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Background To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors. Methods The BrdU assay, Annexin-V/PI assay, TRAP staining and immunofluorescence were performed to explore the effect of LA on the proliferation, apoptosis and differentiation of OC precursors in vitro and in vivo. Flow cytometry was performed to sort primary osteoclast precursors and CD4(+) T cells and to analyze the change in the expression of target proteins in osteoclast precursors. A recruitment assay was used to test how LA and Cadhein-11 regulate the recruitment of OC precursors. RT-PCR and Western blotting were performed to analyze the changes in the mRNA and protein expression of genes related to the PI3K-AKT pathway and profibrotic genes. Safranin O-fast green staining, H&E staining and TRAP staining were performed to analyze the severity of bone resorption and accumulation of osteoclasts. Results LA promoted the expression of CXCL10 and Cadherin-11 in CD115(+) precursors through the PI3K-AKT pathway. We found that CXCL10 and Cadherin-11 were regulated by the activation of CREB and mTOR, respectively. LA-induced overexpression of CXCL10 in CD115(+) precursors indirectly promoted the differentiation of osteoclast precursors through the recruitment of CD4(+) T cells, and the crosstalk between these two cells promoted bone resorption in bone metastasis from CRC. On the other hand, Cadherin-11 mediated the adhesion between osteoclast precursors and upregulated the production of specific collagens, especially Collagen 5, which facilitated fibrotic changes in the tumor microenvironment. Blockade of the PI3K-AKT pathway efficiently prevented the progression of bone metastasis caused by lactate. Conclusion LA promoted metastatic niche formation in the tumor microenvironment through the PI3K-AKT pathway. Our study provides new insight into the role of LA in the progression of bone metastasis from CRC. DasE7LVW6tcKsMdapJmhMF Video Abstract

Benefiting from rich knowledge and the exceptional ability to understand text, large language models like ChatGPT have shown great potential in English clinical environments. However, the performance of ChatGPT in non-English clinical settings, as well as its reasoning, have not been explored in depth. This study aimed to evaluate ChatGPT's diagnostic performance and inference abilities for retinal vascular diseases in a non-English clinical environment. In this cross-sectional study, we collected 1226 fundus fluorescein angiography reports and corresponding diagnoses written in Chinese and tested ChatGPT with 4 prompting strategies (direct diagnosis or diagnosis with a step-by-step reasoning process and in Chinese or English). Compared with ChatGPT using Chinese prompts for direct diagnosis that achieved an F -score of 70.47%, ChatGPT using English prompts for direct diagnosis achieved the best diagnostic performance (80.05%), which was inferior to ophthalmologists (89.35%) but close to ophthalmologist interns (82.69%). As for its inference abilities, although ChatGPT can derive a reasoning process with a low error rate (0.4 per report) for both Chinese and English prompts, ophthalmologists identified that the latter brought more reasoning steps with less incompleteness (44.31%), misinformation (1.96%), and hallucinations (0.59%) (all P<.001). Also, analysis of the robustness of ChatGPT with different language prompts indicated significant differences in the recall (P=.03) and F -score (P=.04) between Chinese and English prompts. In short, when prompted in English, ChatGPT exhibited enhanced diagnostic and inference capabilities for retinal vascular disease classification based on Chinese fundus fluorescein angiography reports. ChatGPT can serve as a helpful medical assistant to provide diagnosis in non-English clinical environments, but there are still performance gaps, language disparities, and errors compared to professionals, which demonstrate the potential limitations and the need to continually explore more robust large language models in ophthalmology practice.

Wound management is an important issue that places enormous pressure on the physical and mental health of patients, especially in cases of infection, where the increased inflammatory response could lead to severe hypertrophic scars (HSs). In this study, a hydrogel dressing was developed by combining the high strength and toughness, swelling resistance, antibacterial and antioxidant capabilities. The hydrogel matrix was composed of a double network of polyvinyl alcohol (PVA) and agarose with excellent mechanical properties. Hyperbranched polylysine (HBPL), a highly effective antibacterial cationic polymer, and tannic acid (TA), a strong antioxidant molecule, were added to the hydrogel as functional components. Examination of antibacterial and antioxidant properties of the hydrogel confirmed the full play of the efficacy of HBPL and TA. In the in vivo studies of methicillin-resistant Staphylococcus aureus (MRSA) infection, the hydrogel had shown obvious promotion of wound healing, and more profoundly, significant suppression of scar formation. Due to the common raw materials and simple preparation methods, this hydrogel can be mass produced and used for accelerating wound healing while preventing HSs in infected wounds. [Display omitted] •A double physical network hydrogel with robust, anti-fatigue and anti-swelling properties was fabricated.•Hydrogel loaded with hyperbranched polylysine and tannic acid exhibited remarkable antibacterial and antioxidant effects.•Hydrogel treatment promoted infected wound healing, reduced inflammation and accelerated vascularization.•Strategies to mitigate bacterial infection and oxidative stress inhibited hypertrophic scars formation.

