Combined use of chemical dust suppressant and herbaceous plants for tailings dust control.

Tailings dust can negatively affect the surrounding environment and communities because the tailings are vulnerable to wind erosion. In this study, the effects of halides (sodium chloride [NaCl], calcium chloride [CaCl2], and magnesium chloride hexahydrate [MgCl2·6H2O]), and polymer materials (polyacrylamide [PAM], polyvinyl alcohol [PVA], and calcium lignosulfonate [LS]) were investigated for the stabilization of tailings for dust control. Erect milkvetch (Astragalus adsurgens), ryegrass (Lolium perenne L.), and Bermuda grass (Cynodon dactylon) were planted in the tailings and sprayed with chemical dust suppressants. The growth status of the plants and their effects on the mechanical properties of tailings were also studied. The results show that the weight loss of tailings was stabilized by halides and polymers, and decreased with increasing concentration and spraying amount of the solutions. The penetration resistance of tailings stabilized by halides and polymers increased with increasing concentration and spraying amount of the solutions. Among the halides and polymers tested, the use of CaCl2 and PAM resulted in the best control of tailings dust, respectively. CaCl2 solution reduces the adaptability of plants and therefore makes it difficult for grass seeds to germinate normally. PAM solutions are beneficial for the development of herbaceous plants. Among the three herbaceous species, ryegrass exhibited the best degree of development and was more suitable for growth in the tailings. The ryegrass plants planted in the tailings sprayed with PAM grew the best, and the root-soil complex that formed increased the shear strength of the tailings.

Orthogonal printing of uniform nanocomposite monolayer and oriented organic semiconductor crystals for high-performance nano-crystal floating gate memory.

Inkjet printing is of great interest in the preparation of optoelectronic and microelectronic devices due to its low cost, low process temperature, versatile material compatibility, and ability to precisely manufacture multi-layer devices on demand. However, interlayer solvent erosion is a typical problem that limits the printing of organic semiconductor devices with multi-layer structures. In this study, we proposed a solution to address this erosion problem by designing polystyrene-block-poly(4-vinyl pyridine)-grafted Au nanoparticles (Au@PS-b-P4VP NPs). With a colloidal ink containing the Au@PS-b-P4VP NPs, we obtained a uniform monolayer of Au nano-crystal floating gates (NCFGs) embedded in the PS-b-P4VP tunneling dielectric (TD) layer using direct-ink-writing (DIW). Significantly, PS-b-P4VP has high erosion resistance against the semiconductor ink solvent, which enables multi-layer printing. An active layer of semiconductor crystals with high crystallinity and well-orientation was obtained by DIW. Moreover, we developed a strategy to improve the quality of the TD/semiconductor interface by introducing a polystyrene intermediate layer. We show that the NCFG memory devices exhibit a low threshold voltage (<3 V), large memory window (66 V), stable endurance (>100 cycles), and long-term retention (>10 years). This study provides universal guidance for printing functional coatings and multi-layer devices.

Combining nanoparticle albumin-bound paclitaxel with camrelizumab in advanced soft tissue sarcoma: activity, safety, and future perspectives.

Background: It is still uncertain whether Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and programmed cell death protein 1 (PD-1) inhibitor have synergistic effects on metastatic soft tissue sarcomas (STSs). The purpose of this study was to evaluate the safety and activity of nab-paclitaxel plus camrelizumab (a PD-1 inhibitor) in patients with advanced STS who had previously failed chemotherapy. Methods: In this single-center, open-label, single-arm phase II clinical trial, patients with advanced (unresectable or metastatic) STS who had previously failed chemotherapy received up to six cycles of nab-paclitaxel plus camrelizumab, whereas camrelizumab treatment was continued for up to 1 year. The median progression-free survival (PFS), objective response rate (ORR) and safety were collected and evaluated. Results: This trial included 40 patients (28 men and 12 women). The overall ORR was 22.5%, and the median PFS was 1.65 months (95% confidence interval [CI], 1.3-2.0 months). Patients with epithelioid sarcoma demonstrated a longer PFS compared with those with other histological subtypes (2.3 months vs. 1.5 months, respectively); however, this difference was not significant. Patients who had received only one line of previous chemotherapy had a significantly longer PFS compared with those who had undergone two or more lines of previous chemotherapy (2.8 months vs. 1.3 months, respectively, p = 0.046). In terms of safety, the toxicity of this combination therapy is mild and no serious adverse events have occurred. Conclusion: Nab-paclitaxel plus camrelizumab exhibited modest activity and mild toxicity in treating epithelioid sarcoma, angiosarcoma, and fibrosarcoma. The overall effectiveness of this treatment regimen for advanced STS is relatively low. Further research on combining nab-paclitaxel with effective drugs, including chemotherapy and targeted agents, for these specific STS subtypes is needed.

Recent progress in the synthesis and applications of covalent organic framework-based composites.

Covalent organic frameworks (COFs) have historically been of interest to researchers in different areas due to their distinctive characteristics, including well-ordered pores, large specific surface area, and structural tunability. In the past few years, as COF synthesis techniques developed, COF-based composites fabricated by integrating COFs and other functional materials including various kinds of metal or metal oxide nanoparticles, ionic liquids, metal-organic frameworks, silica, polymers, enzymes and carbon nanomaterials have emerged as a novel kind of porous hybrid material. Herein, we first provide a thorough summary of advanced strategies for preparing COF-based composites; then, the emerging applications of COF-based composites in diverse fields due to their synergistic effects are systematically highlighted, including analytical chemistry (sensing, extraction, membrane separation, and chromatographic separation) and catalysis. Finally, the current challenges associated with future perspectives of COF-based composites are also briefly discussed to inspire the advancement of more COF-based composites with excellent properties.

Indole-3-carboxaldehyde ameliorates ionizing radiation-induced hematopoietic injury by enhancing hematopoietic stem and progenitor cell quiescence.

Indole-3-carboxaldehyde (I3A), one of tryptophan metabolites derived from gut microbiota, extends the lifespan of mice after high-dose ionizing radiation exposure. Persistent myelosuppression is the most common and fatal complication for victims of nuclear accidents and patients undergoing radiotherapy, with few therapeutic options available. However, whether and how I3A protects ionizing radiation-induced hematopoietic toxicity remain unknown. In this study, we demonstrated that I3A treatment effectively ameliorated radiation-induced hematopoietic injury through accelerating peripheral blood cells recovery, promoting bone marrow cellularity restoration and enhancing functional HSPC regeneration. Additionally, I3A also suppressed intracellular reactive oxygen species production and inhibited apoptosis in irradiated HSPCs. Mechanistically, I3A treatment significantly increased HSPC quiescence, thus conferring HSPCs with resistance against radiation injury. Finally, I3A treatment could improve survival of lethally irradiated mice. Taken together, our data suggest that I3A acts as a gut microbiota-derived paracrine factor that regulates HSPC regeneration and may serve as a promising therapeutic agent for ionizing radiation-induced myelosuppression.

Argon-helium knife cryoablation plus programmed cell death protein 1 inhibitor in the treatment of advanced soft tissue sarcomas: there is no evidence of the synergistic effects of this combination therapy.

Background: Effective treatment for advanced soft tissue sarcomas (STSs) is necessary for improved outcomes. Previous studies have suggested that cryoablation can have a synergistic effect with programmed cell death protein-1 (PD-1) inhibitor in the treatment of malignancy. This study aimed to clarify the efficacy and safety of argon-helium knife cryoablation in combination with PD-1 inhibitor in the treatment of STSs. Methods: Retrospectively collected and analyzed the clinical data of patients with advanced STS who underwent cryoablation and PD-1 inhibitor between March 2018 and December 2021. Results: This study included 27 patients with advanced STS. In terms of target lesions treated with cryoablation, 1 patient achieved complete response, 15 patients had partial response (PR), 10 patients had stable disease, and 1 patient had progressive disease. This corresponded to an overall response rate of 59.3% and a disease control rate of 96.3%. In terms of distant target lesions untreated with cryoablation, only two patients had a PR compared to the diameter of the lesion before ablation. The combination therapy was relatively well tolerated. None of the patients experienced treatment-related death or delayed treatment due to adverse events. Conclusion: Cryoablation combined with PD-1 inhibitors in the therapy of advanced STS is safe and can effectively shrink the cryoablation-target lesion. However, there is no evidence of the synergistic effects of this combination therapy.

Effect of soluble salts in electrolytic manganese residue on its geotechnical characteristics.

Electrolytic Manganese Residue (EMR) is a solid waste containing soluble sulfate, discharged by electrolytic manganese industries. The accumulation of EMR in ponds poses a significant hazard to both safety and the environment. This study utilized innovative geotechnical test techniques to conduct a series of tests, investigating the effect of soluble salts on the geotechnical characteristics of EMR. The results revealed that soluble sulfates had a significant impact on the geotechnical characteristics of the EMR. In particular, the infiltration of water leached away the soluble salts, causing a non-uniform particle size distribution and decreasing the shear strength, stiffness, and liquefaction resistance of the EMR. Nevertheless, an increase in the stacking density of EMR could improve its mechanical characteristics and inhibited the dissolution of soluble salts. Therefore, increasing the density of stacked EMR, ensuring the effectiveness and non-obstruction of the water interception facilities, and reducing rainwater infiltration could be effective measures to enhance the safety and reduce the environmental hazard of EMR ponds.

Experimental study on dynamic behavior of polyacrylamide-reinforced tailings.

Earthquakes are a significant factor that contributes to tailings dam failure. Generally, the seismic stability of a tailings dam can be increased by improving the dynamic properties of tailings. The dynamic properties of tailings can be improved effectively using polymers. In this study, the dynamic properties of polyacrylamide-reinforced tailings were investigated via a sequence of dynamic triaxial tests. The content of polyacrylamide in the test sample was 0.3%. Test results show that the cyclic liquefaction resistance, initial dynamic shear modulus, dynamic shear modulus, and dynamic shear modulus ratio of polyacrylamide-reinforced tailings were slightly greater than those of unreinforced tailings. The damping ratio of polyacrylamide-reinforced tailings was lower than that of unreinforced tailings when the dynamic shear strain exceeded 0.038%. The increase in the dynamic pore water pressure of polyacrylamide-reinforced tailings during cyclic loading decelerated significantly compared with that of unreinforced tailings. The revised Zeng model can effectively described the changes in dynamic pore-water pressure of unreinforced and polyacrylamide-reinforced tailings. The polyacrylamide can improve the structural stability of the tailings specimen and also improve the dynamic properties of the tailings, thereby enhancing the seismic stability of the tailings dam.

Association of hepatitis B virus DNA levels with overall survival for advanced hepatitis B virus-related hepatocellular carcinoma under immune checkpoint inhibitor therapy.

BACKGROUND: High hepatitis B virus (HBV) DNA level is an independent risk factor for postoperative HBV-associated liver cancer recurrence. We sought to examine whether HBV DNA level and antiviral therapy are associated with survival outcomes in patients with advanced hepatocellular carcinoma (HCC) treated with anti-programmed cell death protein 1 (PD-1)based immunotherapy. METHODS: This single-institution retrospective analysis included 217 patients with advanced HBV-related HCC treated from 1 June 2018, through 30 December 2020. Baseline information was compared between patients with low and high HBV DNA levels. Overall survival (OS) and progression-free survival (PFS) were compared, and univariate and multivariate analyses were applied to identify potential risk factors for oncologic outcomes. RESULTS: The 217 patients included in the analysis had a median survival time of 20.6 months. Of these HBV-associated HCC patients, 165 had known baseline HBV DNA levels. Baseline HBV DNA level was not significantly associated with OS (P = 0.59) or PFS (P = 0.098). Compared to patients who did not receive antiviral therapy, patients who received antiviral therapy had significantly better OS (20.6 vs 11.1 months, P = 0.020), regardless of HBV DNA levels. Moreover, antiviral status (adjusted HR = 0.24, 95% CI 0.094-0.63, P = 0.004) was an independent protective factor for OS in a multivariate analysis of patients with HBV-related HCC. CONCLUSIONS: HBV viral load does not compromise the clinical outcome of patients with HBV-related HCC treated with anti-PD-1-based immunotherapy. The use of antiviral therapy significantly improves survival time of HBV-related HCC patients.

Efficacy and safety of sintilimab plus doxorubicin in advanced soft tissue sarcoma: A single-arm, phase II trial.

Background: Chemoimmunotherapy is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this combination treatment in patients with metastatic soft tissue sarcoma (STS) are currently limited. This study evaluated the safety and efficacy of a programmed cell death protein 1 (PD-1) inhibitor plus doxorubicin in patients with advanced STS who failed previous systemic therapy. Methods: This was a single-center, single-arm, open-label phase II trial. Patients with unresectable or metastatic STS who had previously failed systemic therapy were enrolled. Patients received up to six cycles of doxorubicin and sintilimab (a PD-1 inhibitor), while sintilimab treatment continued for up to 2 years. Primary outcomes were objective response rate (ORR) and safety. Univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and progression-free survival (PFS). Results: A total of 38 patients (20 men and 18 women) were enrolled in this study. The overall ORR was 39.5%, disease control rate was 71.1%, and the median PFS was 4.5 months [95% confidence interval (CI), 3.0-8.5 months]. The adverse events (AEs) associated with the combined treatment were mild, manageable, and well-tolerated. The most common grade 3 or higher AEs were hematologic, including leukopenia (21.1%), anemia (18.4%), and thrombocytopenia (18.4%). Patients with undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated liposarcoma had a significantly longer PFS than those with other pathological subtypes [hazard ratio (HR) = 0.42, 95% CI 0.21-0.83; p = 0.013]. There was no significant difference in the median PFS between patients who had previously received anthracycline-based chemotherapy and those who had not (HR = 0.74, 95% CI 0.34-1.58, p = 0.43). Conclusion: Sintilimab plus doxorubicin is a safe and promising treatment for patients with advanced STS who have failed previous systemic therapy (including anthracycline-based chemotherapy). The efficacy of this combination therapy in UPS and dedifferentiated liposarcoma is superior to that in other sarcomas. Clinical Trial Registration: https://www.chictr.org.cn, registration number: ChiCTR1900027009.

Sintilimab maintenance therapy post first-line cytokine-induced killer cells plus chemotherapy for extensive-stage small cell lung cancer.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6-13.0) months, median PFS1 was 5.5 (95% CI: 5.0-6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5-4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy. Clinical trial registration: ClinicalTrials.gov (NCT03983759).

Combination of Low-Dose Gemcitabine and PD-1 Inhibitors for Treatment in Patients With Advanced Malignancies.

Purpose: This study determined the efficacy of low-dose gemcitabine combined with programmed death-1 (PD-1) inhibitors for treating multiple malignancies, providing a cost-effective and safe treatment option. Study Design: This study included 61 patients with advanced solid tumors treated with low-dose gemcitabine combined with PD-1 inhibitors at the Henan Cancer Hospital between January 2018 and February 2022. We retrospectively reviewed medical records to evaluate several clinical factors, including progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and objective response to treatment. Results: Sixty-one patients received treatment with low-dose gemcitabine combined with PD-1 inhibitors. The objective response rate (ORR) was 29.5% and the disease control rate (DCR) was 62.3%. The median PFS was 4.3 months (95% confidence interval, 2.3 to 6.3 months) and the median OS was 15.0 months (95% confidence interval, 8.8 to 21.2 months). Hematological toxicity, mainly leukopenia or thrombocytopenia, was the most common AE, with any-grade and grade 3/4 hematological toxicity reported in 60.7 and 13.1% of patients, respectively. Conclusions: Low-dose gemcitabine combined with PD-1 inhibitors may offer a novel treatment option for patients with advanced malignancies.

ResNet-BiLSTM: A Multiscale Deep Learning Model for Heartbeat Detection Using Ballistocardiogram Signals.

As the heartbeat detection from ballistocardiogram (BCG) signals using force sensors is interfered by respiratory effort and artifact motion, advanced signal processing algorithms are required to detect the J-peak of each BCG signal so that beat-to-beat interval can be identified. However, existing methods generally rely on rule-based detection of a fixed size, without considering the rhythm features in a large time scale covering multiple BCG signals. Methods. This paper develops a deep learning framework based on ResNet and bidirectional long short-term memory (BiLSTM) to conduct beat-to-beat detection of BCG signals. Unlike the existing methods, the proposed network takes multiscale features of BCG signals as the input and, thus, can enjoy the complementary advantages of both morphological features of one BCG signal and rhythm features of multiple BCG signals. Different time scales of multiscale features for the proposed model are validated and analyzed through experiments. Results. The BCG signals recorded from 21 healthy subjects are conducted to verify the performance of the proposed heartbeat detection scheme using leave-one-out cross-validation. The impact of different time scales on the detection performance and the performance of the proposed model for different sleep postures are examined. Numerical results demonstrate that the proposed multiscale model performs robust to sleep postures and achieves an averaged absolute error (E abs) and an averaged relative error (E rel) of the heartbeat interval relative to the R-R interval of 9.92 ms and 2.67 ms, respectively, which are superior to those of the state-of-the-art detection protocol. Conclusion. In this work, a multiscale deep-learning model for heartbeat detection using BCG signals is designed. We demonstrate through the experiment that the detection with multiscale features of BCG signals can provide a superior performance to the existing works. Further study will examine the ultimate performance of the multiscale model in practical scenarios, i.e., detection for patients suffering from cardiovascular disorders with night-sleep monitoring.

Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study.

BACKGROUND: There is increasing evidence that combination therapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and programmed cell death protein 1 (PD-1) inhibitor is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this treatment combination for patients with metastatic soft tissue sarcoma (STS) are currently limited. METHODS: The clinical data of patients with metastatic STS who received nab-paclitaxel plus PD-1 inhibitor (sintilimab) therapy between January 2019 and February 2021 were retrospectively analyzed. The effectiveness and safety of the combined treatment were evaluated in terms of the median progression-free survival (PFS), estimated using the Kaplan-Meier method. The univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and PFS. All statistical analyses were two-sided; P < 0.05 was considered statistically significant. RESULTS: A total of 28 patients treated with nab-paclitaxel plus sintilimab were enrolled in this study. The objective response rate was 25%, the disease control rate was 50%, and the median PFS was 2.25 months (95% CI = 1.8-3.0 months). The most common grade 1 or 2 adverse events (AEs) were alopecia (89.3%; 25/28), leukopenia (25.0%; 7/28), fatigue (21.4%; 6/28), anemia (21.4%; 6/28), and nausea (21.4%; 6/28). The most common grade 3 AEs were neutropenia (10.7%; 3/28) and peripheral neuropathy (10.7%; 3/28). No grade 4 AEs were observed. Among the present study cohort, patients with angiosarcoma (n = 5) had significantly longer PFS (P = 0.012) than patients with other pathological subtypes, including undifferentiated pleomorphic sarcoma (n = 7), epithelioid sarcoma (n = 5), fibrosarcoma (n = 4), synovial sarcoma (n = 3), leiomyosarcoma (n = 2), pleomorphic liposarcoma (n = 1), and rhabdomyosarcoma (n = 1); those who experienced three or more AEs had significantly longer median PFS than those who experienced less than three AEs (P = 0.018). CONCLUSION: Nab-paclitaxel plus PD-1 inhibitor is a promising treatment regimen for advanced STS. Randomized controlled clinical trials are required to further demonstrate its efficacy and optimal application scenario.

Clinical Experience with Apatinib and Camrelizumab in Advance Clear Cell Sarcoma: A Retrospective Study.

PURPOSE: Advanced clear cell sarcoma (CCS) is a rare subtype of sarcoma with few effective treatments. Evidence shows that apatinib is efficacious and safe for CCS. This study aimed to assess the safety and efficacy of apatinib and/or camrelizumab (a PD-1 inhibitor) in treating advanced CCS. METHODS: We retrospectively reviewed 12 patients with advanced CCS who received apatinib and/or camrelizumab therapy between November 2018 and July 2021. Standard descriptive statistics were employed for continuous variables and categorical variables (number and percentage). RESULTS: Of the 12 CCS patients, 3 had a partial response (PR), and 4 had stable disease (SD). Among the 5 patients treated with apatinib monotherapy, 1 PR and 2 SD were found, and the addition or replacement of camrelizumab after progressive disease (PD) did not work. In the 4 patients who received apatinib plus camrelizumab combination therapy, 1 PR and 1 SD were found. All 3 patients who received camrelizumab first had PD, and 1 PR and 1 SD were found after adding apatinib. Grade 3 or 4 adverse events were significantly more common in the apatinib plus camrelizumab combination therapy than in the apatinib or camrelizumab monotherapy, and these included increased aspartate aminotransferase and increased alanine aminotransferase levels. CONCLUSION: Apatinib has promising effectiveness for CCS. Camrelizumab efficacy for the treatment of clear cell sarcoma is inconclusive. The efficacy of apatinib and PD-1 inhibitors in CCS need to be further investigated in prospective clinical trials.

The Sequence of Chemotherapy and Toripalimab Might Influence the Efficacy of Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer-A Phase II Study.

Background: There is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored. Methods: This open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020; 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC) (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experimental group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was safety and disease-free survival. Results: Thirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was performed in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (p = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in the control group had a PD-L1 CPS of 10, and pCR was achieved; the remaining 13 all had ≤1, and 11 of the 13 patients received surgery in which two (in the experimental group) achieved pCR. Two patients endured ≥grade 3 adverse events, and one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery. Conclusions: Although the primary endpoint was not met, the initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day, and further large-sample clinical trials are needed to verify this. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03985670.

Toxic Epidermal Necrolysis-Like Reaction Following Combination Therapy With Camrelizumab and Apatinib for Advanced Gallbladder Carcinoma.

