Asynchrony of primary tumor and mediastinal lymph nodes response after neoadjuvant immunotherapy plus chemotherapy in a patient with stage IIIA non-small-cell lung cancer: a case report.

With the rapid development of immunotherapy, the efficacy and feasibility of neoadjuvant immunotherapy for early resectable non-small-cell lung cancer (NSCLC) has been demonstrated. However, there are still difficulties and controversies in evaluating the efficacy of neoadjuvant immunotherapy. In our report, we described a 43-year-old female patient who was diagnosed with stage IIIA (cT1N2M0) pulmonary adenocarcinoma. After two cycles of neoadjuvant immunotherapy (sintilimab) combined with chemotherapy, according to imaging evaluation, the efficacy of the primary lesion was evaluated as stable disease and the mediastinal lymph nodes were evaluated as partial response. However, the postoperative pathological evaluation showed the primary lesion was pathological complete response and the mediastinal lymph nodes were major pathological response. This indicated that neoadjuvant chemo-immunotherapy was effective for both primary and mediastinal lymph nodes, but regression of the lesions was not synchronous. This study provided a complete process of neoadjuvant treatment, illustrating the effectiveness and safety of neoadjuvant chemo-immunotherapy to a certain extent. It is also suggested that the evaluation of neoadjuvant immunotherapy should be combined with imaging and pathology, and the primary tumor and lymph nodes should be evaluated, respectively.

TPFusion: Texture Preserving Fusion of Infrared and Visible Images via Dense Networks.

In this paper, we design an infrared (IR) and visible (VIS) image fusion via unsupervised dense networks, termed as TPFusion. Activity level measurements and fusion rules are indispensable parts of conventional image fusion methods. However, designing an appropriate fusion process is time-consuming and complicated. In recent years, deep learning-based methods are proposed to handle this problem. However, for multi-modality image fusion, using the same network cannot extract effective feature maps from source images that are obtained by different image sensors. In TPFusion, we can avoid this issue. At first, we extract the textural information of the source images. Then two densely connected networks are trained to fuse textural information and source image, respectively. By this way, we can preserve more textural details in the fused image. Moreover, loss functions we designed to constrain two densely connected convolutional networks are according to the characteristics of textural information and source images. Through our method, the fused image will obtain more textural information of source images. For proving the validity of our method, we implement comparison and ablation experiments from the qualitative and quantitative assessments. The ablation experiments prove the effectiveness of TPFusion. Being compared to existing advanced IR and VIS image fusion methods, our fusion results possess better fusion results in both objective and subjective aspects. To be specific, in qualitative comparisons, our fusion results have better contrast ratio and abundant textural details. In quantitative comparisons, TPFusion outperforms existing representative fusion methods.

Successful treatment of Afatinib plus Apatinib using for a lung adenocarcinoma patient with HER-2 V659D mutation: a rare case report.

Lung cancer is one of the most important and lethal cancers in the world. Human epidermal growth factor 2 (HER2) is a member of the erbB receptor tyrosine kinase family. The incidence of HER2 kinase domain mutations in adenocarcinoma of lung ranges from 1% to 3%. HER2 V659D mutation is located in the trans-membrane domain (TMD) with only a few cases reported before, and importantly, there were no more standard and effective ways for this kind of diseases until now. Afatinib irreversibly blocks all kinase-competent HER family members. Apatinib is one of the small-molecule oral anti-angiogenesis-targeted agents developed firstly in China, and it's a highly selective inhibition of the activity of VEGFR-2. This report presents an advanced lung adenocarcinoma patient with HER2 V659D mutation who was treated with combination of Afatinib and Apatinib. He achieved good efficacy and tolerable adverse reactions.

Revealing the spatio-temporal variability of evapotranspiration and its components based on an improved Shuttleworth-Wallace model in the Yellow River Basin.

Identifying the spatio-temporal variations of evapotranspiration (ET) from its components (soil evaporation and plant transpiration) can greatly improve our understanding of water-cycle and biogeochemical processes. However, partitioning evapotranspiration into evaporation (E) and transpiration (T) at regional scale with high accuracy still remains a challenge. This study has aimed to reveal the spatio-temporal variations of evapotranspiration and its components by using an improved Shuttleworth-Wallace (SWH) model to partition ET in the Yellow River Basin during 1981-2010. The environmental factors affecting the spatial and temporal variations of evapotranspiration and its components were also assessed. Results showed that the mean annual ET, T and E in the Yellow River Basin were 372.18 mm, 179.64 mm, and 192.54 mm, respectively, over the last 30 years. The spatial pattern of mean annual ET and T displayed a decreasing trend from southeast to northwest in the Yellow River Basin, and the temporal variation showed a significant increasing trend with rates of 1.72 mm yr-1 and 1.54 mm yr-1, respectively. It meant that T accounted for the variations of ET, while E showed no significant changes in recent decades. Moreover, the normalized differential vegetation index (NDVI) and temperature were identified as the main factors controlling the variations of ET and T in the Yellow River Basin. Among them, the area with NDVI as the dominant factor for ET and T could reach 63.82% and 78.47% of the whole basin respectively. However, the variations of E were affected by complex factors, and evaporation in the western alpine region was mainly controlled by temperature. Our findings are expected to not only have implications for developing sustainable policies of water management and ecological restoration in this region, but also provide valuable insight in methodology of ET partitioning in regional or global scale.

The role of ERp44 in glucose and lipid metabolism.

Endoplasmic Reticulum Protein 44 (ERp44) is a member of the PDI family, named for a molecular weight of 44 kD. White adipose tissue has metabolic and endocrine functions that are important to metabolism. The role of ERp44 in glucose and lipid metabolism is not known yet. The current study was undertaken to investigate the implication of ERp44 in glucose and lipid metabolism. In this study, we generated and characterized ERp44-/- mice. We used type 2 diabetes models and ERp44 knockout mice to show the implication of ERp44 in glucose and lipid metabolism. Knockout newborns had lower blood glucose compared to wild-type. Adult knockouts had abnormal intraperitoneal, glucose, insulin and pyruvic acid tolerance. Lipocytes were smaller and fewer in knockout mice compared to wild-type. Knockouts resisted to high-fat diet-induced obesity. ERp44 expression in white adipose tissue decreased significantly in type 2 diabetes models. Results suggest that ERp44 is closely associated with glucose and lipid metabolism.

[Synthesis and Fluorescence Properties of Rare Earth Ions Co-Doped CaMoO(4)].

In this paper, a series of CaMoO4 phosphor co-doped rare earth ions were prepared with chemistry co-precipitation method. The concentration of Pr(3+)/Tb(3+) and temperature had obvious influence on the luminescent properties. The crystal structures and spectrum characteristics of the samples were identified with X-ray powder diffraction (XRD) and fluorescence spectrophotometer (PL). According to XRD analysis, the main diffraction peaks of samples are consistent with the standard card (JCPDS 29-0351) of the diffraction peak data. This showed doped rare earth ions did not change matrix lattice structure. The emission spectrum excited by 275 nm exhibit sharp lines peaking at 488, 560, 621 and 560 nm assigned to the (3)P(0)­(3)H(4), (3)P(0)­(3)H(5)，(1)D(2)­(3)H(4) and (3)P(0)­(3)F(2) transitions of the Pr(3+) ions. The intensity of fluorescence reached the strongest when the concentration of the doping amount was 3%. The optimum calcination temperatures of CaMoO(4)∶0.03Pr(3+) and CaMoO(4)∶0.05Tb(3+) were 800 and 600 ℃. Furthermore, the intensity of excitation spectra and emission spectra are dependent on the concentration of the doping amount. The emission spectra intensities of CaMoO(4)∶Pr(3+) phosphors decrease and CaMoO(4)∶Tb(3+) phosphors firstly increase and then decrease because of concentration quenching effect with increasing Pr(3+) and Tb(3+) concentration. In addition, the luminescence properties of Pr(3+) ion in CaMoO(4)∶0.03Pr(3+), yTb(3+) system could be evidently improved with co-doping of Tb(3+) ions which was due to the efficient energy transfer process from Tb(3+) to Pr(3+) ions.

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice.

AIMS/HYPOTHESIS: CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain- and loss-of-function experiments and to further decipher the underlying molecular mechanisms. METHODS: A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3' untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments. RESULTS: CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose- and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3' UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose- and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. CONCLUSIONS/INTERPRETATION: We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

Biomass pyrolysis liquid to citric acid via 2-step bioconversion.

BACKGROUND: The use of fossil carbon sources for fuels and petrochemicals has serious impacts on our environment and is unable to meet the demand in the future. A promising and sustainable alternative is to substitute fossil carbon sources with microbial cell factories converting lignocellulosic biomass into desirable value added products. However, such bioprocesses require tolerance to inhibitory compounds generated during pretreatment of biomass. In this study, the process of sequential two-step bio-conversion of biomass pyrolysis liquid containing levoglucosan (LG) to citric acid without chemical detoxification has been explored, which can greatly improve the utilization efficiency of lignocellulosic biomass. RESULTS: The sequential two-step bio-conversion of corn stover pyrolysis liquid to citric acid has been established. The first step conversion by Phanerochaete chrysosporium (P. chrysosporium) is desirable to decrease the content of other compounds except levoglucosan as a pretreatment for the second conversion. The remaining levoglucosan in solution was further converted into citric acid by Aspergillus niger (A. niger) CBX-209. Thus the conversion of cellulose to citric acid is completed by both pyrolysis and bio-conversion technology. Under experimental conditions, levoglucosan yield is 12% based on the feedstock and the citric acid yield can reach 82.1% based on the levoglucosan content in the pyrolysis liquid (namely 82.1 g of citric acid per 100 g of levoglucosan). CONCLUSION: The study shows that P. chrysosporium and A. niger have the potential to be used as production platforms for value-added products from pyrolyzed lignocellulosic biomass. Selected P. chrysosporium is able to decrease the content of other compounds except levoglucosan and levoglucosan can be further converted into citric acid in the residual liquids by A. niger. Thus the conversion of cellulose to citric acid is completed by both pyrolysis and bio-conversion technology.

