Obesity and aging are major risk factors for diseases such as Type 2 diabetes mellitus, dementia, and osteoporosis. High-fat diet (HFD) consumption is one of the most important factors contributing to obesity. To elucidate and provide resources on how long-term HFD to aging (LHA) affects the bone marrow and solid organs, we established an LHA mice model and demonstrated that LHA caused a shift from osteogenesis to adipogenesis in the bone marrow microenvironment. Single-cell transcriptomics of bone marrow cells highlighted LHA-driven perturbations in immune cell populations with distinct metabolic adaptations to LHA. We demonstrated that bone marrow macrophages of the LHA group upregulated Chil3 and Fabp4, which are associated with inflammatory response and regulation of adipocytes. Moreover, we identified the Ptn-Sdc3 axis and Cxcl12-Cxcr4 axis between bone marrow macrophages and brain epithelial cells as possible candidates for crosstalk between bone marrow and brain in LHA mice. Our findings indicated the bone marrow microenvironment as a central hub of LHA-induced pathology, where adipogenic reprogramming and myeloid cell dysfunction collectively drive skeletal and systematic inflammation. This resource highlights therapeutic opportunities targeting bone marrow to mitigate obesity-accelerated aging.

Astragalus membranaceus and Codonopsis pilosula are widely used in traditional chinese medicine for the treatment of diabetes because of their notable hypoglycemic pharmacological effects. Studies have indicatedthat the active compounds in the Astragalus-Codonopsis herb pair may exert their hypoglycemic effects through the modulation of the insulin receptor (IRSP) signaling pathway. In this study, the rhamnolitrin and folic acid were confirmed as the key active components in the Astragalus-Codonopsis herb pair that regulate the IRSP, with their synergistic mechanisms in Type 2 Diabetes Mellitus (T2DM) being further systematically explored by network pharmacology combined with DFT theoretical calculation, molecular docking, molecular dynamics simulation and alanine scanning mutation technology. The results suggest that GSK3β is a critical target through which rhamnolitrin and folic acid exert their anti-diabetic effects. Subsequent molecular docking and molecular dynamics simulations confirmed that both active compounds selected in this study can bind stably with the GSK3β protein. Further alanine scanning mutagenesis experiments validated the importance of key amino acid residues in ligand-receptor interactions. Finally, DFT theoretical calculations provided a detailed elucidation of the binding mechanism between the core components (rhamnolitrin and folic acid) and the target protein GSK3β. This study not only revealed the molecular mechanism of Astragalus-Codonopsis for the treatment of type 2 diabetes, provided a theoretical basis for its clinical application, but also provided a potential molecular target for the development of new anti-diabetes drugs.

Diabetes mellitus is strongly associated with accelerated intervertebral disc degeneration, a condition that significantly contributes to lower back pain and reduced quality of life. Emerging evidence indicates that advanced glycation end products (AGEs) are key mediators in the pathophysiology of disc degeneration through the stimulation of inflammatory pathways, promotion of oxidative stress, and induction of extracellular matrix modifications. This review critically examines current literature on the role of AGEs in diabetic disc degeneration and evaluates potential therapeutic interventions aimed at mitigating these deleterious effects. Targeting AGEs represents a promising therapeutic avenue to mitigate diabetic intervertebral disc degeneration. The current evidence supports the rationale for further investigation into AGE inhibitors, cross-link breakers, and receptor for AGEs modulators as potential treatment strategies. However, to translate these findings into clinical practice, well-designed clinical trials are required to validate the efficacy and safety of these interventions, as well as to optimize treatment protocols.

