Genipin-crosslinked nanocarrier systems demonstrate enhanced physicochemical and therapeutic performance across multiple platforms, including nanoparticles, liposomes, hydrogels, nanogels, and lipid-based systems. These systems consistently achieve 25-35% amine crosslinking efficiency, resulting in improved structural stability, higher drug encapsulation efficiency, and sustained release profiles compared with non-crosslinked or synthetically crosslinked counterparts. Preclinical evidence indicates that approximately 25-35% of reported studies include in vivo validation, demonstrating prolonged systemic circulation, enhanced tumor accumulation, significant tumor growth inhibition, and reduced off-target toxicity. Mechanistically, genipin induces mitochondrial dysfunction via UCP2 inhibition, leading to elevated intracellular ROS levels, modulation of Bax/Bcl-2 balance, activation of caspase cascades, and suppression of NF-κB, PI3K/Akt/mTOR, and STAT3 signaling pathways. These effects collectively promote apoptosis, ferroptosis, anti-angiogenesis, and inhibition of metastasis. Integration of genipin into nanocarriers improves pharmacokinetic parameters, including increased half-life, enhanced bioavailability, and reduced systemic clearance, while enabling synergistic therapeutic strategies such as chemo-, gene-, and phototherapy. Compared with conventional crosslinkers, genipin exhibits markedly lower cytotoxicity and superior biocompatibility, supporting higher cell viability and reduced inflammatory responses. However, challenges remain, including slower crosslinking kinetics, formulation variability, scalability limitations, and insufficient long-term in vivo safety data. Overall, genipin-based nanocarriers demonstrate significant potential as multifunctional platforms for improving the efficacy and safety of cancer therapy, though further translational and clinical validation is required.
Genetic abnormalities cause cancer, a heterogeneous disease. These abnormalities comprise unregulated proliferation, invasion, and metastasis. Transcriptional factors are altered by dysregulation, like DNA methylation, histone modifications, and chromatin remodeling, during tumor formation, progression, and resistance to therapy. These can be reversed and transmitted to subsequent generations. Consequently, tumor suppressor genes can be deactivated without altering DNA sequences. Epigenetic markers have been detected in carcinomas, sarcomas, hematological malignancies, and organ-specific tumors, influencing diagnostic accuracy, prognosis assessment, and treatment strategies. Several epigenetic drugs have been developed due to recent advances in epigenetic research. These include DNA methyltransferase inhibitors, histone deacetylase inhibitors and novel modulators focusing on RNA methylation and chromatin regulation. These pharmaceuticals may facilitate normal gene expression restoration, enhance the sensitivity of treatment-resistant malignancies and improve the efficacy of conventional and immunotherapeutic interventions. Significant challenges, such as tumor heterogeneity, limited target specificity, and off-target toxicity, continue to impede widespread clinical application; others are less challenging. The integration of comprehensive epigenetic profiling with precision oncology frameworks presents transformative opportunities to tailor treatment programs, initiate therapy sooner and enhance long-term patient outcomes. Increasing cancer's epigenome knowledge has led to increased interest in developing personalized, mechanism-based treatments addressing cancer's dynamic and adaptive nature. Alterations in genes and the regulation of their expression contribute to the onset of cancer. These changes are referred to as epigenetic modifications. They do not alter the DNA sequence itself; nevertheless, they do affect cellular behavior. In many cancers, essential protective genes remain silent while harmful genes are activated by mechanisms such as DNA methylation, histone modifications, and the influences of small RNA molecules. These alterations can facilitate the proliferation, dissemination, and resistance of cancer cells to treatment. Epigenetic alterations are notable for their reversibility, rendering them viable targets for novel therapeutic interventions. Certain hematological malignancies currently utilize treatments that specifically target these changes, known as epidrugs. Researchers are also investigating its application in different types of cancers. Researchers are developing novel methodologies to detect cancer in blood samples by examining these epigenetic modifications. This may assist in early diagnosis and monitoring the efficacy of treatment. Challenges remain, such as treatment resistance and individual variability; nevertheless, the integration of epigenetic therapy with other modalities may yield improved outcomes. Overall, understanding and targeting epigenetic alterations is an innovative and promising approach to enhance the personalization and efficacy of cancer treatment in the future.
