OBJECTIVE:To evaluate the association between post-induction MRI response after induction chemotherapy and final treatment response in locally advanced rectal cancer (LARC) patients undergoing total neoadjuvant therapy. METHODS:This retrospective study included LARC patients who underwent induction chemotherapy-based total neoadjuvant therapy followed by total mesorectal excision (TME). MRI tumor regression grade and tumor longitudinal length reduction rate (TLLR) were used to assess post-induction response. MRI tumor regression grade and diffusion-weighted imaging were used to determine preoperative MRI complete response (mriCR). The primary outcome was the pathological complete response (pCR). RESULTS:The current study included 224 patients (56 [IQR 49-65] years). Good responders at post-induction evaluation were associated with higher mriCR (OR 3.78, p < 0.001), higher pCR (OR 4.41, p < 0.001), and better recurrence-free survival (p < 0.001). CONCLUSION:Post-induction evaluation was associated with later mriCR, pCR, and recurrence-free survival in LARC patients undergoing total neoadjuvant therapy, supporting future study on response-adapted neoadjuvant strategies.
This is a light-hearted yet affectionate exploration of the quirks, contradictions, and enduring mysteries of peer review. Through the legendary Reviewer #2 and other familiar academic encounters, this satire celebrates the frustrations, resilience, and ultimately indispensable role of peer review in strengthening scientific scholarship.
Deoxysphingolipids (dSLs) are atypical sphingolipids that accumulate in several pathological settings, yet their impact on hematologic malignancies is poorly understood. Here, we investigate the pathways and mechanisms of deoxysphinganine (dSA) cytotoxicity in lymphoma cells and its potential as a therapeutic agent. dSA exhibited markedly greater cytotoxicity than canonical sphingoid bases in lymphoma cell lines, yet induced only cytostatic effects in normal human T cells, indicating a therapeutically exploitable window. Inhibition of ceramide synthase blocked the generation of deoxy(dihydro)ceramides, prevented mitochondrial depolarization, caspase activation, ER stress, and DNA damage, establishing CerS-dependent deoxysphingolipids as essential mediators of dSA-induced death. Mechanistically, dSA engaged a mitochondrial apoptotic pathway, with DNA damage occurring downstream of mitochondrial permeabilization and caspase activation, while PERK-driven ER stress occurred in parallel and was dispensable for cytotoxicity. Subtype-specific engagement of ER stress and DNA damage further suggests that dSL signaling is shaped by lineage context. The differential sensitivity between malignant lymphoid cells and normal T cells, together with the central role of CerS-derived deoxy(dihydro)ceramides, highlights deoxysphingolipid metabolism as a druggable vulnerability in lymphoma. These findings support further exploration of dSA-based strategies and targeted modulation of dSL synthesis as a novel therapeutic avenue for non-solid hematologic malignancies.
BACKGROUND:Early-onset colorectal cancer (EOCRC) incidence is increasing despite declining rates among older adults. We evaluated long-term and recent EOCRC trends. METHODS:SEER data (1975-2023) were analyzed for EOCRC incidence overall and by sex, race, and tumor site. A contemporary cohort (2019-2023) assessed stage and 3-year overall survival (OS). RESULTS:EOCRC incidence accelerated during 2019-2023 (AAPC 8.3%), contrasting with declining incidence among adults ≥65 years. Mortality increased among individuals <50 years. Incidence rose faster among females than males (9.1% vs 7.6%) and for rectal versus colon cancer (9.0% vs 4.5%). Black patients more often presented with stage IV disease than White patients (33.9% vs 29.3%) and had lower 3-year OS (67.3% vs 76.2%). CONCLUSIONS:EOCRC incidence has accelerated markedly, accompanied by increasing mortality among younger adults. These trends underscore the need for earlier diagnosis, improved risk stratification, and equitable care.
BACKGROUND:Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) impair platelet hemostasis, but their effect on bleeding after elective colectomy is unknown. METHODS:Using the TriNetX US Collaborative Network (2017-2024), adults undergoing elective colectomy were compared across six 1:1 propensity score-matched contrasts, each prespecified to address a distinct source of confounding: primary (SSRI/SNRI vs non-users), active-comparator (high-vs low-SERT affinity, for confounding by indication), class-specific (SSRI-only and SNRI-only vs non-users) and head-to-head (SNRI vs SSRI, for agent pooling), and incident new-user (for prevalent-user bias). The primary outcome was a 30-day bleeding composite. RESULTS:After matching, 8738 patients per arm comprised the primary cohort (all SMDs <0.10). SSRI/SNRI use raised 30-day bleeding (RR 1.29, 95% CI 1.11-1.50; NNH 104). Findings were consistent in SSRI-only (RR 1.22, 1.02-1.45), SNRI-only (RR 1.53, 1.15-2.04), and incident users (RR 1.29, 1.05-1.60). Active-comparator and head-to-head contrasts were non-significant. CONCLUSION:Perioperative SSRI/SNRI use is associated with a modest, bleeding-specific 30-day risk increase that persists in new initiators, supporting perioperative bleeding awareness without routine discontinuation.
Whether the fecal metabolome differs according to intensive low-density lipoprotein cholesterol (LDL-C) target achievement among statin-treated patients is unclear. In this cross-sectional study, 124 statin-treated adults with chronic disease were stratified by fasting LDL-C into a target-achieved group (< 70 mg/dL, n = 52) and a target-not-achieved group (≥ 70 mg/dL, n = 72). Stool samples were profiled by untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry, and multivariable models adjusted for age, sex, chronic kidney disease, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were used to identify metabolites independently associated with target achievement. Statin dose, treatment duration and glucose-lowering therapy were also compared between the groups. Paired 16S rRNA gene sequencing data available for a subset (n = 86) were used for integrative correlation and network analyses. Partial least-squares discriminant analysis showed separation between the two groups. Eight annotated metabolites-glutamine, glutamate, phenylalanine, N-acetyl-L-phenylalanine, L-methionine, N-acetyl-L-methionine, lysine, and N-methyl-D-aspartic acid, predominantly amino acids and their derivatives-were present at lower fecal levels in participants who achieved the LDL-C target. Metabolite set enrichment analysis implicated amino acid and nitrogen metabolism, and multiomics network analysis identified an Anaerotruncus-centered amino acid module with high degree centrality. In conclusion, LDL-C target achievement under statin therapy was associated with a coherent "low fecal amino acid" signature and an Anaerotruncus-linked microbe-metabolite hub. These findings suggest that intestinal nutrient handling and gut microbial amino acid metabolism may contribute to variability in LDL-C response, and they warrant prospective mechanistic evaluation.
Metabolic dysfunction-associated liver disease (MASLD) arises from the accumulation of triglycerides within the liver. MASLD can advance to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. Monoacylglycerol acyltransferase 2 (MOGAT2) is essential for triglyceride synthesis and plays a significant role in regulating lipid metabolism. Here, we demonstrate the ability of a new human MOGAT 2 inhibitor, VB-85387, to inhibit the development of MASLD/MASH and further define its effects on the key metabolic pathways that progress MASH development. MASLD/MASH was induced using a methionine, choline-deficient diet (LMCD) or by streptozotocin treatment combined with high fat diet feeding (STAM-HFD). VB-85387 significantly mitigated the severity of MASLD and reduced signs of MASH in mice subjected to these two distinct diets. VB-85387-treated mice exhibited decreased fibrosis, evidenced by reduced hepatic triglyceride concentrations, hydroxyproline levels, and collagen deposition. NAS scores were consistently lower in VB-85387-treated mice across both models. VB-85387-treated mice showed induced PPARα signaling and reduced SREBP transcription, demonstrating a likely role for VB-85387 in regulating lipogenesis and fatty acid β-oxidation. STAM-HFD treated mice showed lower NF-κBp65 activation, which was associated with lower TNFα expression. IL-1β and IFNβ levels were also both reduced, suggesting VB-85387 can reduce pro-inflammatory pattern recognition receptor signaling. In addition, treatment suppressed IL-4/IL-6-dependent JAK activation. Overall, VB-85387 inhibited MASLD development by reducing liver triglyceride levels, fibrosis, and meta-inflammatory signaling. VB-85387 was as effective or superior to the MOGAT2 inhibitor phase I clinical trial drug BMS-963272 in reducing MASLD and fibrosis. VB-85387 has considerable potential for developing therapeutics targeting MASLD/MASH.
