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Revisiting the Shape Convention of Transformer Language Models

arXiv:2602.06471v2 Announce Type: replace-cross Abstract: The architectural shape of dense Transformers has remained remarkably stable: narrow-wide-narrow feed-forward networks (FFNs) consume most non-embedding parameters. Motivated by theoretical and empirical evidences that residual wide-narrow-wide (hourglass) MLPs remain expressive despite bottlenecks, we revisit whether this architectural convention is necessary for dense language models. We study Hourglass Transformers, which replace the conventional FFN with residual stacks of hourglass sub-MLPs and use hourglass attention to decouple residual-stream width from attention width. This exposes a practical depth-width trade-off: compressing the FFN intermediate dimension allows wider hidden states and fewer layers at matched parameter budgets. Across model scales from 113M to 8B parameters, Hourglass Transformers achieve language-modeling and downstream performance comparable to conventional Transformers, while improving training compute efficiency by $8.7\%$ at matched average downstream accuracy across the 906M, 3B, and 8B scales. After long-context extension, the 8B Hourglass model also outperforms its matched conventional baseline across 4k-64k context lengths. At 64k context, the reduced attention layer count lowers both computation and KV-cache requirements, yielding up to $1.93\times$ faster token decoding and $50\%$ lower KV-cache memory at the 1B scale. These results identify hourglass structures as a practical architecture-efficiency alternative for compute- and latency-conscious Transformer design.
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A clinically derived lipid-endothelial signature links serum multi-omics to immune exclusion and clinical stratification in hepatocellular carcinoma

Ther Adv Med Oncol. 2026 Aug 31;18:17588359261481797. doi: 10.1177/17588359261481797. eCollection 2026.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is driven by extensive metabolic reprogramming, vascular remodeling, and immune microenvironmental dysfunction. Although numerous stratification signatures have been proposed, few are grounded in clinically derived serum multi-omics and biologically linked to endothelial remodeling, endothelial regulation, and immune exclusion.

OBJECTIVES: This study aimed to identify a serum-derived lipid-endothelial program associated with immune exclusion and clinical stratification in HCC.

DESIGN: A translational multi-omics study integrating clinically collected serum samples, public transcriptomic cohorts, single-cell RNA sequencing, and experimental validation.

METHODS: Proteomic and metabolomic sequencing was performed on serum samples from patients with HCC and normal controls. Dysregulated pathways were integrated with transcriptomic data from TCGA-LIHC and ICGC-LIRI-JP cohorts to identify genes jointly associated with lipid metabolism and leukocyte transendothelial migration. A risk score was calculated using the expression of PON1, TXNRD1, CLDN4, CLDN6, CYP2C9, and CTSA. Higher expression of TXNRD1, CLDN4, CLDN6, and CTSA contributed to a higher risk score, whereas PON1 and CYP2C9 contributed protective coefficients. Immune contexture, tumor mutation burden, and exploratory therapeutic sensitivity patterns were further evaluated using transcriptome-based drug sensitivity prediction, followed by single-cell RNA sequencing and experimental expression validation.

RESULTS: Serum multi-omics analysis revealed prominent dysregulation of lipid metabolic pathways and leukocyte transendothelial migration-related processes in HCC. Integrative analysis identified a six-gene lipid-endothelial signature (PON1, TXNRD1, CLDN4, CLDN6, CYP2C9, and CTSA) that stratified patients into high- and low-risk groups. In the TCGA-LIHC cohort, high-risk patients had significantly poorer overall survival than low-risk patients (log-rank P < 0.0001), and this survival-stratifying association was externally supported in the ICGC-LIRI-JP cohort (log-rank P = 0.016). The high-risk phenotype was associated with immune-excluded features, distinct somatic mutation patterns, and altered predicted sensitivity to several selected anticancer agents. Single-cell analysis and experimental assays further supported the association between the six-gene program, malignant epithelial states, endothelial-related remodeling, and immune microenvironmental heterogeneity.

CONCLUSION: This study defines a clinically derived lipid-endothelial program associated with immune exclusion, adverse prognosis, and potential differences in therapeutic vulnerability in HCC. The proposed signature provides a biologically informed framework for prognostic assessment and may support future evaluation of targeted interventions in HCC.

PMID:42682961 | PMC:PMC13530516 | DOI:10.1177/17588359261481797

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