J Exp Clin Cancer Res. 2023 Aug 4;42(1):193. doi: 10.1186/s13046-023-02743-9.

ABSTRACT

Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.

PMID:37542343 | PMC:PMC10401883 | DOI:10.1186/s13046-023-02743-9

Front Oncol. 2023 Jul 19;13:1131011. doi: 10.3389/fonc.2023.1131011. eCollection 2023.

ABSTRACT

INSTRUCTION: Lynch syndrome (LS) is the most common inherited cancer predisposition disorder of colorectal cancer (CRC) which is associated with pathogenic variants in 4 mismatch repair (MMR) genes. Here, we reported a multi-generation Chinese family clinically diagnosed with LS.

METHODS: To identify the underlying pathogenic gene variants, 30 whole blood samples and 4 colorectal cancer tissue samples and their clinical data were obtained from this four-generation family. Microsatellite instability-high (MSI) testing, immunohistochemistry (IHC), and Whole-Exome Sequencing (WES) were performed to identify the MMR/MSI and the underlying gene variants. The minigene splicing assay and in vitro splicing assay were used to explore the function of this variant.

RESULTS: MSI-H and dMMR was revealed by the MSI testing and IHC, Whole-Exome Sequencing (WES) in 3 patients successfully identified a splicing variant (c.793-1G>A) in intron 4 of MSH2. Sanger sequencing validated the WES results, and all the "healthy" individuals carrying the variant have been identified in the family by PCR. Bioinformatics analysis and in vitro minigene assay showed that the pathogenic variant affected the splicing process of MSH2 gene to generate 2 kinds defective transcription products, and consequently reduced the expression of MSH2 protein. The mutation carriers were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years because they both have a higher risk of LS.

DISCUSSION: We found a pathogenic splicing variant (rs863225397, c.793-1G>A) of MSH2 gene, and furtherly confirmed that this mutation plays an important role in LS patients of this pedigree based on the vitro study. Our study indicates that one splicing mutation in the MSH2 gene (c.793-1G>A) causes LS and highlights the importance of LS gene testing.

PMID:37538120 | PMC:PMC10395827 | DOI:10.3389/fonc.2023.1131011

Int J Pharm. 2023 Aug 1:123289. doi: 10.1016/j.ijpharm.2023.123289. Online ahead of print.

ABSTRACT

The production of 3D printed pharmaceuticals has thrived in recent years, as it allows the generation of customised medications in small batches. This is particularly helpful for patients who need specific doses or formulations, such as children. Compounding pharmacies seek alternatives to conventional solid oral doses, opting for oral liquid formulations. However, ensuring quality and stability, especially for pH-sensitive APIs like omeprazole, remains a challenge. This paper presents the application of semi-solid extrusion 3D printing technology to develop patient-tailored medicinal gummies, with an eye-catching appearances, serving as an innovative omeprazole pharmaceutical form for paediatric use. The study compares 3D printing hydrogels with dissolved omeprazole to hydrogels loaded with gastro-resistant omeprazole pellets, a ground-breaking approach.. Gastro-resistance and dissolution profiles were studied using different methods for better comparison and to emphasize the significance of the assay's methodology. Both developed formulas exhibit proper rheology, good printability, and meet content and mass uniformity standards. However, the high gastro-resistance and suitable release profile of 3D printed chewable semi-solid doses with enteric pellets highlight this as an effective strategy to address the challenge of paediatric medication.

PMID:37536640 | DOI:10.1016/j.ijpharm.2023.123289

Arch Toxicol. 2023 Aug 3. doi: 10.1007/s00204-023-03563-8. Online ahead of print.

ABSTRACT

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratory rhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

PMID:37537419 | DOI:10.1007/s00204-023-03563-8

Adv Biol (Weinh). 2023 Aug 3:e2300194. doi: 10.1002/adbi.202300194. Online ahead of print.

ABSTRACT

Cilia are best known and most studied for their manifold functions enabling proper embryonic development. Loss of cilia or dysfunction thereof results in a great variety of congenital malformations and syndromes. However, there are also cilia-driven conditions, which manifest only later in life, such as polycystic kidney disease. Even degenerative diseases in the central nervous system have recently been linked to alterations in cilia biology. Surprisingly though, there is very little knowledge regarding cilia in normally aged organisms absent any disease. Here, it is provided evidence that cilia in naturally aged mice are considerably elongated in the kidney and pancreas, respectively. Moreover, such altered cilia appear to have become dysfunctional as indicated by changes in cellular signaling.

