Publications

BACKGROUND: Brain-infiltrating tumour cells from high-grade glioma remain shielded from drug treatments by the blood-brain barrier, leading to inevitable recurrence. Microbubble-enhanced transcranial focused ultrasound (MB-FUS) enables controlled blood-brain barrier opening (BBBO), permitting localised drug delivery. We aimed to assess safety and feasibility of MB-FUS plus standard-of-care chemotherapy for individuals with high-grade glioma.

METHODS: BT008NA was an open-label, single-arm, phase 1/2 trial conducted at five sites in the USA and Canada (part of the ReFOCUSED Consortium). Key eligibility criteria were participants with newly diagnosed high-grade glioma (glioblastoma as per WHO 2016 classification), aged 18-80 years, with normal organ function, a baseline Karnofsky Performance Status score of 70 or higher, who had received maximal safe resection and 6-week chemoradiotherapy and were to start standard-of-care monthly adjuvant temozolomide chemotherapy (150 mg/m2 of body surface area). MRI-guided, 220 kHz transcranial MB-FUS treatments were delivered in periresectional (tumour-infiltrative) regions, on any of the first 3 days of a 28-day temozolomide cycle, for up to six cycles. Primary outcomes were safety (adverse events) and feasibility (BBBO: new contrast enhancement on post-procedure T1-weighted MRI). Protocol-prespecified secondary outcomes were overall survival and progression-free survival. Analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03551249 (USA) and NCT03616860 (Canada), and is closed to enrolment.

FINDINGS: Between Oct 16, 2018, and March 9, 2022, we enrolled 34 participants, all evaluable for prespecified primary and secondary endpoints, with a mean age of 51·5 years (SD 13·0) and median follow-up 44·5 months (95% CI 34·9-57·3). By self-reporting, 18 (53%) participants were female and 16 (47%) male, 28 (82%) were White, and 34 (100%) were non-Hispanic. 176 adverse events were captured: 54 (31%) chemotherapy-related, 10 (6%) disease-related, 87 (49%) related to undergoing MB-FUS (40 [46%] grade 1, 46 [53%] grade 2, and one [1%] grade 3), and 25 (14%) unrelated. Two (1%) of the adverse events were grade 5 (disease-related deaths), three (2%) grade 4 (temozolomide-related haematological abnormalities), and eight (5%) grade 3 (three [2%] temozolomide-related, one [1%] MB-FUS-related, three [2%] disease-related, and one [1%] unrelated); these occurred across seven (21%) of 34 participants. No treatment-related deaths occurred during the trial. BBBO was visualised in all treatments. Median overall survival was 31·3 months (95% CI 21·1-not reached) and median progression-free survival was 13·5 months (9·9-26·9) with patient-specific disease courses found concordant with trajectories of MB-FUS-enriched plasma cell-free DNA.

INTERPRETATION: MB-FUS plus temozolomide is a safe combinatorial therapeutic approach for individuals with high-grade glioma, with the potential to improve survival and enable non-invasive plasma biomarker-based disease surveillance (sono-liquid biopsy), warranting randomised controlled trials.

FUNDING: National Institutes of Health and Insightec.

BACKGROUND: The efficacy of resection in IDH-mutant grade 2 gliomas remain controversial since terminology for the extent of resection has been inconsistently applied across studies. We aimed to establish a standardised classification for the extent of resection and assess the association between supramaximal resection and survival across molecular subtypes.

METHODS: In this international, multicentre, retrospective study, patients aged 18 years and older with newly diagnosed grade 2 IDH-mutant glioma were identified from institutional databases across 16 centres in the USA, Europe, and Asia between between Sept 1, 1993, and May 10, 2024. We used Cox proportional hazard regressions to analyse the associations between residual tumour and progression-free survival and overall survival. Patients were stratified according to a previously postulated classification system based on residual tumour volume. A cohort of patients from UCSF diagnosed between Feb 16, 1998, and Nov 14, 2017, was used for geographically and institutionally independent external validation.

FINDINGS: We identified 1391 patients with newly diagnosed IDH-mutant grade 2 gliomas, with a median follow-up of 81 months (95% CI 78-85). 728 patients (379 with astrocytoma and 349 with oligodendroglioma) received no first-line treatment beyond surgery, allowing us to study the isolated effects of resection. Patients with maximal T2-fluid attenuated inversion recovery (T2-FLAIR) resection (class 2; 0-5 cm3 remnant) had superior progression-free and overall survival compared with submaximal T2-FLAIR resection (class 3; 5-25 cm3 remnant) or minimal T2-FLAIR resection (class 4; >25 cm3 remnant), with 10-year survival rates of 82% (95% CI 76-87) versus 75% (62-84) versus 48% (29-65; p<0·0001) and 5-year progression-free survival rates of 44% (38-50) versus 25% (16-34) versus 12% (4-24; p<0·0001), respectively. Resection beyond T2-FLAIR borders (class 1) provided survival benefits, with a 10-year survival rate of 98% (95% CI 92-99) and a 5-year progression-free survival rate of 83% (76-88) for supramaximal T2-FLAIR resection (class 1). Associations between survival and extensive resection were evident after 3 years in astrocytomas, whereas survival curves separated after 6-8 years in oligodendrogliomas. The prognostic relevance of the four-tier classification was conserved in multivariable analyses, in 625 patients receiving first-line chemotherapy or radiotherapy (with or without chemotherapy), and in the external UCSF cohort of 381 patients with IDH-mutant grade 2 gliomas.

INTERPRETATION: The proposed RANO classification for extent of resection could serve as a tool for prognostic stratification. Although associations between survival and extensive surgery are evident sooner in patients with astrocytoma, supramaximal resection also translates into survival benefits for patients with oligodendrogliomas.

FUNDING: None.

BACKGROUND: The surrogacy value of distant disease-free survival for overall survival has not been validated in neoadjuvant randomised controlled trials (RCTs) for early breast cancer. Here, we assess the trial-level surrogacy value of distant disease-free survival for overall survival.

METHODS: In this pooled analysis, we included individual patient data from RCTs of neoadjuvant therapy for early breast cancer conducted by the German Breast Group (GBG) and the German Gynecological Oncology Breast Study Group (AGO-B) with available data on distant disease-free survival and overall survival. We used the trial-level measure of surrogacy R2trial from two-stage meta-analytical copula methods to quantify the association between treatment effects on overall survival and distant disease-free survival, overall and in prespecified clinical and pathological subgroups. According to ReSEEM guidelines, R2trial values of 0·7 or higher represent strong correlations, values between 0·69 and 0·5 represent moderate correlations, and values of less than 0·5 represent weak correlations.

FINDINGS: 11 RCTs, with a total of 15 neoadjuvant treatment comparisons and 12 247 patients, were included in the analysis. Overall, there was a strong association between copula model-based hazard ratios (HRs) for overall survival and copula model-based HRs for distant disease-free survival (R2trial=0·91 [95% CI 0·82-1·00]). No significant heterogeneity of results was observed across the majority of subgroups analysed (pheterogeneity>0·05 in all subgroups), with the exception of subgroups defined by tumour molecular features, such as tumour progesterone receptor status, HER2 status, and molecular subtypes. For molecular subtypes, the R2trial for the association between distant disease-free survival and overall survival was higher than 0·7, indicating strong surrogacy in hormone receptor-negative and HER2-negative tumours (R2trial=0·89 [95% CI 0·75-1·00]) and hormone receptor-negative and HER2-positive tumours (0·73 [0·36-1·00]), and below the 0·5 threshold for weak surrogacy in hormone receptor-positive and HER2-negative tumours (0·33 [0·00-0·83]) and hormone receptor-positive and HER2-positive tumours (0·11 [0·00-0·55]; pheterogeneity=0·021).

INTERPRETATION: With adequate follow-up, distant disease-free survival is a robust surrogate endpoint for predicting final overall survival outcomes in neoadjuvant RCTs for early breast cancer in most contexts. However, the distant disease-free survival surrogacy appears to be weak for the hormone receptor-positive and HER2-negative and for the hormone receptor-positive and HER2-positive molecular subtypes. These latter findings warrant further investigation in more recent RCTs enrolling higher-risk patient populations.

FUNDING: None.

Despite the central role of p53 suppression in cancer pathogenesis, the promise of therapeutic p53 reactivation remains unrealized, with targeted and combination chemotherapies limited by efficacy, toxicity, and delivery. To overcome these challenges, we introduce a triple-action proteolysis targeting chimera (TAPTAC) that simultaneously targets three oncogenic mechanisms to reactivate apoptosis. TAPTAC1 diverts HDM2 from degrading p53 to eliminating oncogenic targets such as BET proteins, while also blocking HDMX-mediated sequestration, thereby maximizing p53 reactivation in concert with cancer protein degradation. TAPTAC1 outperforms combination treatments and PROTACs that target HDM2 and BET proteins, but not HDMX, and is broadly effective in wild-type (WT) p53 cancers, including mouse models of osteosarcoma and leukemia. Importantly, TAPTAC1 leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity. With WT p53 retained in 90% of pediatric and 50% of adult cancers, TAPTACs provide a therapeutic platform for addressing key limitations of prior anti-cancer strategies.

BACKGROUND: Obesity and chronic inflammation are associated with an elevated risk of diverticulitis. However, the underlying mechanisms, particularly the role of circulating metabolites are not well understood.

METHODS: We derived metabolomic signatures of metabolic dysfunction (body mass index, waist circumference, C-peptide, and adiponectin) and inflammation (C-reactive protein, interleukin 6, and tumor necrosis factor receptor superfamily 1B). We then predicted metabolomic signatures among 7888 participants who were free of diverticulitis at blood collection in Nurses' Health Study (NHS), NHSII, and Health Professional Follow-up Study (HPFS) and evaluated their association with risk of diverticulitis incidence, recurrence, and surgery.

FINDINGS: Metabolomic signatures explained 32% of the variation in the metabolic dysfunction markers and 29% of the variation in inflammation markers. Both signatures were significantly associated with an increased risk of diverticulitis. The multivariable-adjusted hazard ratio (HR) for incident diverticulitis comparing participants in the highest quartile to those in the lowest was 1.97 (95% confidence interval [CI]: 1.52-2.54; P-trend<0.0001) for the metabolic dysfunction signature and 1.40 (95% CI: 1.08-1.81; P-trend = 0.02) for the inflammation signature. Metabolic dysfunction signature was additionally associated with an increased risk of diverticulitis recurrence (extreme-quartile HR: 1.80; 95% CI: 1.10-2.96; P-trend = 0.004) and surgery requirement (HR: 2.99; 95% CI: 1.56-5.70; P-trend = 0.005).

INTERPRETATION: Both metabolomic signatures of metabolic dysfunction and inflammation were significantly associated with incident diverticulitis. The metabolic dysfunction signature showed a more robust association with diverticulitis recurrence and surgery requirement. Our results suggest a role of circulating metabolites in metabolic and inflammatory pathways in diverticulitis pathogenesis.

FUNDING: This study was supported by grants from the National Institutes of Health (UM1 CA186107, R01 CA49449, U01CA176726, R01 CA67262, U01 CA167552). ATC is an American Cancer Society Research Professor. WM is supported by the National Institutes of Health (K01DK135854-01A1), American Gastroenterological Association (AGA2021-13-01), and MGH Claflin Distinguished Scholar Award. ATC, ELG, and LLS are supported by National Institutes of Health (R01 DK101495). MD is supported by the National Institutes of Health/National Cancer Institute (NIH/NCI K00CA274714, K99CA297022). LLS is supported by National Institute of Health (NIDDK 1 R01DK131694). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

We report an 87-year-old female with a history of intellectual disability, severe speech impairment and behavioral issues. She was globally delayed in childhood. In adolescence, she had hallucinations, behavioral issues and was institutionalized. Her behavioral issues were treated, and her medical and behavioral course was stable until her 80's when she began to decline cognitively. She died at age 87. Exome sequencing revealed a novel predicted damaging missense variant (c.1913T>G; p.Met638Arg; NM_001136196.2) in the gene encoding Transportin-2 (TNPO2). Heterozygous variants in TNPO2 have been recently associated with an intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; MIM:619556). Postmortem pathological examination of her brain revealed focal neuronal depletion in the dentate gyrus, CA1, and hilar regions of the hippocampus. These findings are consistent with human gene expression data showing normal to increased expression of TNPO2 in the dentate gyrus and CA1 region of the hippocampus. We suggest that the p.(Met638Arg) variant in TNPO2 is potentially disease-causing and associated with IDDHISD.

Men who have sex with men (MSM) with a history of childhood sexual abuse (CSA) are more likely to report crystal methamphetamine use and condomless anal intercourse (CAI) than MSM without CSA. MSM with CSA may benefit less in HIV prevention interventions due to long-term psychological effects. Data are from a pilot randomized, controlled trial testing an integrated HIV risk reduction and behavioral activation counseling intervention vs standard of care among MSM with methamphetamine use disorder, which showed effects at reducing CAI. We conducted a secondary analysis (N = 38) to preliminarily assess whether CSA moderated the intervention effects on the two primary outcomes: CAI acts with men whose HIV serostatus was either positive or unknown (1) overall (CAI overall) and (2) while under the influence of methamphetamine (CAI with methamphetamine). At the immediate postintervention assessment, the interaction term between CSA and intervention arm was not statistically significant for either outcome, indicating no moderation effect. However, at the 3-month postintervention assessment, the interaction term was significant for both outcomes. At this time point, for those without CSA, there was a significantly lower number of CAI acts in the intervention condition vs the comparison condition for both outcomes. For those with CSA, however, there was no significant difference between the intervention and comparison conditions for CAI overall, although for the outcome CAI with methamphetamine, the intervention condition had higher levels. Future HIV prevention interventions among MSM with methamphetamine use disorder should consider screening for CSA and addressing CSA-related psychological distress, which may potentially preserve intervention effects.

The transformation of a two-dimensional epithelial sheet into various three-dimensional structures is a critical process in generating the diversity of animal forms. Previous studies of epithelial folding have revealed diverse mechanisms driven by epithelium-intrinsic or -extrinsic forces. Yet little is known about the biomechanical basis of epithelial splitting, which involves extreme folding and eventually a topological transition breaking the epithelial tube. Here, we leverage tracheal-esophageal separation (TES), a critical and highly conserved morphogenetic event during tetrapod embryogenesis, as a model system for interrogating epithelial tube splitting. We identify an evolutionarily conserved, compressive force exerted by the mesenchyme surrounding the epithelium, as being necessary to drive epithelial constriction and splitting. The compressive force is mediated by localized convergent flow of mesenchymal cells towards the epithelium. Sonic hedgehog (SHH) secreted by the epithelium functions as an attractive cue for mesenchymal cells. Removal of the mesenchyme, inhibition of cell migration, or loss of SHH signaling all abrogate TES, which can be rescued by externally applied pressure. These results unveil the biomechanical basis of epithelial splitting and suggest plausible mesenchymal origins of tracheal-esophageal birth defects.

SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2' site, before membrane fusion can occur. Here, we report a cryo-EM structure of S2 fragment after the S2' cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2' cleavage accelerates membrane fusion, probably by stabilizing membrane fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations show substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangle causal proteomic perturbations from TET2 CHIP. Lastly, we identify plasma proteins shared between CHIP and CAD.