Search Results (1,363)

Background/Objectives: The standard surgical treatment of muscle-invasive bladder cancer (MIBC) comprises neoadjuvant systemic therapy followed by radical cystectomy (RC). However, a notable number of patients achieve a favorable response to neoadjuvant systemic therapy, a finding associated with improved outcomes, and questioning the necessity of RC in this subset of patients. The objective of this review is to summarize the available evidence regarding the feasibility, efficacy and toxicity of bladder-preserving chemoradiotherapy (CRT) following clinical response (CR) to neoadjuvant systemic therapy in patients with MIBC. Methods: A literature search was performed using the PubMed database to identify studies evaluating the use of CRT for bladder preservation in MIBC patients with CR following neoadjuvant therapy. Results: Clinical complete response (cCR) rates to neoadjuvant systemic treatment ranged from 31% to 87.5%, with subsequent CRT enabling 50–97% of responders to retain their bladder. Long-term outcomes were favorable for cCR patients, with 3- to 5-year overall survival (OS) ranging from 65% to 89%, disease-free survival (DFS) of 64–86%, and bladder-intact survival up to 80%. Achievement of cCR, T2 tumor stage, absence of concomitant carcinoma in situ or hydronephrosis, and complete transurethral resection of the bladder tumor (TURBT) were prognostic factors for improved oncologic outcomes. Treatment-related toxicity was generally acceptable, concerning mainly hematological and gastrointestinal events, while severe late toxicity was uncommon. Conclusions: Bladder-preserving CRT is a promising, effective, and well-tolerated option for MIBC patients achieving CR to neoadjuvant systemic therapy. While further prospective validation and longer follow-up are required before it can universally replace radical cystectomy in this subset of patients, advances in neoadjuvant treatments, imaging and molecular biomarkers may improve response assessment and patient selection for bladder preservation. Full article

Heyndrickxia coagulans is widely used for industrial L-lactic acid production, but carbon catabolite repression (CCR) and its link to fermentative metabolism remain poorly understood. A ccpA deletion mutant (ΔccpA) and a complementation strain (C-ccpA) were constructed to investigated the physiological, enzymatic, and transcriptomic consequences of CcpA loss. Deletion of ccpA completely abolished glucose-mediated CCR, enabling simultaneous glucose–xylose co-utilization, and triggered a marked shift from L-lactic to mixed-acid fermentation, with an 82.5% reduction in lactate titer accompanied by 24.1-fold and 51.6-fold increases in acetate and formate, respectively. Enzyme activity assays showed that L-lactate dehydrogenase activity was reduced by half, whereas acetate kinase activity increased nearly six-fold. Transcriptomic analysis revealed downregulation of ldhL and upregulation of pflB and ackA. Scale-up fermentation in a 5 L bioreactor confirmed that the wild type directed 90.2% of carbon flux to lactate (yield, 0.95 g/g glucose), compared with only 24.5% in the mutant. All phenotypes were fully restored upon complementation. These results demonstrate that CcpA is as an indispensable dual regulator of both CCR and L-lactic fermentation, providing a foundation for rational metabolic engineering of H. coagulans. Full article

Bone metastasis is a devastating complication of advanced osteotropic malignancies, notably breast, prostate, lung carcinomas, and malignant melanoma, and remains a primary driver of mortality. Historical paradigms have conceptualized skeletal dissemination almost exclusively as a hematogenous process wherein circulating tumor cells colonize receptive bone marrow niches. However, this model fails to reconcile why lymph node metastasis consistently serves as a potent predictor of bone involvement even though therapeutic lymphadenectomy rarely prevents distant spread. This discordance suggests that lymph nodes function not merely as passive reservoirs but as active ‘evolutionary gateways’ that sculpt bone-tropic metastatic clones. In this review, we introduce the Lymphatic–Bone Axis, a framework integrating lymphatic biology into models of bone metastasis. We synthesize emerging evidence elucidating how the lymph node microenvironment primes tumor cells through CCR7-CXCR4 switching, induction of osteomimicry programs, and metabolic reprogramming that favors survival within the bone marrow. We also discuss preclinical data demonstrating direct intranodal intravasation via high endothelial venules (HEVs), providing a rapid route into the systemic circulation that bypasses the thoracic duct. Beyond consolidating current knowledge, we outline a research agenda for dissecting this axis, including longitudinal single-cell transcriptomic mapping and functional assessments of lymph node-derived tumor cells. Finally, we consider translational implications, highlighting why bone-targeted agents alone may prove insufficient once cells are conditioned within lymphatic niches. By mechanistically linking lymphatic priming to skeletal colonization, this review informs the rational design of multimodal therapeutic approaches that jointly target lymphatic transit and the bone microenvironment. Full article

The blood–brain barrier (BBB), a core component of the neurovascular unit (NVU), meticulously regulates material exchange between the blood and brain parenchyma, serving as a critical barrier for maintaining the homeostasis of the central nervous system (CNS). Neuroinflammation, a pivotal response of the CNS to injury and disease, can disrupt NVU homeostasis when excessive or persistent, acting as a core pathogenic driver of various intractable neurological disorders. Chemokines, as key signaling molecules guiding the directional migration of immune cells, form the central hub mediating the dynamic regulation of neuroinflammation and the BBB. However, existing studies mostly focus on single disease systems or chemokine families, neglecting the bidirectional heterogeneity of different chemokine axes in BBB regulation and the common regulatory rules across diseases, while lacking systematic exploration of clinical translation challenges caused by the redundancy and spatiotemporal heterogeneity of the chemokine network. This review systematically clarifies the bidirectional regulatory effects of the core axes of the three major chemokine families (e.g., CCL2/CCR2, CXCL12/CXCR4, CX3CL1/CX3CR1) on the BBB. For the first time, we integrate a multi-dimensional regulatory model based on concentration, location, and time to analyze their molecular mechanisms and regulatory heterogeneity in promoting BBB disruption under pathological conditions versus mediating barrier repair and neuroprotection under specific spatiotemporal conditions. Combined with advancements in cutting-edge models such as microfluidic chips, we discuss the clinical translation progress of chemokine research, including potential biomarkers and targeted therapeutic strategies, and propose precise breakthrough paths for the two core challenges of network redundancy and spatiotemporal heterogeneity. Finally, we construct a complete research framework for chemokine-mediated regulation of NVU homeostasis, providing novel insights and directions for restoring BBB function and treating intractable neurological diseases. Full article

Cancer cachexia, characterized by severe body weight loss, negatively affects patient quality of life and survival. Although moderate exercise benefits healthy and chronically ill individuals, and the effect of exercise in cachexia generally appears beneficial, conflicting results have been reported in cancer-associated cachexia. This study examined the effects of moderate aerobic exercise in a rat cancer model, focusing on molecular crosstalk among tumors, serum, and skeletal muscle. Male Sprague-Dawley rats were divided into Non-Cancer, Cancer, and Cancer + Exercise (Ex) groups. Cancer was induced with an intraperitoneal injection of 7,12-dimethylbenz[a]anthracene (DMBA), and the Cancer + Ex group completed an eight-week treadmill regimen. Tibialis anterior muscle, serum, and tumor tissues were analyzed by RNA sequencing. DMBA injection produced sarcoma-like tumors, reduced body weight, elevated inflammatory mediators, and activated muscle atrophy genes (Fbxo32). Exercise led to progressive intolerance, further weight loss, lower muscle mass, and larger tumors. Transcriptomic profiling revealed exacerbated cachexia signatures and suppressed energy metabolism genes in exercised cancer rats. Bioinformatic analysis of serum proteins and tissue transcriptomes identified enhanced chemokine-receptor signaling, including pro-tumorigenic (CXCL6_CXCR2) and pro-cachexia (CCL19_CXCR3, CCL5_CCR3, CXCL11_CXCR3) interactions. These findings suggest that in a pro-inflammatory cancer context, late-onset moderate exercise may worsen cachexia and stimulate tumor progression. Thus, exercise protocols should be cautiously tailored in cancer settings. Full article

