Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells.

BACKGROUND: Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA's full potential, this study introduces a novel approach for CTC enrichment from DLAs. METHODS: DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations. RESULTS: Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes. CONCLUSIONS: In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.

Cellular Metabolism of Substance P Produces Neurokinin-1 Receptor Peptide Agonists with diminished cyclic AMP Signaling.

Substance P (SP) is released from sensory nerves in arteries and heart. It activates neurokinin-1 receptors (NK1R) causing vasodilation, immune modulation, and adverse cardiac remodeling. The hypothesis was tested that SP and SP metabolites activate different second messenger signaling pathways. Macrophages, endothelial cells and fibroblasts metabolized SP to N- and C-terminal metabolites to varying extents. SP 5-11 was the most abundant metabolite followed by SP 1-4, SP 7-11, SP 6-11, SP 3-11 and SP 8-11. In NK1R expressing HEK293 cells, SP and some C-terminal SP metabolites stimulate the NK1R promoting dissociation of several Ga proteins including Gas and Gaq from their bg subunits. SP increases intracellular calcium concentrations ([Ca]i) and cyclic AMP (cAMP) accumulation with similar -log EC50 values of 8.5±0.3 and 7.8±0.1 M, respectively. N-Terminal metabolism of SP by up to 5 amino acids and C-terminal deamidation of SP produce peptides that retain activity to increase [Ca]i but not to increase cAMP. C-Terminal metabolism results in loss of both activities. Thus, [Ca]i and cAMP signaling are differentially affected by SP metabolism. To assess the role of N-terminal metabolism, SP and SP 6-11 were compared on cAMP-mediated activities in NK1R expressing 3T3 fibroblasts. SP inhibits NFkB activity, cell proliferation and wound healing and stimulates collagen production. SP 6-11 had little or no activity. COX-2 expression is increased by SP but not SP 6-11. Thus, metabolism may select the cellular response to SP by inhibiting or re-directing the second messenger signaling pathway activated by the NK1R.

Molecular Imaging and Therapy of Differentiated Thyroid Carcinoma in Adults.

ABSTRACT: Differentiated thyroid carcinoma (DTC) has been increasing in incidence in the United States over the last several decades, although mortality rates have remained low. Radioactive iodine therapy (RAI-T) has been a mainstay of treatment for DTC since the 1940s. Imaging of DTC before and after RAI-T primarily focuses on molecular imaging of the sodium iodide symporter. The expanding understanding of the molecular profile of DTC has increased available treatment options. Incorporation of risk stratification to treatment approaches has led to deintensification of both surgical and nonsurgical treatments, leading to decreased morbidity without compromising disease control.

Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics.

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater ß-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for ß-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased ß-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.

Change in resting state functional connectivity following working memory training in individuals with repetitive negative thinking.

BACKGROUND: Repetitive negative thinking (RNT) symptoms, which are characterized by pervasive, uncontrollable negative thoughts, are common in individuals with mood, anxiety, and traumatic stress disorders. Inability to regulate the contents of working memory is a hypothesized etiological factor in RNT, suggesting that training to improve working memory may be beneficial. This study examined the effects of working memory training on resting state functional connectivity (rsFC) in individuals with elevated RNT and whether such changes would be associated with clinical improvement. METHODS: We conducted a secondary analysis of pre-post resting state data collected as part of a randomized controlled trial [NCT04912089] of working memory training interventions (n=42) compared to a waitlist control group (n=23). We hypothesized that individuals completing training would show increased rsFC between the two key intrinsic connectivity networks - default mode network (posterior cingulate cortex; PCC) and frontoparietal network (dorsolateral prefrontal cortex; dlPFC). We explored whether magnitude of rsFC change was associated with change in RNT symptom severity. RESULTS: rsFC increased between the PCC and regions including frontal and parietal cortex in the training group relative to waitlist. Increased connectivity between the PCC and superior frontal cortex was associated with RNT symptom reduction. CONCLUSIONS: These data provide evidence that working memory training can modulate neural circuitry at rest in individuals with RNT. Results align with accounts of working memory training effects on large-scale neurocircuitry changes and suggest that these changes may contribute to clinical promise of this type of intervention on transdiagnostic RNT symptoms.

