Close agreement between modeled and observed time-activity curves (TACs) does not necessarily imply accurate recovery of the underlying kinetic parameters. We evaluated this distinction using a partially observed four-compartment renogram model with a latent reservoir and observed left kidney, right kidney, and bladder TACs. Six de-identified renograms provided patient-derived reference parameter vectors for synthetic recovery experiments with added noise, together with analyses of temporal sampling, optimizer behavior, initialization, and numerical identifiability. Median total NRMSE values relative to the clean synthetic TACs were on the order of 10 − 3 , indicating excellent TAC reconstruction. Parameter recovery was substantially less uniform: some rate constants were recovered accurately, whereas others exhibited multiplicative errors of tens to hundreds, repeated boundary contact, or compensation involving the latent reservoir. Repeated optimizations also converged consistently to incorrect parameter vectors while preserving excellent TAC fits. The scaled residual Jacobian was numerically full rank but severely ill-conditioned, and several 95% profile likelihood intervals remained open at the optimization bounds. These findings demonstrate that TAC fit quality alone is insufficient to assess parameter reliability. TAC reconstruction, parameter recovery, numerical rank, boundary behavior, optimizer stability, and profile likelihoods provide complementary evidence and should be interpreted together when evaluating partially observed kinetic models.
Carbon ion radiotherapy (CIRT), characterized by high linear energy transfer and increased relative biological effectiveness (RBE), offers distinct physical precision and radiobiological potency in the treatment of radioresistant and anatomically complex tumors. As clinical adoption expands, the focus has shifted from technical feasibility to rational integration with other treatment modalities to optimize the therapeutic ratio. This review summarizes the biological rationale and clinical evidence for 3 principal CIRT-based combination strategies. We compare these strategies across their respective sources of benefit, levels of evidence, toxicity constraints, and applicable clinical settings. Mixed-beam approaches employ photons or protons to cover larger treatment volumes and carbon ions to boost residual or high-risk disease. They should be distinguished from emerging multi-ion therapy, which integrates multiple ion species to jointly optimize linear energy transfer and RBE-weighted dose. Immunotherapy may convert local tumor control into systemic antitumor responses but carries immune-related toxicity and challenges in lymphocyte preservation. Chemoradiotherapy and mechanism-based radiosensitization may combine CIRT with systemic therapy or exploit specific biological vulnerabilities, although CIRT-specific evidence remains heterogeneous. Future studies should prioritize biomarker-guided patient selection, mechanism-matched combinations, immune-related dosimetric optimization, standardized toxicity assessment, and prospective validation to enable precise, scalable clinical translation.
This study investigated time-dependent group-level changes in chemical exchange saturation transfer (CEST) signals in a mouse model and explored utility in identifying stroke onset time. Multiparametric magnetic resonance imaging (diffusion weighted imaging, arterial spin labeling, and CEST) was conducted on 12 normal and 26 ischemic mice. Imaging findings were validated by immunohistochemical analysis. CEST parameters in infarct and penumbra were compared between strokes within 4.5 h and over 4.5 h. Correlations, regression, and receiver operating characteristic curves evaluated performance. Infarct guanidine, magnetization transfer (MT), nuclear Overhauser enhancement (NOE) (-3.5 ppm), and NOE (-1.6 ppm) significantly differed between groups and associated with onset time (P < .01). MT, NOE (-3.5 ppm), NOE (-1.6 ppm) showed significant associations with onset time in univariate logistic regression (P < .05). The NOE (-3.5 ppm) achieved an area under the curve of 0.848 (95% CI: 0.655-1.000), outperforming apparent diffusion coefficient (z = -2.397, P = .017) and cerebral blood flow (z = -2.271, P = .0271). NOE (-3.5 ppm) signals and lipid peroxidation both declined progressively with ischemic duration. These findings indicate that NOE (-3.5 ppm) signal attenuation parallels lipid peroxidation and may indicate progressive membrane lipid loss in ischemia.
Despite the increased water content in fibrotic livers, numerous studies reported a decrease in apparent diffusion coefficient (ADC) in liver fibrosis. We argue that the ADC decrease in fibrotic livers is due to the “T2 shine-through” of ADC, as the longer T2 in liver fibrosis leads to less signal decay between the low and high b -value images. The metric slow diffusion coefficient (SDC), predominantly measuring Brownian motion of water molecules, was proposed to mitigate the difficulties associated with this “T2 shine-through” of ADC. This study calculated ADC and SDC of 1 rat study with liver fibrosis induced by biliary duct ligation (BDL), and 3 sets of human liver fibrosis data. To tease out the menopausal effect on liver SDC, only the results of men's livers were analyzed for the human datasets. The rat study showed that liver ADC decreased stepwise (in weeks after BDL procedure) following fibrosis induction, and SDC increased stepwise. In human studies, all 3 datasets consistently showed that advanced fibrosis had a liver ADC lower than that of earlier stage fibrosis; advanced fibrosis had a liver SDC higher than that of earlier stage fibrosis.
Potent STING agonists are among the most promising strategies for reversing immunosuppression in “cold” tumors, but in vivo antitumor efficacy is frequently limited by dose-limiting systemic toxicity and inadequate tumor selectivity. To achieve localized STING activation and robust systemic immunity, we combined STING agonism with photodynamic therapy (PDT), creating a carrier-free nanoplatform (Ce6&SR717 NPs) through self-assembly of SR717 (STING agonist) and Ce6 (chlorin e6, photosensitizer). This excipient-free design achieves maximum drug loading, alleviates carrier-related safety issues, and realizes the spatiotemporally synchronized activation of PDT-induced immunogenic cell death and STING signaling through irradiation, which establishes an auto-amplifying cycle of on-site antigen release and systemic immune priming. In the murine breast cancer model, Ce6&SR717 NPs plus laser irradiation dramatically increased CD8 + T-cell infiltration within the tumor, triggered strong systemic antitumor immunity, and suppressed both primary and distant tumors. Collectively, these results identify Ce6&SR717 NPs as a safe and efficient modality for synergistic photo-immunotherapy of immunologically cold tumors.
