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Patients with postoperative tumor-associated bone defects need both chemotherapy and bone repair in the shifted disease states, but chemotherapy resistance, severe side-effects, and poor bone regeneration result in tumor recurrence and therapy failure. Herein, we develop an injectable and tumor microenvironment (TME)-modulated hydrogel composed of bio-responsive drug-loaded mesoporous bioactive glass nanoparticles (MBGN), gelatin (Gel), and oxidized chondroitin sulfate (OCS) for tumor-associated bone defects closed-loop management. The TME-modulated hydrogels can deplete protons and glutathione (GSH) within residual tumor tissues with sustained drug responsive-release capability, therefore interfering TME and overcoming cancer resistance, and also reducing off-target effects. Mechanistically, in the early state of treatment, acidic environment of TME will break the Schiff's base bond network of hydrogels, thus deliver drug-loaded nanoparticles into tumor cells. Subsequently, the pH-responsive amide bonds, GSH-responsive disulfide bonds and acidity-degradable nanocarriers of drug-loaded nanoparticles can induce ROS stress and mitochondrial-related damage, activating the p16-CYLD tumor suppressor pathway to induce apoptosis and inhibit metastasis. In the late state of treatment, the hydrogels shifted into regenerative scaffolds to exert long-lasting osteogenesis effects. Overall, the TME-modulated hydrogels can orchestrate steady bone repair and avoid tumor recurrence, achieving closed-loop management of postoperative tumor-associated bone defects.

Background and objectivesMost primary progressive aphasia (PPA) literature is based on English language users. Linguistic features that vary from English, such as logographic writing systems, are underinvestigated. The current study characterized the dysgraphia phenotypes of patients with PPA who write in Chinese and investigated their diagnostic utility in classifying PPA variants.MethodsThis study recruited 40 participants with PPA and 20 cognitively normal participants from San Francisco, Hong Kong, and Taiwan. We measured dictation accuracy using the Chinese Language Assessment for PPA (CLAP) 60-character orthographic dictation test and examined the occurrence of various writing errors across the study groups. We also performed voxel-based morphometry analysis to identify the gray matter regions correlated with dictation accuracy and prevalence of writing errors.ResultsAll PPA groups produced significantly less accurate writing responses than the control group and no significant differences in dictation accuracy were noted among the PPA variants. With a cut score of 36 out of 60 in the CLAP orthographic dictation task, the test achieved sensitivity and specificity of 90% and 95% in identifying Chinese participants with PPA vs controls. In addition to a character frequency effect, dictation accuracy was affected by homophone density and the number of strokes in semantic variant PPA and logopenic variant PPA groups. Dictation accuracy was correlated with volumetric changes over left ventral temporal cortices, regions known to be critical for orthographic long-term memory. Individuals with semantic variant PPA frequently presented with phonologically plausible errors at lexical level, patients with logopenic variant PPA showed higher preponderance towards visual and stroke errors, and patients with nonfluent/agrammatic variant PPA commonly exhibited compound word and radical errors. The prevalence of phonologically plausible, visual, and compound word errors was ne