Homologous recombination repair (HRR) deficiency is associated with improved immunotherapy responses in non-small cell lung cancer (NSCLC) patients. The HRR genes <i>BRCA1</i>/<i>2</i> are key regulators of DNA repair, yet their impact on the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Using single-cell sequencing and multi-omics data, we characterized <i>BRCA1/2</i> mutation-associated transcriptional programs, immune cell composition, and functional alterations in T cells, investigating the molecular and immune architecture of BRCA-mutant LUAD patients. <i>BRCA1</i>/<i>2</i> mutations were associated with increased genomic instability and poor prognosis in LUAD patients, but predicted better clinical outcomes following immune checkpoint blockade (ICB) treatment. <i>BRCA1</i> mutations correlated with an upregulated type I IFN/IFN-γ signature and CD8<sup>+</sup> T cell activation. <i>BRCA2</i> mutations were associated with alveolar/stress/inflammatory responses and enhanced MHC-II antigen presentation, linked to CD4<sup>+</sup> T cell differentiation. Both alterations coincided with reduced CD28 co-stimulation and CTL activity, hinting at immune evasion. We identified two tissue-resident memory T cell (Trm) subsets as predictors of clinical outcomes and ICB response. <i>BRCA1</i> mutations were associated with CD8<sup>+</sup> Trm expansion, whereas <i>BRCA2</i> mutations were linked to tumor CD4<sup>+</sup> Trm expansion and peripheral T/NK cell cytotoxicity. Furthermore, a cancer-promoting program activated by <i>BRCA1</i> mutation was vulnerable to histone deacetylase inhibitors, which inhibited LUAD tumor growth. This study provides a preliminary characterization of the BRCA-mutant TME in LUAD patients, revealing distinct transcriptional and immune patterns that highlight differences in <i>BRCA1/2</i>-associated molecular architecture and offer a framework for improving therapy efficacy in LUAD.
Science Journals
Using the lipid biomarker apolipoprotein B (apoB) may help improve cardiovascular disease risk assessment, particularly in younger adults, a recent study found.
This randomized clinical trial evaluates whether embolization of the middle meningeal artery as an adjunct to surgical drainage reduces recurrence and poor outcomes in patients with symptomatic chronic subdural hematoma compared with surgical drainage alone.
To the Editor Age-adjusted thresholds are used to improve the diagnostic yield of D-dimer testing in suspected pulmonary embolism, but prospective management data in suspected deep vein thrombosis (DVT) have been limited. In a recent study reported by Dr Le Gal and colleagues, the primary outcome focused on patients with D-dimer values between the conventional cutoff and their age-adjusted cutoff. Use of the age-adjusted cutoff increased the proportion of negative D-dimer results from 24.5% to 31.9% by identifying 161 additional patients with D-dimer values between 500 µg/L and their age-adjusted threshold.
To the Editor The ADJUST-DVT study prospectively validated the use of an age-adjusted D-dimer threshold to exclude suspected DVT. Although this represents an important methodological advance, several aspects warrant critical appraisal.
To the Editor In the Spinal Manipulation and Patient Self-Management for Preventing Acute to Chronic Back Pain (PACBACK) randomized clinical trial, Dr Bronfort and colleagues reported that clinician-supported biopsychosocial self-management, alone or combined with spinal manipulation, led to statistically significant but small reductions in low back pain–related disability over 12 months vs guideline-based medical care, without differences in pain intensity. The time-averaged, adjusted between-group differences in the Roland-Morris Disability Questionnaire (RMDQ; range, 0-24) scores were −1.2 points for supported self-management and −1.1 points for supported self-management with spinal manipulation. A 2- to 3-point change on the RMDQ has been proposed as a minimally important difference, although such thresholds can vary by population and estimation approach. Even when a modest mean difference coexists with large improvements for some individuals, it remains uncertain whether the observed disability signal reflects gains in physical capacity, improved coping with symptoms, or changes in appraisal of activity limitation.
And what if the whole thing works—the small white pill dissolving in the acid of his stomach, finding the blood, crossing into the brain where the receptor opens, the synapse strengthens, and what happened is not all he is— what if tonight he sleeps without the dream and tomorrow he sits across from his daughter, his hands flat on the table, just hands, and the plate he passes her is only a plate, not a thing that could become a thing, and she learns this in her body the way we learn without language, without knowing we’re learning, until one day she’s a woman who doesn’t flinch when a man walks into a room—just a man, just a room, just a house—I hand him the cup and he looks at me and I think: what if this is the beginning of something I’ll never see the end of, what if it’s already traveling out of my hands toward a future where a girl I’ll never meet lives without the alphabet of danger, and I move to the next window, the next cup, the next invisible repair, not knowing what I’ve done, if I’ve done anything at all.
Perhaps surprising in the emerging world of personalized, precision medicine, the physiologic targets of many pharmacologic agents, especially psychiatric medicines, remain poorly understood, even as they continue to be widely prescribed. Similarly, exactly how poetry and other art forms have their profound effects on us also remains mysterious, even as research into possible underlying neural pathway activation proceeds (albeit less intensively). In the poem “Mechanism of Action,” the clinician’s faith in treatments prescribed without fully knowing how they work is intriguingly compared with how we may also just as hopefully rely on art for its therapeutic effects. The speaker of the poem wonders at the possible potency of a drug, “the small white pill” he administers to a patient, and whether it might not only modulate minute neural structures, as “the receptor opens” and “the synapse strengthens,” but also change the course of entire lives. Just as the medicine crosses the blood-brain barrier, so then poetry crosses into the realm of dreams and imagination, perhaps influencing the same neural circuitry and reshaping our thinking “the way we learn without language,/without knowing we’re learning,/until one day she’s a woman who doesn’t flinch/when a man walks into a room.” The medication, and the speaker’s belief in its healing effects, diffuses through the pharmacology of poetry into us as readers, as we too feel intoxicated by the twin power and uncertainty of “the next invisible repair, not knowing/what I’ve done, if I’ve done anything at all.”
