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BACKGROUND: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. PATIENTS AND METHODS: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). RESULTS: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. CONCLUSIONS: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals. ispartof: ANNALS OF ONCOLOGY vol:33 issue:10 pages:1052-1060 ispartof: location:England status: published

BACKGROUND CONTEXT: For patients with multilevel degenerative cervical myelopathy, laminectomy and posterior cervical fusions (PCFs) with instrumentation are widely accepted technique for symptom relief. However, hardware failure is not rare which results in neck pain or even permanent neurological leision. The prevalence of hardware-related complications of laminectomy and posterior cervical fusions (PCFs) with instrumentation are lack of in-depth study. PURPOSE: To investigate risk factors of hardware failure after laminectomy and posterior cervical fusions (PCFs) with instrumentation in patients with degenerative cervical myelopathy. STYDU DESIGN: single-center, retrospective study. METHODS: Fifty-six patients who underwent laminectomy and posterior cervical fusions (PCFs) with instrumentation between January 2019 and January 2021 were included in a single institution. Patients were divided into the hardware failure group (n = 14) and no hardware failure group (n = 42). The sex, age, screw density, end vertebra (C7 or T1), cervical sagittal alignment parameters (C2-C7 lordosis, C2-C7 sagittal vertical axis, T1 slope, CL correction), and regional Hounsfield units (HU) of screw trajectory, morbidity of osteoporosis were collected and compared between the two groups. RESULTS: The mean overall follow-up was 20.6 months (range, 12–30 months). There were no significant statistical differences in general information (age, gender, follow-up period) of patients between the two groups. The differences of fusion rate, fixation levels and screw density between the two groups were not statistically significant (p > 0.05). The failure rate of the fixation endpoint at T1 was lower than that at C7 (9% vs. 36.3%) (p 0.05). The hardware failure rate in cases without osteoporosis was lower than that in cases with osteoporosis (14.3% vs. 57.1%) (p CONCLUSION: Hardware failure was not uncommon after laminectomy and PCFs with instrumentation in patients with degenerative cervical myelopathy. Osteoporosis, fixation ended at C7, and low regional HU of screw trajectory were the independent risk factors.

Purpose Plenty of studies have examined the long term effect of weight loss on bone mineral density. This study aimed to explore the effects of 10% weight loss on early changes in bone metabolism as well as the possible influencing factors. Methods Overweight and obese outpatients (BMI > 24.0 kg/m2) were recruited from the nutrition clinic and followed a calorie-restricted, high-protein, low-carbohydrate diet program. Dietary intake, body composition, serum procollagen type I N-propeptide (PINP), β-Crosslaps, PTH, 25(OH) VitD, a series of inflammatory cytokines and adipokines were measured for the participants before starting to lose weight and after 10% weight loss (NCT 04207879). Results A total of 75 participants were enrolled and 37 participants achieved a weight loss of at least 10%. It was found that PINP decreased (p = 0.000) and the β-Crosslaps increased (p = 0.035) in female participants. Decreases in PTH (p = 0.001), serum IL-2 (p = 0.013), leptin (p = 0.001) and increases in 25(OH) VitD (p = 0.001), serum ghrelin (p = 0.033) were found in 37 participants after 10% of their weight had been lost. Change in PINP was detected to be significantly associated with change in lean body mass (r = 0.418, p = 0.012) and change in serum ghrelin(r = − 0.374, p = 0.023). Conclusions Bone formation was suppressed and bone absorption was increased in female subjects after a 10% weight loss. Bone turnover was found to be associated with lean body mass and affected by the circulating ghrelin level.

In July 2022, large spots were observed on the leaves of tobacco in Guangxi province, China, whose shape was round and elliptical or irregular. The margins of spots were brown or dark brown with a pale yellow centre and several small black fruiting bodies. The pathogen was isolated by tissue isolation. Diseased leaves collected were cut into small pieces, sterilized with 75% ethanol for 30s and 2% sodium hypochlorite (NaCIO) for 60s, and rinsed with sterile deionized water for three times. Each air-dried tissue segment was cultured on potato dextrose agar (PDA) and incubated at 28℃ for 5 to 7 days in the dark (Wang et al. 2022). A total of six isolates were isolated, with differences in colony shape, edge type and colony colour, and aerial mycelium morphology, with the colony shape round or subrounded, and the edge rounded crenate, dentate or sinuate. The color of the colony was initially light yellow, then gradually changed to yellow and dark yellow. After 3-4 days, white aerial mycelia gradually grew up, which was peony-like or covered the whole colony, thus the color of the colony appeared white, and then gradually changed to orange, gray or nearly black, and all six isolates rarely produced conidia, which was consistent with the description of previous reports(Mayonjo and Kapooria 2003, Feng et al. 2021, Xiao et al. 2018). Conidia were hyaline, aseptate, and falcate, with the size of 7.8 to 12.9 × 2.2 to 3.5 μm. For molecular identification, the colony PCR method was used to amplify the internal transcribed spacer(ITS), actin(ACT), chitin synthase(CHS), and beta-tubulin(TUB2) loci of the six isolates using primer pairs ITS1/ITS4, ACT-512F/ACT-783R, CHS-79F/CHS-354R, and T1/Bt2b, respectively(Cheng et al. 2014). Partial sequences were amplified, sequenced, and uploaded to GenBank (GenBank accession Nos. OP484886，OP518265，OP518266，OP756065，OP756066, and OP756067 for ITS, OP620430 to OP620435 for ACT, OP620436 to OP620441 for CHS, and OP603924 to OP603929 for TUB2). These sequences had 99 to 100% similarity with C. truncatum isolates C-118(ITS), TM19(ACT), OCC69(CHS), and CBS 120709(TUB2) in GenBank. Homology matching was performed using BLAST and a phylogenetic tree was constructed using the Neighbor-Joining (NJ) method using MEGA (7.0) software based on ITS, ACT, CHS, and TUB2 sequences, which showed that all six isolates clustered in the same score as the C. truncatum. A pathogenicity test was performed with healthy tobacco infected with mycelial plugs (about 5 mm in diameter) of six isolates of C. truncatum from a 5-day-old culture, while negative controls on the other leaves were inoculated with sterile PDA plugs. All plants were placed in a greenhouse at 25℃ to 30℃ with 90% relative humidity. The experiment was conducted three times. Five days later, all inoculated leaves had diseased spots, whereas no symptoms appeared on negative controls. The same pathogen, C. truncatum, was identified from the inoculated leaves on the basis of morphological and molecular charchseristics as described above, fulfilling Koch’s postulates. In this study, it is the first time to report that the anthracnose on tobacco was caused by C. truncatum. Thus, this work provides a foundation for controlling tobacco anthracnose in the future.

Objectives To evaluate the ability of post-chemo-radiotherapy (CRT) diffusion-weighted-MRI apparent diffusion coefficient (ADCmean) and 18F-FDG PET maximum standardized uptake value (SUVmax) to predict disease-free survival (DFS) in head and neck squamous cell carcinoma (HNSCC), and to determine whether this ability is influenced by human papillomavirus oropharyngeal cancer (HPV-OPC) status. Methods This prospective cohort observational study included 65 participants (53 male, mean ± SD age 59.9 ± 7.9 years, 46 HPV-OPC) with stage III or IV HNSCC. Primary tumour and nodal ADCmean (pre-treatment, 6- and 12-weeks post-CRT) and SUVmax (12-weeks post-CRT) were measured. Variables were compared with 2-year DFS (independent t-test/Mann–Whitney test) and overall DFS (Cox regression), before and after accounting for HPV-OPC status. Variables were also compared between HPV-OPC and other HNSCC subgroups after stratifying for DFS. Results Absolute post-CRT ADCmean values predicted 2-year DFS and overall DFS for all participants (p = 0.03/0.03, 6-week node; p = 0.02/0.03 12-week primary tumour) but not in the HPV-OPC subgroup. In participants with DFS, percentage interval changes in primary tumour ADCmean at 6- and 12-weeks were higher in HPV-OPC than other HNSCC (p = 0.01, 6 weeks; p = 0.005, 12 weeks). The 12-week post-CRT SUVmax did not predict DFS. Conclusion Absolute post-CRT ADCmean values predicted DFS in HNSCC but not in the HPV-OPC subgroup. Amongst participants with DFS, post-CRT percentage interval changes in primary tumour ADCmean were significantly higher in HPV-OPC than in other HNSCC. Knowledge of HPV-OPC status is crucial to the clinical utilisation of post-CRT DWI-MRI for the prediction of outcomes.

Gastric cancer (GC) is a kind of digestive tract malignancy that has very high morbidity and mortality, making it crucial to find new drug treatments. Vitexin is a kind of flavonoid compound, which has anti-tumor, anti-inflammatory, analgesic and antiviral effects, etc. However, the specific role of vitexin in GC is still unclear. In this study, the expression of the survival rate and apoptosis was detected by CCK-8 and flow cytometry after vitexin acted on cells. Plasmid transfection technique was used to overexpress PI3K. Expression of PI3K/AKT/mTOR pathway-related proteins, autophagic-related proteins (Atg14, beclin-1, P62) and apoptotic-related proteins (bcl-2, Bax, cleaved caspase3) were detected by Western blot. We found that the cell survival rate decreased with the increasing time and dosage of vitexin. When vitexin acted on cells, the expression of p-PI3K, p-AKT and p-mTOR was significantly decreased, the degree of autophagy was increased, and the apoptosis rate was obviously increased. However, the overexpression of PI3K, the level of autophagy and apoptosis rate of cells which were given vitexin significantly decreased. In conclusion, Vitexin induces autophagy by inhibiting PI3K/AKT/mTOR signaling pathway, thereby inhibiting proliferation and promoting apoptosis of GC cells.

In this paper, we propose an improved Generalize Finite Integration Method with Volterra operator to solve multi-dimensional biharmonic equations. The novelty of the proposed method is that its mth order integration matrix will be exactly formulated by using Volterra operator. This leads to a significant improvement in the accuracy of the approximation. Furthermore, the original strict requirement of uniformly distributed collocation points is waived in the proposed method due to the use of piecewise polynomials. This contributes to another distinct advantage in placing collocation points for problems with geometrically complex domains. Four numerical examples are constructed to demonstrate these advantages. Comparisons on the accuracies obtained from quadrature formulas with and without Volterra operator are given. Numerical results indicate that the proposed method is capable for solving multi-dimensional biharmonic equations with superior efficiency, higher accuracy and fewer memory usage.

Background Pancreatic ductal adenocarcinoma (PDAC) does not respond to immune checkpoint inhibitors (ICI) therapy as single agent treatments including anti-PD-1 antibody. One of the mechanisms for the resistance of PDAC to ICI is now attributed to the immunosuppressive microenvironment (TME) in PDAC. Myeloid cells are thought to be the predominant immunosuppressive cells in the TME. Human interleukin-8 (IL-8) is a pro-inflammatory chemokine in the CXC family and has the capability of recruiting myeloid cells into the TME to promote tumor progression and immune escape. Therefore, several anti-IL-8 blockade antibodies were developed including HuMax-IL8 and B108-IL8, which both are fully human IgG1 kappa monoclonal antibodies. We therefore tested whether anti-IL-8 antibodies can potentiate anti-tumor activity of anti-PD-1 antibody in a humanized model of PDAC. Materials and Methods We reconstituted the immune system of the NGS mice with ex vivo activated human T cells and a combination of CD14+ and CD16+ myeloid cells after the mice were orthotopically implanted with human PDAC cells. 10x single nuclei RNA-Seq data processing was further performed to analyze differentially expressed genes among certain cell clusters. Results Our results showed that anti-PD-1 antibody alone had a minimal anti-tumor activity when mice was reconstituted with ex vivo activated T cells. Interestingly, the infusion of the combination of CD14+ and CD16+ myeloid cells together with anti-PD-1 antibody resulted in a modest anti-tumor activity. Adding either HuMAX-IL8 or B108-IL8 led to a significantly enhanced anti-tumor activity. Both CD14+ and CD16+ myeloid cells appeared to be needed for the full anti-tumor activity of IL-8 blockade because mice infused with only CD14+ myeloid cells did not respond to IL-8 blockade and mice infused with only CD16+ myeloid cells responded partially to IL-8 blockade. This result suggested that the target of IL-8 is mainly present in CD16+ myeloid cells and is likely to be granulocytes. Tumor infiltrating immune cells were isolated and demonstrated that IL-8 blockade increases CD45+CD11b+CD15+CD14- myeloid cells, which is known to comprise neutrophils and granulocytic myeloid derived suppressive cells (G-MDSC), in the tumors. Reconstitution of the mice with myeloid cells led to a decrease of CD8+ T cells in the tumors; however, IL-8 blockade brought the CD8+ T cell number back to the baseline. Consistent with an effect of IL-8 blockade on the increase of CD15+CD14- myeloid cells, single nuclear RNA sequencing analysis of the tumor tissues showed that the innate immune response and cytokine response pathways in the myeloid cell cluster were activated by IL-8 blockade. Conclusions This result suggested that IL-8 blockade did not simply inhibit myeloid cells as previously anticipated, but potentiated myeloid cells for the innate immune response and concomitant production of type I cytokines. Such immune responses may subsequently activate the effector T cells as the single nuclear RNA sequencing analysis demonstrated enhanced activation signals in the T cell cluster from the tumors treated by anti-IL-8 antibodies. Taken together, this study supports further testing of anti-IL-8 antibodies including B108-IL8 and HuMax-IL8 in combination with anti-PD-1 antibodies for PDAC treatment. Disclosure Information P. Li: None. N. Rozich: None. J. Wang: None. J. Gai: None. J. Wang: None. Y. Xu: None. B. Herbst: None. R. Yu: A. Employment (full or part-time); Significant; NovaRock. S. Muth: None. N. Niu: None. K. Li: None. V. Fune: None. A. Osipov: None. C. Wolfgang: None. M. Lei: A. Employment (full or part-time); Significant; NovaRock. T. Liang: None. L. Zheng: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Bristol-Meyer Squibb, Merck, iTeos, Amgen, NovaRock, Inxmed, Halozyme. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Alphamab, Mingruzhiyao. F. Consultant/Advisory Board; Significant; Biosion, Alphamab, NovaRock, Akrevia/Xilio, Ambrx, Novagenesis, Datarevive, Snow Lake Capitals, Mingruzhiyao. Other; Significant; Aduro Biotech.

Near-infrared spectroscopy (NIRS) is an effective and efficient technique for evaluating coal quality. The original spectra might be contaminated by scattering interference and random noise. We propose a novel artifact removal framework to recover the buried information and to overcome limitations of currently available preprocessing techniques, such as the multiplicative scatter correction (MSC), as well as a smoothing process. The two-step framework is mainly constructed by MSC and Savitzky–Golay convolution (S-SGC) . Moreover, a particle swarm optimization (PSO) algorithm is used to search the optimal parameters within the framework. In addition, the spectra are collected from coal samples with different particle sizes (i.e., 0.2 and 3 mm), which may carry different characteristics and interfering information. We have analyzed seven kinds of coal properties, such as moisture (%), ash (%), volatile matter (%), and heating value (MJ/kg) via partial least square regression (PLSR) models in order to verify the effectiveness of the proposed method. The results show that the proposed two-step method provides superior performances for zooming in the spectral characteristic peaks and filtering the random noise simultaneously, which mainly benefits from the appropriate combination of MSC and S-SGC.

Cell migration plays an important role in physiological and pathological processes where the fibrillar morphology of extracellular matrice (ECM) could regulate the migration dynamics. To mimic the morphological characteristics of fibrillar matrix structures, low-voltage continuous electrospinning was adapted to construct straight, wavy, looped and gridded fibre patterns made of polystyrene (of fibre diameter ca. 3 μm). With microfibres deposited onto non-passivated surfaces, cells were permitted to explore their different shapes in response to the directly-adhered fibre, as well as to the neighbouring patterns. For all the patterns studied, analysing cellular migration dynamics of MDA-MB-231 (a highly migratory breast cancer cell line) demonstrated a switch in behaviour when the pattern features approach the upper limit of the cell minor axis. Our findings suggest that, although cells dynamically adjust their shapes in response to different fibrillar environments during migration, their ability to divert from an existing fibre track is limited by the size along the cell minor axis. We therefore conclude that the upper limit of cell minor axis might act as a guide for the design of microfibre patterns for different purposes of cell migration.

