Enhancing Readability of Online Patient-Facing Content: The Role of AI Chatbots in Improving Cancer Information Accessibility.

BACKGROUND: Internet-based health education is increasingly vital in patient care. However, the readability of online information often exceeds the average reading level of the US population, limiting accessibility and comprehension. This study investigates the use of chatbot artificial intelligence to improve the readability of cancer-related patient-facing content. METHODS: We used ChatGPT 4.0 to rewrite content about breast, colon, lung, prostate, and pancreas cancer across 34 websites associated with NCCN Member Institutions. Readability was analyzed using Fry Readability Score, Flesch-Kincaid Grade Level, Gunning Fog Index, and Simple Measure of Gobbledygook. The primary outcome was the mean readability score for the original and artificial intelligence (AI)-generated content. As secondary outcomes, we assessed the accuracy, similarity, and quality using F1 scores, cosine similarity scores, and section 2 of the DISCERN instrument, respectively. RESULTS: The mean readability level across the 34 websites was equivalent to a university freshman level (grade 13±1.5). However, after ChatGPT's intervention, the AI-generated outputs had a mean readability score equivalent to a high school freshman education level (grade 9±0.8). The overall F1 score for the rewritten content was 0.87, the precision score was 0.934, and the recall score was 0.814. Compared with their original counterparts, the AI-rewritten content had a cosine similarity score of 0.915 (95% CI, 0.908-0.922). The improved readability was attributed to simpler words and shorter sentences. The mean DISCERN score of the random sample of AI-generated content was equivalent to "good" (28.5±5), with no significant differences compared with their original counterparts. CONCLUSIONS: Our study demonstrates the potential of AI chatbots to improve the readability of patient-facing content while maintaining content quality. The decrease in requisite literacy after AI revision emphasizes the potential of this technology to reduce health care disparities caused by a mismatch between educational resources available to a patient and their health literacy.

Galactosylated hydroxyl-polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning-induced liver failure.

Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose-conjugated hydroxyl polyamidoamine dendrimer (D4-Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)-induced liver failure. D4-Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non-Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4-Gal conjugated to N-acetyl cysteine (NAC) was tested in a mouse model of APAP-induced liver failure. A single intravenous dose of a conjugate of D4-Gal and NAC (Gal-d-NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4-Gal is effective in targeting and delivering therapies to hepatocytes and Gal-D-NAC has the potential to salvage and treat liver injury with a broader therapeutic window.

Review of Current Accepted Practices in Identification of the Breast Lumpectomy Tumor Bed.

Purpose: Of the 260,000 women diagnosed with breast cancer annually in the United States, more than 60% are treated with breast-conserving surgery or lumpectomy, followed by radiation to decrease the chance of local recurrence. More than 70% of breast cancer recurrences are localized to the original tumor cavity. Hence, targeted radiation therapy after lumpectomy is critical for recurrence prevention. With 30,000 patients annually opting for oncoplastic reconstruction of the breast after lumpectomy to improve cosmesis, the resulting tissue rearrangement increases the difficulty for radiation oncologists to accurately delineate the cavity when planning radiation therapy. Owing to the absence of a standardized protocol, it is important to assess the efficacy of various methods used to mark the tumor cavity for improved delineation. Methods and Materials: A keyword search and analysis was used to compile relevant articles on PubMed (National Center for Biotechnology Information). Results: Currently, a common practice for tumor cavity localization is applying titanium surgical clips to the borders of lumpectomy cavity. Tissue movement and seroma formation both impact the positioning of surgical clips within the tumor cavity and lead to significant interobserver variability. Furthermore, the main application of surgical clips is to control the small vessels during surgery, and that can create confusion when the same clips are used for tumor bed localization. All alternative solutions present more precise tumor bed delineation but possess individual concerns with workflow integration, patient comfort, and accuracy. Though liquid-based fiducials were found to be the most effective for delineating tumor cavities, there are still drawbacks for clinical use. Conclusions: These findings should encourage medical innovators to develop novel techniques for tumor cavity marking to increase delineation accuracy and effectively target at-risk tissue. Future solutions in this space should consider the properties of liquid-based fiducial markers to improve radiation oncologists' ability to precisely delineate the tumor cavity.

B cell acute lymphoblastic leukemia cells mediate RANK-RANKL-dependent bone destruction.

Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL-driven bone destruction, we examined the p53 -/-; Rag2 -/-; Prkdcscid/scid triple mutant (TM) mice and p53 -/-; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed Rankl, encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD.Prkdcscid/scidIl2rgtm1Wjl /SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin-Fc (rOPG-Fc) protected the bone from B-ALL-induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL-mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.

Overexpression of GαS in Murine Osteoblasts In Vivo Leads to Increased Bone Mass and Decreased Bone Quality.

GαS is a heterotrimeric G protein that transduces signals from activated G protein-coupled receptors on the cell surface to stimulate adenylyl cyclase/cyclic adenosine monophosphate (AMP) signaling. GαS plays a central role in mediating numerous growth and maintenance processes including osteogenesis and bone turnover. Decreased GαS expression or activating mutations in GαS both affect bone, suggesting that modulating GαS protein levels may be important for bone health and development. To examine the effects of increased osteoblastic GαS expression on bone development in vivo, we generated transgenic mice with GαS overexpression in osteoblasts (HOM-Gs mice) driven by the 3.6-kilobase (kb) Col1A1 promoter. Both male and female HOM-Gs mice exhibit increased bone turnover with overactive osteoblasts and osteoclasts, resulting in a high bone mass phenotype with significantly reduced bone quality. At 9 weeks of age, HOM-Gs mice have increased trabecular number, volumetric BMD (vBMD), and bone volume; however, the bone was woven and disorganized. There was also increased cortical bone volume despite an overall reduction in size in HOM-Gs mice along with increased cortical porosity and brittleness. The skeletal phenotype of HOM-Gs mice progressed into maturity at 26 weeks of age with further accrual of trabecular bone, whereas WT mice lost trabecular bone at this age. Although cortical bone volume and geometry were similar between mature HOM-Gs and WT mice, increased porosity persisted and the bone was weaker. At the cellular level, these alterations were mediated by an increase in bone resorption by osteoclasts and an overwhelmingly higher increase in bone formation by osteoblasts. In summary, our findings demonstrate that high osteoblastic GαS expression results in aberrant skeletal development in which bone production is favored at the cost of bone quality. © 2017 American Society for Bone and Mineral Research.

Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism.

Cleidocranial dysplasia (CCD) is an autosomal dominant human disorder characterized by abnormal bone development that is mainly due to defective intramembranous bone formation by osteoblasts. Here, we describe a mouse strain lacking the E3 ubiquitin ligase RNF146 that shows phenotypic similarities to CCD. Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of WNT3a-induced ß-catenin activation and reduced Fgf18 expression in osteoblasts. We show that FGF18 induces transcriptional coactivator with PDZ-binding motif (TAZ) expression, which is required for osteoblast proliferation and differentiation through transcriptional enhancer associate domain (TEAD) and runt-related transcription factor 2 (RUNX2) transcription factors, respectively. Finally, we demonstrate that adipogenesis is enhanced in Rnf146-/- mouse embryonic fibroblasts. Moreover, mice with loss of RNF146 within the osteoblast lineage had increased fat stores and were glucose intolerant with severe osteopenia because of defective osteoblastogenesis and subsequent impaired osteocalcin production. These findings indicate that RNF146 is required to coordinate ß-catenin signaling within the osteoblast lineage during embryonic and postnatal bone development.

RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146.

Bone undergoes continuous remodeling due to balanced bone formation and resorption mediated by osteoblasts and osteoclasts, respectively. Osteoclasts arise from the macrophage lineage, and their differentiation is dependent on RANKL, a member of the TNF family of cytokines. Here, we have provided evidence that RANKL controls the expression of 3BP2, an adapter protein that is required for activation of SRC tyrosine kinase and simultaneously coordinates the attenuation of ß-catenin, both of which are required to execute the osteoclast developmental program. We found that RANKL represses the transcription of the E3 ubiquitin ligase RNF146 through an NF-κB-related inhibitory element in the RNF146 promoter. RANKL-mediated suppression of RNF146 results in the stabilization of its substrates, 3BP2 and AXIN1, which consequently triggers the activation of SRC and attenuates the expression of ß-catenin, respectively. Depletion of RNF146 caused hypersensitivity to LPS-induced TNF-α production in vivo. RNF146 thus acts as an inhibitory switch to control osteoclastogenesis and cytokine production and may be a control point underlying the pathogenesis of chronic inflammatory diseases.

A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism.

Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues (404)Glu and (405)Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment.