Factors Associated with Abnormal Mammogram Results Among Low-Income Uninsured Populations in Medically Underserved And Rural Texas Regions.

Background: This study investigated the potential associations between neighborhood characteristics, rurality, ethnicity/race, and breast cancer screening outcomes in designated Health Professional Shortage Areas in Central Texas. Limited access to preventive medical care can impact screening rates and outcomes. Previous research on the effects of factors such as rurality, neighborhood socioeconomic status, and education level on cancer prevention behaviors has yielded inconsistent results. Materials and Methods: We analyzed data from a state-funded breast and cervical cancer screening programs for disadvantaged and medically underserved individuals. A mixed-effects logistic regression model was used to assess the impact of residency characteristics (rurality, educational attainment, unemployment, and poverty) on abnormal breast cancer screening outcomes, with individual level (age, ethnicity, race, and education) as control variables. Results: During the studied time, there were 1,139 women screened and 134 abnormal mammograms found. Residency characteristics were not significantly associated with abnormal mammography outcomes at 0.05. However, individual factors are strongly associated with abnormal screening results. Non-Hispanic or Latino white women had increased odds of abnormal clinical outcomes compared with Hispanic or Latino women (OR = 2.03, CI 1.25-3.28; p = 0.004). Additionally, women residing in counties with more than 30% of the population completing college had increased odds of abnormal mammogram outcomes compared with counties with less than 15% college attainment (OR = 2.89, CI 0.99-8.38; p = 0.051). Conclusions: This study found a significant correlation between area-level educational characteristics and abnormal mammography outcomes. Future research should explore the contextual risk factors influencing breast cancer occurrence and develop targeted interventions for this population.

Bayesian-frequentist hybrid inference framework for single cell RNA-seq analyses.

BACKGROUND: Single cell RNA sequencing technology (scRNA-seq) has been proven useful in understanding cell-specific disease mechanisms. However, identifying genes of interest remains a key challenge. Pseudo-bulk methods that pool scRNA-seq counts in the same biological replicates have been commonly used to identify differentially expressed genes. However, such methods may lack power due to the limited sample size of scRNA-seq datasets, which can be prohibitively expensive. RESULTS: Motivated by this, we proposed to use the Bayesian-frequentist hybrid (BFH) framework to increase the power and we showed in simulated scenario, the proposed BFH would be an optimal method when compared with other popular single cell differential expression methods if both FDR and power were considered. As an example, the method was applied to an idiopathic pulmonary fibrosis (IPF) case study. CONCLUSION: In our IPF example, we demonstrated that with a proper informative prior, the BFH approach identified more genes of interest. Furthermore, these genes were reasonable based on the current knowledge of IPF. Thus, the BFH offers a unique and flexible framework for future scRNA-seq analyses.

Milk-derived extracellular vesicles functionalized with anti-tumour necrosis factor-α nanobody and anti-microbial peptide alleviate ulcerative colitis in mice.

Ulcerative colitis (UC) manifests clinically with chronic intestinal inflammation and microflora dysbiosis. Although biologics can effectively control inflammation, efficient delivery to the colon and colon epithelial cells remains challenging. Milk-derived extracellular vesicles (EV) show promise as an oral delivery tool, however, the ability to load biologics into EV presents challenges to therapeutic applications. Here, we demonstrate that fusing cell-penetrating peptide (TAT) to green fluorescent protein (GFP) enabled biologics loading into EV and protected against degradation in the gastrointestinal environment in vitro and in vivo after oral delivery. Oral administration of EV loaded with anti-tumour necrosis factor-α (TNF-α) nanobody (VHHm3F) (EVVHH) via TAT significantly reduced tissue TNF-α levels and alleviated pathologies in mice with acute UC, compared to VHH alone. In mice with chronic UC, simultaneously introducing VHH and an antimicrobial peptide LL37 into EV (EVLV), then administering orally improved intestinal barrier, inflammation and microbiota balance, resulted in relief of UC-induced depression and anxiety. Collectively, we demonstrated that oral delivery of EVLV effectively alleviated UC in mice and TAT efficiently loaded biologics into EV to confer protection from degradation in the gastrointestinal tract. This therapeutic strategy is promising for UC and is a simple and generalizable approach towards drug-loaded orally-administrable EV treatment for other diseases.

