Harnessing an elastic flow instability to improve the kinetic performance of chromatographic columns.

Despite decades of research and development, the optimal efficiency of slurry-packed HPLC columns is still hindered by inherent long-range flow heterogeneity from the wall to the central bulk region of these columns. Here, we show an example of how this issue can be addressed through the straightforward addition of a semidilute amount (500 ppm) of a large, flexible, synthetic polymer (18 MDa partially hydrolyzed polyacrylamide, HPAM) to the mobile phase (1% NaCl aqueous solution, hereafter referred to as "brine") during operation of a 4.6 mm × 300 mm column packed with 10µm BEHTM 125 Å particles. Addition of the polymer imparts elasticity to the mobile phase, causing the flow in the interparticle pore space to become unstable above a threshold flow rate. We verify the development of this elastic flow instability using pressure drop measurements of the friction factor versus Reynolds number. In prior work, we showed that this flow instability is characterized by large spatiotemporal fluctuations in the pore-scale flow velocities that may promote analyte dispersion across the column. Axial dispersion measurements of the quasi non-retained tracer thiourea confirm this possibility: they reveal that operating above the onset of the instability improves column efficiency by greater than 100%. These experiments thereby suggest that elastic flow instabilities can be harnessed to mitigate the negative impact of trans-column flow heterogeneities on the efficiency of slurry-packed HPLC columns. While this approach has its own inherent limitations and constraints, our results lay the groundwork for future targeted development of polymers that can impart elasticity when dissolved in commonly used liquid chromatography mobile phases, and can thereby generate elastic flow instabilities to help improve the resolution of HPLC columns.

Gabapentinoid prescribing patterns and predictors utilizing neural networks: An analysis across emergency departments Nationwide between 2012 and 2021.

BACKGROUND: Gabapentinoids increasingly utilized for neuropathic pain, possibly to curb opioid prescribing. At the same time, data suggest subsequent increases in misuse and overdose of gabapentinoids, often in mixed overdoses. We sought to determine national trends and characteristics of gabapentinoid prescribing, including co-use with opioids, from the emergency department (ED). METHODS: This is a retrospective review of the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2012 to 2021. Our primary outcome was the trend in ED visits in which gabapentinoids were prescribed at discharge. Secondarily, we identified trends in gabapentinoid and opioid co-prescribing and gabapentin and pregabalin prescribing at ED discharge. We examined demographic data and used descriptive statistics, Shapiro Wilke's test, Pearson's Spearman's rho (SR) or Pearson's correlation coefficient (PC) as applicable. Neural networks were used to identify the most important predictors of opioid utilization during the same visit. RESULTS: Between 2012 and 2021, there were an estimated 7,242,694 (0.53% of all ED visits) visits in which gabapentinoids were prescribed at ED discharge. Prescriptions increased from a total of 138,479 (0.1%) in 2012 to 893,495 (0.63%) in 2021 (PC: 0.85, p < 0.001). Opioids were co-prescribed in 27.2% of all visits in which gabapentinoids were prescribed, with no change over time (PC: -0.47, p = 0.09). Pregabalin prescription increased linearly over time (PC: 0.64, p = 0.02). The most important predictors of opioid administration or co-prescribing were whether an alternative provider (e.g., consult or nurse practitioner) saw the patient (100%), insurance (94.4%), age (75.9%), and region (75.2%). CONCLUSION: Despite an association of misuse and overdose, often associated with opioids, gabapentinoids were increasingly prescribed at ED discharge. While these agents may be safer alternatives to opioids, misuse may be an associated consequence of increased prescribing, which warrants further investigation.

mosGraphGPT: a foundation model for multi-omic signaling graphs using generative AI.

Generative pretrained models represent a significant advancement in natural language processing and computer vision, which can generate coherent and contextually relevant content based on the pre-training on large general datasets and fine-tune for specific tasks. Building foundation models using large scale omic data is promising to decode and understand the complex signaling language patterns within cells. Different from existing foundation models of omic data, we build a foundation model, mosGraphGPT, for multi-omic signaling (mos) graphs, in which the multi-omic data was integrated and interpreted using a multi-level signaling graph. The model was pretrained using multi-omic data of cancers in The Cancer Genome Atlas (TCGA), and fine-turned for multi-omic data of Alzheimer's Disease (AD). The experimental evaluation results showed that the model can not only improve the disease classification accuracy, but also is interpretable by uncovering disease targets and signaling interactions. And the model code are uploaded via GitHub with link: https://github.com/mosGraph/mosGraphGPT.

Surgery Outcomes of Prolene Suture Gonioscopy-Assisted Transluminal Trabeculotomy (GATT): Up to 4 Years Follow-Up and Prognostic Factors.