Greater social jetlag predicts poorer NIH Toolbox crystallized cognitive and academic performance in the Adolescent Brain Cognitive Development (ABCD) study.

Academic performance plays a crucial role in long-term educational attainment and occupational function. Chronotype refers to an individual's daily tendencies for times for waking, activity, and sleep. Social jetlag reflects the mismatch between an individual's chronotype and their social schedule. Because school typically starts early in the morning, later chronotype is often associated with daytime sleepiness, insufficient sleep, and poor academic performance. However, the relationship between academic performance, chronotype, and social jetlag has not been extensively examined in large samples like the Adolescent Brain Cognitive Development (ABCD) study. We hypothesized that greater social jetlag would predict poorer cognitive and academic performance. Year 2 (ages 11-14) cross-sectional data from the ABCD cohort (n = 6,890 adolescents) were used to evaluate academic performance (i.e. self-reported past year grades), NIH Toolbox cognitive performance measures, chronotype, and social jetlag from the Munich Chronotype Questionnaire. We found that later chronotype and greater social jetlag predicted poorer cognitive and academic performance with small effect sizes. Our findings emphasize the importance of individual differences in chronotype and social jetlag when designing class schedules, as aligning school activities with student optimal sleep-wake times may contribute to improved academic performance.

Use of serum evaluation of contraceptive and ovarian hormones to assess reduced risk of pregnancy among women presenting for emergency contraception in a multicenter clinical trial.

OBJECTIVES: To evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. STUDY DESIGN: We used standard chemiluminescent assays to evaluate endogenous hormones (estradiol, progesterone, follicle stimulating hormone, luteinizing hormone) and liquid chromatography-tandem triple quadrupole mass spectrometry to simultaneously analyze concentrations of ethinylestradiol, dienogest, norelgestromin (NGMN), norethindrone (NET), gestodene, levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate, medroxyprogesterone acetate (MPA), and drospirenone in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥80 kg reporting no recent use of hormonal contraception. RESULTS: We enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of progestin (MPA [n = 58, 11.2%], LNG [50, 9.6%], ENG [11, 2.1%], NET [5, 0.96%], NGMN [3, 0.06%], or drospirenone [1, 0.02%]). LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in eight other women: ENG/MPA (1), ENG/LNG (2), and MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive (MPA ≥ 0.1 ng/mL, n = 19; NGMN/LNG ≥ 0.2 ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4). We detected concentrations of serum progesterone ≥ 3 ng/mL, indicative of luteal phase (postovulation) status, in an additional 194 (37.3%) samples. CONCLUSIONS: More than one-third of enrolled in our clinical trial of oral EC had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception. These results would have decreased the expected risk of pregnancy in the study. IMPLICATIONS: Many participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using noninferiority designs or historical controls.

Emergency contraception for individuals weighing 80 kg or greater: A randomized trial of 30 mg ulipristal acetate and 1.5 mg or 3.0 mg levonorgestrel.