Expanding the Potential of Neoantigen Vaccines: Harnessing Bacille Calmette-Guérin Cell-Wall-Based Nanoscale Adjuvants for Enhanced Cancer Immunotherapy.

Personalized antitumor immunotherapy utilizing neoantigen vaccines holds great promise. However, the limited immunogenicity of existing recognized neoantigens and the inadequate stimulation of antitumor immune responses by conventional adjuvants pose significant challenges. To address these limitations, we developed a nanovaccine that combines a BCG bacterial cell wall skeleton (BCG-CWS) based nanoscale adjuvant (BCNA) with peptide neoantigens (M27 and M30). This integrated approach provides an efficient translational strategy for cancer immunotherapy. The BCNA nanovaccine, formulated with PLGA as an emulsifier, exhibits excellent biocompatibility and superior antigen presentation compared with conventional BCG-CWS adjuvants. Subcutaneous immunization with the BCNA-based nanovaccine effectively targets lymph nodes, eliciting robust innate and tumor-specific immune responses. Importantly, our findings demonstrate that BCNAs significantly enhance neoantigen immunogenicity while minimizing acute systemic toxicity. Furthermore, when combined with a mouse PD-L1 antibody, our strategy achieves complete tumor elimination in 60% of cases and prevents 25% of tumor growth in a melanoma mouse model. In conclusion, our BCNA-based nanovaccine represents a promising avenue for advancing personalized therapeutic neoantigen vaccines and holds significant implications for enhancing personalized immunotherapy and improving patient outcomes in the field of cancer treatment.

RSPO3 induced by Helicobacter pylori extracts promotes gastric cancer stem cell properties through the GNG7/ß-catenin signaling pathway.

BACKGROUND: Helicobacter pylori (H. pylori) accounts for the majority of gastric cancer (GC) cases globally. The present study found that H. pylori promoted GC stem cell (CSC)-like properties, therefore, the regulatory mechanism of how H. pylori promotes GC stemness was explored. METHODS: Spheroid-formation experiments were performed to explore the self-renewal capacity of GC cells. The expression of R-spondin 3 (RSPO3), Nanog homeobox, organic cation/carnitine transporter-4 (OCT-4), SRY-box transcription factor 2 (SOX-2), CD44, Akt, glycogen synthase kinase-3ß (GSK-3ß), p-Akt, p-GSK-3ß, ß-catenin, and G protein subunit gamma 7 (GNG7) were detected by RT-qPCR, western blotting, immunohistochemistry (IHC), and immunofluorescence. Co-immunoprecipitation (CoIP) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were performed to identify proteins interacting with RSPO3. Lentivirus-based RNA interference constructed short hairpin (sh)-RSPO3 GC cells. Small interfering RNA transfection was performed to inhibit GNG7. The in vivo mechanism was verified using a tumor peritoneal seeding model in nude mice. RESULTS: H. pylori extracts promoted a CSC-like phenotype in GC cells and elevated the expression of RSPO3. RSPO3 knockdown significantly reduced the CSC-like properties induced by H. pylori. Previous studies have demonstrated that RSPO3 potentiates the Wnt/ß-catenin signaling pathway, but the inhibitor of Wnt cannot diminish the RSPO3-induced activation of ß-catenin. CoIP and LC-MS/MS revealed that GNG7 is one of the transmembrane proteins interacting with RSPO3, and it was confirmed that RSPO3 directly interacted with GNG7. Recombinant RSPO3 protein increased the phosphorylation level of Akt and GSK-3ß, and the expression of ß-catenin in GC cells, but this regulatory effect of RSPO3 could be blocked by GNG7 knockdown. Of note, GNG7 suppression could diminish the promoting effect of RSPO3 to CSC-like properties. In addition, RSPO3 suppression inhibited MKN45 tumor peritoneal seeding in vivo. IHC staining also showed that RSPO3, CD44, OCT-4, and SOX-2 were elevated in H. pylori GC tissues. CONCLUSION: RSPO3 enhanced the stemness of H. pylori extracts-infected GC cells through the GNG7/ß-catenin signaling pathway.