While temperature and acidity dominate the design of zeolite catalysts for olefin cracking, the role of reaction time as an independent variable governing pathway dynamic remains elusive. This study integrates experimental and simulation methods to unravel the dynamic competition among carbenium ion cracking, thermal cracking and Confined Catalytic Radical (CCR) pathways during 1-pentene cracking on H-ZSM-5 zeolite at 650 °C. Analysis of the optimum performance envelope (OPE) curves for cracking products revealed that, in the initial reaction stage, the CCR mechanism significantly enhances ethylene yield. As the reaction time prolongs, C₅+ olefins in the gas phase undergo further cracking on the zeolite surface, markedly increasing the contribution of the carbenium ion pathway. Molecular simulations indicate that C₅+ olefins exhibit stronger adsorption capacity but lower diffusion coefficients on H-ZSM-5, and this adsorption–diffusion disparity is a key factor influencing the evolution of 1-pentene cracking pathways. Concurrently, thermal cracking reactions are also enhanced with increasing residence time, which is unfavorable for ethylene formation. This work elucidates the time-dependent evolution of 1-pentene cracking pathways and the regulatory role of intraparticle mass transfer, providing a theoretical basis for optimizing light olefin selectivity through the adjustment of reaction time and catalyst structure. Full article

The formation of hard/brittle layers (HBLs) forming in proximity to the transition-layer interface during the welding process of stainless steel clad plates constitutes a pivotal element in determining the limitations on joint homogeneity and toughness. In order to elucidate their formation mechanisms and develop viable suppression routes, S31603/Q420qENH clad plates were utilised to fabricate five butt joints. This was achieved by varying the carbon content of the welding consumables and the heat input in the transition layer. A programme was conducted that combined microstructural and microhardness characterisation, mechanical testing, and numerical welding simulations. The findings indicate that base-layer consumables with comparatively elevated carbon content (w(C) ≥ 0.06%) expeditiously engender a constricted, localised hardened band in close proximity to the transition-layer interface. This is characterised by the predominance of martensite and Cr-rich compounds of the M_xCr_y type, which function as the principal genesis of bending cracks. Conversely, the utilisation of low-carbon welding consumables has been shown to markedly reduce interfacial carbon activity and C-Cr segregation, thereby suppressing the precipitation of M_xCr_y phases and effectively decreasing the overall thickness of the HBLs. Further numerical analysis shows that moderately increasing the transition-layer heat input lowers the T_8/5 cooling rate and shifts the cooling path away from the martensite region. This transforms the interfacial microstructure from a localised hardened band into a more uniform, graded structure. These findings provide an engineerable process-control strategy for enhancing both microstructural uniformity and toughness in stainless steel clad joints. Full article

Oncometabolites and hypoxia-regulated exosomes orchestrate hypoxia-inducible factor (HIF)–driven macrophage reprogramming across chronic cardiometabolic and oncologic conditions. In type 2 diabetes (T2D) and obesity, regional hypoxia in expanding white adipose tissue (WAT) reconfigures macrophage immunometabolism and chemokine signaling, recruits C-C chemokine receptor 2 (CCR2⁺) monocytes, and skews adipose-tissue macrophages toward M1-like programs that sustain low-grade inflammation and blunt the physiological M1-to-M2 transition during wound repair. In atherosclerotic plaques, lipid-core hypoxia stabilizes HIF-1α, amplifies nuclear factor kappa-light-chain-enhancer of activated B cells/reactive oxygen species (NF-κB/ROS) signaling, increases matrix metalloproteinase-2/-9 (MMP-2/-9) release, and reduces ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux, weakening the fibrous cap. In tumors, poorly perfused niches accumulate lactate and succinate, which act as paracrine cues. Lactate activates PKA/cAMP pathways and promotes immunosuppressive tumor-associated macrophages (TAMs), whereas succinate signals through succinate receptor 1 (SUCNR1) to reinforce HIF-1α–dependent transcription and M2-like programming. In parallel, hypoxia-regulated exosomes deliver microRNAs such as miR-301a-3p, which suppress phosphatase and tensin homolog (PTEN) and activate PI3Kγ, thereby augmenting immunosuppression and programmed death-ligand 1 (PD-L1) expression. Clinically, this hypoxia–oncometabolite–exosome triad links oxygen debt with macrophage state, plaque destabilization, impaired wound repair, and tumor immune escape. Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003–2025), prioritizing mechanistic and translational studies on hypoxia–HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer. Full article