PMID:37537358 | DOI:10.1002/adbi.202300194

Br J Cancer. 2023 Aug 3. doi: 10.1038/s41416-023-02380-1. Online ahead of print.

ABSTRACT

BACKGROUND: This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC).

METHODS: The trial included Phase Ib escalation and expansion parts and a randomised Phase II part versus enzalutamide alone. Primary endpoints in the Phase Ib escalation, Phase Ib expansion and Phase II parts were maximum tolerated dose (MTD), prostate-specific antigen response and investigator-assessed progression-free survival (PFS), respectively. Patients in the Phase Ib escalation and Phase II parts had progressed on/after docetaxel/abiraterone.

RESULTS: In the Phase Ib escalation (n = 10), no dose-limiting toxicities were reported, and xentuzumab 1000 mg weekly plus enzalutamide 160 mg daily (Xe1000 + En160) was defined as the MTD and recommended Phase 2 dose. In the Phase Ib expansion (n = 24), median PFS was 8.2 months, and one patient had a confirmed, long-term response. In Phase II (n = 86), median PFS for the Xe1000 + En160 and En160 arms was 7.4 and 6.2 months, respectively. Subgroup analysis suggested trends towards benefit with Xe1000 + En160 in patients whose tumours had high levels of IGF1 mRNA or PTEN protein. Overall, the combination was well tolerated.

CONCLUSIONS: Xentuzumab plus enzalutamide was tolerable but lacked antitumour activity in unselected patients with mCRPC.

CLINICAL TRIAL REGISTRATION: EudraCT number 2013-004011-41.

PMID:37537253 | DOI:10.1038/s41416-023-02380-1

J Can Acad Child Adolesc Psychiatry. 2023 Aug;32(3):177-184. Epub 2023 Aug 1.

ABSTRACT

Psychiatric disorders are common co-existing conditions in children with epilepsy and can precede or follow epilepsy onset. Therefore, when selecting anti-seizure medications (ASMs) for children with epilepsy, in addition to seizure control, careful consideration of behavioral and psychotropic effects (BPEs) is critical, as they can have a negative impact on ASM adherence and quality of life. The goal in supporting children with epilepsy is an individualized approach to maximize seizure control and minimize negative BPEs. A previous history of a psychiatric disorder is the most significant risk factor for negative BPEs. Therefore, systematic screening for psychiatric symptoms can guide ASM selection and prompt intervention as needed. Besides familiarity with different ASM profiles, awareness of risk factors for negative BPEs including rapid dose titrations and weaning schedules, polypharmacy, high ASM doses, and drug interactions are important. In children with co-existing psychiatric disorders, ASMs with mood stabilizing, behavior regulating or anxiolytic properties may be preferred choices. Overall, a comprehensive and coordinated approach, with family psychoeducation and a mutual understanding of clinical aspects between the disciplines of neurology and psychiatry will enable better outcomes in children with epilepsy. Further pediatric "real-world" studies will expand knowledge of BPEs and potential risk factors. For some children, timely epilepsy surgery or precision therapies targeting a pathological defect may reduce the ASM burden in a child's life and subsequent BPEs. The ability to predict an individual child's susceptibility to negative BPEs with valid biomarkers may become available in the near future with advances in pharmacogenomics and technology.

PMID:37534124 | PMC:PMC10393354

Pharmgenomics Pers Med. 2023 Jul 27;16:739-746. doi: 10.2147/PGPM.S412430. eCollection 2023.