The old oncology approach, which considered the clinical and performance status as the most relevant diseases course and well-being indexes, has been recently replaced by a care system also focusing on a person's characteristics and needs. This study analyzed the role of physical symptoms, illness awareness, individual activities and social contexts on anxious/depressive symptoms and mental health in localized (LP) and advanced/metastatic (AMP) cancer patients. Socio-demographic and medical information was gathered. The Revised Illness Perception Questionnaire, Hospital and Depression Anxiety Scale, and Mental Health Continuum Short-Form were administered. One hundred and thirteen patients, 75 LP and 38 AMP, aged 27-82, were enrolled. Unique patterns of difficulties and resources emerged at different stages of cancer. AMP reported a worse quality of life in perceived illness persistence and treatments control, anxious/depressive symptoms, and psychological well-being. In LP, higher levels of anxious/depressive symptoms were associated with lack of hobbies, and higher perceived illness control was linked to higher mental health. LP did not report higher well-being than AMP. No significant differences in flourishing persons distributions were detected among groups. A multivariable model showed that the independent presence of pain and partner influenced higher levels of mental health more in AMP than in LP. Tailored intervention should enhance individuals' mental health and active resources mobilization.
Dynamic conformal arc (DCA) and volumetric modulated arc therapy (VMAT) are widely used for linear accelerator-based single-isocenter multi-target stereotactic radiosurgery (SRS) in treating multiple brain metastases. DCA offers advantages in delivery efficiency, quality assurance, and dose gradient steepness. However, DCA produces suboptimal conformity for challenging targets, including large postoperative cavities, irregularly shaped lesions, or tumors adjacent to critical organs-at-risk (OARs). VMAT improves conformity for complex targets but may be unnecessary for simple lesions within the same treatment plan. BrainLAB, Munich, Germany, recently developed a hybrid planning technique that applies VMAT arcs to one challenging lesion while using DCA for the remaining targets within a single plan. Ten patients with 73 planning target volumes (PTVs) were retrospectively replanned using four techniques: DCA, Hybrid (BrainLAB Elements, v4.0), Varian RapidArc® (RA), and HyperArc (HA). Dosimetric endpoints included the Radiation Therapy Oncology Group (RTOG) conformity index (CI), Paddick conformity index (PCI), gradient index (GI), normal brain volume exposures (V23-V5 Gy), and maximum doses to critical organs at risk (OARs). Efficiency metrics included monitor units and beam-on time. All techniques achieved ≥95% PTV coverage. VMAT-based plans (RA, HA) demonstrated superior conformity (median CI 1.03-1.11, PCI 0.85-0.90) compared with DCA (CI 1.41, PCI 0.68). Hybrid planning (CI 1.40, PCI 0.71) improved overall conformity versus DCA and achieved VMAT-like performance for VMAT-applied targets (CI 1.07, PCI 0.89). DCA exhibited the lowest GI; Hybrid maintained the low GI for VMAT-applied targets, while improving conformity. HA minimized normal brain exposure, while RA produced highest V5-V8 Gy. Hybrid resembled DCA in high-dose volumes while avoiding RA's extensive low-dose exposure. OAR maximum doses showed no significant differences. Hybrid had the longest beam-on time due to additional arcs. Hybrid planning enhances conformity for challenging targets while preserving favorable DCA characteristics for remaining lesions. Despite longer beam-on times, Hybrid offers a practical solution for single-isocenter multi-target SRS cases involving irregular cavities or OAR-adjacent lesions.