PRCIS: Long-term success was achievable after GATT. GATT performed at early stage of glaucoma had better surgery outcomes. Trabeculoplasty may compromise surgery success. PURPOSE: To evaluate the long-term effectiveness of prolene suture gonioscopy-assisted transluminal trabeculotomy (GATT) and identify factors that may affect surgical outcomes. PATIENTS AND METHODS: This is a retrospective cohort study of adult patients with prolene suture GATT performed by a single surgeon at 1 medical center. RESULTS: Of the 145 eyes from 124 patients studied, intraocular pressure was reduced from 22.1±7.8 to 15.1±3.2 and 15.1±3.5 mm Hg, and the number of glaucoma medications was reduced from 3.2±1.1 to 1.3±1.4 and 1.4±1.5 at postoperative years 3 and 4, respectively. Ninety-three and 71 eyes completed a 3- and 4-year follow-up, with 44% of the eyes at year 4 remaining medication free. Compared with eyes with combined GATT/cataract extraction (CE), eyes with GATT alone had significantly more preoperative medications and a higher reoperation rate (31% vs. 16.5%). Eyes with prior trabeculoplasty had a higher reoperation rate (28.8%) than those without (16.1%). Kaplan-Meier survival analysis revealed that GATT/CE eyes without trabeculoplasty had a longer median time to failure (48 mo) than GATT/CE eyes with trabeculoplasty (18 mo), and GATT eyes with or without trabeculoplasty (9 and 12 mo, respectively). CONCLUSION: Prolene suture GATT successfully reduced IOP. Eyes with more preoperative medications responded less well to GATT. Prior laser trabeculoplasty was associated with poorer outcomes. Further study is needed to verify these findings.

Lattice Dynamics of Quasi-2D Perovskites from First Principles.

We present the vibrational properties and phonon dispersion for quasi-2D hybrid organic-inorganic perovskites (BA)2CsPb2I7, (HA)2CsPb2I7, (BA)2(MA)Pb2I7, and (HA)2(MA)Pb2I7 calculated from first principles. Given the highly complex nature of these compounds, we first perform careful benchmarking and convergence testing to identify suitable parameters to describe their structural features and vibrational properties. We find that the inclusion of van der Waals corrections on top of generalized gradient approximation (GGA) exchange-correlation functionals provides the best agreement for the equilibrium structure relative to experimental data. We also investigate the impact of the molecular orientation on the equilibrium structure of these layered perovskite systems. Our results suggest ground state ferroelectric alignment of molecular dipoles in the out-of-plane direction is unlikely and support the assignment of the centrosymmetric space group for the low-temperature phase of (HA)2(MA)Pb2I7. Finally, we compute vibrational properties under the harmonic approximation. We find that stringent energy cut-offs are required to obtain well-converged phonon properties, and once converged, the harmonic approximation can capture key physics for such a large, hybrid inorganic-organic system with vastly different atom types, masses, and interatomic interactions. We discuss the obtained phonon modes and dispersion behavior in the context of known properties for bulk 3D perovskites and ligand molecular crystals. While many vibrational properties are inherited from the parent systems, we also observe unique coupled vibrations that cannot be associated with vibrations of the pure constituent perovskite and ligand subphases. Energy dispersion of the low energy phonon branches primarily occurs in the in-plane direction and within the perovskite subphase and arises from bending and breathing modes of the equatorial Pb-I network within the perovskite octahedral plane. The analysis herein provides the foundation for future investigations on this class of materials, such as exciton-phonon coupling, phase transitions, and general temperature-dependent properties.

Subcutaneous vs Intravenous Trastuzumab/Pertuzumab: A Time and Motion Substudy of a Phase II Trial of Adjuvant Trastuzumab/Pertuzumab for Stage I HER2+ Breast Cancer (ADEPT trial).

PURPOSE: The time required for in-clinic drug administration can substantially affect breast cancer patients' quality of life. Subcutaneous (SC) drug administration, as opposed to intravenous (IV), may reduce this time commitment. This study sought to estimate the difference in time burden between IV and SC administration of trastuzumab and pertuzumab (HP). METHODS: We prospectively enrolled a subcohort of patients participating in the ADEPT trial (ClinicalTrials.gov identifier: NCT04569747, investigating adjuvant HP plus endocrine therapy for stage I human epidermal growth factor receptor 2-positive breast cancer) to this single-arm crossover time and motion substudy. Patients received two cycles of IV HP followed by two cycles of SC HP. During each cycle, time points in drug preparation and administration were captured. The primary end point was total patient time in the treatment chair. Additional end points included total patient treatment experience time and total pharmacy workflow time. A sample size of 22 patients was estimated to provide 90.7% power with two-sided alpha .05 to detect a difference of 70 minutes in the primary end point by treatment arm (IV v SC). RESULTS: Twenty-two patients were enrolled. The mean total patient time in the treatment chair was 61.8 minutes shorter with SC versus IV HP (22.5 v 84.3 minutes; P < .0001). The mean total patient treatment experience time (incorporating time spent waiting for treatment initiation and time spent in the treatment chair) was 81.8 minutes shorter for SC administration (96 v 177.8 minutes; P < .0001). The pharmacy workflow time was 78.2 minutes shorter for SC versus IV formulation (41 v 119.2 minutes; P < .0001). CONCLUSION: SC administration of HP shortened patient time burden by approximately 1 hour. SC drug administration can facilitate faster workflows for health care professionals and improve patients' breast cancer treatment experience.

Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.

Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimer's-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in C. elegans. Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimer's disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.

Unmasking Carcinoid Syndrome in a Chronic Obstructive Pulmonary Disease (COPD) Patient: A Rare Presentation with Wheezing and Angioedema.

Carcinoid syndrome is a rare condition resulting from neuroendocrine tumors (NETs) that secrete vasoactive substances like serotonin. This report describes the case of a 61-year-old man with a history of chronic obstructive pulmonary disease (COPD) and hypertension who presented with new-onset angioedema, loss of consciousness, and a fall. He had been treated for COPD exacerbations during ER visits without improvement and was unaware of a prior mesenteric carcinoid tumor diagnosis from 2012. The next emergency evaluation revealed significant airway and facial edema necessitating intubation. Imaging and biopsy identified a well-differentiated grade 1 NET with extensive liver metastases. Laboratory tests showed elevated levels of serum serotonin, chromogranin A, and 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA). Post-discharge, a PET scan confirmed metastatic lesions primarily in the liver and small bowel, with an unresectable mesenteric mass. The patient was treated with lanreotide and became symptom-free. This case underscores the need to consider carcinoid syndrome in patients with COPD presenting with unexplained respiratory symptoms, as timely diagnosis and treatment can significantly enhance patient outcomes.

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

Representation of navigational affordances and ego-motion in the occipital place area.

Humans effortlessly use vision to plan and guide navigation through the local environment, or "scene". A network of three cortical regions responds selectively to visual scene information, including the occipital (OPA), parahippocampal (PPA), and medial place areas (MPA) - but how this network supports visually-guided navigation is unclear. Recent evidence suggests that one region in particular, the OPA, supports visual representations for navigation, while PPA and MPA support other aspects of scene processing. However, most previous studies tested only static scene images, which lack the dynamic experience of navigating through scenes. We used dynamic movie stimuli to test whether OPA, PPA, and MPA represent two critical kinds of navigationally-relevant information: navigational affordances (e.g., can I walk to the left, right, or both?) and ego-motion (e.g., am I walking forward or backward? turning left or right?). We found that OPA is sensitive to both affordances and ego-motion, as well as the conflict between these cues - e.g., turning toward versus away from an open doorway. These effects were significantly weaker or absent in PPA and MPA. Responses in OPA were also dissociable from those in early visual cortex, consistent with the idea that OPA responses are not merely explained by lower-level visual features. OPA responses to affordances and ego-motion were stronger in the contralateral than ipsilateral visual field, suggesting that OPA encodes navigationally relevant information within an egocentric reference frame. Taken together, these results support the hypothesis that OPA contains visual representations that are useful for planning and guiding navigation through scenes.

Nurses' attitudes, beliefs and knowledge of sleep health in residential aged care: An integrative literature review.

AIM: To identify, synthesize and evaluate primary research on registered nurses' (RN) knowledge, attitudes and beliefs about sleep health and sleep health management of older adults living in residential aged care. DESIGN: Integrative review. DATA SOURCES: Medline, Embase and CINAHL databases from inception to September 2023. REVIEW METHODS: Databases were searched using a combination of key words, subject heading terms. All abstracts and full-text articles were screened by two researchers. Qualitative synthesis of the included articles was conducted. Inductive content analysis was used to identify themes and analyse data. RESULTS: A total of 923 abstracts were screened resulting in a final yield of 13 articles. Three themes were identified: (i) RN experience with sleep-disturbed residents, (ii) the emotional burden of sleep disturbances on RN and, (iii) organizational barriers to promoting resident's healthy sleep. Inappropriate administration of benzodiazepines and psychotropic drugs to manage residents' sleep disturbances was a major issue and lack of resources in residential aged care to facilitate sleep. There were concerns on nursing activity that disturbed residents' sleep and striking a balance between facilitating sleep and meeting managerial expectations was challenging. CONCLUSION: This review identified that nurses' decision-making has an integral role in the management of sleep health in residents in aged care. Whilst evidence-based guidelines for managing sleep in residential aged care are available, there is a lack of translation to practice. Understanding RN perspectives is critical to improving sleep health models of care in residential aged care. IMPACT: This review found that RN are attuned to the implications of sleep disturbance in residential aged care but are constrained by current sleep health models of care. PATIENT OR PUBLIC CONTRIBUTION: Not applicable.

Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis.

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges.

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

State Department of Motor Vehicles Reporting Mandates of Dementia Diagnoses and Dementia Underdiagnosis.

Importance: With older drivers representing the fastest growing segment of the driver population and dementia prevalence increasing with age, policymakers face the challenge of balancing road safety and mobility of older adults. In states that require reporting a dementia diagnosis to the Department of Motor Vehicles (DMV), individuals with dementia may be reluctant to disclose symptoms of cognitive decline, and clinicians may be reluctant to probe for those symptoms, which may be associated with missed or delayed diagnoses. Objective: To assess whether DMV reporting policies for drivers with dementia are associated with primary care clinicians' underdiagnosing dementia. Design, Setting, and Participants: This cross-sectional study used data from the 100% Medicare fee-for-service program and the Medicare Advantage plans from 2017 to 2019 on 223 036 primary care clinicians with at least 25 Medicare patients. Statistical analysis was performed from July to October 2023. Exposures: State DMV reporting policies for drivers with dementia. Main Outcomes and Measures: The main outcome was a binary variable indicating whether the clinician underdiagnosed dementia or not. Each clinician's expected number of dementia cases was estimated using a predictive model based on patient characteristics. Comparing the estimation with observed dementia diagnoses identified clinicians who underdiagnosed dementia vs those who did not, after accounting for sampling errors. Results: Four states have clinician reporting mandates, 14 have mandates requiring drivers to self-report dementia diagnoses, and 32 states and the District of Columbia do not have explicit requirements. Among primary care clinicians in states with clinician reporting mandates (n = 35 620), 51.4% were female, 91.9% worked in a metropolitan area, and 19.9% of the patient panel were beneficiaries dually eligible for Medicare and Medicaid. Among primary care clinicians in states with patient self-reporting mandates (n = 57 548), 55.7% were female, 83.1% worked in a metropolitan area, and 15.4% of the patient panel were dually eligible for Medicare and Medicaid. Among clinicians in states without mandates, 55.7% were female, 83.0% worked in a metropolitan area, and 14.6% of the patient panel were dually eligible for Medicare and Medicaid. Clinicians in states with clinician reporting mandates had an adjusted 12.4% (95% CI, 10.5%-14.2%) probability of underdiagnosing dementia compared with 7.8% (95% CI, 6.9%-8.7%) in states with self-reporting and 7.7% (95% CI, 6.9%-8.4%) in states with no mandates, an approximately 4-percentage point difference (P < .001). Conclusions and Relevance: Results of this cross-sectional study of primary care clinicians suggest that mandatory DMV policies for clinicians to report patients with dementia may be associated with a higher risk of missed or delayed dementia diagnoses. Future research is needed to better understand the unintended consequences and the risk-benefit tradeoffs of these policies.

Chronic exercise improves hepatic acylcarnitine handling.

Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Advance Care Planning Among Sexual Minority Men: Sociodemographic, Health Care, and Health Status Predictors.

Objectives: Advance care planning (ACP) specifies decision-making surrogates and preferences for serious illness or end-of-life medical care. ACP research has largely neglected sexual minority men (SMM), a population that experiences disparities in health care and health status. Methods: We examined formal and informal ACP among SMM ages 40+ in the Multicenter AIDS Cohort Study (N = 1,071). Results: For informal ACP (50%), younger SMM and men with past cardiovascular events had greater odds of planning; single men had lower odds of planning. For formal ACP (39%), SMM with greater socioeconomic status had greater odds of planning; SMM who were younger, of racial/ethnic minority identities, who were single or in a relationship without legal protections, and who lacked a primary care home had lower odds of planning. Discussion: Findings warrant further exploration of both informal and formal planning. More equitable, culturally-humble engagement of SMM may facilitate access, uptake, and person-centered planning.

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

A comparison of the outcomes of pulmonary versus extrapulmonary extensive-stage small cell carcinoma.

BACKGROUND: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1-0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features. AIMS: We conducted a retrospective cohort study comparing the outcomes of extensive-stage (ES) SCLC and EPSCC. METHODS: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and overall response rates (ORRs). RESULTS: Three hundred and eighty-four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5-1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58-1.46, P = 0.74) and ORR were 73% versus 68%. CONCLUSIONS: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics.