A clinician's perspective on boron neutron capture therapy: promising advances, ongoing trials, and future outlook.

PURPOSE: This comprehensive review aims to provide a unique clinical perspective on the latest advances and ongoing boron neutron capture therapy (BNCT) trials for various cancers. METHODS: We critically analyzed clinical data from BNCT trials for head and neck cancer, glioblastoma, melanoma, meningioma, breast cancer, and liver tumors. We investigated differences in tumor responses and normal tissue toxicities among trials and discussed potential contributing factors. We also identified the limitations of early BNCT trials and proposed strategies to optimize future trial design. RESULTS: BNCT has shown promising results in treating head and neck cancer, with high response rates and improved survival in patients with recurrent disease. In glioblastoma, BNCT combined with surgery and chemotherapy has demonstrated survival benefits compared to standard treatments. BNCT has also been successfully used for recurrent high-grade meningiomas and shows potential for melanomas, extramammary Paget's disease, and liver tumors. However, differences in tumor responses and toxicities were observed among trials, potentially attributable to variations in treatment protocols, patient characteristics, and evaluation methods. CONCLUSIONS: BNCT is a promising targeted radiotherapy for various cancers. Further optimization and well-designed randomized controlled trials are needed to establish its efficacy and safety. Future studies should focus on standardizing treatment protocols and addressing limitations to guide clinical decision-making and research priorities.

From Bone Remodeling to Wound Healing: An miR-146a-5p-Loaded Nanocarrier Targets Endothelial Cells to Promote Angiogenesis.

Wound healing is a complex challenge that demands urgent attention in the clinical realm. Efficient angiogenesis is a pivotal factor in promoting wound healing. microRNA-146a (miR-146a) inhibitor has angiogenic potential in the periodontal ligament. However, free microRNAs (miRNAs) are poorly delivered into cells due to their limited tissue specificity and low intracellular delivery efficiency. To address this hurdle, we developed a nanocarrier for targeted delivery of the miR-146a inhibitor into endothelial cells. It is composed of a polyethylenimine (PEI)-modified mesoporous silica nanoparticle (MSN) core and a pentapeptide (YIGSR) layer that recognizes endothelial cells. In vitro, we defined that the miR-146a inhibitor and adiponectin (ADP) can modulate angiogenesis and the remodeling of periodontal tissues by activating the ERK and Akt signaling pathways. Then, we confirm the specificity of YIGSR to endothelial cells, and importantly, the nanocarrier effectively delivers the miR-146a inhibitor into endothelial cells, promoting angiogenesis. In a C57 mouse skin wound model, the miR-146a inhibitor is successfully delivered into endothelial cells at the wound site using the nanocarrier, resulting in the formation of new blood vessels with strong CD31 expression. Additionally, no significant differences are found in the expression levels of inflammatory markers interleukin-6 and tumor necrosis factor-α. This outcome not only brings new strategies for angiogenesis but also exhibits broader implications for bone remodeling and wound healing. The breakthrough holds significance for future research and clinical interventions.

Study on breast cancerization and isolated diagnosis in situ by HOF-ATR-MIR spectroscopy with deep learning.

Mid-infrared (MIR) spectroscopy can characterize the content and structural changes of macromolecular components in different breast tissues, which can be used for feature extraction and model training by machine learning to achieve accurate classification and recognition of different breast tissues. In parallel, the one-dimensional convolutional neural network (1D-CNN) stands out in the field of deep learning for its ability to efficiently process sequential data, such as spectroscopic signals. In this study, MIR spectra of breast tissue were collected in situ by coupling the self-developed MIR hollow optical fiber attenuated total reflection (HOF-ATR) probe with a Fourier transform infrared spectroscopy (FTIR) spectrometer. Staging analysis was conducted on the changes in macromolecular content and structure in breast cancer tissues. For the first time, a trinary classification model was established based on 1D-CNN for recognizing normal, paracancerous and cancerous tissues. The final predication results reveal that the 1D-CNN model based on baseline correction (BC) and data augmentation yields more precise classification results, with a total accuracy of 95.09%, exhibiting superior discrimination ability than machine learning models of SVM-DA (90.00%), SVR (88.89%), PCA-FDA (67.78%) and PCA-KNN (70.00%). The experimental results suggest that the application of 1D-CNN enables accurate classification and recognition of different breast tissues, which can be considered as a precise, efficient and intelligent novel method for breast cancer diagnosis.

A detrimental role of endothelial S1PR2 in cardiac ischemia-reperfusion injury via modulating mitochondrial dysfunction, NLRP3 inflammasome activation, and pyroptosis.

Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effects on cardiovascular functions via S1P receptors, but its effects on cardiac I/R injury are not fully understood. Plasma lipidomics analysis by mass spectrometry revealed that sphingosine lipids, including sphingosine 1-phosphate (S1P), were significantly down-regulated following cardiac I/R injury in mice. The reduced S1P levels were also observed in the plasma of coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI) compared with those without PCI. We found that S1P exerted a cardioprotective effect via endothelial cell (EC)-S1PR1, whereas EC-S1PR2 displayed a detrimental effect on cardiac I/R. Our data showed that EC-specific S1pr2 loss-of-function significantly lessened inflammatory responses and diminished cardiac I/R injury, while EC-specific S1pr2 gain-of-function aggravated cardiac I/R injury. Mechanistically, EC-S1PR2 initiated excessive mitochondrial fission and elevated ROS production via RHO/ROCK1/DRP1 pathway, leading to NLRP3 inflammasome activation and subsequent cell pyroptosis, thereby exacerbating inflammation and I/R injuries. Furthermore, RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA to specifically knockdown S1PR2 in endothelial cells significantly ameliorated cardiac I/R injury. Taken together, our investigations demonstrate that EC-S1PR2 induces excessive mitochondrial fission, which results in NLRP3 inflammasome activation and subsequently triggers cell pyroptosis, ultimately exacerbating inflammatory responses and aggravating heart injuries following I/R.

Cbfß regulates Wnt/ß-catenin, Hippo/Yap, and Tgfß signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis.

As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that CBFB (subunit of a heterodimeric Cbfß/Runx1, Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion of Cbfb in tamoxifen-induced Cbfbf/f;Col2a1-CreERT mice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed that Cbfß deficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/Yap signaling and Tgfß signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreased Cbfß and Yap expression and increased active ß-catenin expression in articular cartilage, while local AAV-mediated Cbfb overexpression promoted Yap expression and diminished active ß-catenin expression in OA lesions. Remarkably, AAV-mediated Cbfb overexpression in knee joints of mice with OA showed the significant protective effect of Cbfß on articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression of Cbfß may be the cause of OA. Moreover, Local admission of Cbfb may rescue and protect OA through decreasing Wnt/ß-catenin signaling, and increasing Hippo/Yap signaling and Tgfß/Smad2/3 signaling in OA articular cartilage, indicating that local Cbfb overexpression could be an effective strategy for treatment of OA.

Effect of preheating-induced denaturation of proteins and oleosomes on the structure of protein and soymilk properties.

In this paper, effects of preheating-induced denaturation of proteins and oleosomes on protein structure and soymilk quality were studied. The protein in soybeans baked at 55 °C (B-55) and 85 °C (B-85) showed an increase of ß-sheet content by 3.2 % and a decrease of α-helix content by 3.3 %, indicating that proteins were gradually unfolded while oleosomes remained intact. The protein resisted thermal denaturation during secondary heating, and soymilks were stable as reflected by a small d3,2 (0.4 µm). However, raw soymilk from soybeans baked at 115 °C (B-115), steamed for 1 min (ST-1) and 5 min (ST-5) presented oleosomes destruction and lipids aggregates. The proteins were coated around the oil aggregates. The ß-turn content from soybeans steamed for 10 min (ST-10) increased by 9.5 %, with a dense network where the OBs were tightly wrapped, indicating the serious protein denaturation. As a result, the soymilks B-115 or steamed ones were unstable as evidenced by the serious protein aggregation and larger d3,2 (5.65-12.48 µm). Furthermore, the soymilks were graininess and the protein digestion was delayed due to the formation of insoluble protein aggregates. The flavor and early-stage lipid digestion of soymilk from steamed soybeans was improved owing to lipid release.

Inhibitory effect of flavonoids on multidrug and toxin extrusion protein 1 function: Implications for food/herb-drug interaction and drug-induced kidney injury.

Multidrug and toxin extrusion protein 1 (MATE1), an efflux transporter mainly expressed in renal proximal tubules, mediates the renal secretion of organic cationic drugs. The inhibition of MATE1 will impair the excretion of drugs into the tubular lumen, leading to the accumulation of nephrotoxic drugs in the kidney and consequently potentiating nephrotoxicity. Screening and identifying potent MATE1 inhibitors can predict or minimize the risk of drug-induced kidney injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions. Our objective was to investigate the inhibitory effects of flavonoids on MATE1 in vitro and in vivo and to assess the effects of flavonoids on cisplatin-induced kidney injury. Thirteen flavonoids exhibited significant transport activity inhibition (>50%) on MATE1 in MATE1-MDCK cells. Among them, the six strongest flavonoid inhibitors, including irisflorentin, silymarin, isosilybin, sinensetin, tangeretin, and nobiletin, markedly increased cisplatin cytotoxicity in these cells. In cisplatin-induced in vivo renal injury models, irisflorentin, isosilybin, and sinensetin also increased serum creatinine and blood urea nitrogen levels to different degrees, especially irisflorentin, which exhibited the most potent nephrotoxicity with cisplatin. The pharmacophore model indicated that the hydrogen bond acceptors at the 3, 5, and 7 positions may play a critical role in the inhibitory effect of flavonoids on MATE1. Our findings provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions and avoiding the exacerbation of drug-induced kidney injury via MATE1 mediation.

Enhancing the nonlinear rheological property and digestibility of mung bean flour gels using controlled microwave treatments: Effect of starch debranching and protein denaturation.

In this study, we examined the possibility of using industrial microwave processing to enhance the gelling properties and reduce the starch digestibility of mung bean flour (MBF). MBF (12.6 % moisture) was microwaved at a power of 6 W/g to different final temperatures (100-130 °C), and then its structural and functional properties were characterized. The microwave treatment had little impact on the crystalline structure or amylose content of the starch, but it roughened the starch granule surfaces and decreased the short-range ordered structure and degree of branching. In addition, the extent of mung bean protein denaturation caused by the microwave treatment depended on the final temperature. Slightly denaturing the proteins (100 °C) did not affect the nature of the gels (protein phase dispersed in a starch phase) but the gel network became more compact. Moderately denaturing the proteins (110-120 °C) led to more compact and homogeneous starch-protein double network gels. Excessive protein denaturation (130 °C) caused the gel structure to become more heterogeneous. As a result, the facilitated tangles between starch chains by more linear starch molecules after debranching, and the protein network produced by moderate protein denaturation led to the formation of stronger gel and the improvement of plasticity during large deformation (large amplitude oscillatory shear-LAOS). Starch recrystallization, lipid complexion, and protein network retard starch digestion in the MBF gels. In conclusion, an industrial microwave treatment improved the gelling and digestive properties of MBF, and Lissajous curve has good adaptability in characterizing the viscoelasticity of gels under large deformations.

Synovial fluid research based on SERS and SERRS for enhanced detection of biomarkers in staged osteoarthritis.

Surface-enhanced (resonance) Raman scattering (SER(R)S) can extremely enhance Raman intensity of samples, which is helpful for detecting synovial fluid (SF) that does not show Raman activity under normal conditions. In this study, SER(R)S spectra of SF from three different osteoarthritis (OA) stages were collected and analyzed for OA progress, finding that the content of collagen increased throughout the disease, while non-collagen proteins and polysaccharides decreased sharply at advanced OA stage accompanied by the increase of phospholipid. The spectral features and differences were enhanced by salting-out and centrifugation. Much more information on biomolecules at different OA stages was disclosed by using SERRS for the first time, these main trace components (ß-carotene, collagen, hyaluronic acid, nucleotide, and phospholipid) can be used as potential biomarkers. It indicates that SERRS has a more comprehensive ability to assist SERS in seeking micro(trace) biomolecules as biomarkers and facilitating accurate and efficient diagnosis and mechanism research of OA.

Deficiency of Cbfß in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFß, and Wnt/ß-catenin signaling pathways.

Osteoarthritis (OA) is the most prevalent degenerative joint disorder, causing physical impairments among the elderly. Core binding factor subunit ß (Cbfß) has a critical role in bone homeostasis and cartilage development. However, the function and mechanism of Cbfß in articular cartilage and OA remains unclear. We found that Cbfßf/fAggrecan-CreERT mice with Cbfß-deficiency in articular cartilage developed a spontaneous osteoarthritis-like phenotype with articular cartilage degradation. Immunofluorescence staining showed that Cbfßf/fAggrecan-CreERT mice exhibited a significant increase in the expression of articular cartilage degradation markers and inflammatory markers in the knee joints. RNA-sequencing analysis demonstrated that Cbfß orchestrated Hippo/Yap, TGFß/Smad, and Wnt/ß-catenin signaling pathways in articular cartilage, and Cbfß deficiency resulted in the abnormal expression of downstream genes involved in maintaining articular cartilage homeostasis. Immunofluorescence staining results showed Cbfß deficiency significantly increased active ß-catenin and TCF4 expression while reducing Yap, TGFß1, and p-Smad 2/3 expression. Western blot and qPCR validated gene expression changes in hip articular cartilage of Cbfß-deficient mice. Our results demonstrate that deficiency of Cbfß in articular cartilage leads to an OA-like phenotype via affecting Hippo/Yap, TGFß, and Wnt/ß-catenin signaling pathways, disrupting articular cartilage homeostasis and leading to the pathological process of OA in mice. Our results indicate that targeting Cbfß may be a potential therapeutic target for the design of novel and effective treatments for OA.

Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic ß cells.

Pancreatic ß cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as ß cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in ß cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in ß cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in ß cells.

lncRNA JPX Promotes Tumor Progression by Interacting with and Destabilizing YTHDF2 in Cutaneous Melanoma.

Aberrant long noncoding RNAs just proximal to Xist (lncRNA JPX) expression levels have been detected in multiple tumors. However, whether JPX is involved in melanoma progression remains unclear. Our study showed that JPX expression is significantly increased in melanoma tissues and cell lines. To clarify the effect of JPX on cutaneous melanoma, we successfully generated JPX-overexpressing or JPX-knockdown A375 and A2058 cells. CCK-8, colony formation EdU, Transwell, and cell-cycle phase assays were performed, and subcutaneously implanted tumor models were used to determine the function of JPX in cutaneous melanoma. The results showed that JPX knockdown reduced the proliferation and migration of malignant melanoma cells both in vitro and in vivo. To further elucidate the molecular mechanism of JPX-induced cutaneous melanoma deterioration, we performed RNA pull-down, RNA immunoprecipitation, coimmunoprecipitation, Western blot, and RNA-sequence analyses. JPX can directly interact with YTHDF2 and impede the protection of YTHDF2 from ubiquitin-specific protease 10 (USP10), which promotes its deubiquitination. Thus, JPX decreases protein stability and promotes the degradation of YTHDF2, thereby stabilizing BMP2 mRNA and activating AKT phosphorylation. Overall, our study revealed a novel effect of JPX on YTHDF2 ubiquitination, suggesting the possibility of blocking the JPX/USP10/YTHDF2/BMP2 axis as a prospective therapeutic approach for cutaneous melanoma. IMPLICATIONS: This study highlights the ubiquitination effect of USP10 and JPX on YTHDF2 in cutaneous melanoma, and proposes that the JPX/USP10/YTHDF2/BMP2 axis may be a prospective therapeutic target for cutaneous melanoma.

Graphene-Wrapped ZnO Nanocomposite with Enhanced Room-Temperature Photo-Activated Toluene Sensing Properties.

Graphene-wrapped ZnO nanocomposites were fabricated by a simple solvothermal technology with a one-pot route. The structure and morphology of these as-fabricated samples were systematically characterized. The adding of graphene enhanced the content of the oxygen vacancy defect of the sample. All gas-sensing performances of sensors based on as-prepared samples were thoroughly studied. Sensors displayed an ultrahigh response and exceptional selectivity at room temperature under blue light irradiation. This excellent and enhanced toluene gas-sensing property was principally attributed to the synergistic impacts of the oxygen vacancy defect and the wrapped graphene in the composite sensor. The photo-activated graphene-wrapped ZnO sensor illustrated potential application in the practical detection of low concentrations of toluene under explosive environments.

Comparison of extraction processes, characterization and intestinal protection activity of Bletilla striata polysaccharides.

We optimized the extraction process of Bletilla striata polysaccharides using orthogonal design, Box-Behnken design (BBD), and genetic algorithm-back propagation (GA-BP), then compared and evaluated them to confirm that the combination of BBD and GA-BP neural networks was capable of increasing polysaccharide yields and antioxidant activity. The optimal extraction parameters were as follows: liquid-to-solid ratio of 15 mL/g, extraction power of 450 W, and extraction time of 34 min. Under these conditions, the polysaccharide yield and antioxidant activity were 8.29 ± 0.50 % and 26.20 ± 0.28 (mM FE/mg). Subsequently, the polysaccharide was purified to obtain purified Bletilla striata polysaccharides 1 (pBSP1) with a Mw of 255.172 kDa. Scanning electron microscope (SEM), ultraviolet-visible detector (UV), fourier transform infrared spectrometer (FTIR), high performance liquid chromatography (HPLC), X-ray diffraction (XRD), nuclear magnetic resonance (NMR) and periodate oxidation were used to analyze the structure of pBSP1. The results showed pBSP1 had a smooth surface and a rough interior, with a composition of α-D conformation glucose (18.23 %) and ß-D conformation mannose (53.77 %), and an amorphous crystal structure. According to the results of thermogravimetric and rheological tests, pBSP1 exhibits good thermal stability and viscoelastic behavior. Furthermore, pBSP1 protected lipopolysaccharide (LPS)-induced GES - 1 and Caco2 cells, the results showed pBSP1(400 µg/mL) lowered TEER synthesis in Caco2 cells as well as apoptosis and reactive oxygen species (ROS) production in both cells, indicating that pBSP1 may have an intestine protective effect.

Effect of femtosecond laser process parameters on the thermal denaturation degree of skin tissue.

The influence of femtosecond laser parameters on the degree of thermal denaturation was studied experimentally. The relationship between the degree of thermal denaturation and the characteristic parameters of skin microstructure and the secondary structure of skin tissue proteins in characterizing the degree of thermal damage was analyzed. The results showed the interaction of laser power, laser power, and scanning speed had a significant effect on the degree of thermal denaturation; greater degrees of thermal denaturation were associated with larger second-order moments of the texture angle of the skin microtissue and smaller entropy values and contrast, indicating a greater degree of thermal damage; and higher peak temperature, the lower peak intensity of Raman spectra, decrease in the percentage area of α-helix fitted curves and increase in the percentage area of ß-sheet and ß-turn fitted curves indicate that the protein is denatured to a large extent that means thermal damage is large.

Cbfß regulates Wnt/ß-catenin, Hippo/Yap, and TGFß signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis.

As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that Cbfß, (subunit of a heterodimeric Cbfß/Runx1,Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion of Cbfß in tamoxifen-induced Cbfßf/fCol2α1-CreERT mice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed that Cbfß deficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/YAP signaling and TGF-ß signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreased Cbfß and Yap expression and increased active ß-catenin expression in articular cartilage, while local AAV-mediated Cbfß overexpression promoted Yap expression and diminished active ß-catenin expression in OA lesions. Remarkably, AAV-mediated Cbfß overexpression in knee joints of mice with OA showed the significant protective effect of Cbfß on articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression of Cbfß may be the cause of OA. Moreover, Local admission of Cbfß may rescue and protect OA through decreasing Wnt/ß-catenin signaling, and increasing Hippo/Yap signaling and TGFß/Smad2/3 signaling in OA articular cartilage, indicating that local Cbfß overexpression could be an effective strategy for treatment of OA.

Experimental study on the mechanical properties and thermal damage of laser welding the ruptured flexor digitorum longus tendons.

To investigate the influence of laser parameters on the performance of tendon tissue, experiments were conducted and the process of laser-assisted tendon welding was studied. Several conclusions were drawn by analyzing the effects of laser parameters on the tensile strength, microstructure, and collagen content of tendon tissue incisions. The optimal parameters for laser welding tendon tissue were found to be a laser power of 5 W, a scanning speed of 150 mm/s, and a defocus amount of 0 mm, resulting in a laser energy density of 32.164 J/cm2 . At these parameters, the percentage of inactivated cells due to thermal damage was only 23.78%, and the tensile strength of the tendon tissue incisions reached 0.61 MPa. Additionally, the collagen content around the incision was measured to be 33.679%, composed of type I and type III collagens, with the latter accounting for 50.714% of the total collagen content.

Lichenoid dermatitis following PD-1 inhibitor-induced toxic epidermal necrolysis: a case report and literature review.

Immune checkpoint inhibitors such as anti-PD-1 receptor antibodies have been shown to be effective in patients with advanced gastric cancer. However, there is a growing concern about immune-related adverse events. A case of a patient with gastric adenocarcinoma who developed toxic epidermal necrolysis (TEN) induced by sintilimab and subsequently developed lichenoid dermatitis is reported. TEN was diagnosed according to a history of sintilimab use, clinical symptoms and physical examination. During hospitalization, the patient developed recurrent fever caused by bacteremia and recovered from TEN after anti-infection and anti-inflammatory treatments. However, when TEN was controlled, the patient developed the lesional manifestations of lichenoid dermatitis. To date, no cases of lichenoid dermatitis after TEN have been reported following the use of PD-1 inhibitors.

PD-1 inhibitors are drugs that help fight stomach cancer but can sometimes cause skin problems. Most skin problems are minor and do not have a serious impact on the patient's health. However, life-threatening skin problems such as toxic epidermal necrolysis (TEN) can sometimes happen. This case report describes a patient with stomach cancer who had lichenoid dermatitis (another skin problem) after TEN, following the treatment of his cancer with PD-1 inhibitors. To the best of our knowledge, it is very rare to experience both skin problems after treating cancer with PD-1 inhibitors. This rare phenomenon is reported to bring more attention to it. More research is needed to determine how to treat this problem better.

Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF-ß signaling pathway.

The hepatic vascular niche plays an important role in the pathological process of liver fibrosis. Liver sinusoidal endothelial cells (LSECs) predominantly compose hepatic vascular niches. Endothelial cell (EC)-expressing sphingosine 1-phosphate receptor 2 (S1pr2) plays an essential role in the regulation of vascular functions. Nevertheless, it remains unknown whether liver LSEC-S1pr2 might modulate pathological liver fibrosis. In this study, liver fibrosis was induced by hepatotoxin carbon tetrachloride (CCl4 ). The expression of S1pr2 is significantly downregulated in liver sinusoidal endothelial cells after CCl4 treatment. The loss of S1pr2 in LSECs significantly alleviated liver fibrosis after chronic insult, whereas the overexpression of S1pr2 in LSECs accentuated liver fibrogenesis. In vivo experiments further revealed that the deficiency of S1pr2 in LSECs dampened hepatic stellate cell (HSC) activation, while overexpression of S1pr2 in LSECs enhanced HSC activation with more extracellular matrix component production. Mechanistically, LSEC-S1pr2 activates the YAP signaling pathway to potentiate the transactivation of TGF-ß, which acts on HSCs in a paracrine manner, and thus aggravated liver fibrosis. Taken together, our results uncover a novel pathological mechanism of liver fibrosis in which LSEC-S1pr2 plays an important role in modulating the development of liver fibrosis, providing a future novel therapy target against liver fibrogenesis.