Combination therapeutic mode is likely to be the key to enhance the efficacy of immunotherapy in a wider range of cancer patients. Herein, we conducted an open-label, single-arm, multicenter, phase ...II clinical trial that enrolled patients with advanced solid tumors who had progressed after standard treatments.
Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Liposomal irinotecan (80mg/m
, dose could be adjusted to 60 mg/m
for intolerable cases) was intravenously (IV) administered once within 48 hours after radiotherapy. Then, camrelizumab (200mg IV, q3w) and anti-angiogenic drugs were given regularly until disease progression. The primary endpoint was objective response rate (ORR) in the target lesions evaluated by investigators per RECIST 1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse events (TRAEs).
Between November 2020 and June 2022, 60 patients were enrolled. The median follow-up was 9.0 months (95% confidence interval (CI) 5.5-12.5). Of 52 evaluable patients, the overall ORR and DCR were 34.6% and 82.7%, respectively. Fifty patients with target lesions were evaluable, the ORR and DCR of the target lesions were 35.3% and 82.4%, respectively. The median progression-free survival was 5.3 months (95% CI 3.6, 6.2), and the median overall survival was not reached. TRAEs (all grades) occurred in 55 (91.7%) patients. The most common grade 3-4 TRAEs were lymphopenia (31.7%), anemia (10.0%), and leukopenia (10.0%).
The combination of radiotherapy, liposomal irinotecan, camrelizumab, and anti-angiogenesis therapy demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors.
https://clinicaltrials.gov/ct2/home, identifier NCT04569916.
Background
Immune checkpoint inhibitor (ICI) combination therapies have shown promise in the first‐line treatment of advanced biliary tract cancer (BTC). However, the best partner remains to be ...validated. Moreover, progress on biomarkers predicting the efficacy of ICI in BTC is slow. This study aimed to assess the efficacy and investigate reliable predictive biomarkers of programmed cell death protein‐1 (PD‐1) antibody combination therapy in the first‐line treatment of advanced BTC.
Methods
Clinical data from patients with advanced BTC who received chemotherapy or anti‐PD‐1 combination therapy as first‐line were collected. The primary outcome was overall survival (OS). Biomarkers, including peripheral blood inflammation scores, genetic alterations, and tumor microenvironment were investigated.
Findings
Sixty‐four patients were recruited and divided into four treatment groups: chemotherapy, anti‐PD‐1 plus chemotherapy, anti‐PD‐1 plus targeted therapy, and triple group (anti‐PD‐1 plus chemotherapy and targeted therapy). The median OS was 7.9, 11.3, 12.8, and 28.7 months, respectively. Compared to chemotherapy, mOS significantly prolonged in the triple group (p = 0.031). It showed that patients with five different peripheral blood inflammation scores had significantly prolonged mOS (p < 0.05). Genetic testing results suggested that patients with poor survival all had TP53 mutations and higher levels of KRAS and ERBB2 mutations. Low FOXP3/CD8 ratio was associated with prolonged OS (p = 0.029). With CD4‐low, CD8‐high, CD56‐positive, CD163‐high, FOXP3‐high and MPO‐high in TME as one factor, we calculated PLUS score according to the number of factors. The high‐PLUS (>2) group showed significantly superior OS (p = 0.003).
Interpretation
First‐line anti‐PD‐1 combination therapy was superior to chemotherapy, and triple therapy significantly improved survival. Peripheral blood immune‐inflammation score, FOXP3/CD8 ratio, and PLUS have potential as biomarkers for predicting the efficacy of first‐line anti‐PD‐1 therapy in advanced BTC.
To solve the problem of blockage of crystallization in tunnel drainage pipes in hard water area, electric field devices are designed and applied in the transversal tunnel drainage pipe according to ...the fundamental law of crystallization. Laboratory tests were carried out to test the crystallizing tunnel drainage pipe under the effect of electric field in order to study the law of electric field impact on crystallization in tunnel drainage pipes in hard water area. The test results indicate that the arranged circumferential and parallel plate electric field devices can form an electrical field within a narrow and small space inside the pipe and influence the ion movement in water and adsorption performance between crystals and the pipe. Under the condition of full flow, the amount of crystals in the ordinary pipe without electric field treatment increases progressively along water flow direction and remains relatively uniform later. The amount of crystals along the water flow direction of the pipe treated with circumferential and parallel plate electric fields presents signs of fluctuation in the early stage and then stableness later. The amount of crystals in the fluctuating section is higher and lower in the uniform section, and its uniform section length is longer than that in ordinary pipes. Under the condition of full current, crystallizing speed declines with elapse of running time. After the electric field is imposed, crystallizing acceleration progressively decreased to a relatively lower level. Comparing three voltages of 5 V, 12 V, and 24 V, the effect of scale inhibition under 5 V is superior. When water amount in the pipe varies, the effects of scale inhibition under different electric field modes are different. The electric field effect causes the changes of the external form of calcium carbonate crystal and its surface abrasion, porous crystal, and structural looseness.
•The PCM-integrated building envelope is investigated in terms of efficiency and power consumption.•The enthalpy-porous model by considering the interface between solid and liquid phases is ...implemented.•The PCM layer has shown different behaviour during seasonal changes with a negative performance in cold weather.•The melting point and corresponding liquid fraction effects on the energy-saving are investigated.•Realistic data for radiation, ambient temperature, wind speed and wall structure are considered.
The PCM-integrated building envelope has shown significant potential in energy management and heating/cooling loads reduction. However, PCM layer performance highly depends on environmental conditions, configuration and its thermo-physical properties. The right choice of these characteristic features is great of importance since it may cause inverse effects.
So, in this comprehensive study, the performance of PCM wallboard under realistic sessional weather and solar radiation by considering different values of melting points (22, 24 and 26 °C) is investigated. To capture the solid/liquid interface and liquid fraction, the precise enthalpy-porous model, as well as the actual heat transfer chain consisting of radiation, convection and conduction from the environment to the room ambient, are implemented.
The results showed that the PCM layer is not always advantageous and more than 5% negative impact on energy loss is observed. So, the performance is highly dependent on other key factors including the environmental conditions and its volumetric amount. Also, the existence of optimum values for PCM layer thickness regarding the costs and wall density is observed for different types of PCM. The effect of the melting point on energy-saving is another significant parameter that has shown a considerable impact on appropriate PCM selection for specific regional conditions.
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In addition to abnormal liver inflammation, the main symptoms of non-alcoholic steatohepatitis (NASH) are often accompanied by gastrointestinal digestive dysfunction, consistent with the concept of ...spleen deficiency (SD) in traditional Chinese medicine. As an important metabolic sensor, whether peroxisome proliferator-activated receptor alpha (PPARα) participates in regulating the occurrence and development of NASH with SD (NASH-SD) remains to be explored.
Clinical liver samples were collected for RNA-seq analysis. C57BL/6J mice induced by folium sennae (SE) were used as an SD model. qPCR analysis was conducted to evaluate the inflammation and metabolic levels of mice. PPARα knockout mice (PPARα
) were subjected to SE and methionine-choline-deficient (MCD) diet to establish the NASH-SD model. The phenotype of NASH and the inflammatory indicators were measured using histopathologic analysis and qPCR as well.
The abnormal expression of PPARα signaling, coupled with metabolism and inflammation, was found in the results of RNA-seq analysis from clinical samples. SD mice showed a more severe inflammatory response in the liver evidenced by the increases in macrophage biomarkers, inflammatory factors, and fibrotic indicators in the liver. qPCR results also showed differences in PPARα between SD mice and control mice. In PPARα
mice, further evidence was found that the lack of PPARα exacerbated the inflammatory response phenotype as well as the lipid metabolism disorder in NASH-SD mice.
The abnormal NR signaling accelerated the vicious cycle between lipotoxicity and inflammatory response in NAFLD with SD. Our results provide new evidence for nuclear receptors as potential therapeutic targets for NAFLD with spleen deficiency.
Glycosylated hemoglobin A1c (HbA1c) level has strong relevance to microvascular disorders, which are also thought to be the current main aspect of sudden sensorineural hearing loss (SSNHL), so we aim ...to elucidate the association of the HbA1c level with the severity, types, and prognosis of SSNHL. In this study, comparative analyses based on propensity score matching of the severity, types, and prognosis of SSNHL with the HbA1c level in 116 patients diagnosed as SSNHL were conducted, where they were divided into diabetes mellitus (DM) group and non-DM group. We finally found that, among patients with SSNHL, diabetic patients had a higher HbA1c level, more severe hearing loss, and poorer prognosis than non-diabetic patients. The HbA1c level was found to be significantly correlated with the severity and types of SSNHL, while no strong relevance was found between the higher HbA1c level and the poorer prognosis of SSNHL.
The injury of femoral head varies among femoral head fractures (FHFs). In addition, the injury degree of the femoral head is a significant predictor of femoral neck fracture (FNF) incidence in ...patients with FHFs. However, the exact measurement methods have yet been clearly defined based on injury models of FHFs. This study aimed to design a new measurement for the injury degree of the femoral head on 2D and 3D models with computed tomography (CT) images and investigate its association with FHFs with FNF.
A consecutive series of 209 patients with FHFs was assessed regarding patient characteristics, CT images, and rate of FNF. New parameters for injury degree of femoral head, including percentage of maximum defect length (PMDL) in the 2D CT model and percentage of fracture area (PFA) in the 3D CT-reconstruction model, were respectively measured. Four 2D parameters included PMDLs in the coronal, cross-sectional and sagittal plane and average PMDL across all three planes. Reliability tests for all parameters were evaluated in 100 randomly selected patients. The PMDL with better reliability and areas under curves (AUCs) was finally defined as the 2D parameter. Factors associated with FNF were determined by binary logistic regression analysis. The sensitivity, specificity, likelihood ratios, and positive and negative predictive values for different cut-off values of the 2D and 3D parameters were employed to test the diagnostic accuracy for FNF prediction.
Intra- and inter-class coefficients for all parameters were ≥0.887. AUCs of all parameters ranged from 0.719 to 0.929 (
< 0.05). The average PMDL across all three planes was defined as the 2D parameter. The results of logistic regression analysis showed that average PMDL across all three planes and PFA were the significant predictors of FNF (
< 0.05). The cutoff values of the average PMDL across all three planes and PFA were 91.65% and 29.68%. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, predictive positive value and negative predictive value of 2D (3D) parameters were 91.7% (83.3%), 93.4% (58.4%), 13.8 (2.0), 0.09 (0.29), 45.83% (10.87%), and 99.46% (98.29%).
The new measurement on 2D and 3D injury models with CT has been established to assess the fracture risk of femoral neck in patients with FHFs in the clinic practice. 2D and 3D parameters in FHFs were a feasible adjunctive diagnostic tool in identifying FNFs. In addition, this finding might also provide a theoretic basis for the investigation of the convenient digital-model in complex injury analysis.
Currently, neoadjuvant chemotherapy is a standard therapeutic strategy for breast cancer, as it can provide timely and individualized chemo-sensitivity information and is beneficial for ...custom-designing subsequent treatment strategies. To accurately select candidates for neoadjuvant chemotherapy, the association between various immunohistochemical biomarkers of primary disease and tumor response to neoadjuvant chemotherapy has been investigated, and results have shown that certain pathological indicators evaluated after neoadjuvant chemotherapy are associated with long-term prognosis. The Food and Drug Administration (FDA) has recommended that complete pathological response can be used as a surrogate endpoint for neoadjuvant chemotherapy, which is related to better prognosis. Considering that residual tumor persists in the majority of patients after neoadjuvant chemotherapy, the value of various pathological indicators of residual disease in predicting the long-term outcomes is being extensively investigated. This review summarizes and compares various predictive and prognostic indicators for patients who have received neoadjuvant chemotherapy, and analyzes their efficacy in different breast cancer subtypes.
This study proposes a workflow of collaborative noninvasive detection of gastrointestinal diseases (GD). It includes several wet and dry experiments and analysis, such as: blood sample collection and ...detection of serum metabolites; (ii) MGCE record collection and learning of image features; (iii) the inference of correlations between serum metabolite signatures and image embedding signatures. This new collaborative noninvasive identification pipeline and potential metabolite biomarkers with image auxiliary diagnosis should be valuable for gastrointestinal disease and other complex diseases.
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Gastrointestinal diseases are complex diseases that occur in the gastrointestinal tract. Common gastrointestinal diseases include chronic gastritis, peptic ulcers, inflammatory bowel disease, and gastrointestinal tumors. These diseases may manifest a long course, difficult treatment, and repeated attacks.
Gastroscopy and mucosal biopsy are the gold standard methods for diagnosing gastric and duodenal diseases, but they are invasive procedures and carry risks due to the necessity of sedation and anesthesia. Recently, several new approaches have been developed, including serological examination and magnetically controlled capsule endoscopy (MGCE). However, serological markers lack lesion information, while MGCE images lack molecular information.
This study proposes combining these two technologies in a collaborative noninvasive diagnostic scheme as an alternative to the standard procedures. We introduce an interpretable framework for the clinical diagnosis of gastrointestinal diseases. Based on collected blood samples and MGCE records of patients with gastrointestinal diseases and comparisons with normal individuals, we selected serum metabolite signatures by bioinformatic analysis, captured image embedding signatures by convolutional neural networks, and inferred the location-specific associations between these signatures.
Our study successfully identified five key metabolite signatures with functional relevance to gastrointestinal disease. The combined signatures achieved discrimination AUC of 0.88. Meanwhile, the image embedding signatures showed different levels of validation and testing accuracy ranging from 0.7 to 0.9 according to different locations in the gastrointestinal tract as explained by their specific associations with metabolite signatures. Overall, our work provides a new collaborative noninvasive identification pipeline and candidate metabolite biomarkers for image auxiliary diagnosis. This method should be valuable for the noninvasive detection and interpretation of gastrointestinal and other complex diseases.
Objective:
A potential solution for islet transplantation and drug discovery vis-à-vis treating diabetes is the production of functional islets in a three-dimensional extracellular matrix. Although ...several scaffold materials have been reported as viable candidates, a clinically applicable one that is injectable and can maintain long-term functionality and survival of islet pancreatic beta-cells (β-cells) is far from being established.
Results:
In the current study, we evaluated a ready-to-use and injectable hydrogel’s impact on β-cells’ function and viability, both in vitro and in vivo. We found that β-cells in high concentration with hydrogels functionalized via Arg-Gly-Asp (RGD) demonstrated better viability and insulin secretory capacity in vitro. Moreover, it is a biocompatible hydrogel that can maintain β-cell proliferation and vascularization without stimulating inflammation after subcutaneous injection. Meanwhile, modifying the hydrogel with RGD can maintain β-cells’ secretion of insulin, regulating the blood glucose levels of mice with streptozotocin-induced diabetes.
Conclusions:
Thus, these preliminary results indicate that this RGD-modified hydrogel is a potential extracellular matrix for islet transplantation at extrahepatic sites, and they also provide a reference for future tissue engineering study.
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