Glioma represents one of the most aggressive tumors in the central nervous system, with clinical management facing significant challenges including high recurrence rates and therapeutic resistance. Ferroptosis, an iron-dependent form of cell death, holds potential for glioma treatment, yet tumor cells frequently develop evasion mechanisms. This study elucidates the molecular mechanisms by which hypoxic microenvironment confers ferroptosis resistance in glioma cells, focusing on the pivotal role of the HIF-1α/SREBP1 signaling axis and its downstream effectors FASN and SCD1. Our experimental results demonstrate that hypoxic conditions significantly upregulate HIF-1α expression and confer resistance to RSL3-induced ferroptosis. Mechanistic studies reveal that HIF-1α promotes SREBP1 activation, which subsequently upregulates FASN and SCD1 expression to suppress lipid peroxidation.Furthermore, the HIF-1α-specific inhibitor PX-478 effectively reverses hypoxia-induced ferroptosis resistance and significantly enhances tumor cell sensitivity to ferroptosis inducers. In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies.
BACKGROUND:Lipoprotein(a) [Lp(a)] reflects inherited atherothrombotic risk, whereas the C-reactive protein-triglyceride-glucose index (CTI) integrates systemic inflammation, triglyceride-related lipid disturbance, and glucose-related metabolic stress. Their individual and joint association with angiographic coronary lesion burden in acute coronary syndrome (ACS) remain incompletely defined. We examined whether CTI complements Lp(a) in characterizing coronary lesion burden in ACS. MATERIALS AND METHODS:This retrospective, single-center study included 2,836 consecutive patients with ACS who underwent coronary angiography. Coronary lesion burden was assessed using continuous Gensini score, a high Gensini score, and multivessel disease (MVD). Multivariable regression, restricted cubic spline analyses, CTI-stratified analyses, incremental receiver operating characteristic analyses, and internally validated machine-learning analyses with SHAP interpretation were performed. RESULTS:Higher Lp(a) and CTI level were both associated with greater coronary lesion burden. Compared with Lp(a) <75 nmol/L, Lp(a) ≥175 nmol/L was associated with high Gensini score (OR, 1.51 [95% CI, 1.17-1.96]) and MVD (OR, 1.69 [95% CI, 1.27-2.26]). Each 1-SD increase in CTI was associated with high Gensini score (OR, 1.47 [95% CI, 1.35-1.60]) and MVD (OR, 1.18 [95% CI, 1.08-1.28]). Among inflammatory-lipid indices, CTI showed the most consistent associations and provided the largest numerical incremental discrimination beyond Lp(a). The associaton between ver high Lp(a) and coronary lesion burden was more pronounced at higher CTI levels, particular for MVD. Machine-learning analyses further supported the relevance of both CTI and Lp(a). CONCLUSIONS:In patients with ACS, higher Lp(a) and CTI level were associated with greater angiographic coronary lesion burden. CTI may complement Lp(a) by capturing inflammatory-metabolic status, supporting their joint assessment for more refined characterization of lesion-burden risk in ACS.
Lipoprotein metabolism is significantly different between mice and humans thus making it difficult to model disorders of human lipid metabolism in transgenic mice. Systemic lipoprotein metabolism is predominantly governed by hepatocytes, and mice with humanized livers display human-like lipid profiles. Here we report a highly efficient method to knock out genes in human hepatocytes while retaining their ability to repopulate immune deficient rodents. As proof-of-principle Fah deficient, immune compromised mice were repopulated with Apolipoprotein B (APOB) knockout human hepatocytes. Mice humanized with knockout cells recapitulated typical features of human hypobetalipoproteinemia. We conclude that at least some human lipid metabolism disorders can be modeled in liver chimeric mice using human knockout hepatocytes.
BACKGROUND:Complication incidence alone may inadequately reflect surgical quality in heterogeneous healthcare systems. This study evaluated postoperative outcomes, complication severity, and failure-to-rescue (FTR) within a mixed healthcare system using Clavien-Dindo classification and risk-adjusted analysis. METHODS:A retrospective cohort study of 968 consecutive general surgical procedures performed across three institutions between 2015 and 2025 was conducted. Procedures included elective and emergency surgery across multiple surgical specialties. Postoperative complications were classified using Clavien-Dindo criteria. Severe complications were defined as grade III-V events. Multivariable logistic regression analysis was performed to identify independent predictors of severe postoperative complications. Model discrimination, calibration, and internal validation were assessed using AUC-ROC, Hosmer-Lemeshow testing, Brier score, and bootstrap resampling. RESULTS:Overall complication incidence was 2.8%, with severe complications (Clavien-Dindo III-V) accounting for 85.2% of adverse events. Emergency surgery was associated with higher complication rates and greater complication severity. The overall FTR rate was 11.1%. In multivariable analysis, higher ASA classification (OR 3.08, 95% CI 1.70-5.61; p < 0.001), emergency surgery (OR 5.45, 95% CI 1.70-17.48; p = 0.004), operative time (OR 1.11 per 10-min increase, 95% CI 1.04-1.19; p = 0.003), and male sex (OR 7.02, 95% CI 1.57-31.39; p = 0.011) were independently associated with severe postoperative complications. Healthcare setting was not independently associated after adjustment. The model demonstrated good discrimination and calibration (AUC-ROC 0.895; optimism-corrected AUC 0.870). CONCLUSIONS:In this mixed healthcare system, low overall complication rates coexisted with a disproportionately high burden of severe postoperative morbidity. Risk-adjusted analysis suggests that patient condition, emergency surgical burden, and operative factors exert greater influence on severe complications than healthcare setting alone. Integrating complication severity and FTR analysis may provide a more meaningful assessment of surgical quality in heterogeneous healthcare environments.
INTRODUCTION:Barriers to patient follow-up after short-term surgical trips (STSTs) are multifactorial. Follow-up is essential for identifying and managing complications. Compliance greater than 90% was achieved in a previously implemented community-based follow-up protocol. We hypothesized decreased follow-up rates after a two-year hiatus from the COVID-19 pandemic. METHODS:Retrospective review of STSTs from 2017 to 2019 (pre-pandemic) vs 2022-2024 (post-pandemic) at Kabala Government Hospital, Sierra Leone. Consistent follow-up protocol was used across trips, emphasizing patient education and community recruitment. Patient and operative details were compared. RESULTS:381 patients included across six STSTs. Post-pandemic patients were older. Similar surgeries were performed (hernia repairs and hydrocelectomies). Post-pandemic STSTs demonstrated at least 90% follow-up rates, similar to pre-pandemic without difference in complication rates. This result was also consistent when variables were controlled for in a multivariable regression analysis CONCLUSIONS: High postoperative follow-up rates in rural Sierra Leone were sustained despite hiatus due to the COVID-19 pandemic. Incorporating local communities can achieve consistently high follow-up rates and accountability at low cost. Others may consider adapting this multifaceted protocol to improve sustainable follow-up rates.
Background Short gut syndrome (SGS) after extensive small bowel resection (SBR) is associated with intestinal failure associated liver disease (IFALD). Previously, we identified Annexin A2 (Anxa2) hepatocytes with fibrotic transcriptional alterations in a murine intestinal failure model. This study investigates Anxa2’s role in the pathogenesis of IFALD. Methods Wild type 8 to 12-week-old C57BL/6J (WT control) and B6J.129X1-Anxa2tm1Kah/Mmmh (A2KO) female mice underwent sham or 75% proximal SBR and sacrificed 10-weeks post-operatively. Liver injury was assessed with serum markers, histology and bulk RNA sequencing. Results A2KO SBR liver showed a reduction in liver injury marked by reduction in serum transaminases, liver steatosis, and liver fibrosis. Bulk RNA sequencing found A2KO SBR liver has upregulation of gene sets related to oxidative response and beta-oxidation with reduction in fibrotic and innate immune system responses. Conclusions Anxa2 appears to be a putative factor in fibrogenesis with multifactorial roles. Targeting Anxa2 may serve as a novel therapeutic approach in both IFALD and other liver pathologies.
INTRODUCTION:In Mexico, where surgical residents receive formal academic grades, the effect of on-call schedules on educational outcomes has not been previously evaluated. METHODS:This retrospective cohort study analyzed general surgery residents at a tertiary academic center. A structural change in 2020 created two cohorts: an every-third-day (Q3) schedule with 24-h shifts (2012-2015) and an every-fourth-day (Q4) schedule with 24-h shifts (2017-2021). Academic performance was obtained from institutional records and compared using appropriate statistical tests. RESULTS:Sixty-three residents were included (Q3: n = 33; Q4: n = 30). Q4 residents achieved higher median scores in core curriculum (88.9 vs. 85.5, P < 0.001) and overall assessments (90.96 vs. 89.20, P < 0.001), while Q3 residents had slightly higher clinical activity scores (93.00 vs. 91.57, P < 0.001). CONCLUSION:Less frequent on-call schedules were associated with improved academic performance.
