Pulmonary sclerosing pneumocytoma mimicking a low-grade primary malignancy: A case report.

INTRODUCTION: Pulmonary sclerosing pneumocytoma (PSP) is a rare benign tumor classified as a pulmonary adenoma. It presents as a solitary pulmonary nodule without any specific findings, often posing a diagnostic challenge. We herein present a case of a PSP with a short volume doubling time (VDT) comparable to low-grade pulmonary malignancies. CASE PRESENTATION: A 27-year-old female presented to the emergency department with a fever that had persisted for the past two days. An incidental finding on chest screening computed tomography (CT) revealed a 9 mm pulmonary nodule with a round shape and smooth margin, suggestive of a benign etiology. Follow-up CT one year later revealed an enlarged nodule exhibiting a VDT of 249 days. A thoracoscopic lingulectomy was performed, and the histopathological examination revealed papillary and diffuse proliferation of epithelial-like cells. The epithelial cells were positive for cytokeratin (CKAE1/AE3) and thyroid transcription factor 1 (TTF1), whereas the stromal cells were positive for TTF1 but negative for CKAE1/AE3. Those results were consistent with the diagnosis of a PSP. DISCUSSION: PSPs typically present as incidental pulmonary nodules with no specific findings, often posing a diagnostic challenge. The radiographic features of PSPs have mainly been explored based on the morphological findings and metabolic activity, with limited research on their growth rate, represented by the VDT. CONCLUSION: PSPs may exhibit rapid growth, demonstrating a short VDT similar to that of low-grade pulmonary malignancies. Comprehensive diagnostic testing not based solely on the growth rate for this rare condition is essential.

Hepatic arterial infusion of autologous CD34+ cells for hepatitis C virus-related decompensated cirrhosis: A multicenter, open-label, exploratory randomized controlled trial.

Introduction: In this multicenter clinical study, we aimed to investigate the efficacy and safety of the transhepatic arterial administration of granulocyte-colony stimulating factor (G-CSF)-mobilized autologous peripheral blood (PB)-CD34+ cells compared with standard therapy in patients with decompensated cirrhosis type C. Methods: Patients were randomly assigned (2:1) to the CD34+ cell transplant (CD34+ cell) or standard-of-care (SOC) group and followed up for 52 weeks. The primary endpoints were the non-progression rate of Child-Pugh (CP) scores at 24 weeks post-enrollment and the safety of the protocol treatment. Results: Fourteen patients (CD34+ cell group: 10; SOC group: 4) were enrolled. CP scores at 24 weeks had a non-progression rate of 90% in the CD34+ cell group and 100% in the SOC group, with no significant difference between groups. Importantly, 4 out of 10 patients in the CD34+ cell group exhibited an improvement from decompensated to compensated cirrhosis, whereas all patients in the SOC group remained in decompensated cirrhosis. With regard to secondary endpoints, a trend toward increased serum albumin levels in the CD34+ cell group was noted. Serious adverse events (SAEs) occurred in three patients in the CD34+ cell group and in one patient in the SOC group. No causal relationship was observed between all SAEs and G-CSF, leukapheresis, or cell transplantation in the CD34+ cell group. No patients died and no hepatocellular carcinoma occurred within the study period. Conclusions: PB-CD34+ cell infusion therapy may have the potential to circumvent the decompensated stage of cirrhosis, thus avoiding the need for liver transplantation.

Ex-vivo expanded CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice.

BACKGROUND: In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34+ cells in treating MASH livers. MATERIALS AND METHODS: Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34+ cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation. RESULTS: Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/Irf7/Stat1/Cxcl10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver. CONCLUSIONS: These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.