A Novel Cargo Delivery System-AnCar-ExoLaIMTS Ameliorates Arthritis via Specifically Targeting Pro-Inflammatory Macrophages.

Macrophages are heterogenic phagocytic cells that play distinct roles in physiological and pathological processes. Targeting different types of macrophages has shown potent therapeutic effects in many diseases. Although many approaches are developed to target anti-inflammatory macrophages, there are few researches on targeting pro-inflammatory macrophages, which is partially attributed to their non-s pecificity phagocytosis of extracellular substances. In this study, a novel recombinant protein is constructed that can be anchored on an exosome membrane with the purpose of targeting pro-inflammatory macrophages via antigen recognition, which is named AnCar-ExoLaIMTS . The data indicate that the phagocytosis efficiencies of pro-inflammatory macrophages for different AnCar-ExoLaIMTS show obvious differences. The AnCar-ExoLaIMTS3 has the best targeting ability for pro-inflammatory macrophages in vitro and in vivo. Mechanically, AnCar-ExoLaIMTS3 can specifically recognize the leucine-rich repeat domain of the TLR4 receptor, and then enter into pro-inflammatory macrophages via the TLR4-mediated receptor endocytosis pathway. Moreover, AnCar-ExoLaIMTS3 can efficiently deliver therapeutic cargo to pro-inflammatory macrophages and inhibit the synovial inflammatory response via downregulation of HIF-1α level, thus ameliorating the severity of arthritis in vivo. Collectively, the work established a novel gene/drug delivery system that can specifically target pro-inflammatory macrophages, which may be beneficial for the treatments of arthritis and other inflammatory diseases.

Metastasectomy for metastatic melanoma in the era of effective systemic therapy.

INTRODUCTION: Effective systemic therapy (EST) in patients with metachronous metastatic melanoma (MMM) improves survival and alters surgical decision-making. Surgical metastasectomy is another treatment option, however, it is unclear if metastasectomy confers survival benefit. This study seeks to identify any survival benefit associated with surgical management of MMM. METHODS: Patients with MMM from 2009 to 2021 were grouped by receipt of metastasectomy and treatment era (pre-versus post-EST). Overall survival (OS) was calculated from date of metastasis and evaluated with Kaplan-Meier analysis. RESULTS: Our dataset identified 226 patients with MMM; 32% were diagnosed pre-EST. On Kaplan-Meier analysis, OS was improved for patients undergoing treatment post-versus pre-EST (p < 0.001). In the post-EST era, metastasectomy was associated with an increase in OS compared to no resection (p = 0.022). CONCLUSIONS: In the post-EST group, EST paired with metastasectomy was associated with improved OS compared to the pre-EST group, suggesting persistent evidence of a survival benefit from metastasectomy.

Nano-optogenetic CAR-T Cell Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy emerges as an effective cancer treatment. However, significant safety concerns remain, such as cytokine release syndrome (CRS) and "on-target, off-tumor" cytotoxicity, due to a lack of precise control over conventional CAR-T cell activity. To address this issue, a nano-optogenetic approach has been developed to enable spatiotemporal control of CAR-T cell activity. This system is comprised of synthetic light-sensitive CAR-T cells and upconversion nanoparticles acting as an in situ nanotransducer, allowing near-infrared light to wirelessly control CAR-T cell immunotherapy.

Cost-effectiveness analysis of pembrolizumab versus chemotherapy as first-line treatment for mismatch-repair-deficient (dMMR) or microsatellite-instability-high (MSI-H) advanced or metastatic colorectal cancer from the perspective of the Chinese health-care system.