The mechanisms underlying meningeal lymphatic vessel (mLV)-mediated immune cell clearance after stroke remain unclear. Using a mouse middle cerebral artery occlusion model, we performed single-cell RNA sequencing to analyze post-ischemic meningeal macrophages. In vitro co-culture and CCR2 inhibition (RS504393) validated the CCL2-CCR2 axis between lymphatic endothelial cells and macrophages. Macrophage trafficking to mLVs and cervical lymph nodes was assessed by Evans Blue tracing and F4/80 immunofluorescence. We utilized VEGF-C to enhance meningeal lymphatic vessel function and concomitantly evaluated neurological deficits, brain edema, and neuroinflammation. Ischemia expanded meningeal macrophages, whose crosstalk with lymphatic endothelial cells relied on CCL2-CCR2 axis. CCR2 inhibition impaired macrophage trafficking to mLVs and cervical lymph nodes, worsening edema, motor deficits, and inflammation, whereas VEGF-C enhanced mLV drainage and improved outcomes. We identify a novel mechanism where in mLVs recruit macrophages via CCL2 for perivascular clearance post-ischemia. Combining VEGF-C with modulation of the CCL2-CCR2 axis presents a promising synergistic therapeutic strategy for stroke. Full article

Background/Objective: Periodontitis and osteoporosis frequently co-occur after menopause, yet the immune–bone pathways linking oral and skeletal phenotypes remain incompletely defined. This study investigated whether periodontitis severity and low bone mineral density (BMD) in postmenopausal women are associated with convergent systemic inflammaging and immunosenescence phenotypes and with a salivary RANKL/OPG imbalance. Methods: In this cross-sectional study, 280 postmenopausal women were assigned to a 2 × 2 factorial design based on periodontal status (severe vs. no/mild) and BMD status (low vs. normal; DXA T-score). Full-mouth periodontal measurements (PD, CAL, BOP, plaque index, tooth count; stage/grade) were recorded. Salivary RANKL and OPG were quantified, and the RANKL/OPG ratio was calculated. Systemic inflammaging markers (hs-CRP, IL-6, TNF-α) and CMV IgG were assessed, and T-cell immune-aging phenotypes were profiled by flow cytometry (CD3, CD4, CD8, CD45RA, CCR7, CD28, CD57, KLRG1, PD-1, CD27). Results: Severe periodontitis and low BMD were each associated with higher salivary RANKL/OPG ratios and greater systemic inflammatory burden, with modest interaction effects. Immune-aging profiles showed higher proportions of late-differentiated CD8+ phenotypes, and CMV seropositivity was strongly associated with immunosenescence markers. Conclusions: In postmenopausal women, periodontal destruction and low BMD were aligned with osteoclastogenic and immune-aging signatures, consistent with oral–skeletal immune crosstalk. Findings should be interpreted as associative rather than causal, and longitudinal observational studies are warranted to clarify temporality. Full article

Background: The management of rectal cancer has evolved toward response-adapted strategies, including organ preservation in selected patients achieving a clinical complete response (cCR) after neoadjuvant treatment. However, most available evidence derives from clinical trials, and data from real-world clinical practice remain limited. Methods: We conducted a retrospective observational cohort study including consecutive patients with rectal adenocarcinoma treated at a tertiary referral center between January 2021 and December 2025. Baseline clinical, tumor-related, and treatment characteristics were collected. Tumor response was assessed using clinical, endoscopic, and radiological criteria. The primary endpoint was the rate of clinical complete response and the implementation of watch-and-wait strategies. Secondary endpoints included recurrence patterns and exploratory oncologic outcomes according to baseline tumor characteristics. Results: A total of 229 patients were identified, of whom 148 were evaluable for treatment response. Clinical complete response was documented in 56 patients (37.8%), and a watch-and-wait strategy was implemented in 42 patients (28.4%). Higher cCR rates were observed in patients with stage I–II disease and in tumors measuring < 4 cm on baseline magnetic resonance imaging, with cCR rates exceeding 55% in this subgroup. Tumors ≥ 4 cm showed substantially lower response rates. Clinical complete responses were observed across both short-course radiotherapy plus chemotherapy and long-course chemoradiotherapy regimens in patients with small tumors and early-stage disease. Tumor distance from the anal verge was not consistently associated with response. With a median follow-up of 26 months in the watch-and-wait group, five recurrences were observed, including three local recurrences. Conclusions: In this real-world cohort, baseline tumor size and clinical stage were the main determinants of clinical complete response and eligibility for organ-preservation strategies in rectal cancer. Small tumors (<4 cm) showed high response rates regardless of neoadjuvant regimen. These findings support response-adapted, individualized treatment strategies and highlight the importance of tumor burden in selecting candidates for non-operative management in routine clinical practice. Full article

Immunoglobulin G (IgG) is a central component of humoral immunity in coronavirus disease 2019 (COVID-19); however, increasing evidence suggests that infection-induced IgG repertoires exert immunomodulatory effects beyond classical antiviral functions. In this study, we investigated whether IgG from patients with moderate or severe COVID-19 directly modulates human peripheral γδ T cells and whether these effects are associated with disease severity-dependent IgG idiotype profiles. Purified IgG from non-exposed healthy controls, moderate COVID-19 patients, or severe COVID-19 patients was incubat-ed with peripheral blood mononuclear cells from healthy donors. γδ T cell phenotype, subset distribution, homing markers, and cytokine production were assessed by flow cytometry, while direct IgG–cell interactions were evaluated using fluorescent IgG binding assays. In parallel, proteomic profiling using human proteome microarrays was performed to identify γδ T cell-expressed protein targets recognized by COVID-19-induced IgG. IgG from SARS-CoV-2-infected individuals selectively reduced Vγ9⁺Vδ2⁺ γδ T cells, altered memory differentiation, downregulated CCR5, CCR6, and CD161 expression, and reshaped cytokine production in a severity-dependent manner. COVID-19 IgG bound directly to the γδ T cell membrane without inducing apoptosis, indicating a non-cytotoxic mechanism of modulation. Proteomic analysis revealed a marked expansion and diversification of γδ T cell-associated IgG targets in COVID-19, particularly in severe disease, with enrichment of pathways related to immune signaling and inflammation. Collectively, these findings identify γδ T cells as direct functional targets of SARS-CoV-2-induced IgG repertoires and demonstrate that disease severity shapes IgG idiotype networks with distinct immunomodulatory capacities. This work highlights a previously underappreciated antibody-mediated mechanism contributing to immune dysregulation in COVID-19. Full article