ABSTRACT

The application of pharmacogenetics in oncology is part of the routine clinical practice. In particular, genotyping of dihydropyrimidine dehydrogenase (DPYD) and UDP-glucuronosyltransferase (UGT1A1) is crucial to manage the treatment of patients taking fluoropyrimidines and irinotecan. The unique approach of our laboratory to the pharmacogenetic diagnostic service in oncology is to combine two real-time PCR methods, LightSNiP assay (TIB MOLBIOL), and more recently FRET (Fluorescent Resonance Energy Transfer) probes technology (Nuclear Laser Medicine), plus TaqMan assay (Thermo Fisher) for the confirmation of the presence of variant alleles on DNA from a second extraction. We found that both the FRET and LightSNiP assays, where detection occurs by melting curve analysis, offer an advantage over the competing TaqMan technology. Whereas unexpected genetic variants may be missed using a mutation-specific TaqMan assay, the information thus obtained can be useful to adjust the therapy in case of unexpected post-treatment toxicity. The combination of TaqMan and FRET assays helped us to achieve more accurate genotyping and a correct result for the patient. The added value of the DPYD FRET assay is the possibility of detecting, with the same amplification profile of the polymorphisms detailed in the guidelines, also the c.2194G>A (*6 rs1801160), cited in the recommendations as a variant to be investigated in case of severe toxicity. Regarding the UGT1A1 (TA)n promoter polymorphism (rs3064744), the distinctive and positive feature of the FRET assay is to allow clearly identifying all those potential variant alleles, including the (TA)5 and (TA)8 alleles, that are frequent in African Americans. Our clinical practice emphasizes the importance of not only rapid and easy-to-use assays, such as the new FRET ones, but also of accurate and comprehensive genotyping for good pharmacogenetic diagnostic activity.

PMID:37534027 | PMC:PMC10390719 | DOI:10.2147/PGPM.S412430

Nat Commun. 2023 Aug 2;14(1):4646. doi: 10.1038/s41467-023-39521-2.

ABSTRACT

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

PMID:37532724 | DOI:10.1038/s41467-023-39521-2

Patient Educ Couns. 2023 Jul 17;115:107904. doi: 10.1016/j.pec.2023.107904. Online ahead of print.

ABSTRACT

OBJECTIVE: Previous research has not objectively assessed patients' comprehension of their pharmacogenomic test results. In this study we assessed understanding of patients who had undergone cytochrome P450 2C19 (CYP2C19) pharmacogenomic testing.

METHODS: 31 semi-structured interviews with patients who underwent CYP2C19 testing after cardiac catheterization and had been sent a brochure, letter, and wallet card explaining their results. Answers to Likert and binary questions were summarized with descriptive statistics. Qualitative data were analyzed using a grounded theory approach, with particular focus on categorization.

RESULTS: No participants knew the name of the gene tested or their metabolizer status. Seven participants (23%) knew whether the testing identified any medications that would have lower effectiveness or increased adverse effects for them at standard doses ("Adequate Understanding"). Four participants (13%) read their results from the letter or wallet card they received but had no independent understanding ("Reliant on Written Materials"). Ten participants remembered receiving the written materials (32%).

CONCLUSION: A majority of participants who had undergone CYP2C19 PGx testing did not understand their results at even a minimal level and would be unable to communicate them to future providers.

PRACTICE IMPLICATIONS: Further research is necessary to improve patient understanding of PGx testing and their results, potentially through improving patient-provider communication.

PMID:37531788 | DOI:10.1016/j.pec.2023.107904

Expert Rev Clin Pharmacol. 2023 Aug 2. doi: 10.1080/17512433.2023.2244417. Online ahead of print.

ABSTRACT

INTRODUCTION: Opioids are potent analgesics commonly used to manage children's moderate to severe perioperative pain in children. A wide range of short and long-acting opioids are used to treat surgical pain and will be reviewed in this article.

AREAS COVERED: Both short- and long-acting opioids contain unique therapeutic benefits and adverse effects; however, due to the side effect profile and safety concerns, lack of familiarity, and evidence with long-acting opioids to treat surgical pain, shorter-acting opioids have traditionally been used in children. Almost all opioids work by binding to the mu receptor. Methadone, a long-acting opioid, is an exception because it also has beneficial N-methyl-D-aspartate antagonist properties. Clinically methadone's properties could translate to improved analgesic outcomes, reduced risk of adverse events, less risk for acute hyperalgesia, tolerance and abuse potential, faster recovery, and reduced risk for chronic persistent surgical pain. This review article summarizes and compares the evidence of commonly used short and long-acting opioids for perioperative pain control in the pediatric population.

EXPERT OPINION: Individualized methadone therapy using pharmacogenomics has the potential to transform opioid use in pain management by improving patient safety and analgesic outcomes, thereby addressing the gaps in current standardized ERAS protocols.

