Association of Delta Neutrophil Index with the 30-day Mortality in Adult Cardiac Surgical Patients.

Purpose: This study aimed to assess the predictive accuracy of 30-day mortality with delta neutrophil index (DNI) in adult cardiac surgical patients. Methods: This study enrolled patients who underwent cardiac surgery under general anesthesia between March 2016 and May 2022 at a tertiary hospital in the Republic of Korea. DNI was measured preoperatively, on postoperative arrival to the surgical intensive care unit (ICU), and 12, 24, 48, and 72 h postoperatively. Receiver operating characteristic (ROC) analysis was employed to identify the prediction accuracy of DNI. An area under ROC curve (AUROC) ≥0.700 was defined as satisfactory predictive accuracy. An optimal cutoff point for the DNI value to maximize predictive accuracy was revealed in the ROC curve, where [sensitivity + specificity] was maximum. Results: This study included a total of 843 patients in the final analyses. The mean age of the study population was 66.9±12.2 years and 38.4% of them were female patients. The overall 30-day mortality rate was 5.2%. Surgery involving the thoracic aorta, history of prior cardiac surgery, or emergency surgery were associated with a higher mortality rate. The DNI showed satisfactory predictive accuracy at 24 h, 48 h, and 72 h postoperatively, with AUROC of 0.729, 0.711, and 0.755, respectively. The optimal cutoff points of DNI at each time point were 3.2, 3.8, and 2.3, respectively. Conclusions: Postoperative DNI is a good predictor of 30-day mortality after cardiac surgery and has the benefit of no additional financial costs or time.

Si-Containing Reverse-Gradient Block Copolymer for Inorganic Pattern Amplification in EUV Lithography.

Although extreme ultraviolet lithography (EUVL) has emerged as a leading technology for achieving high quality sub-10 nm patterns, the insufficient pattern height of photoresist patterns remains a challenge. Directed self-assembly (DSA) of block copolymers (BCPs) is expected to be a complementary technology for EUVL due to its ability to form periodic nanostructures. However, for a combination with EUV patterns, it is essential to develop advanced BCP systems that are suited to inorganic-containing EUV photoresists and offer improved resolution limits, pattern quality, and etch resistance. Here, we report a reverse-gradient BCP system, poly[(styrene-gradient-pentafluorostyrene)-b-4-tert-butyldimetilsiloxystyrene] [P(S-g-PFS)-b-P4BDSS] BCP, which enables universally vertically oriented lamellae even in the absence of a neutral layer, while also containing a Si-containing block with high etch resistance. The gradient block, characterized by a gradual compositional transition from the block junction to the tail, plays a crucial role in creating an adequate surface energy contrast that energetically drives the formation of perpendicular lamellae without neutral layer. When used as a pattern height enhancement layer in EUVL, a high aspect ratio (3.29) of patterns was achieved, thereby offering a supplementary solution for next-generation EUVL.

The Effect of Botulinum Toxin A on the NADPH Oxidase System and Ischemia-Reperfusion Injury.

BACKGROUND: Despite the increasing popularity of various materials for ischemia-reperfusion (I/R) injury mitigation, research on botulinum toxin type A (BoNTA) remains limited. This study assesses BoNTA's efficacy in protecting flaps from I/R injury by inhibiting the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system and reducing reactive oxygen species (ROS) production. METHODS: Seventy-six Sprague-Dawley rats were studied. We examined the effects of BoNTA on superoxide production in four rats using a lucigenin-enhanced chemiluminescence assay (LECL). Another group of 60 rats had their superficial inferior epigastric artery (SIEA) flaps treated with either BoNTA or saline and clamped for 0, 1, and 4 hours before reperfusion. Flap survival and histological outcomes were assessed five days post-operation. ROS production in SIEA flaps and femoral vessels was analyzed in 12 additional rats, post-I/R injury. RESULTS: The LECL results showed that the BoNTA group had significantly lower superoxide production compared to controls, with notable reductions at 4 hours. While no significant differences were noted at the 0 and 1-hour marks, the 4-hour mark showed significant protective effects in BoNTA-treated groups. The survival rate was 90% for BoNTA-treated rats versus 60% for controls ( P = 0.028). Significant reductions in ROS were also observed in the 4-hour I/R group. CONCLUSIONS: BoNTA effectively protects against I/R injury by inhibiting the NADPH oxidase system and reducing ROS levels. These results support further investigation into the specific mechanisms of NADPH oxidase inhibition by BoNTA and its potential clinical applications, given its safety profile. CLINICAL RELEVANCE STATEMENT: The findings from the present study are expected to provide a basis for clinical studies regarding this use of BoNTA.

