BackgroundBasilar artery occlusion (BAO) is a rare stroke type, with subtypes like vertebrobasilar tandem occlusion (VBTO), complicating treatment. Mechanical thrombectomy (MT) is increasingly used, but evidence on its safety and effectiveness in VBTO compared to isolated BAO (iBAO) remains limited.MethodsPubMed, Cochrane Central, Embase, Web of Science, and ScienceDirect were searched till May 2025. The risk ratios (RR) were pooled along with 95% Confidence intervals (CI) under the random effects model using Review Manager. The Newcastle Ottawa Scale and GRADE assessment were used to assess the quality of studies and certainty of evidence. Successful recanalization was defined as a Thrombolysis in Cerebral Infarction (TICI) score of ≥2b. The modified Rankin Scale (mRS) is a scale used to assess the severity of stroke, with functional independence defined as an mRS score of 0-2. Publication bias was assessed using funnel plots and Egger's regression test.ResultsNine studies, pooling a total of 737 patients, were included in this analysis. MT showed no significant difference in functional independence in the VBTO group compared to the iBAO group (RR = 1.25; 95% CI: 0.73, 2.12; p = .42). The successful recanalization was also comparable between the VBTO and iBAO arms when MT was performed (RR = 0.96; 95%CI 0.81, 1.13; p = .60). The risk of symptomatic intracerebral hemorrhage (sICH) was significantly increased when MT was performed in the VBTO arm compared to the iBAO group (RR = 2.20; 95%CI : 1.09, 4.46]; p = .03). The mortality rates were also comparable between the two groups (RR = 1.28; 95% CI 0.78, 2.10; p = .33). Also, in the VBTO patients, the successful recanalization rate showed no significant difference between the clean and dirty road techniques (RR = 1.04; 95% CI 0.90, 1.20; p = .63).ConclusionWhen MT was performed on VBTO and iBAO patients, the efficacy endpoints-such as functional independence and successful recanalization-and the safety endpoint of mortality were comparable. However, the risk of sICH was higher in the VBTO group.
Publications by Year: 2025
2025
The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2-Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved amongst at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.
BACKGROUND AND AIMS: Financial toxicity, the combined objective burden and subjective distress that affects patients' medical care, is not well described in patients with IBD. We aimed to characterize financial toxicity in patients with IBD.
METHODS: We designed and administered a de-identified survey to patients with IBD. The primary outcome, financial toxicity, was defined as a score <22 on the COST-FACIT scale, a validated measure. We constructed multivariable logistic regression models to evaluate associations adjusting for age, sex, race, type of IBD, IBD medications, household income and education level.
RESULTS: Respondents (n=669) had a median age of 49 years, were 62% female and 92% White. 52% were currently treated with advanced IBD-therapy and 58% reported IBD in remission/minimal activity. 53% were employed full-time. 61% had an annual household income ≥$100,000. 69% had private insurance and 31% had Medicare.21% reported trouble paying medical bills in the past year; 34% of working adults missed work in the past 7 days because of IBD. 39% experienced financial toxicity. Adjusting for confounders, adults <65 years were more likely to experience toxicity than older adults (aOR: 6.78, 95%CI: 2.60-17.65). Those with education less than a Bachelor's Degree (aOR: 2.73, 95%CI: 1.70-4.37), annual household income <$60,000 (aOR: 3.71, 95%CI: 2.14-6.42) and women were more likely to experience financial toxicity (aOR: 1.90; 95%CI: 1.28-2.81).
CONCLUSIONS: Financial toxicity was prevalent among patients with IBD, particularly among younger adults, those with lower income and education and women. Enquiring about financial toxicity should be incorporated into IBD clinical practice.
Early diagnosis is crucial for the effective treatment of rheumatoid arthritis because continuing inflammation can lead to irreversible joint damage. However, current diagnostic methods lack tissue-specific guidelines to monitor the progressive course of degenerative joint diseases. Here, we demonstrate that cartilage-targeting fluorophores (CARFs) exhibit a remarkable cartilage-specific affinity and offer advanced imaging capabilities in the near-infrared II (NIR-II) window, characterized by minimal tissue scattering and negligible autofluorescence. CARFs show little to no toxicity, both in vitro (up to 100 μM) and in vivo (3 μmol/kg via intravenous injection), suggesting clinical potential. Furthermore, CARFs in the NIR-II window enable the precise visualization of cartilage lining, serving as a reliable diagnostic indicator for the early detection of arthritis in preclinical mouse models. CARFs are NIR fluorescence-emitting targeted contrast agents for prognostic imaging of joint tissue, with the potential to revolutionize applications in tissue engineering, joint surgery, and drug development for inflammatory diseases.
Vimentin, a type III intermediate filament protein, has gained recognition as a multifunctional regulator within the tumor microenvironment (TME). While traditionally considered a hallmark of epithelial-to-mesenchymal transition (EMT), vimentin is increasingly understood as a structural and signaling hub essential for the functional complexity of mesoderm-derived and EMT-transitioned cells. It bridges cytoskeletal architecture with key signaling networks, linking cellular plasticity to mechanotransduction, immune modulation, and metabolic regulation. This unique versatility underlies vimentin's essential role in supporting the migratory, remodeling, and adaptive behaviors required in contexts such as wound healing, inflammation, and tissue remodeling-capabilities that cancer cells have co-opted to their advantage. Indeed, vimentin's pervasive expression across aggressive cancers reflects its ability to scaffold and coordinate the cytoskeletal and signaling rewiring needed for malignancy. This review provides an integrated overview of vimentin's diverse roles in the TME, emphasizing its contributions to tumor invasiveness, immune regulation, and metabolic adaptation. We conclude by discussing how these insights may inform the development of vimentin-centered strategies to improve therapeutic outcomes in cancer.
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: 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.
The contributions of specific growth factors (GFs) to hair follicle maintenance during aging remain poorly understood. The GF TGFα affects postnatal hair morphogenesis, and its loss leads to wavy hairs in young mice. Whether TGFα is required for proper hair follicle function during aging has not been explored. In this study, we find that loss of TGFα results in severe progressive alopecia, leading to an almost complete absence of back hairs in aged mice. Deep hair phenomics shows that the progressive hair loss is associated with a switch of hair-type proportions toward zigzag hairs, increased hair waviness, decreased hair length, and increased trichoptilosis with multiple hair breakage points. Hair loss is associated with a progressive dilatation of the upper hair follicle, which showed keratinocyte differentiation abnormalities. Metabolomic analyses of epidermal sheets identified diminished levels of prostaglandin H2 in Tgfa-/- mice. Transcriptomic analyses linked the hair loss in aged Tgfa-/- mice to upregulation of genes involved in retinyl ester synthesis in keratinocytes, which resulted in increased retinyl stearate in skin of aged Tgfa-/- mice. Collectively, these findings identify TGFα as a critical regulator of hair follicles during aging, whose loss leads to progressive alopecia, associated with dysregulation of prostaglandin and retinoid metabolism.
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.
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.