PMID:37531096 | DOI:10.1080/17512433.2023.2244417

J Am Geriatr Soc. 2023 Aug 2. doi: 10.1111/jgs.18524. Online ahead of print.

NO ABSTRACT

PMID:37529936 | DOI:10.1111/jgs.18524

Pharmacogenomics. 2023 Aug 2. doi: 10.2217/pgs-2023-0098. Online ahead of print.

ABSTRACT

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura. The results of 17 years of uninterrupted work by RIBEF, the Declaration of Mérida/T'Hó and the call for the Dr José María Cantú Award for studies focused on the pharmacogenetics of native populations in Latin America were presented.

PMID:37529900 | DOI:10.2217/pgs-2023-0098

Ther Adv Rare Dis. 2023 Jul 29;4:26330040231188979. doi: 10.1177/26330040231188979. eCollection 2023 Jan-Dec.

ABSTRACT

BACKGROUND: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases.

OBJECTIVE: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies.

METHODS: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews.

RESULTS: The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues.

CONCLUSIONS: The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.

PMID:37529076 | PMC:PMC10387802 | DOI:10.1177/26330040231188979

Psychiatr Serv. 2023 Aug 2:0. doi: 10.1176/appi.ps.20220537. Online ahead of print.

ABSTRACT

OBJECTIVE: Pharmacogenetic testing (PGx) for patients experiencing depression has been associated with modest improvements in symptoms. However, little is known about providers' use of PGx, including how and for whom providers use the test results in clinical decision making. In this article, results from qualitative interviews on the experience of providers participating in a pragmatic trial of PGx are described; implications of the providers' experiences are highlighted to inform future implementation of PGx.

METHODS: Interviews were conducted with providers participating in the trial (N=61) who treated veterans who had depression. Questions were informed by the Consolidated Framework for Implementation Research. A rapid analytic approach was used.

RESULTS: Two main themes were identified: perceptions regarding which patients would likely benefit from PGx and approaches to using the test results in prescribing. Providers generally expressed positive experiences with using PGx results. However, the providers varied in application of the test results to clinical decision making regarding medications, were uncertain about how much to rely on the results, and differed in perceptions about which patients would benefit from PGx.

CONCLUSIONS: To support future implementation, policies and procedures are needed, as well as mechanisms to support ongoing provider education on PGx.

PMID:37528698 | DOI:10.1176/appi.ps.20220537

Nicotine Tob Res. 2023 Aug 1:ntad133. doi: 10.1093/ntr/ntad133. Online ahead of print.

ABSTRACT

INTRODUCTION: Alaska Native and American Indian (ANAI) people have a smoking prevalence of 23%. Nicotine metabolite ratio (NMR) and genetic testing may enable tailored selection of tobacco cessation medication. The purpose of this study was to evaluate the relative contributions of NMR, cessation medication, demographics, and tobacco use history to cessation.

METHODS: Participants were recruited into an observational cohort study consisting of a baseline visit prior to their quit date and 6 week follow-up. Demographic and tobacco use surveys and blood, urine, and breath samples were collected at each visit. Electronic health records were queried for cessation medications. NMR was categorized into slow or normal nicotine metabolism phenotypes (<0.31 and ≥0.31 respectively). The main outcome was cessation at 6 weeks. Analyses consisted of descriptive statistics, medication/phenotype concordance, and estimates of relative risk of quitting.

RESULTS: We enrolled 151 ANAI adults who smoked cigarettes daily. Two-thirds had normal nicotine metabolism phenotype. Retrospective medication/phenotype concordance was 39%. The overall quit rate was 25%. No demographic factors or tobacco use history were associated with quit success. Varenicline and bupropion increased the likelihood of quitting (RR=2.93 [1.42, 6.03] and RR=2.52 [1.12, 5.64] respectively) compared to nicotine replacement therapy. Non-optimal medication/phenotype concordance decreased likelihood of quit success (RR=0.44 [0.22, 0.91]) compared to optimal concordance.

CONCLUSION: This exploratory study found associations between quit success and tobacco cessation medication as well as medication/phenotype concordance. Additional research is needed to assess use of NMR for treatment selection among ANAI people.

IMPLICATIONS: These results broadly support additional community-engaged research to improve medication/phenotype concordance in tribal health settings. Such interventional research holds promise to improve expectations, quit success, and health outcomes amongst individuals attempting to quit smoking.