Tailoring Mechanical Reliability in Transparent ZnO-Zincone Thin-Film Electrodes with Organic Interlayer Interfaces and Thickness.

To address the inherent brittleness of conventional transparent conductive oxides, researchers have focused on enhancing their flexibility. This is achieved by incorporating organic films to construct organic-inorganic hybrid layer-by-layer nanostructures, where the interlayer thickness and interface play pivotal roles in determining the properties. These factors are contingent on the type of material, processing conditions, and specific application requirements, making it essential to select the appropriate conditions. In this study, ZnO-zincone nanolaminate thin films were fabricated using atomic layer deposition and molecular layer deposition in various structural configurations. Transmission electron microscopy, X-ray diffraction, and scanning electron microscopy were used to conduct a thorough analysis of the thin-film growth and structural transformations resulting from the deposition conditions. Furthermore, the influence of structural differences at the interfaces on the mechanical properties of the films was investigated by employing both tensile and compression-bending fatigue tests. This comprehensive examination reveals noteworthy variations in the mechanical responses of the films. Thin films characterized by internal porosity and an intermixed amorphous structure demonstrated enhanced compressive toughness, whereas rigid organic layers improved flexibility. These findings offer valuable insights into the development of flexible, transparent multilayer films.

Epithelial-mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer.

BACKGROUND: We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy. METHODS: PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed. RESULTS: RNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-ß (TGFß). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFß production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration. CONCLUSIONS: Tumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.

Multicolor Inks of Black Phosphorus for Midwave-Infrared Optoelectronics.

Black phosphorus (bP) based ink with a bulk bandgap of 0.33 eV (λ = 3.7 µm) has recently been shown to be promising for large-area, high performance mid-wave infrared (MWIR) optoelectronics. However, the development of multicolor bP inks expanding across the MWIR wavelength range has been challenging. Here a multicolor ink process based on bP with spectral emission tuned from 0.28 eV (λ = 4.4 µm) to 0.8 eV (λ = 1.5 µm) is demonstrated. Specifically, through the reduction of bP particle size distribution (i.e., lateral dimension and thickness), the optical bandgap systematically blueshifts, reaching up to 0.8 eV. Conversely, alloying bP with arsenic (bP1- xAsx) induces a redshift in the bandgap to 0.28 eV. The ink processed films are passivated with an infrared-transparent epoxy for stable infrared emission in ambient air. Utilizing these multicolor bP-based inks as an infrared light source, a gas sensing system is demonstrated that selectively detects gases, such as CO2 and CH4 whose absorption band varies around 4.3 and 3.3 µm, respectively. The presented ink formulation sets the stage for the advancement of multiplex MWIR optoelectronics, including spectrometers and spectral imaging using a low-cost material processing platform.

Efficacy of live and inactivated recombinant Newcastle disease virus vaccines expressing clade 2.3.4.4b H5 hemagglutinin against H5N1 highly pathogenic avian influenza in SPF chickens, Broilers, and domestic ducks.

A Newcastle disease virus (NDV)-vectored vaccine expressing clade 2.3.4.4b H5 Hemagglutinin was developed and assessed for efficacy against H5N1 highly pathogenic avian influenza (HPAI) in specific pathogen-free (SPF) chickens, broilers, and domestic ducks. In SPF chickens, the live recombinant NDV-vectored vaccine, rK148/22-H5, achieved complete survival against HPAI and NDV challenges and significantly reduced viral shedding. Notably, the live rK148/22-H5 vaccine conferred good clinical protection in broilers despite the presence of maternally derived antibodies. Good clinical protection was observed in domestic ducks, with decreased viral shedding. It demonstrated complete survival and reduced cloacal viral shedding when used as an inactivated vaccine from SPF chickens. The rK148/22-H5 vaccine is potentially a viable and supportive option for biosecurity measure, effectively protecting in chickens against the deadly clade 2.3.4.4b H5 HPAI and NDV infections. Furthermore, it aligns with the strategy of Differentiating Infected from Vaccinated Animals (DIVA).

Primary Solid Pseudopapillary Tumor of the Ovary: A Case Report and Review of the Literature.