Despite their major impact on cancer treatment, immune checkpoint inhibitors (ICI) are frequently associated with immune-related adverse events (irAE). Growing evidence suggests that the occurrence of irAE may be correlated with enhanced ICI efficacy, although the underlying mechanisms remain unknown. Most studies investigating the role of the gut microbiome in oncology have relied on sequencing approaches, particularly shotgun metagenomics. Although microbiome profiling revealed strong associations between specific bacterial taxa and clinical outcomes, it has limitations, including an inability to detect low-abundance bacteria and to recover live cultivable bacteria. To overcome these limitations, we combined shotgun metagenomics and culturomics on fecal samples collected from patients with melanoma and non-small cell lung cancer (NSCLC), at baseline and at the onset of immune related (ir)-colitis. We first validated across three independent cohorts of 589 patients with melanoma or NSCLC treated with ICI that grade ≥ 2 irAE were associated with significantly longer overall survival (OS) and progression-free survival (PFS). Complementary analysis using shotgun metagenomics and culturomics revealed that patients who developed grade ≥ 2 irAE had a lower alpha diversity compared to those who did not develop grade ≥ 2 irAE. Metagenomics results showed enrichment of Ruminococcus gnavus and Streptococcus vestibularis at baseline in grade ≥ 2 irAE patients, while Clostridium paraputrificum and Streptococcus spp. were isolated by culturomics from baseline stool samples from ir-colitis patients. Longitudinal analysis of paired stool samples revealed a shift in microbiome composition with enrichment of Paraclostridium bifermentans and Clostridium paraputrificum, lower lipopolysaccharide and higher flagellin concentrations at baseline compared with the time of ir-colitis. Fecal microbiome transplantation from a patient with ir-colitis into mice induced surrogate markers of colonic inflammation and enhanced the anti-tumor activity of combined anti-PD-1/CTLA-4. P. bifermentans isolated from this patient sample demonstrated direct epithelial barrier disruption in Caco-2 monolayers, characterized by decreased ZO-1 and Occludin immunofluorescence signal and increased TNF-α and IL-1β expression. Moreover, in the dextran sodium sulfate (DSS) colitis model, P. bifermentans worsened weight loss. In a separate tumor model, it amplified the anti-tumor effect of dual ICI. This beneficial effect was also maintained after treatment with P. bifermentans < 3 kDa filtered supernatant. Altogether, our results suggest that P. bifermentans promotes subclinical colitis while increasing the efficacy of dual ICI. This provides a potential microbiome-derived link between irAE and improved anti-tumor responses. Video Abstract.
With the development of new sequencing technologies, metagenomic next-generation sequencing (mNGS) has become a diagnostic tool for respiratory tract infections. Patients with cancer may develop pneumonia caused by infections or antitumor therapy. Therefore, pneumonia in patients with cancer is more complex than that in healthy individuals. Currently, few reports are available on the use of mNGS for diagnosing pneumonia in patients with cancer. In this retrospective study, 14 patients with cancer diagnosed with pneumonia in March 2023 were enrolled from the Emergency Department of the Chinese Academy of Medical Sciences Cancer Hospital. Sputum samples from the patients were examined using conventional tests and mNGS to identify pathogens. The mNGS and conventional test results were compared to assess the diagnostic yield in patients with cancer. The overall pathogen detection rate of mNGS was 64.29% (9/14), with corresponding diagnostic sensitivity, specificity, false-negative rate and false-positive rate of 90.00%, 25.00%, 10.00% and 75.00%, respectively. Among 13 paired sputum specimens, mNGS exhibited a numerically higher pathogen detection rate (61.54%, 8/13) than conventional diagnostic assays (38.46%, 5/13). McNemar's paired chi-square test demonstrated no statistically significant difference between the two detection methods (p = 0.37), and Kappa concordance analysis generated a coefficient of 0.27 (p = 0.23), suggesting poor inter-method consistency. Compared with conventional tests, mNGS detected additional pathogens in 8 specimens and identified a greater number of pathogens in 9/14 (64%) samples. Moreover, mNGS results led to diagnostic revisions and subsequent antimicrobial therapy adjustments in 64% (9/14) of enrolled patients. Additionally, mNGS detected antibiotic resistance genes in five patients, which provided guidance for antibiotic selection. Metagenomic next-generation sequencing (mNGS) showed potential value in pathogen detection, as it appeared to identify pathogens more rapidly and comprehensively than conventional methods. It may provide auxiliary support for the diagnosis and treatment of pneumonia in this vulnerable population.
Introduction Postoperative temporary facial nerve dysfunction (TFND) is a common complication after parotidectomy, and the tumor location is believed to influence its risk. This study aimed to evaluate the relationship between tumor location and postoperative TFND, as well as to assess the effects of lobe involvement and surgical approach. Methods This prospective observational study was conducted at Bangladesh Medical University, Dhaka, between June 2022 and December 2023, and 35 patients with parotid neoplasms who underwent surgery were enrolled in this study. Preoperative magnetic resonance imaging was used to determine the tumor location (anterior/posterior, superior/inferior, superficial/deep), and lobe involvement was confirmed intraoperatively. Facial nerve function was assessed via the House-Brackmann grading system on postoperative day 2 and at one and three months. Univariate and multivariate logistic regression were performed to analyze the TFND risk factors. Results The participants had a mean age of 48.80 ± 11.92 years, with a female predominance. Pleomorphic adenoma was the most common tumor type (60%). TFND occurred in 54.3% of patients on postoperative day 2, 51.4% at one month, and 45.7% at three months, most commonly involving the marginal mandibular branch. On multivariate analysis, anterior tumor location (OR: 25.05; 95% CI: 1.29-484.05; p = 0.033), bilobar involvement (OR: 21.84; 95% CI: 1.13-421.84; p = 0.041), and total conservative parotidectomy (OR: 20.89; 95% CI: 1.05-413.72; p = 0.046) were significantly associated with increased risk of TFND on postoperative day 2. At one month, anterior tumor location remained a significant predictor (OR: 31.75; 95% CI: 2.02-497.19; p = 0.014). At three months, anterior tumor location (OR: 13.59; 95% CI: 1.72-107.22; p = 0.013) and bilobar involvement (OR: 10.14; 95% CI: 1.39-73.92; p = 0.022) remained independently associated with persistent TFND. No significant association was observed between TFND and age, sex, tumor size, or histopathology. Conclusion Anterior tumor location, bilobar involvement, and extensive surgery significantly increase TFND risk and persistence. These findings suggest that careful preoperative imaging-based localization and meticulous surgical planning may help reduce the risk of TFND in parotid surgery.
Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening condition characterized by thrombocytopenia, microangiopathic haemolytic anaemia, and end-organ ischemia. Association of TTP with acute cholecystitis is rare, with only two cases reported in literature. We report the third case of TTP associated with acute cholecystitis in an African-American female with systemic lupus erythematosus (SLE). She presented with fever and abdominal pain; laboratory testing revealed acute on chronic thrombocytopenia, and imaging confirmed acute acalculous cholecystitis. This initially led to a misdiagnosis of immune thrombocytopenia (ITP), and she was treated with antibiotics, intravenous immunoglobulin, and steroids without improvement. She subsequently developed neurological symptoms with laboratory evidence of haemolysis raising a concern for thrombotic microangiopathy. Emergent plasmapheresis was initiated for suspected TTP, resulting in improvement of her symptoms. Low ADAMTS13 activity subsequently confirmed the diagnosis. This case highlights the importance of recognizing atypical presentations of TTP to initiate prompt life-saving treatment.
Coronary heart disease (CHD) is a common cardiovascular disease with high incidence and mortality rates. This study aims to explore the role of KMT2E-AS1 in the progression of CHD and its potential regulatory mechanisms. The research included 135 CHD patients and 103 healthy volunteers. And CHD patients were categorized into major adverse cardiovascular events (MACE) and non-MACE groups. Differential expression of KMT2E-AS1 in various groups and its diagnostic value were analyzed. Correlation of KMT2E-AS1 expression with myocardial injury markers was investigated. The predictive potential of KMT2E-AS1 for MACE risk was evaluated. The interaction between KMT2E-AS1 and miR-2681-5p was verified, and their effects on human aortic smooth muscle cells (HASMCs) proliferation, inflammation, and oxidative stress response were examined. KMT2E-AS1 is significantly downregulated in the CHD and MACE group. KMT2E-AS1 is significantly negatively correlated with myocardial injury markers, such as Gensini score, creatine kinase-myocardial band, cardiac troponin I, and N-terminal pro-B-type natriuretic peptide. KMT2E-AS1 exhibits favorable diagnostic performance for the occurrence of CHD and serves as an independent protective factor against MACE following surgery. KMT2E-AS1 directly targets and regulates miR-2681-5p. Moreover, KMT2E-AS1 overexpression promotes proliferation, alleviates inflammation, and oxidative stress response in oxidized low-density lipoprotein-induced HASMCs, while miR-2681-5p overexpression counteracts the effects of KMT2E-AS1 overexpression. KMT2E-AS1 is a promising biomarker for predicting CHD occurrence and postoperative MACE risk. KMT2E-AS1 protects HASMCs and inhibits CHD progression by targeting miR-2681-5p.
To evaluate the safety and efficiency of a novel computed tomography (CT)-guided hookwire localization technique, aiming to enable parenchyma-sparing wedge resection using video-assisted thoracoscopic surgery (VATS) for small, hilar-proximal, ground-glass opacity (GGO)-dominant nodules. Localizing hilar-proximal GGOs remains challenging. For small, hilar-proximal, GGO-dominant lung nodules, there is no consensus regarding the optimal surgical approach. This was a multicenter retrospective study from January 2023 to July 2025 including 79 patients with subpleural pulmonary nodules ≤ 2 cm in diameter and consolidation-to-tumor ratio (CTR) ≤ 0.25 located near the hilum. Patients underwent preoperative CT-guided hookwire localization using transfissural or traversing-lobe approach, followed by uniportal VATS wedge resection. Resection was performed using ultrasonic dissection with limited stapler use to maximize lung preservation. 79 nodules (median, 7 mm, range 6-20 mm) were successfully localized. Minor asymptomatic pneumothorax occurred after localization in 12 patients and small pulmonary hemorrhage in 10 patients. The median operative time was 15.0 minutes (range 10-28 minutes). Histopathology confirmed 9 adenocarcinoma in situ, 53 minimally invasive adenocarcinoma, 14 invasive adenocarcinoma, and 3 benign lesions. 10 patients experienced persistent air leak > 72h and no other major complications occurred. Median postoperative hospital stay was 3 days (range 2 - 6 d). At a median follow-up of 17.3 months, no local recurrences or deaths have been detected. This novel CT-guided hookwire localization strategy proved highly effective for small, hilar-proximal, GGO-dominant lung nodules, facilitating their successful removal by VATS wedge resection with parenchyma-sparing technique.
Dysregulation of transcription factors is a hallmark of lung tumorigenesis, and Sex-determining region Y-box 9 (SOX9) has emerged as a putative master regulator at the intersection of development and malignancy. Building on evidence from lung and other solid tumors, we summarize how aberrant SOX9 expression, shaped by epigenetic modification, post-translational regulation, and non-coding RNAs, drives proliferation, survival, invasion, and therapy resistance. In lung cancer, SOX9 appears to orchestrate a stem-like, plastic cell state, promoting epithelial-mesenchymal transition (EMT), metastatic dissemination, and remodeling of the tumor microenvironment (TME). These context-dependent functions position SOX9 both as an oncogenic driver and, in selected settings, as a modulator of treatment response. This review integrates current mechanistic and translational data to frame SOX9 as a clinically actionable node within key signaling circuits relevant to non-small cell and small cell lung cancer. We highlight emerging strategies that directly or indirectly target SOX9, including interference with upstream pathways, epigenetic reprogramming, and RNA-based approaches designed to modulate SOX9 expression or activity. Finally, we propose SOX9 as a dual biomarker and therapeutic handle to guide rational combination therapies aimed at overcoming drug resistance and improving patient stratification. By connecting molecular insight with unmet clinical needs, this article outlines a conceptual roadmap for SOX9-centered therapeutic approaches in lung cancer. A key novelty of this review is the integration of SOX9-centered molecular mechanisms with therapeutic resistance, biomarker potential, and emerging indirect targeting strategies in lung cancer, thereby providing a translational framework for future SOX9-guided interventions.
Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) are two of the most frequently employed molecular imaging modalities for interrogating biological processes in living systems. A significant number of recently developed probes are based on radiometals. Radiometal-based compounds use a chelator for radionuclide complexation and linkage to a targeting molecule. In practice, selecting the "right" chelator has consequences that extend well beyond simple coordination chemistry, influencing labeling conditions, probe stability, in vivo behavior, and ultimately diagnostic performance. As a result, both acyclic and cyclic chelators have been explored extensively. Acyclic chelators, such as DTPA, HBED, DFO, and HYNIC, are attractive because they can be labeled rapidly under mild conditions, but their in vivo stability is not always sufficient for clinical use. In contrast, macrocyclic chelators, such as DOTA, NOTA, TETA, and sarcophagines, are more kinetically inert, though they often demand higher temperatures or more stringent labeling parameters. Over the past decades, several innovations have been made, such as [18F]AlF-NOTA chemistry, optimized DFO derivatives for 89Zr, and copper-specific sarcophagines. This emerging landscape of PET and SPECT radiotracers has broadened the range of applications from neuroendocrine tumors to FAPI-based probes and to theranostic strategies. The refinement and development of bifunctional chelators that allow radiometals to be bound to peptides, antibodies, and nanoparticles without loss of biological activity is opening up new avenues. The field is working toward more kit-based, user-friendly chelators that are applicable to a broad range of radionuclides. In this review, we summarize recent progress in chelator design and show how it is shaping the future of molecular imaging and targeted radionuclide therapy.
Antibody-drug conjugates (ADCs) have transformed the therapeutic landscape of solid tumors; however, responses remain heterogeneous and complex to predict. In addition, a growing number of multiple ADC targets are either approved or in late-stage clinical development, such as NECTIN-4, HER2, or TROP2 for metastatic urothelial cancer. Spatial multiomics-representing next-generation methods that couple high-plex RNA sequencing and multiplex protein imaging with precise x-y-z coordinates within tissues-offer a direct way to correlate (ADC) antigen expression, cell state information, and micro-anatomical context with patient treatment outcomes. In this review, we highlight suitability and technological advancements in current spatial transcriptomics and proteomics approaches to decode modes of action and resistance to ADCs and extract biological insights, particularly in metastatic urothelial cancer-and propose an integrative framework that combines spatial readouts with machine and/or deep learning-driven analytics to stratify patients, forecast on- and off-target toxicities, and guide next-generation linker-payload designs or combination therapies.
Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications. Deficiency of adenosine deaminase 2 (DADA2) is a rare genetic condition that causes inflammation and can affect multiple organs. We studied how often the liver is involved in DADA2 and whether simple, noninvasive tests can help detect liver involvement and track response to treatment. We found that DADA2 can cause problems with tiny blood vessels inside the liver called porto‐sinusoidal vascular disease (PSVD). PSVD can increase pressure in the portal vein system (portal hypertension), which may cause enlargement of the spleen, low platelet counts, development of enlarged veins in the oesophagus (varices), and fluid accumulation in the abdomen (ascites). In our cohort, clinical signs of portal hypertension were documented in 14% of patients, and 5% developed complications such as bleeding from varices or ascites. Because liver disease was largely silent, we evaluated practical ways to identify it early. More than half of patients had an enlarged spleen at baseline, and spleen size adjusted for height (the spleen‐to‐height ratio) emerged as a sensitive marker of liver involvement. Treatment with anti‐tumour necrosis factor medications led to a reduction in the spleen‐to‐height ratio in most treated patients, suggesting improvement in liver disease. We recommend routine screening for liver involvement in DADA2, with SH ratio and platelet counts, selective liver biopsy and endoscopy for suspected portal hypertension, and baseline hepatology evaluation prior to stem cell transplantation.
Osteosarcoma (OS) is an aggressive bone malignancy characterized by genomic instability and extensive extracellular matrix (ECM) remodeling. Members of the ADAMTS family are matrix-associated proteases implicated in tumorigenesis; however, their roles in OS remain poorly defined. This study provides a comprehensive genomic, transcriptomic, and functional analysis of the ADAMTSs in OS, with particular focus on ADAMTS-3. Copy number alterations and mRNA expressions of ADAMTS genes were analyzed using the TCGA datasets. Gene set enrichment analysis and co-expression analyses identified biological processes associated with ADAMTS-3. Mechanistic studies investigated tumor necrosis factor-alpha (TNF-α) regulation of ADAMTS-3 in OS cells. Genomic profiling revealed frequent amplification and high mRNA expression of ADAMTS4, ADAMTS12, ADAMTS16, and ADAMTS17, indicating potential oncogenic activity. ADAMTS-3 was markedly overexpressed in OS tissues and cell lines, showing strong positive correlations with inflammatory (IL6, STAT3, NF-κB) and matrix-remodeling (MMP2, MMP9) genes. Functional enrichment indicated that ADAMTS-3 is associated with ECM organization, immune response regulation, and epithelial-mesenchymal transition. Mechanistically, TNF-α induced ADAMTS-3 transcription via activation of MEK, PI3K, JNK, and NF-κB pathways, with STAT3 and NF-κB by enhancing promoter activity. These findings identify ADAMTS-3 as an inflammation-responsive gene that links inflammatory signaling to ECM remodeling and tumor invasiveness in OS, representing a potential molecular bridge.
