demonstrated mean terminal half-life of 18-22 days, and evidence of weight loss at the higher doses. In the Phase 2, weight loss was minimal following biweekly dosing of MBL949 for 14 weeks. MBL949 was safe and generally tolerated in humans over the dose range tested, adverse events of the gastrointestinal system were the most frequent observed. CONCLUSION: The prolonged half-life of MBL949 supports biweekly dosing in patients. MBL949 had an acceptable safety profile. The robust weight loss observed in nonclinical species did not translate to weight loss efficacy in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT05199090.

Correction: 2-Methyl-4-chlorophenoxyacetic acid (MCPA) sorption and desorption as a function of biochar properties and pyrolysis temperature.

[This corrects the article DOI: 10.1371/journal.pone.0291398.].

Molecular Dynamical and Quantum Mechanical Exploration of the Site-Specific Dynamics of Cy3 Dimers Internally Linked to dsDNA.

Performing spectroscopic measurements on biomolecules labeled with fluorescent probes is a powerful approach to locating the molecular behavior and dynamics of large systems at specific sites within their local environments. The indocarbocyanine dye Cy3 has emerged as one of the most commonly used chromophores. The incorporation of Cy3 dimers into DNA enhances experimental resolution owing to the spectral characteristics influenced by the geometric orientation of excitonically coupled monomeric units. Various theoretical models and simulations have been utilized to aid in the interpretation of the experimental spectra. In this study, we employ all-atom molecular dynamics simulations to study the structural dynamics of Cy3 dimers internally linked to the dsDNA backbone. We used quantum mechanical calculations to derive insights from both the linear absorption spectra and the circular dichroism data. Furthermore, we explore potential limitations within a commonly used force field for cyanine dyes. The molecular dynamics simulations suggest the presence of four possible Cy3 dimeric populations. The spectral simulations on the four populations show one of them to agree better with the experimental signatures, suggesting it to be the dominant population. The relative orientation of Cy3 in this population compares very well with previous predictions from the Holstein-Frenkel Hamiltonian model.

Structure of anellovirus-like particles reveal a mechanism for immune evasion.

Anelloviruses are nonpathogenic viruses that comprise a major portion of the human virome. Despite being ubiquitous in the human population, anelloviruses (ANVs) remain poorly understood. Basic features of the virus, such as the identity of its capsid protein and the structure of the viral particle, have been unclear until now. Here, we use cryogenic electron microscopy to describe the first structure of an ANV-like particle. The particle, formed by 60 jelly roll domain-containing ANV capsid proteins, forms an icosahedral particle core from which spike domains extend to form a salient part of the particle surface. The spike domains come together around the 5-fold symmetry axis to form crown-like features. The base of the spike domain, the P1 subdomain, shares some sequence conservation between ANV strains while a hypervariable region, forming the P2 subdomain, is at the spike domain apex. We propose that this structure renders the particle less susceptible to antibody neutralization by hiding vulnerable conserved domains while exposing highly diverse epitopes as immunological decoys, thereby contributing to the immune evasion properties of anelloviruses. These results shed light on the structure of anelloviruses and provide a framework to understand their interactions with the immune system.

The Pathobiology of Behavioral Changes in Multiple System Atrophy: An Update.

While cognitive impairment, which was previously considered a red flag against the clinical diagnosis of multiple system atrophy (MSA), is a common symptom of this rare neurodegenerative disorder, behavioral disorders are reported in 30 to 70% of MSA patients. They include anxiety, apathy, impaired attention, compulsive and REM sleep behavior disorders (RBD), and these conditions, like depression, are early and pervasive features in MSA, which may contribute to disease progression. Despite changing concepts of behavioral changes in this synucleinopathy, the underlying pathophysiological and biochemical mechanisms are poorly understood. While specific neuropathological data are unavailable, neuroimaging studies related anxiety disorders to changes in the cortico-limbic system, apathy (and depression) to dysfunction of prefrontal-subcortical circuits, and compulsive behaviors to impairment of basal ganglia networks and involvement of orbito-frontal circuits. Anxiety has also been related to α-synuclein (αSyn) pathology in the amygdala, RBD to striatal monoaminergic deficit, and compulsive behavior in response to dopamine agonist therapy in MSA, while the basic mechanisms of the other behavioral disorders and their relations to other non-motor dysfunctions in MSA are unknown. In view of the scarcity of functional and biochemical findings in MSA with behavioral symptoms, further neuroimaging and biochemical studies are warranted in order to obtain better insight into their pathogenesis as a basis for the development of diagnostic biomarkers and future adequate treatment modalities of these debilitating comorbidities.

Change in spinal bone mineral density as estimated by Hounsfield units following osteoporosis treatment with romosozumab, teriparatide, denosumab, and alendronate: an analysis of 318 patients.

OBJECTIVE: The purpose of this study was to determine the effect of osteoporosis medications on opportunistic CT-based Hounsfield units (HU). METHODS: Spine and nonspine surgery patients were retrospectively identified who had been treated with romosozumab for 3 to 12 months, teriparatide for 3 to 12 months, teriparatide for > 12 months, denosumab for > 12 months, or alendronate for > 12 months. HU were measured in the L1-4 vertebral bodies. One-way ANOVA was used to compare the mean change in HU among the five treatment regimens. RESULTS: In total, 318 patients (70% women) were included, with a mean age of 69 years and mean BMI of 27 kg/m2. There was a significant difference in mean HU improvement (p < 0.001) following treatment with romosozumab for 3 to 12 months (n = 32), teriparatide for 3 to 12 months (n = 30), teriparatide for > 12 months (n = 44), denosumab for > 12 months (n = 123), and alendronate for > 12 months (n = 100). Treatment with romosozumab for a mean of 10.5 months significantly increased the mean HU by 26%, from a baseline of 85 to 107 (p = 0.012). Patients treated with teriparatide for > 12 months (mean 23 months) experienced a mean HU improvement of 25%, from 106 to 132 (p = 0.039). Compared with the mean baseline HU, there was no significant difference after treatment with teriparatide for 3 to 12 months (110 to 119, p = 0.48), denosumab for > 12 months (105 to 107, p = 0.68), or alendronate for > 12 months (111 to 113, p = 0.80). CONCLUSIONS: Patients treated with romosozumab for a mean of 10.5 months and teriparatide for a mean of 23 months experienced improved spinal bone mineral density as estimated by CT-based opportunistic HU. Given the shorter duration of effective treatment, romosozumab may be the preferred medication for optimization of osteoporotic patients in preparation for elective spine fusion surgery.

Quantitative Measurement of HER2 Expression in Non-Small Cell Lung Cancer With a High-Sensitivity Assay.

Recently, low human epidermal growth factor receptor 2 (HER2) protein expression has been proposed as a predictive biomarker for response to the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in metastatic breast cancer. HER2 expression in non-small cell lung cancer (NSCLC) patients has never been carefully measured, and little is known about the frequency of cases with unamplified but detectable levels of the protein. Although some HER2-targeted therapies have been studied in NSCLC patients, they have been restricted to those with genomic ERBB2 gene alterations, which only represent relatively rare cases of NSCLC. Still, emerging investigations of T-DXd in NSCLC have shown promise in patients with unamplified HER2. Taken together, we hypothesize that there may be many cases of NSCLC with levels of HER2 protein expression comparable with levels seen in breast cancer that benefit from T-DXd. Here, we used a previously validated, analytic, quantitative immunofluorescence (QIF) assay that is more sensitive than legacy clinical HER2 immunohistochemistry assays. We measured HER2 protein levels in NSCLC cases to determine the proportion of cases with detectable HER2 expression. Using cell line calibration microarrays alongside our QIF method enabled us to convert HER2 signal into units of attomoles per mm2. We found that over 63% of the 741 analyzed NSCLC cases exhibited HER2 expression above the limit of detection, with more than 17% of them exceeding the lower limit of quantification. Although the threshold for response to T-DXd in breast cancer is still unknown, many cases of NSCLC have expression in a range comparable to breast cancer cases with immunohistochemistry scores of 1+ or 2+. Our assay could potentially select NSCLC cases with a detectable target (ie, HER2) that might benefit from HER2 antibody-drug conjugates, irrespective of ERBB2 genomic alterations.