Cardiovascular and renal complications remain leading causes of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM). Since 2015, large-scale cardiovascular outcome trials (CVOTs) have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduce the risk of major adverse cardiovascular events, cardiovascular mortality, and heart failure hospitalization in patients with T2DM and established cardiovascular disease or high-risk profiles. These findings-originating from landmark trials such as EMPA-REG OUTCOME, LEADER, and SUSTAIN-6-have led to substantial revisions in international guidelines from the European Society of Cardiology, American College of Cardiology, and American Heart Association, which now recommend the use of SGLT2i or GLP-1 RAs, often in conjunction with metformin. SGLT2i have shown robust effects in reducing heart failure hospitalization and slowing the progression of chronic kidney disease, while GLP-1 RAs have demonstrated superior efficacy in reducing atherothrombotic events, particularly non-fatal stroke. Additionally, emerging data supports the complementary use of both drug classes, revealing additive benefits on cardiovascular and renal outcomes without increased toxicity. This narrative review summarizes the mechanisms of action, clinical efficacy, safety profiles, and sex-specific outcomes associated with SGLT2i and GLP-1 RAs. It also highlights key evidence supporting their combined use and underscores their critical role in optimizing long-term outcomes in patients with T2DM and cardiovascular disease.

The gut microbiome plays a critical role in human health through its influence on numerous physiological functions such as metabolism and immunity, with disruptions in microbial communities increasingly linked to metabolic disorders. In a large-scale cohort study in Japan, we investigated the association between gut microbiome profiles and metabolic health. Using 16S rRNA gene sequencing, four-enterotype clustering revealed that the Bacteroides 2 (B2) enterotype was associated with lower alpha-diversity and increased risk of metabolic diseases, particularly obesity (OR = 1.51) and hypertension (OR = 1.49). Refined seven-enterotype clustering further stratified the Ruminococcus, Prevotella, and Bacteroides enterotypes into distinct subtypes, uncovering a novel high-risk Prevotella 2 (P2) enterotype associated with nearly two-fold increased risk of obesity and diabetes mellitus. The B2 and P2 enterotypes were characterized by reduced abundance of beneficial short-chain fatty acid (SCFA) producers (Faecalibacterium, Anaerostipes) and enrichment of opportunistic pathogens (Fusobacterium and Veillonella for B2, Megamonas and Megasphaera for P2). Microbial metabolic influence network analysis revealed enterotype-specific interaction patterns, with R1, R2, and P1 enterotypes demonstrating cooperative production of SCFAs and other metabolites, while B enterotypes displayed synergy in the production of a range of sugar compounds. These findings underscore the utility of refined enterotype clustering as a powerful tool to reveal previously unrecognized gut microbial patterns linked to metabolic risk. By identifying B2 and the newly characterized P2 enterotypes as high-risk microbial profiles, this study opens new avenues for microbiome-based stratification and early intervention in metabolic disease management.

Type 2 diabetes mellitus (T2DM) with cognitive impairment has a high incidence rate globally, and there is a need to investigate the relationship among the glymphatic system, hippocampus microstructure, and cognition in T2DM. The present study aims to delineate changes in the perivascular space index (ALPS-index) among T2DM patients with different cognitive states and investigate any possible correlation between the ALPS-index and the diffusive indicators of the bilateral hippocampi in T2DM. In addition, we seek to identify specific cognitive domains with substantial correlation with the ALPS-index in the general population.

A total of 113 participants were recruited, comprising 37 T2DM patients with normal cognitive function (DMNC), 39 T2DM patients with mild cognitive impairment (DMMCI), and 37 healthy controls (HC). Clinical information, neuropsychological assessments, and experienced multimodal magnetic resonance imaging scans were recorded from all the participants. A noninvasive method was applied to obtain all ALPS-index measures, such as the left, right, and average ALPS-index, along with diffusive indicators of the bilateral hippocampi, comprising fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD).

A statistically marginal difference in the average ALPS-index was noted among HC, DMNC, and DMMCI groups. According to binary logistic regression analysis results, the average ALPS-index significantly altered the cognitive function in T2DM. Partial correlation analyses revealed a positive association between the average ALPS-index and FA, as well as a negative association with MD and RD in the bilateral hippocampi of the T2DM groups. In the general population, partial correlation analysis indicated that the average ALPS-index correlated with the auditory verbal learning test (AVLT) immediate recall scores.

In summary, our findings demonstrated that glymphatic system function in the brain progressively deteriorates with worsening cognitive impairment among T2DM patients. Moreover, T2DM significantly disrupts the relationship patterns between the glymphatic system and bilateral hippocampal microstructure. Thus, the mean ALPS-index may act as a novel neuroimaging biomarker for assessing cognitive function in T2DM.

Mandibular osteoradionecrosis (ORN) is a severe late radiation toxicity affecting 5-10% of patients who receive radiotherapy as part of treatment for head and neck malignancy. ORN can cause permanent disfigurement, dysfunction, pain and infection. There remains little robust evidence supporting the efficacy of medical or surgical management currently offered in clinical practice. Retrospective case series and meta-analyses of observational studies suggest that a repurposed triple drug combination pentoxifylline-tocopherol-clodronate ('PENTOCLO') may be effective in preventing deterioration, promoting healing and ultimately reducing the need for major reconstructive surgery.

The RAPTOR trial is a phase II, open-label, multicentre, randomised controlled trial with a superiority design. Eligible subjects with mandibular ORN are randomised 1:1 to receive standard of care (Arm A) or PENTOCLO plus standard of care (Arm B) for 12 months. The primary outcome measure is time from randomisation to healing of ORN (without the need for surgery), as measured by clinical examination (confirming completely healed oral mucosa), intra-oral clinical photographs and imaging. RAPTOR has an embedded translational sample collection and a methodological component exploring the use of electronic patient-reported outcome measures (ePROM).

The RAPTOR trial is the first randomised controlled clinical trial of PENTOCLO in this clinical setting. The results of this phase II trial will provide robust preliminary evidence on its efficacy and inform the feasibility and appropriateness of a subsequent definitive trial.

RAPTOR is registered with the ISRCTN registry effective date 11th November 2022: Clinical trial of the non-surgical management of radiotherapy damage to the lower jaw ISRCTN34217298, and also registered with the European Clinical Trials Database (Eudra-CT 2022-000728-39).

Kirsten Rat Sarcoma (KRAS) copy number amplification has emerged as an oncogenic driver in colorectal cancer (CRC), in addition to KRAS mutation. However, its clinical significance remains poorly understood. Notably, CRC patients with wild-type KRAS but harboring KRAS amplification have shown resistance to anti-EGFR therapy, representing an unmet clinical need.

In this study, we comprehensively investigated the impact of KRAS amplification-alone and in conjunction with mutation-on clinicopathological characteristics, immune infiltration, and therapeutic response. KRAS copy number variation (CNV) was classified into amplification and non-amplification groups. KRAS mutational status was determined as wild-type (WT) or mutant (MUT) using qPCR and Sanger sequencing. CD8⁺ T lymphocyte infiltration was evaluated by immunohistochemistry in resected CRC specimens. Clinical, immune, and survival data were analyzed in association with KRAS status. RNA-seq was performed to identify differentially expressed genes (DEGs) and enriched pathways. Patient-derived xenograft (PDX) models were used to assess responses to targeted therapies.

We found that KRAS amplification was more frequent in WT KRAS CRC (21.4%) than in MUT KRAS CRC (6.5%). In the WT subgroup, KRAS amplification was associated with poor prognosis and increased KRAS protein expression and downstream pathway activation. In contrast, amplification had little effect in mutant KRAS tumors. KRAS copy number was inversely correlated with CD8⁺ T cell infiltration, suggesting a role in immune evasion. Importantly, low CD8⁺ T cell density combined with KRAS amplification predicted adverse outcomes. Therapeutically, KRAS-amplified PDX models were resistant to anti-EGFR treatment. However, combined MEK and CDK4/6 inhibition overcame this resistance.

KRAS amplification constitutes a distinct oncogenic driver in CRC and a potential biomarker for therapeutic stratification. Our findings support the clinical rationale for dual MEK and CDK4/6 inhibition in KRAS-amplified CRC and highlight the need for biomarker-guided clinical trials to optimize treatment strategies in this subset of patients.