This narrative review examines the efficacy of cardiac resynchronization therapy, including biventricular pacing and conduction system pacing, in patients with cardiac dyssynchrony due to conduction system disease.
This Medical News article discusses findings that genetic variants may affect patients’ responses to glucagon-like peptide-1 receptor agonists such as semaglutide and tirzepatide.
This study aimed to determine whether the US Department of Veterans Affairs (VA) whole health team approach reduces pain interference more than cognitive behavioral therapy and usual care among veterans with chronic pain.
The US Centers for Disease Control and Prevention (CDC) reported that cases of extensively drug-resistant Shigella infections have increased significantly since 2015.
This Medical News article discusses a study linking digital media—particularly social media—use to consistent risks for children’s mental health and development.
This randomized clinical trial examines the safety and efficacy of rapid vs standard antimicrobial susceptibility testing for patients with gram-negative bacilli bloodstream infections.
This Research Letter reports the prespecified 6-month follow-up outcomes of the TIGHT K randomized clinical trial of potassium supplementation thresholds after cardiac surgery.
This trial evaluated whether rapid antimicrobial susceptibility testing (AST) for bloodstream infections (BSIs) caused by gram-negative bacilli (GNB) led to improved clinical outcomes compared with standard testing in regions with high antimicrobial resistance.
Requests for blood from unvaccinated donors may delay care and harm patients’ health, a review published in Transfusion suggests.
Selecting the right antibiotic to treat an infection is the cornerstone of effective antibacterial therapy and lifesaving in severe infections. The growing epidemic of antimicrobial resistance is making decisions about empiric treatment increasingly difficult and elevating the importance of having pathogen susceptibility data. Unfortunately, the time to get this vital information remains agonizingly long. In most microbiology laboratories, organisms must be grown and then tested after isolation from blood culture samples, a process that usually takes more than 24 hours. While awaiting this crucial information, clinicians are faced with a difficult dilemma: choose potentially excessively broad-spectrum antibiotics and risk potentially preventable adverse events or risk ineffective therapy. In nearly all cases, clinicians will choose the former, helping fuel the downward spiral of antimicrobial resistance because broad-spectrum antibiotics increase the selective pressure for resistant organisms, which, in turn, require even broader-spectrum antibiotics.
This JAMA Clinical Guidelines Synopsis summarizes the 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndrome.
Comprehending speech requires deciphering a range of linguistic representations, from phonemes to narratives. Prior research suggests that in single-talker scenarios, the neural encoding of linguistic units follows a hierarchy of increasing temporal receptive windows. Shorter temporal units like phonemes and syllables are encoded by lower-level sensory brain regions, whereas longer units such as sentences and paragraphs are processed by higher-level perceptual and cognitive areas. However, the brain’s representation of these linguistic units under challenging listening conditions, such as a cocktail party situation, remains unclear. In this study, we recorded electroencephalogram (EEG) responses from both normal-hearing and hearing-impaired participants as they listened to individual and dual speakers narrating different parts of a story. The inclusion of hearing-impaired listeners allowed us to examine how hierarchically organized linguistic units in competing speech streams affect comprehension abilities. We leveraged a hierarchical language model to extract linguistic information at multiple levels—phoneme, syllable, word, phrase, and sentence—and aligned these model activations with the EEG data. Our findings showed distinct neural responses to dual-speaker speech between the two groups. Specifically, compared to normal-hearing listeners, hearing-impaired listeners exhibited poorer model fits at the acoustic, phoneme, and syllable levels, as well as the sentence levels, but not at the word and phrase levels. These results suggest that hearing-impaired listeners experience disruptions at both shorter and longer temporal scales, while their processing at medium temporal scales remains unaffected.
In Reply In response to the Letter from Qin and colleagues requesting additional analyses, we would like to point out that we displayed the full range of potential improvement from baseline in the primary outcomes in Figure 2 of our article to allow readers to evaluate where in the distribution of responses the treatments differed. We chose to present the cumulative responder analysis using percentage change from baseline because this scale is more easily understood and interpreted by patients and clinicians. We think most patients and clinicians will have difficulty interpreting what a change in 2, 3, or 8 points on the RMDQ would mean to them. Changes in objective performance outcomes were greater for participants with impaired baseline performance based on normative data (>10 seconds for the Timed Up and Go test [55% of participants]; >10.4 seconds for the repeated sit-to-stand test [74% of participants]). Changes in pain self-efficacy, kinesiophobia (fear of movement), and pain catastrophizing tracked with disability outcomes because there were similar effect sizes favoring supported self-management over medical care at 2, 6, and 12 months. Mediation analyses assessing the impact of changes in self-efficacy, kinesiophobia, and pain catastrophizing on subsequent changes in disability and pain are forthcoming in separate publications.
This Perspective discusses accelerating the implementation of known methods for protecting the health care workforce from burnout.
To the Editor In the ADJUST-DVT study, no symptomatic VTE was reported during 3-month follow-up among patients with non-high clinical probability of VTE and D-dimer levels between 500 µg/L and the age-adjusted cutoff, and substantially reduced ultrasound imaging. These findings are clinically important and consistent with prior diagnostic strategies for VTE.
This JAMA Patient Page describes nitrous oxide misuse, potential complications of acute and long-term misuse, and treatment and prevention measures.