BACKGROUND: In December 2020, Moderna released the mRNA-1273 vaccine. The most common side effects are headache, muscle pain, redness, swelling, and tenderness at the injection site. In addition, there have been dermatological adverse events, such as hypersensitivity reactions. Although rare, various bullous eruptions have been described following vaccination. Bullous pemphigoid has been reported to occur most often after receipt of influenza and the diphtheria-tetanus-pertussis vaccine. To the best of our knowledge, there have been no reports of bullous drug eruptions resulting from mRNA vaccines. CASE SUMMARY: A 66-years-old obese Guyanese male presented with a bullous rash following receipt of a commercial COVID-19 mRNA vaccine. He received the first dose uneventfully. However, within 24 h of receiving the second dose, he developed fever, myalgias, and malaise accompanied by a painful blistering rash of his torso, arms, and legs. His fever and myalgias improved after 24 h, but his painful rash did not, and five days after the initial symptoms, he presented to the hospital. There were many violaceous, poorly demarcated patches on his trunk, arms, and thighs on examination, many of which had large flaccid bullae within, and a few areas on his buttocks, posterior shoulder, and scrotum were eroded. The exam was also significant for lower extremity muscle tenderness, stiffness with preserved strength. A skin biopsy showed epidermal necrosis and sparse perivascular dermatitis concerning Stevens-Johnson syndrome or erythema multiforme. However, in the absence of mucous membrane involvement or targetoid lesions, the diagnosis of an extensive bullous fixed drug eruption was made. CONCLUSION: This case illustrates that the bullae eruption occurred as a result of receiving the Moderna vaccination.

计算流体力学（computational fluid dynamics，CFD）是利用计算机模拟技术对流体流动进行数值计算分析的交叉学科，已被广泛应用于上气道气流动力学的研究中。CFD作为一种新工具，可为鼻腔气流运动提供可视化及量化的研究方法，特别是在分析正常及各种病理状态下的鼻腔气流特性、模拟与指导鼻腔鼻窦手术以及量化评估手术疗效等方面，有很好的应用前景。然而，目前CFD各变量与鼻腔疾病患者临床症状之间的相关性研究仍然较少。本文基于CFD在鼻腔疾病临床应用中的研究进展进行综述。.

Objectives To evaluate the ability of post-chemo-radiotherapy (CRT) diffusion-weighted-MRI apparent diffusion coefficient (ADCmean) and 18F-FDG PET maximum standardized uptake value (SUVmax) to predict disease-free survival (DFS) in head and neck squamous cell carcinoma (HNSCC), and to determine whether this ability is influenced by human papillomavirus oropharyngeal cancer (HPV-OPC) status. Methods This prospective cohort observational study included 65 participants (53 male, mean ± SD age 59.9 ± 7.9 years, 46 HPV-OPC) with stage III or IV HNSCC. Primary tumour and nodal ADCmean (pre-treatment, 6- and 12-weeks post-CRT) and SUVmax (12-weeks post-CRT) were measured. Variables were compared with 2-year DFS (independent t-test/Mann–Whitney test) and overall DFS (Cox regression), before and after accounting for HPV-OPC status. Variables were also compared between HPV-OPC and other HNSCC subgroups after stratifying for DFS. Results Absolute post-CRT ADCmean values predicted 2-year DFS and overall DFS for all participants (p = 0.03/0.03, 6-week node; p = 0.02/0.03 12-week primary tumour) but not in the HPV-OPC subgroup. In participants with DFS, percentage interval changes in primary tumour ADCmean at 6- and 12-weeks were higher in HPV-OPC than other HNSCC (p = 0.01, 6 weeks; p = 0.005, 12 weeks). The 12-week post-CRT SUVmax did not predict DFS. Conclusion Absolute post-CRT ADCmean values predicted DFS in HNSCC but not in the HPV-OPC subgroup. Amongst participants with DFS, post-CRT percentage interval changes in primary tumour ADCmean were significantly higher in HPV-OPC than in other HNSCC. Knowledge of HPV-OPC status is crucial to the clinical utilisation of post-CRT DWI-MRI for the prediction of outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-021-03662-y.