INTRODUCTION: Solid pseudopapillary neoplasms (SPNs) are rare and mainly originate from the pancreas. SPNs originating from the ovary (SPN-O) are extremely rare, and only 13 cases have been reported in the English literature since 2010. CASE: We report a 31-year-old woman with SPN-O accompanied by multiple metastases in the abdominal cavity. The patient underwent staging surgery and cytoreduction. Furthermore, the multidisciplinary board decided on adjuvant chemotherapy with an FP regimen (fluorouracil plus cisplatin) because a microscopic metastasis was discovered in the peritoneum near the appendix. Next-generation sequencing showed some pathologic mutations of oncogenes/cancer-associated genes, including CTNNB1 and TP53. This is the fourteenth case of SPN-O and the first one to demonstrate the TP53 pathogenic mutant variant in SPN-O. The patient showed 8 months of disease-free survival until February 2024. CONCLUSION: The combination of R0 cytoreduction with FOLFIRI chemotherapy appears to be an effective and feasible treatment option.

The Role of Surface Treatment and Coupling Agents for Adhesion between Stainless Steel (SUS) and Polyamide (PA) of Heterojunction Bilayer Composites.

The growing demand for lightweight and durable materials in industries, such as the automotive, aerospace, and electronics industries, has spurred the development of heterojunction bilayer composites, combining the structural integrity of metals with the versatility of polymers. This study addresses the critical interface between stainless steel (SUS) and polyamide 66 (PA66), focusing on the pivotal role of surface treatments and various silane coupling agents in enhancing the adhesion strength of heterojunction SUS/PA66 bilayer composites. Through systematic surface modifications-highlighted by scanning electron microscopy, atomic force microscopy, and contact angle analyses-the study assessed the impact of increasing the surface area, roughness, and energy of SUS. X-ray photoelectron spectroscopy evaluations confirmed the strategic selection of specific silane coupling agents. Although some coupling agents barely influenced the mechanics, notably, aminopropyl triethoxysilane (A1S) and 3-glycidyl oxypropyl trimethoxysilane (ES) significantly enhanced the mechanical properties of the heterojunction bilayer composites, evidenced by the improved lap shear strength, elongation at break, and toughness. These advancements were attributed to the interfacial interactions at the metal-polymer interface. This research underscored the significance of targeted surface treatment and the judicious selection of coupling agents in optimizing the interfacial adhesion and overall performance of metal-polymer composites, offering valuable insights for the fabrication of materials where reduced weight and enhanced durability are paramount.

Ginseng Berry Juice (GBJ) Regulates the Inflammation in Acute Ulcerative Mouse Models and the Major Bioactive Substances Are Ginsenosides Rb3, Rc, Rd, and Re.

Panax ginseng fruit is known to have various biological effects owing to its large amount of saponins such as ginsenosides. In the present study, ginseng berry juice was confirmed to be effective against acute inflammation. Ginseng berry juice was used for analysis of active constituents, antioxidant efficacy, and in vivo inflammation. A high-performance liquid chromatography method was used for analysis of ginsenosides. In an HCl/ethanol-induced acute gastric injury model, microscopic, immunofluorescent, and immunohistochemical techniques were used for analysis of inhibition of gastric injury and mechanism study. In a mouse model of acute gastritis induced with HCl/ethanol, ginseng berry juice (GBJ, 250 mg/kg) showed similar gastric injury inhibitory effects as cabbage water extract (CB, 500 mg/kg, P.O). GBJ dose-dependently modulated the pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and Interleukin-13 (IL-13). GBJ inhibited the activation of Nuclear Factor kappa bB (NF-κB) and suppressed the expressions of cyclooxigenase-2 (COX-2) and prostaglandin 2 (PGE2). The anti-inflammatory effect of GBJ is attributed to ginsenosides which have anti-inflammatory effects. Productivity as an effective food source for acute gastritis was analyzed and showed that GBJ was superior to CB. In addition, as a functional food for suppressing acute ulcerative symptoms, it was thought that the efficacy of gastric protection products would be higher if GBJ were produced in the form of juice rather than through various extraction methods.

Volumetric analysis of artifacts from fiducial markers under cone beam computed tomography.

Abstract Background/purpose: Computer aided implant surgery has been widely adopted in modern implant dentistry. However, absence of reliable anatomic landmarks for superimposing digital data sets for patients with terminal dentition or complete edentulism remained challenging. Utilization of additional fiducial markers intraorally as the reference points for the improvement of accuracy became crucial in implant digital workflow. Nevertheless, the choice of the material for fiducial markers should present the least radiographic artifacts under cone beam computed tomography (CBCT) for better accuracy. The aim of this in vitro study was to investigate the volume of radiographic artifacts generated through different materials under the image of CBCT. Materials and methods: Fifteen dental materials were selected and configured into cubic shape. All the materials were scanned initially with the laboratory scanner as the control groups. The samples were scanned by CBCT machine as test groups and the volume of artifact generated under CBCT images were compared and analyzed using 3D modeling software. Results: Eleven out of fifteen materials could be recognized under CBCT images. Volumetric analysis reported that statistically significant differences among the materials could be noted, and the flowable composite resin presented the least volumetric difference. Lithium disilicate glass-ceramic, flowable composite resin, and gutta-percha presented the least deformation and maintained their cubic shapes. Conclusion: The results of the present study may imply that flowable composite resin compared to all ceramic materials, amalgam and gutta-percha may be a preferable choice when utilized as fiducial markers under CBCT images.

Evaluating the Efficacy of the Erector Spinae Plane Block as a Supplementary Approach to Cardiac Anesthesia during Off-Pump Coronary Bypass Graft Surgery via Median Sternotomy: A Randomized Clinical Trial.

Background: Pain control after off-pump coronary artery bypass graft (OPCAB) facilitates mobilization and improves outcomes. The efficacy of the erector spinae plane block (ESPB) after cardiac surgery remains controversial. Methods: We aimed to investigate the analgesic effects of ESPB after OPCAB. Precisely 56 patients receiving OPCAB were randomly divided into ESPB and control groups. The primary outcome was visual analog scale (VAS) pain scores at 6, 12, 24, and 48 h postoperatively. Secondary outcomes were the dose of rescue analgesics in terms of oral morphine milligram equivalents, the dose of antiemetics, the length of intubation time, and the length of stay in the intensive care unit (ICU). Results: The VAS scores were similar at all time points in both groups. The incidence of severe pain (VAS score > 7) was significantly lower in the ESPB group (50% vs. 15.4%; p = 0.008). The dose of rescue analgesics was also lower in the ESPB group (19.04 ± 18.76, 9.83 ± 12.84, p = 0.044) compared with the control group. The other secondary outcomes did not differ significantly between the two groups. Conclusions: ESPB provides analgesic efficacy by reducing the incidence of severe pain and opioid use after OPCAB.

Augmented-reality-assisted intraoral scanning: A proof-of-concept study.

PURPOSE: The aims of the present study were (a) to compare the scanning time and image count to complete optical scans of a typodont between augmented-reality-assisted intraoral scanning (ARIOS) and intraoral scanning (IOS); (b) to compare the accuracy of the digital casts derived from ARIOS and IOS; (c) to compare participant-related outcomes between ARIOS and IOS. MATERIALS AND METHODS: A multi-session within-subject experiment was conducted to compare ARIOS and IOS. Thirty-one dental students participated in the study. Following a trial session, each participant obtained optical scans under ARIOS and IOS conditions. The time required to complete the scan, and the number of images taken were recorded. Participant feedback was collected using entry, exit, and NASA-Task Load Index (TLX) surveys. The accuracy of the digital casts derived from the optical scans was measured in root mean square error (RMSE). RESULTS: The present study found a 6.8% increase in preference for ARIOS from entry to exit survey. Slightly more participants favored the ARIOS setup compared to IOS; 54.8% of participants favored ARIOS, 9.7% were indifferent, and 35.5% favored IOS. NASA-TLX subscale ratings were higher for IOS in general apart from mental demand. The accuracy of the digital casts between ARIOS and IOS was comparable in RMSE. CONCLUSION: ARIOS was advantageous compared to IOS in ergonomics, improved scanner tracking, and ease of scanner orientation. However additional trials, increased field of view, and better superimposition of scanning status to the target site were improvements desired by the study participants.

CRIF1 deficiency induces FOXP3LOW inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity.

Recently identified human FOXP3lowCD45RA- inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (Tregs). In spite of their implication in tumors, the mechanism for generation of FOXP3lowCD45RA- INS cells in vivo is unclear. We showed that the FOXP3lowCD45RA- cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3lowINS-Tregs with mitochondrial dysfunction and metabolic reprograming. The enhanced glutaminolysis activated α-ketoglutarate-mTORC1 axis, which promoted proinflammatory cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased α-ketoglutarate-derived 2-hydroxyglutarate down-regulated Foxp3 expression by methylating the Foxp3 gene regulatory regions. Furthermore, CRIF1 deficiency-induced Foxp3lowINS-Tregs suppressed tumor growth in an IFN-γ-dependent manner. Thus, CRIF1 deficiency-mediated mitochondrial dysfunction results in the induction of Foxp3lowINS-Tregs including FOXP3lowCD45RA- cells that promote antitumor immunity.

Surgical quality assessment for the prospective study of oncologic outcomes after laparoscopic modified complete mesocolic excision for nonmetastatic right colon cancer (PIONEER study).

BACKGROUND: The modified complete mesocolic excision (mCME) procedure for right-sided colon cancer is a tailored approach based on the original complete mesocolic excision (CME) methodology. Limited studies evaluated the safety and feasibility of laparoscopic mCME using objective surgical quality assessments in patients with right colon cancer. The objectives of the PIONEER study were to evaluate oncologic outcomes after laparoscopic mCME and to identify optimal clinically relevant endpoints and values for standardizing laparoscopic right colon cancer surgery based on short-term outcomes of procedures performed by expert laparoscopic surgeons. MATERIALS AND METHODS: This is an ongoing prospective, multi-institutional, single-arm study conducted at five tertiary colorectal cancer centers in South Korea. Study registrants included 250 patients scheduled for laparoscopic mCME with right-sided colon adenocarcinoma (from the appendix to the proximal half of the transverse colon). The primary endpoint was 3-year disease-free survival. Secondary outcomes included 3-year overall survival, incidence of morbidity in the first 4 weeks postoperatively, completeness of mCME, central radicality, and distribution of metastatic lymph nodes. Survival data will be available after the final follow-up date (June 2024). RESULTS: The postoperative complication rate was 12.9%, with a major complication rate of 2.7%. In 87% of patients, central radicality was achieved with dissection at or beyond the level of complete exposure of the superior mesenteric vein. Mesocolic plane resection with an intact mesocolon was achieved in 75.9% of patients, as assessed through photographs. Metastatic lymph node distribution varied by tumor location and extent. Seven optimal clinically relevant endpoints and values were identified based on the analysis of complications in low-risk patients. CONCLUSIONS: Laparoscopic mCME for right-sided colon cancer produced favorable short-term postoperative outcomes. The identified optimal clinically relevant endpoints and values can serve as a reference for evaluating surgical performance of this procedure.

Histopathologic fate of resected pulmonary pure ground glass nodule: a systematic review and meta-analysis.

Background: Pure ground glass nodules (GGNs) have been increasingly detected through lung cancer screening programs. However, there were limited reports about pathologic characteristics of pure GGN. Here we presented a meta-analysis of the histologic outcome and proportion analysis of pure GGN. Methods: This study included previous pathological reports of pure GGN published until June 14, 2022 following a systematic search. A meta-analysis estimated the summary effects and between-study heterogeneity for pathologic diagnosis of invasive adenocarcinoma (IA), minimally invasive adenocarcinoma (MIA), adenocarcinoma in situ (AIS), and atypical adenomatous hyperplasia (AAH). Results: This study incorporated 24 studies with 3,845 cases of pure GGN that underwent surgery. Among them, sublobar resection was undertaken in 60% of the patients [95% confidence interval (CI): 38-78%, I2=95%]. The proportion of IA in cases of resected pure GGN was 27% (95% CI: 18-37%, I2=95%), and 50% of IA had non-lepidic predominant patterns (95% CI: 35-65%, I2=91%). The pooled proportions of MIA, AIS, and AAH were 24%, 36%, and 11%, respectively. Among nine studies with available clinical outcomes, no recurrences or metastases was observed other than one study. Conclusions: The portion of IA in cases of pure GGN is significantly larger that expected. More than half of them owned invasiveness components if MIA and IA were combined. Furthermore, there were quite number of lesions with aggressive histologic patterns other than the lepidic subtype. Therefore, further attempts are necessary to differentiate advanced histologic subtype among radiologically favorable pure GGN.

A phase 1/2a, dose-escalation, safety, and preliminary efficacy study of the RKP00156 vaginal tablet in healthy women and patients with cervical intraepithelial neoplasia 2.