Concurrent targeting of GSK3 and MEK as a therapeutic strategy to treat pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, drug discovery for PDAC treatment has proven complicated, leading to stagnant therapeutic outcomes. Here, we identify Glycogen synthase kinase 3 (GSK3) as a therapeutic target through a whole-body genetic screening utilizing a '4-hit' Drosophila model mimicking the PDAC genotype. Reducing the gene dosage of GSK3 in a whole-body manner or knocking down GSK3 specifically in transformed cells suppressed 4-hit fly lethality, similar to Mitogen-activated protein kinase kinase (MEK), the therapeutic target in PDAC we have recently reported. Consistently, a combination of the GSK3 inhibitor CHIR99021 and the MEK inhibitor trametinib suppressed the phosphorylation of Polo-like kinase 1 (PLK1) as well as the growth of orthotopic human PDAC xenografts in mice. Additionally, reducing PLK1 genetically in 4-hit flies rescued their lethality. Our results reveal a therapeutic vulnerability in PDAC that offers a treatment opportunity for patients by inhibiting multiple targets.

A solitary pulmonary nodule in a former glass blower mimicking a primary lung adenocarcinoma.

INTRODUCTION: Inhalation of silicon dioxide causes silicosis, a condition that may occur in various industries and work settings. Radiologic findings typically show numerous nodular opacities, while solitary pulmonary nodules are atypical for silicosis. PRESENTATION OF CASE: A 68-year-old woman, a former glassblower, presented with a left solitary pulmonary nodule (13 mm) on chest computed tomography. The nodule enlarged to 23 mm over 6 months, exhibiting an irregular shape, spiculated margin, and rapid growth with a doubling time of 186.4 days. She underwent a left upper lobectomy with a suspicion of lung cancer. The histopathological findings revealed peribronchial lymphocytic infiltration and granulomatous-like structures containing multinucleated giant cells and phagocytic crystalline foreign bodies. These findings were consistent with a foreign body reaction to the glass fragments. DISCUSSION: Inhaled glass fragments may present as a solitary pulmonary nodule after the retirement of a glass blower. Its behavior and radiological features mimicked a primary lung adenocarcinoma. CONCLUSION: Solitary pulmonary nodules due to inhaled glass fragments may mimic a primary lung adenocarcinoma. A definitive diagnosis requires a histological examination in this rare condition.

Mediastinal hematoma as an unusual intrathoracic manifestation of Boerhaave Syndrome: A case report.

INTRODUCTION: Boerhaave Syndrome (BS) is rare but life-threatening condition caused by a sudden increase in the intraluminal pressure due to vomiting. We present a case of BS manifesting as a posterior mediastinal hematoma, indicative of a potentially fatal condition. PRESENTATION OF CASE: A 51-year-old man presented with acute chest pain after vomiting. Enhanced Computed Tomography revealed mediastinal fluid with a left pleural effusion, leading to a diagnosis of BS. Emergency surgery revealed a posterior mediastinal hematoma with active bleeding due to a torn proper esophageal artery. Hemostasis and a wall repair were performed, and the patient was discharged uneventfully. DISCUSSION: This case highlights two important aspects. Firstly, a spontaneous esophageal perforation can manifest as a mediastinal hematoma due to the subpleural arterial injury, delaying bacterial spillage. While preoperative thoracentesis may not always diagnose BS accurately, bloody thoracic drainage can serve as an alternative diagnostic sign. Secondly, the mediastinal hematoma itself poses a serious risk, as it can lead to a catastrophic outcome even before bacterial contamination occurs, emphasizing the necessity of a timely surgical intervention in BS cases. CONCLUSION: BS can manifest as a mediastinal hematoma, and the absence of gastrointestinal content in the thoracic drainage does not rule out the possibility of BS. Prompt surgical intervention remains essential, as a mediastinal hematoma alone can result in a catastrophic outcome. This case highlights the significance of a comprehensive diagnostic assessment for BS.

Polypharmacy and Potentially Inappropriate Medications in Patients With Advanced Cancer: Prevalence and Associated Factors at the End of Life.

Background: Polypharmacy and potentially inappropriate medications (PIMs) impose a burden on patients with advanced cancer near the end of their lives. However, only a few studies have addressed factors associated with PIMs in such patients. Objective: To examine polypharmacy and factors associated with PIMs in end-of-life patients with advanced cancer. Design: Retrospective chart review. Setting/Subjects: We analyzed 265 patients with advanced cancer who died in a palliative care unit (PCU) or at home in a home medical care (HMC) from April 2018 to December 2022 in Japan. Measurements: Sociodemographic, clinical, and prescription data at the time of PCU admission or HMC initiation were collected from electronic medical records. PIMs were assessed using OncPal Deprescribing Guidelines. Results: Patients with advanced cancer with an average age of 76.3 years and median survival days of 20 were included in the analyses. The average number of medications was 6.4 (standard deviation = 3.4), and PIMs were prescribed to 50.2%. Frequent PIMs included antihypertensive medications, peptic ulcer prophylaxis, and dyslipidemia medications. A multivariate logistic regression analysis revealed that age ≥75 years (adjusted odds ratio [aOR] = 2.30, 95% confidence interval [CI] = 1.30-4.05), referral from an outpatient setting compared with inpatient setting (aOR = 2.06, 95% CI = 1.12-3.80), more than two comorbidities (aOR = 1.88, 95% CI = 1.08-3.29), and more than five medications (aOR = 1.84, 95% CI = 1.03-3.28) were associated with PIMs. Conclusions: Medication reconciliation is recommended at the time of transition to a PCU or HMC, especially for older patients with advanced cancer who were referred from an outpatient setting and present more comorbidities and prescriptions.

A tumor endothelial cell-specific microRNA replacement therapy for hepatocellular carcinoma.

Current approved anti-angiogenic drugs (AAD) for hepatocellular carcinoma (HCC) inhibit tumor angiogenesis, but affect the hepatic vasculature resulting in adverse effects. Tumor endothelial cells (TECs) differ from normal endothelial cells. In this study, we aimed to detect TEC-specific miRNAs and develop an anti-angiogenic treatment specific for TECs. We established HCC orthotopic mouse models. TEC-specific miRNAs were detected using a microRNA array. Finally, we evaluated the therapeutic effects of the TEC-specific miRNA agonist cocktail. In total, 260 TEC-specific genes were detected. Among the top ten downregulated TEC-specific miRNAs, miR-139-3p and 214-3p were important for the TEC phenotype. The TEC-specific microRNA agonist cocktail showed significant anti-tumor effects by inhibiting tumor angiogenesis without affecting hepatic vasculatures in HCC orthotopic mouse models. Moreover, it significantly downregulated tip-cell sprouting-related genes. We identified two downregulated TEC-specific miRNAs; microRNA replacement therapy, which targets the downregulated TEC-specific miRNAs, is an effective and promising treatment for HCC.

DIRECTEUR: transcriptome-based prediction of small molecules that replace transcription factors for direct cell conversion.

MOTIVATION: Direct reprogramming (DR) is a process that directly converts somatic cells to target cells. Although DR via small molecules is safer than using transcription factors (TFs) in terms of avoidance of tumorigenic risk, the determination of DR-inducing small molecules is challenging. RESULTS: Here we present a novel in silico method, DIRECTEUR, to predict small molecules that replace TFs for DR. We extracted DR-characteristic genes using transcriptome profiles of cells in which DR was induced by TFs, and performed a variant of simulated annealing to explore small molecule combinations with similar gene expression patterns with DR-inducing TFs. We applied DIRECTEUR to predicting combinations of small molecules that convert fibroblasts into neurons or cardiomyocytes, and were able to reproduce experimentally verified and functionally related molecules inducing the corresponding conversions. The proposed method is expected to be useful for practical applications in regenerative medicine. AVAILABILITY AND IMPLEMENTATION: The code and data are available at the following link: https://github.com/HamanoLaboratory/DIRECTEUR.git.

Impact of Neutrophil Extracellular Traps Identified by Citrullinated Histone H3 Immunohistochemistry for Postoperative Prognosis in Patients with Extrahepatic Cholangiocarcinomas.

BACKGROUND: Neutrophil extracellular traps (NETs) are extracellular chromatin structures composed of cytoplasmic, granular, and nuclear components of neutrophils. Recently, NETs have received much attention for their role in tumor biology; however, their impact on the postoperative prognosis of patients with extrahepatic cholangiocarcinomas (EHCCs) remains unclear. The purpose of this study was to clarify the impact of NETs identified by immunohistochemical citrullinated histone H3 (Cit-H3) staining on postoperative overall survival (OS) in patients with perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC). METHODS: This study included 318 patients with EHCC (PHCC, n = 192; DCC, n = 126) who underwent surgical resection with curative intent. Neutrophils and NETs were identified by immunohistochemistry using antibodies against CD15 and Cit-H3, respectively. Based on the distribution of CD15 and Cit-H3 expression in the tumor bed, the patients were classified into four groups: one negative group and three subgroups of the positive group (diffuse, intermediate, and focal subgroups). RESULTS: No significant difference was found in the postoperative OS rate depending on the distribution of CD15 expression in patients with PHCC or DCC. However, the three subgroups with positive Cit-H3 expression had significantly poorer OS than the negative group for both PHCC and DCC. Moreover, positive Cit-H3 was an independent OS factor in the multivariable analyses of PHCC (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.11-2.59, P = 0.0115) and DCC (HR 2.03; 95% CI 1.21-3.42, P = 0.0057). CONCLUSIONS: The presence of NETs in the tumor microenvironment may have adverse prognostic effects in patients with EHCCs.

Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Combination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME). METHODS: We established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database. RESULTS: The number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells. CONCLUSIONS: In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

The Short- and Long-Term Surgical Results of Consecutive Hepatopancreaticoduodenectomy for Wide-Spread Biliary Malignancy.

BACKGROUND: Cancer-free resection (R0) is one of the most important factors for the long-term survival of biliary carcinoma. For some patients with widespread invasive cancer located between the hilar and intrapancreatic bile duct, hepatopancreaticoduodenectomy (HPD) is considered a radical surgery for R0 resection. However, HPD is associated with high morbidity and mortality rates. Furthermore, previous reports have not shown lymph node metastasis (LNM) status, such as the location or number, which could influence the prognosis after HPD. In this study, first, we explored the prognostic factors for survival, and second, we evaluated whether the LNM status (number and location of LNM) would influence the decision on surgical indications in patients with widely spread biliary malignancy. METHODS: We retrospectively reviewed the medical records of 54 patients who underwent HPD with hepatectomy in ≥2 liver sectors from January 2003 to December 2021 (HPD-G). We also evaluated 54 unresectable perihilar cholangiocarcinoma patients who underwent chemotherapy from January 2010 to December 2021 (CTx-G). RESULTS: R0 resection was performed in 48 patients (89%). The median survival time (MST) and 5-year overall survival rate of the HPD-G and CTx-G groups were 36.9 months and 31.1%, and 19.6 months and 0%, respectively. Univariate and multivariate analyses showed that pathological portal vein involvement was an independent prognostic factor for survival (MST: 18.9 months). Additionally, patients with peripancreatic LNM had worse prognoses (MST: 13.3 months) than CTx-G. CONCLUSIONS: Patients with peripancreatic LNM or PV invasion might be advised to be excluded from surgery-first indications for HPD.

Reconsidering resectable oncological conditions in pancreatic tail cancer: A multicenter retrospective study on prognostic factors in pancreatic tail cancer after resection (HOPS Pt-01).

BACKGROUND: Pancreatic tail cancer (Pt-PC) is generally considered resectable when metastasis is absent, but doubts persist in clinical practice due to the variability in local tumor extent. We conducted a multicenter retrospective study to comprehensively identify prognostic factors associated with Pt-PC after resection. METHODS: We enrolled 100 patients that underwent distal pancreatectomy. The optimal combination of factors influencing relapse-free survival (RFS) was determined using the maximum likelihood method (MLM) and corrected Akaike and Bayesian information criteria (AICc and BIC). Prognostic elements were then validated to predict oncological outcomes. RESULTS: Therapeutic interventions included neoadjuvant treatment in 16 patients and concomitant visceral resection (CVR) in 37 patients; 89 patients achieved R0. Median RFS and OS after surgery were 23.1 and 37.1 months, respectively. AICc/BIC were minimized in the model with ASA-PS (≥2), CA19-9 (≥112 U/mL at baseline, non-normalized postoperatively), need for CVR, 6 pathological items (tumor diameter ≥19.5 mm, histology G1, invasion of the anterior pancreatic border, splenic vein invasion, splenic artery invasion, lymph node metastasis), and completed adjuvant treatment (cAT) for RFS. Regarding the predictive value of these 11 factors, area under the curve was 0.842 for 5-year RFS. Multivariate analysis of these 11 factors showed that predictors of RFS include CVR (hazard ratio, 2.13; 95 % confidence interval, 1.08-4.19; p = 0.028) and cAT (0.38, 0.19-0.76; p = 0.006). CONCLUSIONS: The MLM identified certain Pt-PC cases warranting consideration beyond resectable during clinical management. Particular attention should be paid to conditions requiring CVR, even though immortal time bias remains unresolved with adjuvant treatment.

Validation study for prognostic scoring system for perihilar cholangiocarcinoma surgery using preoperative factors.

PURPOSE: Recently, systemic inflammatory responses (SIR) have been shown to play a pivotal role in the development and progression of cancer. We previously reported that four factors, serum carcinoembryonic antigen (> 7 ng/dL), serum albumin (< 3.5 g/dL), C-reactive protein (> 0.5 mg/dL), and platelet-lymphocyte ratio (PLR; > 150), were independent prognostic factors after perihilar cholangiocarcinoma (PHCC) surgery. We also advocated a prognosis predictive preoperative prognostic score (PPS) using these four factors and showed that PPS could predict patients' prognosis on survival. This retrospective study sought to validate preoperatively available prognostic factors for survival after major hepatectomy as reported previously, including PPS for PHCC. METHODS: We retrospectively validated our PPS score and reported SIR scoring systems using the data of 125 consecutive patients who underwent PHCC surgery from January 2010 to November 2020. RESULTS: PPS was an independent preoperative prognostic factors for survival. The T and N categories were independent prognostic factors. Other SIR scores were not independent preoperative factors in the univariate analysis. Among SIR scores, only the PPS was found to be associated with OS and disease-free survival. The PPS was also associated with histopathological factors (T and N categories). CONCLUSION: PPS could be useful in predicting long-term survival after PHCC and may be a more useful scoring system than other SIR systems.

[Detection and Application of Allostatic Load through Internet of Things Measurements].

Allostatic load refers to a vulnerable state of the nervous system caused by chronic or repeated exposure to challenges of daily life (e.g., psychological stressors) and considered to indicate risk of a transition to pathological state. In this paper, we first introduce a traditional method of assessing allostatic load that utilizes multiple biomarkers. Next, we demonstrate the potential of the Internet of Things (IoT) data sampling method to detect and control the vulnerable state in daily life.

Rhythm Receptive Fields in Striatum of Mice Executing Complex Continuous Movement Sequences.

By the use of a novel experimental system, the step-wheel, we investigated the neural underpinnings of complex and continuous movements. We recorded neural activities from the dorsolateral striatum and found neurons sensitive to movement rhythm parameters. These neurons responded to specific combinations of interval, phase, and repetition of movement, effectively forming what we term "rhythm receptive fields." Some neurons even responsive to the combination of movement phases of multiple body parts. In parallel, cortical recordings in sensorimotor areas highlighted a paucity of neurons responsive to multiple parameter combinations, relative to those in the striatum. These findings have implications for comprehending motor coordination deficits seen in brain disorders including Parkinson's disease. Movement encoding by rhythm receptive fields should streamline the brain's capacity to encode temporal patterns, help to resolve the degrees of freedom problem. Such rhythm fields hint at the neural mechanisms governing effective motor control and processing of rhythmic information.

Anti-PD-L1 antibodies promote cellular proliferation by activating the PD-L1-AXL signal relay in liver cancer cells.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are emerging treatments for advanced hepatocellular carcinoma (HCC); however, evidence has shown they may induce hyperprogressive disease via unexplained mechanisms. METHODS: In this study, we investigated the possible stimulative effect of ICIs on programmed cell death-ligand 1 (PD-L1)-harboring liver cancer cells under immunocompetent cell-free conditions. RESULTS: The sarcomatous HAK-5 cell line displayed the highest expression of PD-L1 among 11 human liver cancer cell lines used in this study. HLF showed moderate expression, while HepG2, Hep3B, and HuH-7 did not show any. Moreover, sarcomatous HCC tissues expressed high levels of PD-L1. We observed approximately 20% increase in cell proliferation in HAK-5 cells treated with anti-PD-L1 antibodies, such as durvalumab and atezolizumab, for 48 h compared with that of those treated with the control IgG and the anti-PD-1 antibody pembrolizumab. No response to durvalumab or atezolizumab was shown in PD-L1-nonexpressing cells. Loss-of-function and gain-of-function experiments for PD-L1 in HAK-5 and HepG2 cells resulted in a significant decrease and increase in cell proliferation, respectively. Phosphorylated receptor tyrosine kinase array and immunoprecipitation revealed direct interactions between PD-L1 and AXL in tumor cells. This was stabilized by extrinsic anti-PD-L1 antibodies in a glycosylated PD-L1-dependent manner. Activation of AXL, triggering signal relay to the Akt and Erk pathways, boosted tumor cell proliferation both in vitro and in xenografted tumors in NOD/SCID mice. CONCLUSION: Collectively, this suggests that anti-PD-L1 antibodies stimulate cell proliferation via stabilization of the PD-L1-AXL complex in specific types of liver cancer, including in HCC with mesenchymal components. SIGNIFICANCE: Therapeutic anti-PD-L1 antibodies promote cell proliferation by stabilizing the PD-L1-AXL complex in PD-L1-abundant neoplasms, including in HCC with mesenchymal components. Such a mechanism may contribute to the development of hyperprogressive disease.

Perovskite Solar Cell Using Isonicotinic Acid as a Gap-Filling Self-Assembled Monolayer with High Photovoltaic Performance and Light Stability.

High photovoltaic performance and light stability are required for the practical outdoor use of lead-halide perovskite solar cells. To improve the light stability of perovskite solar cells, it is effective to introduce a self-assembled monolayer (SAM) between the carrier transport layer and the perovskite layer. Several alternative approaches in their molecular design and combination with multiple SAMs support high photovoltaic conversion efficiency (PCE). Herein, we report a new structure for improving both PCE and light stability, in which the surface of an electron transport layer (ETL) was modified by combining a fullerene-functionalized self-assembled monolayer (C60SAM) and a suitable gap-filling self-assembled monolayer (GFSAM). Small-sized GFSAMs can enter the gap space of the C60SAM and terminate the unterminated sites on the ETL surface. The best GFSAM in this study was formed using an isonicotinic acid solution. After a light stability test for 68 h at 50 °C under 1 sun illumination, the best cell with C60SAM and GFSAM showed a PCE of 18.68% with a retention rate of over 99%. Moreover, following outdoor exposure for six months, the cells with C60SAM and GFSAM exhibited almost unchanged PCE. From the valence band spectra of the ETLs obtained using hard X-ray photoelectron spectroscopy, we confirmed a decrease in the offset at the ETL/perovskite interface owing to the additional GFSAM treatment on the C60SAM-modified ETL surface. Time-resolved microwave conductivity measurements demonstrated that the additional GFSAM improved electron extraction at the C60SAM-modified ETL/perovskite interface.