This study aimed to evaluate the safety, efficacy, and optimal dosing of intraoperative radiotherapy (IORT) as a tumor bed boost in combination with whole-breast irradiation (WBI) in individuals with breast cancer in China undergoing breast-conserving surgery (BCS).

A retrospective analysis was conducted on 217 female patients without metastatic disease who underwent BCS between May 2020 and December 2023 and received INTRABEAM IORT followed by postoperative WBI. Adjuvant therapies were administered as indicated. Evaluated outcomes included recurrence, disease-free survival (DFS), overall survival (OS), wound healing, and the incidence of radiodermatitis.

The cohort ranged in age from 20 to 67 years, with a median age of 48 years. Among them, 18 patients underwent neoadjuvant chemotherapy prior to BCS. Molecular subtypes included Luminal A (25.8%), Luminal B (33.6%), hormone receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive (6.9%), hormone receptor-positive/HER2-positive (12.9%), and triple-negative (20.7%). IORT doses were 10 Gy (n = 189), > 10 to < 20 Gy (n = 9), and 20 Gy (n = 19). At a median follow-up of 20 months (range: 12-55 months), all patients were alive. Disease recurrence was observed in 2.3% (n = 5). Age younger than 45 years (p = 0.044) and tumor size exceeding 2 cm (p = 0.040) identified as independent risk factors of recurrence. The 1-year and 2-year DFS rates were 99.1% and 98.2%, respectively. Most patients (95.4%) achieved complete wound healing within four weeks. Delayed wound healing exceeding two months occurred more frequently among those who received 20 Gy (15.8%) compared to those who received 10 Gy (2.6%) or > 10 to < 20 Gy (0%) (p < 0.001).

The combination of IORT and WBI demonstrated favorable safety and efficacy profiles in individuals with breast cancer in China undergoing BCS. Younger age and tumor size > 2 cm were associated with increased recurrence risk. An IORT dose between 10 and 20 Gy (including 10 Gy), was determined to be optimal, as a 20 Gy dose was associated with increased wound complications without providing survival benefits. Further research is warranted to explore risk-stratified dosing strategies.

Distal pancreatic resection during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is rare, with limited knowledge available. Therefore, a retrospective observational study was conducted using the data registry of a single institution to identify patients that underwent distal pancreatic resection during CRS + HIPEC.

All resected pancreatic specimens were examined for invasive parenchymal tumor infiltration. Pre-, peri-, and postoperative variables and their associations were analyzed.

Over a period of more than a decade, 31 of 1275 patients (2.43%) underwent distal pancreatic resection as part of CRS. Infiltration of the pancreatic parenchyma was confirmed in almost one-third (29.03%) of the cases. Postoperative pancreatic fistulas occurred in 25.81% of patients (87.5% Grade B; 12.5% Grade C). The need for distal pancreatic resection was closely related to tumor burden in the left upper abdomen, with 87% of patients requiring peritonectomy of the left upper abdomen in addition to visceral resection. Pancreatic infiltration (n = 9/31) was diagnosed in 3 cases of gastric carcinoma, 2 cases of colorectal carcinoma, 2 cases of primary peritoneal carcinoma, 1 case of ovarian carcinoma, and 1 case of mucinous appendiceal carcinoma. Postoperative pancreatic fistulas were more frequently associated with primary tumors of the large intestine (87.50% vs. 30.43%; P = 0.0094), and a tendentiously longer total hospital stay was required for the "with pancreatic fistula" group (32.50 ± 19.93 days vs. 21.78 ± 10.14 days), with no impact on patient survival.

Accepting a slightly increased morbidity, distal pancreatic resection is a reasonable approach to achieve complete macroscopic tumor resection. Nonetheless, our study shows that apparent tumor invasion is histologically rare in cases with favorable tumor biology, such as low-grade pseudomyxoma peritonei. Therefore, pancreatic resection should be avoided in cases of mucinous tumors to prevent fistula formation.