Retinal vasculature provides an opportunity for direct observation of vessel morphology, which is linked to multiple clinical conditions. However, objective and quantitative interpretation of the retinal vasculature relies on precise vessel segmentation, which is time consuming and labor intensive. Artificial intelligence (AI) has demonstrated great promise in retinal vessel segmentation. The development and evaluation of AI-based models require large numbers of annotated retinal images. However, the public datasets that are usable for this task are scarce. In this paper, we collected a color fundus image vessel segmentation (FIVES) dataset. The FIVES dataset consists of 800 high-resolution multi-disease color fundus photographs with pixelwise manual annotation. The annotation process was standardized through crowdsourcing among medical experts. The quality of each image was also evaluated. To the best of our knowledge, this is the largest retinal vessel segmentation dataset for which we believe this work will be beneficial to the further development of retinal vessel segmentation.Measurement(s)retinal image segmentationTechnology Type(s)manual segmentationSample Characteristic - OrganismHomo sapiensSample Characteristic - EnvironmenthospitalSample Characteristic - LocationZhejiang Province, China

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in various immune cell types and perform multiple purposes and duties involved in the induction of innate and adaptive immunity. Their capability to propagate immunity makes them attractive targets for the expansion of numerous immunotherapeutic approaches targeting cancer. These immunotherapeutic strategies include using TLR ligands/agonists as monotherapy or combined therapeutic strategies. Several TLR agonists have demonstrated significant efficacy in advanced clinical trials. In recent years, multiple reports established the applicability of TLR agonists as adjuvants to chemotherapeutic drugs, radiation, and immunotherapies, including cancer vaccines. Cancer vaccines are a relatively novel approach in the field of cancer immunotherapy and are currently under extensive evaluation for treating different cancers. In the present review, we tried to deliver an inclusive discussion of the significant TLR agonists and discussed their application and challenges to their incorporation into cancer immunotherapy approaches, particularly highlighting the usage of TLR agonists as functional adjuvants to cancer vaccines. Finally, we present the translational potential of rWTC-MBTA vaccination [irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists Mannan-BAM, TLR ligands, and anti-CD40 agonisticAntibody], an autologous cancer vaccine leveraging membrane-bound Mannan-BAM, and the immune-inducing prowess of TLR agonists as a probable immunotherapy in multiple cancer types.

Objective Increasing evidence suggests that cancer-associated inflammation is associated with poor prognosis in patients with cancer. The role of the neutrophil–lymphocyte ratio (NLR) as a predictor in renal cell carcinoma (RCC) remains controversial. We conducted the meta-analysis to determine the association between NLR and clinical outcome of patients with RCC. Methods and materials Studies were identified from PubMed and EMBASE databases in March 2014. Meta-analysis was performed to generate combined HRs with 95% CIs for overall survival (OS) and recurrence-free/progress-free survival (RFS/PFS). Results 15 cohorts containing 3357 patients were included. Our analysis results indicated that elevated NLR predicted poorer OS (HR=1.82, 95% CI 1.51 to 2.19) and RFS/PFS (HR=2.18, 95% CI 1.75 to 2.71) in patients with RCC. These findings were robust when stratified by study region, sample size, therapeutic intervention, types of RCC and study quality. However, it differed significantly by assessment of the cut-off value defining ‘elevated NLR’ in RFS/PFS (p=0.004). The heterogeneity in our meta-analysis was mild to moderate. Conclusions Elevated NLR indicates a poorer prognosis for patients with RCC. NLR should be monitored in patients with RCC for rational risk stratification and treatment individualisation.

Both spiny and edible amaranths (Amaranthus spinosus and A. tricolor) are exotic annuals in China that produce numerous small seeds every year. Spiny amaranth has become a successful invader and a troublesome weed in Xishuangbanna, but edible amaranth has not, although it is widely grown as a vegetable there. As seed germination is one of the most important life-stages contributing to the ability of a plant to become invasive, we conducted experiments to compare the effects of high temperature and water stress on seed germination in two varieties each of spiny amaranth and edible amaranth. Overall, the seeds of both amaranth species exhibited adaptation to high temperature and water stress, including tolerance to ground temperatures of 70°C for air-dried seeds, which is consistent with their behavior in their native ranges in the tropics. As expected, the invasive spiny amaranth seeds exhibited higher tolerance to both continuous and daily periodic high-temperature treatment at 45°C, and to imbibition-desiccation treatment, compared to edible amaranth seeds. Unexpectedly, edible amaranth seeds exhibited higher germination at extreme temperatures (10°C, 15°C, and 40°C), and at lower water potential (below -0.6 MPa). It is likely that cultivation of edible amaranth has selected seed traits that include rapid germination and germination under stressful conditions, either of which, under natural conditions, may result in the death of most germinating edible amaranth seeds and prevent them from becoming invasive weeds in Xishuangbanna. This study suggests that rapid germination and high germination under stress conditions-excellent seed traits for crops and for many invasive species-might be a disadvantage under natural conditions if these traits are asynchronous with natural local conditions that support successful germination.

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a severe clinical problem and potentially permanent side effect of cancer treatment. For the management of OIPN, accurate diagnosis and understanding of significant risk factors including genetic vulnerability are essential to improve knowledge regarding the prevalence and incidence of OIPN as well as enhance strategies for the prevention and treatment of OIPN. The molecular mechanisms underlying OIPN are complex, with multi-targets and various cells causing neuropathy. Furthermore, mechanisms of OIPN can reinforce each other, and combination therapies may be required for effective management. However, despite intense investigation in preclinical and clinical studies, no preventive therapies have shown significant clinical efficacy, and the established treatment for painful OIPN is limited. Duloxetine is the only agent currently recommended by the American Society of Clinical Oncology. The present article summarizes the most recent advances in the field of studies on OIPN, the overview of the clinical syndrome, molecular basis, therapy development, and outlook of future drug candidates. Importantly, closer links between clinical pain management teams and oncology will advance the effectiveness of OIPN treatment, and the continued close collaboration between preclinical and clinical research will facilitate the development of novel prevention and treatments for OIPN.

Congenital ptosis may be associated with abnormalities of visual development and function, including amblyopia, strabismus and refractive errors. However, the prevalence estimates of these abnormalities vary widely. We performed a systematic review and meta-analysis to estimate the prevalence of amblyopia, strabismus and refractive errors in congenital ptosis. Cochrane, Pubmed, Medline, Embase, and Web of Science were searched by July 2017. We used random/fixed effects models based on a proportion approach to estimate the prevalence. Heterogeneity would be considered signifcant if the p values less than 0.1 and/or I 2 greater than 50%. Subgroup analyses, meta-regression analyses and sensitivity analyses were utilized to explore the potential sources of it. A total of 24 studies selected from 3,633 references were included. The highest prevalence was revealed for myopia with 30.2% (95%CI 3.0–69.8%), followed by 22.7% (95%CI 18.5–27.8%) for amblyopia, 22.2% (95%CI 7.8–63.1%) for astigmatism, 19.6% (95%CI 16.5–23.2%) for strabismus, 17.3% (95% CI 13.1–22.9%) for anisometropia and 4.0% for hyperopia (95%CI 1.8–7.1%). Significant heterogeneity was identified across most estimates. Our findings suggest that amblyopia, strabismus and refractive errors in congenital ptosis are present in much higher percentage. This study highlights the importance of early diagnosis and timely treatment of patients with congenital ptosis.

Yupingfeng (YPF), a famous traditional Chinese medicine, which contains a large array of compounds, has been effectually used in health protection. A two-dimensional liquid chromatography (2D-LC) combined with quadrupole time-of-flight mass spectrometry (QTOF-MS) method was firstly established to separate and identify chemical components in YPF. A total of 33 compounds were identified, including 15 constituents (flavonoids and saponins) in Astragali radix; seven constituents (sesquiterpenoids and polysaccharide) in Atractylodis rhizoma; and 11 constituents (chromone and coumarins) in Saposhnikoviae radix. The corresponding fragmentation pathway of typical substances was investigated. Then, seven active constituents (astragaloside, calycosin, formononetin, cimicifugoside, 4-O-beta-d-glucosyl-5-O-methylvisamminol, sec-O-glucosylhamaudol, and atractylenolide II) derived from three medicinal plants were chosen to further investigate the pharmacokinetic behavior of YPF formula using ultrahigh-performance liquid chromatography with triple quadrupole mass spectrometry system. The method was sensitive, accurate and reliable. We also used the area under the plasma concentration–time curve from zero to infinity (AUC0−∞) as weighting factor to make an integrated pharmacokinetic curve. Results show that the constituents of Saposhnikoviae radix have the best absorption and pharmacokinetic behavior and may play important role in leading to the changes of overall therapeutic effects of YPF. Further study is needed to confirm the association between them.