OBJECTIVES: To compare the efficacy of emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing ≥80 kg. STUDY DESIGN: We enrolled reproductive-aged healthy women in a multicenter, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.0 mg (LNG2X) and ulipristal acetate 30 mg (UPA) (enrollment goal 1200). Key eligibility requirements included regular cycles, weight >/= 80kg, unprotected intercourse within 72 hours, no recent use of hormonal contraception, a negative urine pregnancy test (UPT), and willingness to abstain from intercourse until next menses. To assess our primary outcome of incidence of pregnancy, participants completed home UPTs; if no menses by 2-weeks post-treatment, or a positive UPT, they returned for an in-person visit with quantitative serum human chorionic gonadotropin and ultrasound. RESULTS: We enrolled and randomized 532; 44 were not dosed or not evaluable for primary end point, leaving an analyzable sample of 488 (173 LNG1X, 158 LNG2X, 157 UPA) with similar demographics between groups (mean age 29.6 years [5.74], body mass index 37.09 kg/m2 [6.95]). Five pregnancies occurred (LNG1X n = 1, LNG2X n = 1, UPA n = 3); none occurred during the highest at-risk window (day of ovulation and the 3 days prior). We closed the study before achieving our enrollment goal because the low pregnancy rate in all groups established futility based on an interim blinded analysis. CONCLUSIONS: Although slow enrollment limited our study power, we found no differences in pregnancy rates between EC regimens among women weighing 80 kg or more. Our results are not able to refute or support differences between the treatment arms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clincialtrials.gov Clinical trials#: NCT03537768. IMPLICATIONS: Women weighing 80 kg or more experienced no differences in pregnancy rates between oral EC regimens but due to several significant study limitations including sample size and the lack of a study population at high risk of pregnancy, our results are not able to determine if differences in treatment effectiveness exist.

Checkpoint Inhibitor Monotherapy in Potentially Trial-Eligible or Trial-Ineligible Patients With Metastatic NSCLC in the German Prospective CRISP Registry Real-World Cohort (AIO-TRK-0315).

Introduction: Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of "trial-ineligible" and "potentially trial-eligible" patients. Methods: Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either "potentially trial-eligible" or "trial-ineligible" according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042). Results: Of 746 patients included, 343 patients (46.0%) were classified as "trial-ineligible" and had significantly worse outcomes compared with "potentially trial-eligible" patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2-8.4) versus 10.3 (95% CI: 8.4-13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19-1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4-20.3) versus 25.3 (95% CI: 19.8-30.4) months, hazard ratio of 1.36 (95% CI: 1.10-1.67), p equals 0.004. Conclusions: Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.

How Do Anger and Impulsivity Impact Fast-Food Consumption in Transitional Age Youth?

Introduction: Consumption of fast food has been linked to psychiatric distress, violent behaviors, and impulsivity in adolescents. The relationship between eating fast food, anger, and impulsivity has not been widely investigated. The National Consortium on Alcohol and Neurodevelopment in Adolescence community-based cohort consists of 831 youth, half at elevated risk factors for substance use disorders during adolescence, followed annually. Methods: Impulsivity using Urgency, Premeditation, Perseverance, and Sensation Seeking Impulsive Behavior scale from annual assessments was examined in relation to self-reported fast-food consumption frequency and mobile application questions of anger. This study tested the hypotheses that youth anger may be predicted by fast-food consumption frequency and impulsivity using multiple regression, in addition to whether adolescent fast-food consumption frequency may be predicted by anger and impulsivity. Results: Among youth, higher anger levels and impulsivity predicted greater frequency of fast-food consumption, and greater fast-food consumption frequency and impulsivity predicted higher anger levels. Conclusions: This study's longitudinal findings are consistent with those of other studies that have found fast-food consumption and anger associated with impulsivity and also reveal a bidirectional link between anger and fast-food consumption. These results may point attention to food selection considerations for those at risk of anger and poorer psychiatric outcomes.

Early auditory processing abnormalities alter individual learning trajectories and sensitivity to computerized cognitive training in schizophrenia.