Diet and the gut microbiome are major, interdependent determinants of colorectal cancer (CRC) risk. This review discusses current evidence on how dietary patterns reshape microbial ecology, modulate microbial virulence, and alter host metabolic, inflammatory, and oncogenic pathways to influence colorectal carcinogenesis. We highlight key CRC-associated microbes, including pks⁺ Escherichia coli, Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and Streptococcus gallolyticus, and discuss how diet governs their abundance, toxin production, and oncogenic potential. Mechanistic investigations into diet-microbe interactions reveal how pro-inflammatory, low-fiber Western-style diets foster mucosal inflammation, generation of reactive oxygen and nitrogen species, and genotoxic microbial niches, whereas fiber- and polyphenol-rich diets support protective commensals and production of anti-inflammatory metabolites. We also outline major challenges, including interindividual microbiome variability and limited translational models, and propose future directions for integrating dietary, microbial, and host-targeted strategies for CRC prevention and therapy.
Patients undergoing total gastrectomy (TG) for gastric cancer experience significant weight loss and are at risk for nutritional deficiencies. This study aimed to assess body composition changes following TG, focusing on contribution of skeletal muscle mass loss versus adipose loss. This retrospective analysis examines patients who underwent TG at a major cancer center (2014-2021). Longitudinal analysis with regression identified factors associated with rate of body mass index (BMI) change. Cross-sectional CT scan imaging quantified body mass loss, including skeletal muscle area (SMA), skeletal muscle index (SMI), subcutaneous fat area (SFA), and visceral fat area (VFA). Fifty-two TG patients were identified (median age 63 y; 54% male). Higher preoperative BMI predicted greater postoperative weight loss, with BMI > 30 losing more than BMI < 30 (P < 0.001). Weight loss was non-linear, peaking at 6 months (-17%), stabilizing by 12 months, then gradually increasing (P = 0.039). SMA and SMI decreased by 11% at 6 months for both, respectively, with gradual recovery after 12 months. SFA and VFA decreased significantly over 3 years, with peak fat loss evident at 12 months post-surgery, SFA decreased 64% from baseline and VFA decreased 95% from baseline, with minimal recovery thereafter. Skeletal muscle loss peaked 12 months post-TG, including 66% of males and 77% of females, with slight decreases in low skeletal muscle rates at 24 months. Weight loss post-TG follows a non-linear pattern, with peak loss at 6 months and stabilization at 12 months. Most weight loss is due to loss of visceral and subcutaneous adipose with substantially less muscle loss. Nevertheless, ongoing monitoring for sarcopenia is warranted in both sexes post-TG.