OBJECTIVE: This study aimed to determine the safety and efficacy of the RKP00156 vaginal tablet, a CDK9 inhibitor, in healthy women and patients with cervical intraepithelial neoplasia grade 2 (CIN2). METHODS: We conducted a phase 1/2a clinical trial of RKP00156. In step 1, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered transvaginally to 24 healthy women. In step 2, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered once daily for 4 weeks in 62 patients with CIN2. The primary endpoints of this trial were the safety of RKP00156 and the change in the human papillomavirus (HPV) viral load. RESULTS: A total of 86 patients were enrolled and randomized. RKP00156 administration did not cause serious drug-associated adverse events (AEs). Although no significant difference in the HPV viral load was found between the experimental and placebo groups, a reduction in the HPV viral load was observed in the 25 mg-dose group (-98.61%; 95% confidence interval=-99.83%, 4.52%; p=0.046) after treatment completion in patients with a high HPV viral load, despite a lack of statistical power. No differences in histologic regression and HPV clearance were observed. CONCLUSION: The safety of RKP00156 was proved with no serious AEs. Although the study did not show any significance in histologic regression and HPV clearance, our findings indicate that RKP00156 may have a possibility of short-term inhibitory effect on HPV replication in patients with higher viral loads. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02139267.

Augmented interpretation of HER2, ER, and PR in breast cancer by artificial intelligence analyzer: enhancing interobserver agreement through a reader study of 201 cases.

BACKGROUND: Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) status. However, variability in interpretation among pathologists pose challenges to the accuracy of this classification. This study evaluates the role of artificial intelligence (AI) in enhancing the consistency of these evaluations. METHODS: AI-powered HER2 and ER/PR analyzers, consisting of cell and tissue models, were developed using 1,259 HER2, 744 ER, and 466 PR-stained immunohistochemistry (IHC) whole-slide images of breast cancer. External validation cohort comprising HER2, ER, and PR IHCs of 201 breast cancer cases were analyzed with these AI-powered analyzers. Three board-certified pathologists independently assessed these cases without AI annotation. Then, cases with differing interpretations between pathologists and the AI analyzer were revisited with AI assistance, focusing on evaluating the influence of AI assistance on the concordance among pathologists during the revised evaluation compared to the initial assessment. RESULTS: Reevaluation was required in 61 (30.3%), 42 (20.9%), and 80 (39.8%) of HER2, in 15 (7.5%), 17 (8.5%), and 11 (5.5%) of ER, and in 26 (12.9%), 24 (11.9%), and 28 (13.9%) of PR evaluations by the pathologists, respectively. Compared to initial interpretations, the assistance of AI led to a notable increase in the agreement among three pathologists on the status of HER2 (from 49.3 to 74.1%, p < 0.001), ER (from 93.0 to 96.5%, p = 0.096), and PR (from 84.6 to 91.5%, p = 0.006). This improvement was especially evident in cases of HER2 2+ and 1+, where the concordance significantly increased from 46.2 to 68.4% and from 26.5 to 70.7%, respectively. Consequently, a refinement in the classification of breast cancer molecular subtypes (from 58.2 to 78.6%, p < 0.001) was achieved with AI assistance. CONCLUSIONS: This study underscores the significant role of AI analyzers in improving pathologists' concordance in the classification of breast cancer molecular subtypes.

A well plate-based GelMA photo-crosslinking system with tunable hydrogel mechanical properties to regulate the PTH-mediated osteogenic fate.

Versatile and efficient regulation of the mechanical properties of the extracellular matrix is crucial not only for understanding the dynamic changes in biological systems, but also for obtaining precise and effective cellular responses in drug testing. In this study, we developed a well plate-based hydrogel photo-crosslinking system to effectively control the mechanical properties of hydrogels and perform high-throughput assays. We improved cell biocompatibility by using gelatin methacryloyl (GelMA) with a visible light photo-crosslinking method. Multiple cell-laden GelMA hydrogels were simultaneously and uniformly created using multi-arrayed 520 nm light-emitting diodes in a well plate format. The elastic modulus of the hydrogels can be widely adjusted (0.5-30 kPa) using a photo-crosslinking system capable of independently controlling the light intensity or exposure time for multiple samples. We demonstrate the feasibility of our system by observing enhanced bone differentiation of human mesenchymal stem cells (hMSCs) cultured on stiffer hydrogels. Additionally, we observed that the osteogenic fate of hMSCs, affected by the different mechanical properties of the gel, was regulated by parathyroid hormone (PTH). Notably, in response to PTH, hMSCs in a high-stiffness microenvironment upregulate osteogenic differentiation while exhibiting increased proliferation in a low-stiffness microenvironment. Overall, the developed system enables the generation of multiple cell-laden three-dimensional cell culture models with diverse mechanical properties and holds significant potential for expansion into drug testing.