BACKGROUND: Auditory system plasticity is a promising target for neuromodulation, cognitive rehabilitation and therapeutic development in schizophrenia (SZ). Auditory-based targeted cognitive training (TCT) is a 'bottom up' intervention designed to enhance the speed and accuracy of auditory information processing, which has been shown to improve neurocognition in certain SZ patients. However, the dynamics of TCT learning as a function of training exercises and their impact on neurocognitive functioning and therapeutic outcomes are unknown. METHODS: Forty subjects (SZ, n = 21; healthy subjects (HS), n = 19) underwent comprehensive clinical, cognitive, and auditory assessments, including measurements of auditory processing speed (APS) at baseline and after 1-h of TCT. SZ patients additionally completed 30-hours of TCT and repeated assessments ~10-12 weeks later. RESULTS: SZ patients were deficient in APS at baseline (d = 0.96, p < 0.005) relative to HS. After 1-h of TCT, analyses revealed significant main effects of diagnosis (d = 1.75, p = 0.002) and time (d = 1.04, p < 0.001), and a diagnosis × time interaction (d = 0.85, p = 0.02) on APS. APS learning effects were robust after 1-h in SZ patients (d = 1.47, p < 0.001) and persisted throughout the 30-h of training. Baseline APS was associated with verbal learning gains after 30-h of TCT (r = 0.51, p = 0.02) in SZ. CONCLUSIONS: TCT learning metrics may have prognostic utility and aid in the prospective identification of individuals likely to benefit from TCT. Future experimental medicine studies may advance predictive algorithms that enhance TCT-related clinical, cognitive and functional outcomes.

Post-intensive cardiac care outpatient long-term outreach clinic (PICCOLO clinic): Defining health care needs and outcomes among coronary care unit survivors.

Objective: Patients who survive critical illness endure complex physical and mental health conditions, referred to as post-intensive care syndrome (PICS). The University of Michigan's post-intensive cardiac care outpatient long-term outreach (PICCOLO) clinic is designed for patients recently admitted to the coronary care unit (CCU). The long-term goal of this clinic is to understand post-CCU patients' needs and design targeted interventions to reduce their morbidity and mortality post-discharge. As a first step toward this goal, we aimed to define the post-discharge needs of CCU survivors. Design setting particpants: We retrospectively reviewed case-mix data (including rates of depression, PTSD, disability, and cognitive abnormalities) and health outcomes for patients referred to the PICCOLO clinic from July 1, 2018, through June 30, 2021 at Michigan Medicine. Results: Of the 134 referred patients meeting inclusion criteria, 74 (55 %) patients were seen in the PICCOLO clinic within 30 days of discharge. Patients seen in the clinic frequently screened positive for depression (PHQ-2 score ≥3, 21.4 %) and cognitive impairment (MOCA <26, 38.8 %). Further, patients also reported high rates of physical difficulty (mean WHODAS 2.0 score 28.4 %, consistent with moderate physical difficulty). Consistent with medical intensive care unit (ICU) patients, CCU survivors experience PICS. Conclusion: This work highlights the feasibility of an outpatient care model and the need to leverage information gathered from this care model to develop treatment strategies and pathways to address symptoms of PICS in CCU survivors, including depression, cognitive impairment, and physical disability.

Birth outcomes in relation to neighborhood food access and individual food insecurity during pregnancy in the Environmental Influences on Child Health Outcomes (ECHO)-wide cohort study.

BACKGROUND: Limited access to healthy foods, resulting from residence in neighborhoods with low-food access or from household food insecurity, is a public health concern. Contributions of these measures during pregnancy to birth outcomes remain understudied. OBJECTIVES: We examined associations between neighborhood food access and individual food insecurity during pregnancy with birth outcomes. METHODS: We used data from 53 cohorts participating in the nationwide Environmental Influences on Child Health Outcomes-Wide Cohort Study. Participant inclusion required a geocoded residential address or response to a food insecurity question during pregnancy and information on birth outcomes. Exposures include low-income-low-food-access (LILA, where the nearest supermarket is >0.5 miles for urban or >10 miles for rural areas) or low-income-low-vehicle-access (LILV, where few households have a vehicle and >0.5 miles from the nearest supermarket) neighborhoods and individual food insecurity. Mixed-effects models estimated associations with birth outcomes, adjusting for socioeconomic and pregnancy characteristics. RESULTS: Among 22,206 pregnant participants (mean age 30.4 y) with neighborhood food access data, 24.1% resided in LILA neighborhoods and 13.6% in LILV neighborhoods. Of 1630 pregnant participants with individual-level food insecurity data (mean age 29.7 y), 8.0% experienced food insecurity. Residence in LILA (compared with non-LILA) neighborhoods was associated with lower birth weight [ß -44.3 g; 95% confidence interval (CI): -62.9, -25.6], lower birth weight-for-gestational-age z-score (-0.09 SD units; -0.12, -0.05), higher odds of small-for-gestational-age [odds ratio (OR) 1.15; 95% CI: 1.00, 1.33], and lower odds of large-for-gestational-age (0.85; 95% CI: 0.77, 0.94). Similar findings were observed for residence in LILV neighborhoods. No associations of individual food insecurity with birth outcomes were observed. CONCLUSIONS: Residence in LILA or LILV neighborhoods during pregnancy is associated with adverse birth outcomes. These findings highlight the need for future studies examining whether investing in neighborhood resources to improve food access during pregnancy would promote equitable birth outcomes.

Challenges and controversies in resectable non-small cell lung cancer: a clinician's perspective.

The treatment landscape of resectable early-stage non-small cell lung cancer (NSCLC) is transforming due to the approval of novel adjuvant and neoadjuvant systemic treatments. The European Medicines Agency (EMA) recently approved adjuvant osimertinib, adjuvant atezolizumab, adjuvant pembrolizumab, and neoadjuvant nivolumab combined with chemotherapy, and the approval of other agents or new indications may follow soon. Despite encouraging results, many unaddressed questions remain. Moreover, the transformed treatment paradigm in resectable NSCLC can pose major challenges to healthcare systems and magnify existing disparities in care as differences in reimbursement may vary across different European countries. This Viewpoint discusses the challenges and controversies in resectable early-stage NSCLC and how existing inequalities in access to these treatments could be addressed.

New systemic treatment paradigms in resectable non-small cell lung cancer and variations in patient access across Europe.

The treatment landscape of resectable early-stage non-small cell lung cancer (NSCLC) is set to change significantly due to encouraging results from randomized trials evaluating neoadjuvant and adjuvant immunotherapy, as well as adjuvant targeted therapy. As of January 2024, marketing authorization has been granted for four new indications in Europe, and regulatory approvals for other study regimens are expected. Because cost-effectiveness and reimbursement criteria for novel treatments often differ between European countries, access to emerging developments may lead to inequalities due to variations in recommended and available lung cancer care throughout Europe. This Series paper (i) highlights the clinical studies reshaping the treatment landscape in resectable early-stage NSCLC, (ii) compares and contrasts approaches taken by the European Medicines Agency (EMA) for drug approval to that taken by the United States Food and Drug Administration (FDA), and (iii) evaluates the differences in access to emerging treatments from an availability perspective across European countries.

Social determinants of mental health in major depressive disorder: Umbrella review of 26 meta-analyses and systematic reviews.

There is a growing recognition of the impact of social determinants of mental health (SDoMHs) on people with, or at risk of, developing serious mental illnesses. Yet it is not known how associations of individual SDoMHs with risk for major depressive disorder (MDD) vary and roughly compare with one another. Following PRISMA guidelines, this umbrella review included 26 meta-analyses and systematic reviews that reported odds ratios, effect sizes, and/or pooled prevalence rates of MDD in samples with versus without specified SDoMHs. Childhood emotional, physical, or sexual abuse and neglect; intimate partner violence in females; and food insecurity were significantly associated with increased risk of MDD, with medium effect sizes. Natural disasters, terrorist acts, and military combat during deployment had small-size adverse effects, and homelessness, incarceration, and migration were associated with significantly elevated prevalence of MDD. Conversely, higher levels of parental care were significantly associated with reduced risk of MDD with medium effect sizes. Evidence supports the use of certain interventions at the individual and community level that can reduce the impact of these factors and promote health, although much more research is warranted in this area along with meaningful healthcare and societal policies to accomplish this goal.