PMID:37527452 | DOI:10.1093/ntr/ntad133

JAMA. 2023 Aug 1;330(5):442-453. doi: 10.1001/jama.2023.11676.

ABSTRACT

IMPORTANCE: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies.

OBJECTIVE: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS).

DESIGN, SETTING, AND PARTICIPANTS: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021.

EXPOSURES: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls.

MAIN OUTCOMES AND MEASURES: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema.

RESULTS: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001).

CONCLUSIONS AND RELEVANCE: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

PMID:37526720 | DOI:10.1001/jama.2023.11676

BMC Cancer. 2023 Jul 31;23(1):714. doi: 10.1186/s12885-023-11121-9.

ABSTRACT

BACKGROUND: Precise prognostication is the key to optimum and effective treatment planning for early-stage hormone receptor (HR) positive, HER2/neu negative breast cancer patients. Differences in the breast cancer incidence and tumor anatomical features at diagnosis, pharmacogenomics data between Western and Indian women along with the vast diversity in the economic status and differences in insurance policies of these regions; suggest recommendations put forward for Western women might not be applicable to Indian/Asian women. Opinions from oncologists through a voting survey on various prognostic factors/tools to be considered for planning adjuvant therapy are consolidated in this report for the benefit of oncologists of the sub-continent, SAARC and Asia's LMIC (low and middle-income countries).

METHODS: A three-phase DELPHI survey was conducted to collect opinions on prognostic factors considered for planning adjuvant therapy in early-stage HR+/HER2/neu negative breast cancer patients. A panel of 25 oncologists with expertise in breast cancer participated in the survey conducted in 2021. The experts provided opinions as 'agree' or disagree' or 'not sure' in phases-1 and 2 which were conducted virtually; in the final phase-3, all the panel experts met in person and concluded the survey.

RESULTS: Opinions on 41 statements related to prognostic factors/tools and their implications in planning adjuvant endocrine/chemotherapy were collected. All the statements were supported by the latest data from the clinical trials (prospective/retrospective). The statements with opinions of consensus less than 66% were disseminated in phase-2, and later in phase-3 with supporting literature. In phase-3, all the opinions from panelists were consolidated and guidelines were framed.

CONCLUSIONS: This consensus guideline will assist oncologists of India, SAARC and LMIC countries in informed clinical decision-making on adjuvant treatment in early HR+/HER2/neu negative breast cancer patients.

PMID:37525142 | DOI:10.1186/s12885-023-11121-9

Proc Natl Acad Sci U S A. 2023 Aug 8;120(32):e2303402120. doi: 10.1073/pnas.2303402120. Epub 2023 Jul 31.

ABSTRACT

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca2+ homeostasis, triggering pleiotropic effects in the neuronal system. Genome-wide kinase-MAM interactome screening identifies casein kinase 2 alpha 1 (CK2A1) as a regulator of composition and Ca2+ transport of MAMs. CK2A1-mediated phosphorylation of PACS2 at Ser207/208/213 facilitates MAM localization of the CK2A1-PACS2-PKD2 complex, regulating PKD2-dependent mitochondrial Ca2+ influx. We further reveal that mutations of PACS2 (E209K and E211K) associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity through the disturbance of PACS2 phosphorylation at Ser207/208/213. This, in turn, causes the reduction of mitochondrial Ca2+ uptake and the dramatic increase of the cytosolic Ca2+ level, thereby, inducing neurotransmitter release at the axon boutons of glutamatergic neurons. In conclusion, our findings suggest a molecular mechanism that MAM alterations induced by pathological PACS2 mutations modulate Ca2+-dependent neurotransmitter release.

PMID:37523531 | DOI:10.1073/pnas.2303402120

JAMA Netw Open. 2023 Jul 3;6(7):e2326445. doi: 10.1001/jamanetworkopen.2023.26445.

ABSTRACT

IMPORTANCE: Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.

OBJECTIVE: To evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.

DESIGN, SETTING, AND PARTICIPANTS: This case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.

EXPOSURES: Genetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.

MAIN OUTCOMES AND MEASURES: Molecular findings indicative of genetic disease risk.

RESULTS: Of 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P < .001).

CONCLUSIONS AND RELEVANCE: In this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.

PMID:37523181 | DOI:10.1001/jamanetworkopen.2023.26445