The success of titanium dental implants rely on osseointegration, influenced by surface properties and early immune responses. While sandblasted and acid-etched (SLA) titanium surfaces have shown clinical success, macrophage-mediated immune responses at these interfaces remain poorly understood. Anatase nanostructures have been shown to influence macrophage polarization on smooth titanium, but their effects on micro-rough SLA surfaces are not fully explored. This study investigates the immunomodulatory effects of micro-nanostructured anatase coatings on SLA titanium using human monocyte-derived macrophages (MDMs). M0-MDMs, were cultured and polarized to M1 and M2- macrophages on Ti-machined, Ti-SLA, Ti-SLA-anatase, and coverslip control surfaces for 48 h. Macrophage behavior was assessed using CCK-8 assay, confocal microscopy, SEM, ELISA, and qRT-PCR. All surfaces demonstrated excellent cytocompatibility, with similar macrophage viability across all investigated groups. M1 macrophages showed upregulation of CCR7 and TNF-α, while M2 macrophages expressed CD209 and CCL13 across all surfaces. Importantly, Ti-SLA-anatase did not significantly alter M1 or M2 markers, cytokine secretion, or gene expression, and did not exacerbate inflammatory responses. Micro-nanostructured anatase coatings on SLA titanium are immunologically well-tolerated and do not increase inflammation. These findings, combined with previously reported enhanced osteogenic properties, suggest the clinical potential of anatase-coated SLA surfaces. Full article

Urban green spaces (UGSs) are crucial for public health by supporting leisure-time physical activities (LTPAs), but the mechanisms by which micro-scale UGS features shape different LTPA types remain unclear. In this study, the relationship between the micro-scale features of UGSs and LTPAs was investigated in 63 sample plots of nine comprehensive parks in downtown Shanghai. Using the behavior annotation method and multiple linear regression analysis, we identified significant correlations between the UGS features and LTPA types. The results showed that sitting and chatting (SC) activities had the highest participation rate at 46.84%, while sports and fitness (SF) activities had the lowest at 9.82%. Walking and sightseeing (WS) activities and culture and entertainment (CE) activities accounted for 19.99% and 23.35% of participants, respectively. Spatial accessibility (SA) and canopy coverage ratios (CCRs) were significantly negatively correlated with SC, while seat number (SN), ground-cover density (D_GNC), and three-dimensional green quantity (TGQ) were positively correlated. For WS, SN and tree density (D_TREE) were positively correlated, while TGQ was negatively correlated. CE activities were positively associated with SN, D_TREE, and Shannon’s diversity index of ground-cover (SHI_GNC) but negatively associated with Shannon’s diversity index of trees (SHI_TREE). The regression models explained 65.9%, 38.3%, and 44.3% of the variance in SC, WS, and CE, respectively, while the overall model was not significant for SF. These findings highlight the need to optimize rest facilities, vegetation diversity, and spatial layout in UGS design to accommodate diverse LTPA needs and foster health-oriented environments. The conclusions are mainly applicable to seasons with mild climates, and LTPA characteristics in different seasons require further verification. Full article

Cancer is frequently accompanied by thrombotic complications, but conventional coagulation tests often fail to adequately detect cancer-associated hypercoagulability. In this study, blood from 34 patients with colorectal or gastric cancers (before, during and after 3 months of chemotherapy) and 21 healthy controls was analyzed to obtain a coagulation–fibrinolysis profile (by thromboelastometry) and determine the kinetics of clot contraction (CCR). Patients demonstrated hypercoagulable profiles characterized by shortened clotting time, enhanced clot strength, reduced CCR, and impaired fibrinolysis compared to healthy controls, which was more pronounced in colorectal cancer patients. Parameters related to increased clot formation, impaired CC and delayed fibrinolysis correlated with disease stage. Chemotherapy meaningfully prolonged fibrinolysis, which was further evident in vitro with platinum-based drugs. Our findings reveal, for the first time, a significant inhibition of CCR in cancer patients. Integrating thromboelastometry with CCR measurements may improve stratification of cancer-associated thrombotic risk, which appears to arise from the hemostatic disturbances identified in our study. These may extend the duration of clot presence due to reduced fibrinolysis, while decreasing clot stability through diminished CCR. Therefore, careful monitoring of the precarious balance between thrombotic and bleeding tendencies may hold important implications for the fate of cancer patients. Full article