BackgroundLarge cell lung cancer (LCLC) is an aggressive, undifferentiated subtype of non-small cell lung cancer (N-SCLC) and is now a rare subtype in clinical practice.MethodsData were retrieved from the SEER database, with two analytical cohorts established. Joinpoint regression quantified LCLC incidence trends. Propensity score matching (PSM) balanced baseline characteristics of the survival cohort. Cox regression determined independent overall survival (OS) predictors, restricted cubic spline (RCS) explored non-linear associations between continuous factors and outcomes, and Kaplan-Meier curves with Log-rank tests compared survival differences.ResultsFrom 1992 to 2022, the incidence of LCLC exhibited a significant downward trend (annual percent change [APC] = -12.690%, 95% CI: -13.788 to -11.577, P < 0.001). The most rapid decline was observed during 2005-2015, with an APC of -19.624% (95% CI: -21.955 to -17.224, P < 0.001). Finally, a significant decreasing trend persisted from 2015 to 2022, albeit with a slightly slowed rate (APC = -13.995%, 95% CI: -21.303 to -6.008, P = 0.002). Multivariate analysis identified advanced age, male sex and advanced AJCC stage as independent predictors. Lobectomy and extended lobectomy were associated with improved OS, while no chemotherapy was a risk factor.Conclusions1992-2022 US LCLC incidence decline is attributable to diagnostic drift rather than reduced actual disease burden; our study identified sex, age, AJCC stage, surgical resection extent and chemotherapy as OS predictors for LCLC patients. Notably, SEER lacks modern systemic therapy data, precluding unrigorous extrapolation of its chemoradiotherapy findings to current regimens.
SMARCA4-deficient thoracic tumor (SDTT) is a malignant tumor with a poor prognosis that often presents with distant metastases at the time of clinical diagnosis. Skeletal muscle metastasis is a rare subtype of metastasis patterns, and there are limited studies about SDTT metastasis in skeletal muscle. Herein, we retrospectively analyzed the data of stage IV patients diagnosed with SDTT from May 2009 to June 2024. The clinical and genomic data, imaging features, and treatment information were collected. As a result, the study included 145 patients with metastatic SDTT, 17 with skeletal muscle metastases, and 128 without. The rate of skeletal muscle metastasis in SDTTs was 11.7%. Multivariate Cox regression analysis showed that skeletal muscle metastases (p = 0.014, hazard ratio 95% confidence interval [HR 95% CI] [2.90, 1.25-6.75]) and first-line chemoimmunotherapy (p < 0.001, HR 95% CI [0.31, 0.17-0.56]) were independent prognostic variables. Furthermore, patients with skeletal muscle metastases had a significantly shorter median overall survival (OS) than those without (13.20 vs. 18.6 months, p = 0.021) in metastatic SDTTs. The mutation rate of STK11 and KRAS was higher in the skeletal muscle metastasis group (62.50% vs. 15.52%, p = 0.008; 50.00% vs. 8.62%, p = 0.009). In conclusion, SDTTs exhibited a high rate of skeletal muscle metastases. Skeletal muscle metastases and first-line chemoimmunotherapy were independent prognostic factors for OS in SDTTs.
Despite aggressive surgery and adjuvant therapy, glioblastoma commonly recurs within months. We aimed to identify key genes and microRNAs (miRNAs)- mRNA regulatory networks associated with recurrent glioblastoma and to nominate candidate repurposable drugs. Two mRNA expression datasets (GSE58399 and GSE42669) from GEO were analyzed to identify differentially expressed genes (DEGs) between recurrent and primary tumors. Functional enrichment (Gene Ontology, KEGG) characterized implicated processes and pathways. A protein-protein interaction network (STRING and Cytoscape) identified hub genes. miRWalk 3.0, integrating TargetScan, miRDB, and miRTarBase, predicted miRNAs targeting hub genes and defined miRNA-mRNA interactions. The Connectivity Map (CMap) was used to prioritize small molecules predicted to reverse the DEGs signature. Kaplan-Meier survival analyses assessed associations between candidate genes and patient outcomes. We identified 201 DEGs and constructed a PPI network comprising 180 nodes and 337 edges. Ten hub genes were prioritized. CMap nominated five top candidate compounds- levamisole, chlorzoxazone, ranitidine, atovaquone, and chrysin-as potential therapeutics for glioblastoma recurrence. Synaptotagmin 1 (SYT1) emerged among hub genes and was predicted to be regulated by 12 miRNAs. Elevated SYT1 expression correlated with poorer overall and progression-free survival in recurrent glioblastoma patients. This integrative analysis highlights SYT1 and its upstream miRNAs as candidate biomarkers and potential therapeutic targets in recurrent glioblastoma and proposes several repurposable compounds for experimental validation. Further functional studies and clinical validation are required prior to translation. Collectively, this study offers valuable insights into the regulatory landscape of recurrent glioblastoma and lays the groundwork for more targeted and personalized therapeutic approaches.