Recently, combination regimens based on programmed cell death-1 (PD-1) blockade have become increasingly common in clinical practice for the treatment of cancer. Such combinations significantly improve efficacy, but treatment-related adverse events have also become more complex and severe. Here, we report an acute toxic epidermal necrolysis (TEN)-like reaction in a patient with gallbladder cancer who received camrelizumab (an anti-PD-1 antibody) in combination with apatinib. Interestingly, distinct clinical and pathological characteristics were observed that differed from those of the reported cases of severe cutaneous reactions induced by anti-PD-1 antibodies alone; thus, we speculate that it was induced by the combination of camrelizumab and apatinib. It is worth noting that the TEN-like reaction showed resistance to methylprednisolone initially, which was gradually resolved after the addition of intravenous immunoglobulin (IVIg). Immunohistochemical staining revealed that the skin lesion was infiltrated by moderate numbers of CD4+ T cells and large numbers of CD8+ T cells during the progression of the TEN-like reaction, and mass cytometry by time-of-flight showed a significant reduction in the CD4+ and CD8+ T cell proportions in the peripheral blood after the rash improved. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes. In conclusion, the TEN-like reaction induced by camrelizumab and apatinib deserves clinical attention, and further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.

Axitinib Reverses Resistance to Anti-Programmed Cell Death-1 Therapy in a Patient With Renal Cell Carcinoma.

Owing to broad and notable clinical anti-tumor activity, anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) antibodies have been indicated for almost all types of cancer, and form a part of the current standard of care. However, a large proportion of patients do not respond to anti-PD-1/PD-L1 therapy (primary resistance), and responders often develop progressive disease (acquired resistance). The mechanisms of resistance are complex and largely unknown; therefore, overcoming resistance remains clinically challenging, and data on reversing anti-PD-1 resistance are scarce. Herein, we report the case of a 58-year-old woman with renal cell carcinoma associated with Xp11.2 translocation/transcription factor E3 gene fusion, who had already showed resistance to both anti-PD-1 monotherapy and standard-dose axitinib. However, she finally achieved a partial response with a continuous combination therapy comprising low-dose axitinib and anti-PD-1. We speculate that axitinib played a key role in reversing the primary resistance to anti-PD-1 therapy. Interestingly, we observed that the number of peripheral regulatory T cells increased after the standard-dose axitinib therapy, with accompanied tumor enlargement; however, after the dose was reduced, the number of regulatory T cells decreased gradually, and the tumor regressed. We also reviewed relevant literature, which supported the fact that low-dose axitinib might be more beneficial than standard-dose axitinib in assisting immunotherapy. Given that this is a single-case report, the immunomodulatory effect of axitinib requires further investigation.

T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes.

Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-ß (TCRß) repertoires of the TILs and T cells expanded from paired PD-1+ PBLs, and whether T cells expanded from PD-1+ PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1+ PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRß sequencing data revealed that an average of 11.29% (1.32%-29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1+ PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1+ PBLs was 35.11% (7.23%-78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1+ PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1+ PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes. SIGNIFICANCE: This study harnesses the tumor reactivity of PD-1+ PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer.See related commentary by Ladle, p. 1940.

Experimental study on static and dynamic mechanical properties of phosphogypsum.

Phosphogypsum (PG) is a solid waste product of the wet-process phosphoric acid industry that accumulates in large amounts on the ground, forming PG ponds. In recent years, the amount of PG produced and discharged into ponds has increased significantly with the increase in the market demand for phosphate fertilizers. To enrich the basic knowledge of PG properties and provide basic data for the stability analysis of PG dams, a series of laboratory geotechnical tests, including permeability tests, compressibility tests, triaxial shear tests, and dynamic triaxial tests, were conducted in this study. During the preparation of the test samples, solubility and high-temperature dehydration of PG were considered. The results indicated that PG exhibits medium compressibility and medium to weak permeability characteristics. The stress-strain curves of the triaxial shear tests were divided into three typical stages: initial deformation stage, strain hardening stage, and destruction stage. With increasing dry density and consolidation confining pressure, both the shear strength and deformation modulus significantly increased. The relationship between the deformation modulus and confining pressure gradually changed from linear to logarithmic with increasing density. The liquefaction resistance curves (CSR-NL curves) of PG were expressed by power functions. With increasing dry density, the curves shifted higher and became steeper. Compared with the Hardin-Drnevich model, the Davidenkov model was found to be more suitable for describing the relationship between the dynamic shear modulus ratio and damping ratio of PG and the dynamic shear strain. Furthermore, compared with those of tailings and natural soils, the engineering mechanical properties of PG were relatively poor, which may be related to its uniform particle distribution and neat particle stacking structure.