BACKGROUND: Pembrolizumab is superior to chemotherapy as a first-line treatment for patients with mismatch-repair-deficient (dMMR) or microsatellite-instability-high (MSI-H) advanced or metastatic colorectal cancer (CRC), with a significant long-term survival benefit according to the KEYNOTE-177 trial. The current study aimed to determine whether pembrolizumab is a cost-effective treatment for patients with dMMR/MSI-H advanced or metastatic CRC in China. METHODS: A partitioned survival model (PSM) was developed to simulate patients with dMMR/MSI-H advanced or metastatic CRC based on progression-free survival (PFS), progressive disease (PD) and death. The model was designed using a lifetime horizon, a 6-week cycle, and a 5% discount rate. The patients in the model had metastatic dMMR/MSI-H CRC and had not previously received treatment; these characteristics were similar to those of patients in KEYNOTE-177, a phase 3, open-label randomized clinical trial. The health outcomes and utilities were based on the KEYNOTE-177 trial and published data, respectively. Costs were calculated based on local charges (2022) and published literature. A treatment was deemed cost-effective in China if the incremental cost-effectiveness ratio (ICER) value was less than U.S.$38,142.56 per quality-adjusted life-year (QALY). The robustness of the results was assessed via one-way deterministic and probabilistic sensitivity analyses. RESULTS: Baseline analysis revealed that pembrolizumab provided an additional 2.58 QALYs (3.00 life-year) at an incremental cost of U.S.$78,286.04, resulting in an ICER of U.S.$30,330.15 per QALY, which was below the willingness-to-pay threshold of U.S.$38,142.56 per QALY. When the patient assistance program (PAP) was considered, the ICER became U.S.$1,730.67 per QALY, manifesting absolute cost-effectiveness. The results of sensitivity analyses demonstrated that pembrolizumab was cost-effective in most cases. CONCLUSIONS: Pembrolizumab is a cost-effective first-line treatment for dMMR/MSI-H advanced or metastatic CRC patients in China, especially considering the PAP.

Adverse Childhood Experiences and Preventive Cervical Cancer Screening Behavior.

OBJECTIVES: To examine associations between a history of adverse childhood experiences (ACEs) and receiving preventive cervical cancer screening and to investigate whether number and type of ACE exposures were predictive of cervical cancer screening uptake. SAMPLE & SETTING: Data were from 11,042 adults who completed the 2020 Texas Behavioral Risk Factor Surveillance System survey. The U.S. Preventive Services Task Force guidelines were used to indicate whether individuals had received cervical cancer screening at recommended intervals. METHODS & VARIABLES: Multiple logistic regression analysis was used to predict the likelihood of not having received the recommended preventive cancer screening by number and type of ACE exposures. Chi-square analysis was used to determine associations among demographic characteristics, cancer screening uptake, and ACE number and type. RESULTS: Individuals with one to three ACEs and those with six or more ACEs were statistically more likely not to have received the recommended cervical cancer screenings compared to those with zero ACEs. A history of physical ACEs was associated with 3.88 times the likelihood of not having received the recommended cervical cancer screening. IMPLICATIONS FOR NURSING: To promote timely cervical cancer screening and prevent retraumatization of patients with a history of ACEs, providers should implement trauma-informed care principles in their healthcare settings.

Quantitative dynamic contrast-enhance MRI parameters for rectal carcinoma characterization: correlation with tumor tissue composition.

OBJECTIVE: To investigate the relationship between dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) measurements and the potential composition of rectal carcinoma. METHODS: Twenty-four patients provided informed consent for this study. DCE-MRI was performed before total mesorectal excision. Quantitative parameters were calculated based on a modified Tofts model. Whole-mount immunohistochemistry and Masson staining sections were generated and digitized at histological resolution. The percentage of tissue components area was measured. Pearson correlation analysis was used to evaluate the correlations between pathological parameters and DCE-MRI parameters. RESULTS: On the World Health Organization (WHO) grading scale, there were significant differences in extracellular extravascular space (Ktrans) (F = 9.890, P = 0.001), mean transit time (MTT) (F = 9.890, P = 0.038), CDX-2 (F = 4.935, P = 0.018), and Ki-67 (F = 4.131, P = 0.031) among G1, G2, and G3. ECV showed significant differences in extramural venous invasion (t = - 2.113, P = 0.046). Ktrans was strongly positively correlated with CD34 (r = 0.708, P = 0.000) and moderately positively correlated with vimentin (r = 0.450, P = 0.027). Interstitial volume (Ve) was moderately positively correlated with Masson's (r = 0.548, P = 0.006) and vimentin (r = 0.417, P = 0.043). There was a moderate negative correlation between Ve and CDX-2 (r = - 0.441, P = 0.031). The rate constant from extracellular extravascular space to blood plasma (Kep) showed a strong positive correlation with CD34 expression (r = 0.622, P = 0.001). ECV showed a moderate negative correlation with CDX-2 (r = - 0.472, P = 0.020) and a moderate positive correlation with collagen fibers (r = 0.558, P = 0.005). CONCLUSION: The dynamic contrast-enhanced MRI-derived parameters measured in rectal cancer were significantly correlated with the proportion of histological components. This may serve as an optimal imaging biomarker to identify tumor tissue components.

Enhancement of Light and X-ray Charging in Persistent Luminescence Nanoparticle Scintillators Zn2SiO4:Mn2+, Yb3+, Li.

Persistent luminescence nanoparticle scintillators (PLNS) have been attempted for X-ray-induced photodynamic therapy (X-PDT) because persistent luminescence after ceasing radiation can make PLNS use less cumulative irradiation time and dose to generate the same amount of reactive oxygen species (ROS) compared with conventional scintillators to combat cancer cells. However, excessive surface defects in PLNS reduce the luminescence efficiency and quench the persistent luminescence, which is fatal to the efficacy of X-PDT. Herein, the PLNS of SiO2@Zn2SiO4:Mn2+, Yb3+, Li+ was designed by the energy trap engineering and synthesized by a simple template method, which has excellent X-ray and UV-excited persistent luminescence and continuously tunable emission spectra from 520 to 550 nm. Its luminescence intensity and afterglow time are more than 7 times that of the reported Zn2SiO4:Mn2+ used for X-PDT. By loading a Rose Bengal (RB) photosensitizer, an effective persistent energy transfer from the PLNS to photosensitizer is observed even after the removal of X-ray irradiation. The X-ray dose of nanoplatform SiO2@Zn2SiO4:Mn2+, Yb3+, Li+@RB in X-PDT of HeLa cancer cells was reduced to 0.18 Gy compared to the X-ray dose of 1.0 Gy for Zn2SiO4:Mn for X-PDT. This indicates that the Zn2SiO4:Mn2+, Yb3+, Li+ PLNS have great potential for X-PDT applications.

[Effectiveness analysis of resection and reconstruction of primary bone tumor in pelvic zone â ¡].

Objective: To investigate the effectiveness of complete resection of bone tumor in pelvic zone Ⅱ and reconstruction with allogeneic pelvis, modular prosthesis, and three-dimensional (3D) printing prosthesis. Methods: The clinical data of 13 patients with primary bone tumor in pelvic zone Ⅱ who underwent tumor resection and acetabular reconstruction between March 2011 and March 2022 were retrospectively analyzed. There were 4 males and 9 females with an average age of 39.0 years ranging from 16 to 59 years. There were 4 cases of giant cell tumor, 5 cases of chondrosarcoma, 2 cases of osteosarcoma, and 2 cases of Ewing sarcoma. The Enneking classification of pelvic tumors showed that 4 cases involved zone Ⅱ, 4 cases involved zone Ⅰ and zone Ⅱ, and 5 cases involved zone Ⅱ and zone Ⅲ. The disease duration ranged from 1 to 24 months, with an average of 9.5 months. The patients were followed up to observe the recurrence and metastasis of the tumor, and the imaging examination was performed to observe the status of implant in place, fracture, bone resorption, bone nonunion, and so on. The improvement of hip pain was evaluated by visual analogue scale (VAS) score before operation and at 1 week after operation, and the recovery of hip function was evaluated according to the Musculoskeletal Tumor Society (MSTS) scoring system after operation. Results: The operation time was 4-7 hours, with an average of 4.6 hours; the intraoperative blood loss ranged from 800 to 1 600 mL, with an average of 1 200.0 mL. There was no reoperation or death after operation. All patients were followed up 9-60 months (mean, 33.5 months). No tumor metastasis was found in 4 patients receiving chemotherapy during follow-up. Postoperative wound infection occurred in 1 case, and prosthesis dislocation occurred in 1 case at 1 month after prosthesis replacement. One case of giant cell tumor recurred at 12 months after operation, and the puncture biopsy showed malignant transformation of giant cell tumor, and hemipelvic amputation was performed. The postoperative hip pain significantly relieved, and the VAS score was 6.1±0.9 at 1 week after operation, which was significantly different from the preoperative score (8.2±1.3) ( t=9.699, P<0.001). At 12 months after operation, the MSTS score was 23.0±2.1, including 22.8±2.1 for patients with allogenic pelvis reconstruction and 23.3±2.3 for patients with prosthsis reconstruction. There was no significant difference in the MSTS score between the two reconstruction methods ( t=0.450, P=0.516). At last follow-up, 5 patients could walk with cane assistance and 7 patients could walk without cane assistance. Conclusion: The resection and reconstruction of primary bone tumor in pelvic zone Ⅱ can obtain satisfactory hip function, and the interface of allogeneic pelvis and 3D printing prosthesis have better bone ingrowth, which is more in line with the requirements of biomechanics and biological reconstruction. However, pelvis reconstruction is difficult, the patient's condition should be evaluated comprehensively before operation, and the long-term effectiveness needs further follow-up.

A Diode-Like Dye-Cu Anisotropic Junction in a Coordination Polymer as a Logic State Ratchet for Intratumor Redox Photomodulation.

Redox logic materials offer new avenues to modulate intracellular pathologic redox environment area-specifically, but the unambiguity of redox logic states and their unidirectional and repetitive switchability are challenging to realize. By merging a bistable diisophthalic phenazine dye ligand with CuII salt, a multistable coordination polymer (CP) was constructed, of which the dye-Cu anisotropic junction achieved the diode-like unidirectional electron transfer and logic state ratchet for the first time. Radical cationic CP maintained OFF status with low toxicity in healthy tissues, but was reduced to the neutral SERVO state by the overexpressed glutathione (GSH) in hypoxic tumors. After photoirradiation, the stabilized charge-separated ON status promoted photo-Fenton reaction for reactive oxygen species (ROS) signal transduction, and simultaneously recovered the initial state for catalytic signal amplification of ROS, furnishing intratumor redox photomodulation for therapy.

Clinical application of improved VSD and VSD in the treatment of SSI after abdominal surgery: A retrospective randomized clinical study.

By comparing the efficacy and cost of improved vacuum-sealing drainage devices and vacuum-sealing drainage (VSD) devices in the treatment of postoperative abdominal surgical site infection, the clinical applicability and promotion of improved vacuum-sealing drainage devices were assessed. In our institution, between October 2019 and December 2021, 55 patients with surgical site infection after abdominal surgery were retrospectively analyzed, including 30 patients treated with improved VSD and 25 patients treated with VSD. The efficacy of wound healing, total dressing change cost throughout therapy, total hospital costs, hospital days, and bacterial culture results of wound secretions before and after treatment were compared between the 2 groups. Both groups achieved wound healing following vacuum sealing-drainage treatment, with no significant differences in wound healing time or secondary suture rate. However, the total hospitalization and dressing change costs in the improved VSD group were significantly lower than those in the VSD group. Similar to VSD, improved VSD is effective in the treatment of surgical site infections after abdominal surgery. Compared with VSD, the improved VSD device has lower dressing change costs and total hospitalization costs during the treatment process. The improved VSD has a wide range of applications and is suitable for clinical use and promotion.

Multi-institutional Assessment of Pathologist Scoring HER2 Immunohistochemistry.

The HercepTest was approved 20+ years ago as the companion diagnostic test for trastuzumab in human epidermal growth factor 2 (HER2) or ERBB2 gene-amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. Although this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted on the basis of concordance among small numbers of pathologists without validation in a real-world setting. In this study, we evaluated the concordance and interrater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the Observers Needed to Evaluate Subjective Tests method to determine the plateau of concordance and the minimum number of pathologists needed to estimate interrater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (<1% agreement for 1+ and 3.6% agreement for 2+) in the 4-category HER2 IHC scoring system. The discordance within the IHC 0 cases is also substantial with an overall percent agreement (OPA) of only 25% and poor interrater reliability metrics (0.49 Fleiss' kappa, 0.55 intraclass correlation coefficient). This discordance can be partially reduced by using a 3-category system (28.8% vs 46.5% OPA for 4-category and 3-category scoring systems, respectively). Observers Needed to Evaluate Subjective Tests plots suggest that the OPA for the task of determining a HER2 IHC score 0 from not 0 plateaus statistically around 59.4% at 10 raters. Conversely, at the task of scoring HER2 IHC as 3+ or not 3+ pathologists' concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding the patients in whom the ERBB2 gene is amplified but unacceptably discordant in assigning HER2-low or HER2-negative status for the emerging HER2-low therapies.

Metal-Free Far-Red Light-Driven Photolysis via Triplet Fusion to Enhance Checkpoint Blockade Immunotherapy.

Metal-free long-wavelength light-driven prodrug photoactivation is highly desirable for applications such as neuromodulation, drug delivery, and cancer therapy. Herein, via triplet fusion, we report on the far-red light-driven photo-release of an anti-cancer drug by coupling the boron-dipyrromethene (BODIPY)-based photosensitizer with a photocleavable perylene-based anti-cancer drug. Notably, this metal-free triplet fusion photolysis (TFP) strategy can be further advanced by incorporating an additional functional dopant, i.e. an immunotherapy medicine inhibiting the indoleamine 2,3-dioxygenase (IDO), with the far-red responsive triplet fusion pair in an air-stable nanoparticle. With this IDO inhibitor-assisted TFP system we observed efficient inhibition of primary and distant tumors in a mouse model at record-low excitation power, compared to other photo-assisted immunotherapy approaches. This metal-free TFP strategy will spur advancement in photonics and biophotonics fields.

Neoadjuvant Chemotherapy and Expandable Prosthesis Reconstruction to Treat Osteosarcoma around the Knee in Children.

OBJECTIVE: Survival and reconstruction in osteosarcoma is quite challenging. The study aimed to investigate the prognosis in patients treated with neoadjuvant chemotherapy and determine the clinical outcomes of expandable endoprosthesis reconstruction in children. METHODS: From January 2009 to December 2014, we retrospectively analyzed 29 skeletally immature children (mean age, 10.5 years; range, 6-15 years) with osteosarcoma around the knee. Of the 29 patients who underwent neoadjuvant chemotherapy and limb salvage surgery, an expandable prosthesis was implanted for reconstruction. No patients were missed during follow-up. The evaluation index involved follow-up time, complication, functional results, and lengthening procedures. The survivorship and recurrence were assessed by GraphPad Software, and the function was evaluated by the Musculoskeletal Tumor Society (MSTS) scoring system. RESULTS: A mean follow-up time was 8.9 years (range, 6-12 years), and the overall 5-year survival was 89.1% based on Kaplan-Meier analysis. Three patients suffered a relapse and one underwent amputation. Lung metastasis developed in one patient. At 6 months after the operation, patients had a mean MSTS score of 27 points (range, 24-29). Two patients underwent revision surgery, one for implant infection and one for aseptic loosening. Prognosis is correlated with alkaline phosphatase change after treatment. CONCLUSIONS: Chemotherapy scheme and limb salvage can achieve high survival rates. This expandable prosthesis was associated with good function and low complication rates. The character of expandability could be a method to overcome discrepancies in the growth period.

Child Tobacco Smoke Exposure, Indoor Home Characteristics, and Housing Stability among a National Sample of U.S. Children.

(1) Objectives: To examine the associations of child tobacco smoke exposure (TSE) with home quality and housing instability. (2) Methods. A secondary analysis of 32,066 U.S. 0-11-year-old children from the 2018-2019 National Survey of Children's Health was conducted. Child home TSE status was defined as: no TSE: child lived with no smokers; thirdhand smoke (THS) exposure only: child lived with a smoker(s) who did not smoke indoors; and secondhand smoke (SHS) and THS exposure: child lived with a smoker(s) who smoked indoors. Home quality was assessed by the presence of mold or pesticide use and housing instability was assessed by home ownership, frequency of moves, and number of household members. We conducted weighted multivariable logistic regression and linear regression models while adjusting for important child covariates. (3) Results: In total, 12.3% had home THS exposure only and 1.6% had home SHS and THS exposure. Compared to children with no home TSE, children with home SHS and THS exposure were 2.60 times more likely (95%CI = 1.73, 3.92) to have mold inside their homes; 1.57 times more likely (95%CI = 1.09, 2.26) to live in homes where pesticides were used ≥1 time during the past 12-months; and more likely to have more frequent moves (ß = 1.06, 95%CI = 0.62, 1.50). (4) Conclusions: Children with home TSE have higher rates of mold, pesticide use, frequent moves, and household members compared to children with no home TSE. Children with TSE should also be screened for home quality and housing instability and provided with appropriate interventions and resources.

Enhancing Triplet-Triplet Annihilation Upconversion: From Molecular Design to Present Applications.

Photon upconversion, the process of converting low-energy photons into high-energy ones, has been widely applied for solar energy conversion, photoredox catalysis, and various biological applications such as background-free bioimaging, cancer therapy, and optogenetics. Upconversion materials that are based on triplet-triplet annihilation (TTA) are of particular interest due to their low excitation power requirements (e.g., ambient sunlight) and easily tunable excitation and emission wavelengths. Despite advances that have been made with respect to TTA upconversion (TTA-UC) in the past decade, several challenges remain for near-infrared light-activatable triplet-triplet annihilation upconversion (NIR TTA-UC). These challenges include low upconversion quantum yield, small anti-Stokes shift, and incompatibility with oxygen, the latter of which seriously limits the practical applications of NIR TTA-UC.This Account will summarize the recent research endeavors to address the above-mentioned challenges and the recent new applications. The first part of this Account highlights recent strategies of molecular design to modulate the excited states of photosensitizers and annihilators, two key factors to determine TTA-UC performance. Novel molecular engineering strategies such as the resonance energy transfer method, dimerization of dye units, and the helix twist molecular structure have been proposed to tune the excited states of photosensitizers. The obtained photosensitizers exhibited enhanced absorption of deep tissue penetrable near-infrared (NIR) light, produced a triplet excited state with elevated energy level and prolonged lifetime, and promoted intersystem crossing, leading to an upgraded TTA-UC system with significantly expanded anti-Stokes shift. With respect to the annihilator, the perylene derivatives were systematically explored, and their attached aromatic groups were found to be the key to adjusting the energy levels of both the triplet and singlet excited states. The resultant optimal TTA-UC system exhibits the highest recorded efficiency among NIR TTA-UC systems.Moreover, to resolve the oxygen-induced TTA-UC quenching, enzymatic reactions were recently introduced. More specifically, the glucose oxidase-catalyzed glucose oxidation reaction showed the ability to rapidly consume oxygen to turn on the TTA-UC luminescence in an aqueous solution. The resultant TTA-UC nanoparticle was able to detect glucose and an enzyme related to glucose metabolism in a highly specific, sensitive, and background-free manner. Further, the upconverted singlet excited state of the annihilator was directly utilized as the catalyst or the excited substrate. For example, the modification of annihilators and drug molecules with photolabile linkages can realize the long wavelength light-induced photolysis. Compared to direct short-wavelength-driven photolysis, this sensitized TTA photolysis (TTAP) exhibits superior reaction yield and lower photodamage, which are important in the release of drugs for tumor treatment in vivo. Moreover, the improved upconversion efficiency can enable the successful coupling of NIR TTA-UC with a visible light absorbing photocatalyst for NIR-driven photoredox catalysis. Compared to direct visible-light photocatalysis, TTA-UC mediated NIR photoredox catalysis showed superior product yield especially in large scale reaction systems owing to the deep penetration power of NIR light. More interestingly, among a few promising technology applications, three-dimensional (3D) printing based on photopolymerization can operate with faster speed and energy-input several orders of magnitude lower when the two-photon polymerization is replaced with TTA-UC mediated polymerization. We believe this Account will spur interest in the further development and application of TTA-UC in the areas of energy, chemistry, material science, and biology.