Identification and prognostic biomarkers among ZDHHC4/12/18/24, and APT2 in lung adenocarcinoma.

S-palmitoylases and S-depalmitoylases are differentially expressed in various cancers and several malignant tumors and show a strong prognostic ability. Notwithstanding, the potential clinical impact of S-palmitoylases and S-depalmitoylases, particularly in the prognosis and progression of lung adenocarcinoma (LUAD), has not been clarified. Expression levels of S-palmitoylases and S-depalmitoylases in LUAD were investigated using TCGA. GEPIA was used to evaluate the mRNA levels of S-palmitoylases and S-depalmitoylases at different pathological stages. Metascape was used to investigate the biological significance of S-palmitoylases and S-depalmitoylases. The Kaplan-Meier plotter was used to analyze the prognostic value of S-palmitoylases and S-depalmitoylases. CBioportal was used to analyze gene alterations in S-palmitoylases and S-depalmitoylases. UALCAN was used to examine DNA promoter methylation levels of S-palmitoylases and S-depalmitoylases. Finally, we investigated the relationship between S-palmitoylases, S-depalmitoylases, and tumor-infiltrating immune cells using TIMER. Correlations with immune checkpoint-related genes were determined using the R packages reshape2, ggpubr, ggplot2, and corrplot. PCR was also performed to assess the degree of ZDHHC4/12/18/24 and APT2 transcript expression in lung adenocarcinoma and adjacent normal lung tissues. HPA was utilized to investigate protein levels of S-palmitoylases and S-depalmitoylases in LUAD and normal lung tissue. Our study found that ZDHHC2/3/4/5/6/7/9/12/13/16/18/20/21/23/24, APT1/2, PPT1, LYPLAL1, ABHD4/10/11/12/13 and ABHD17C mRNA expression was significantly upregulated in LUAD, whereas ZDHHC1/8/11/11B/14/15/17/19/22, ABHD6/16A and ABHD17A mRNA expression was significantly downregulated. The functions of the differentially expressed S-palmitoylases and S-depalmitoylases were mainly associated with protein-cysteine S-palmitoyltransferase and protein-cysteine S-acyltransferase activities. Patients with high expression of ZDHHC4/12/18/24, APT2, ABHD4, ABHD11 and ABHD12 had a shorter overall survival. Infiltration of six immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) was closely associated with the expression of ZDHHC4/12/18/24 and APT2. ZDHHC4/12/18/24 and APT2 positively correlated with the immune checkpoint-related gene CD276. We assessed the mRNA levels of ZDHHC4/12/18/24 and APT2 using qRT-PCR and found increased expression of ZDHHC4/12/18/24 in LUAD compared with healty control lung tissues. ZDHHC4/12/18/24, and APT2 are potential prognostic biomarkers of LUAD. Their expression levels could be related to the tumor microenvironment in LUAD.

Imaging findings can't mean everything in the era of immunotherapy: a case report and literature review.

Immune-checkpoint inhibitors (ICIs) play an important role in the treatment of cancers. However, immunotherapy can also induce atypical response patterns, including pseudoprogression, which is challenging to clinicians. We reported a case of non-small-cell lung cancer showing so-called pseudoprogression during the treatment of pembrolizumab and the patient benefited clinically from continued treatment with ICIs. Therefore, beside imaging evaluation, the assessment of Eastern Cooperative Oncology Group performance status score, numerical rating scale score of cancer pain, tumor markers levels, and neutrophil-to-lymphocyte ratio should be used for response evaluation of tumors in the era of immunotherapy. And more accurate evaluation methods and reliable information are urgently needed to better understand the pseudoprogression.

Sometimes drugs can kill cancer cells but rather than getting smaller, as expected, the tumor size increases. This is called 'pseuoprogression', meaning false progression. Here, we report pseudoprogression in a lung cancer patient receiving immunotherapy. The tumor initially got larger, but with continued treatment, it decreased in size.

Ct-based subregional radiomics using hand-crafted and deep learning features for prediction of therapeutic response to anti-PD1 therapy in NSCLC.

PURPOSE: To develop and externally validate subregional radiomics for predicting therapeutic response to anti-PD1 therapy in non-small-cell lung cancer (NSCLC). METHODS: Sixty-six patients from center 1 served as training and internal validation cohorts. Thirty patients from center 2 and thirty patients from center 3 served as external validation 1 and external validation 2 cohorts, respectively. The lesions identified on CT scans were subdivided into two phenotypically consistent subregions by automatic clustering on the patient-level and population-level (denoted as marginal S1 and inner S2). Handcrafted and deep learning-based features were extracted separately from the entire tumor region and subregions, then selected using the intraclass correlation coefficient and least absolute shrinkage and selection operator regression (LASSO). Radiomics signatures (RSs) were built integrating the selected features and correlation coefficients using a logistic regression method. Area under the receiver operating characteristic (ROC) curve (AUC) was calculated to assess the RSs. RESULTS: RSs derived from S1 outperformed those from S2 and the whole tumor region for both handcrafted and deep learning features. The Fusion-RS incorporating the two feature types achieved the best prediction performance in training (AUC = 0.947, 95 % Confidence Interval [CI] 0.905-0.989, SPE = 0.895, SEN = 0.878), internal validation (AUC = 0.875, 95 % CI: 0.782-0.969, SPE = 0.724, SEN = 0.952), external validation 1 (AUC = 0.836, 95 % CI: 0.694-0.977, SPE = 1.000, SEN = 0.533) and external validation 2 (AUC = 0.783, 95 % CI: 0.613-0.953, SPE = 0.765, SEN = 0.692) cohorts. CONCLUSIONS: Subregional radiomics analysis can be useful for predicting therapeutic response to anti-PD1 therapy. The developed Fusion-RS may be considered as a potential non-invasive tool for individual treatment managements.

Development of postoperative bronchopleural fistula after neoadjuvant immunochemotherapy in non-small cell lung cancer: case reports and review of the literature.

BACKGROUND: The advent of immune checkpoint inhibitors has dramatically changed the treatment paradigm for advanced non-small-cell lung cancer (NSCLC). Due to the complexity and diversity of stage III disease, the inclusion of immune checkpoint inhibitors (ICIs) in neoadjuvant treatment regimens is also required. However, immune-related adverse events (irAEs) limit the application of ICIs to a certain extent. Bronchopleural fistula (BPF) is a serious and fatal complication after pneumonectomy that is rarely reported, especially in patients who accept neoadjuvant immunotherapy or chemoimmunotherapy. CASE PRESENTATION: Herein, we reported four patients with postoperative BPF who received a neoadjuvant regimen of sintilimab plus chemotherapy. Postoperative BPF occurred in the late stage in three patients; one patient underwent bronchoscopic fistula repair, and the fistula was closed well after surgery, and the other two patients gradually recovered within 1-2 months after symptomatic treatment with antibiotics. One patient with BPF after left pneumonectomy died of respiratory failure due to pulmonary infection. We also reviewed the literature on the development of postoperative BPF in patients receiving immuno-neoadjuvant therapy to discuss the clinical process further, postoperative pathological changes, as well as risk factors of BPF patients. CONCLUSIONS: Central type lung cancer with stage III may be the risk factors of BPF in cases of neoadjuvant immunochemotherapy for lung cancers patients.

Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage IIIA/IIIB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial.

Background: Some locally advanced (IIIA/IIIB) non-small cell lung cancers (NSCLCs) might have surgical options available. However, information regarding the effectiveness of neoadjuvant immunotherapy for potentially resectable IIIA/IIIB NSCLC is limited. The intent of this investigation was to offer a more favourable alternative to the standard approach of chemoradiotherapy (concurrent or sequential chemoradiotherapy) followed by immunotherapy for potentially resectable stage III NSCLC. Methods: This prospective, single-arm, phase 2 clinical trial (NCT04326153) enrolled treatment-naïve patients with 'potentially resectable' IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection upon initial diagnosis. The study period was between March 20, 2020, and August 20, 2021. Patients underwent neoadjuvant chemoimmunotherapy (sintilimab combined with nab-paclitaxel and carboplatin) for two to three cycles prior to surgical resection of the lung carcinoma and systematic nodal dissection within 30-45 days. The primary endpoint was the 2-year disease-free survival (DFS) rate, with secondary endpoints encompassing major pathological response (MPR) rate, pathological complete response (pCR) rate, overall survival, objective response rate (ORR), downstaging rate, and adverse events (AEs). Tumour immune cell infiltrates, identified via immunohistochemistry, were assessed as biomarkers at baseline and after surgery. Findings: Among 30 patients who received neoadjuvant chemoimmunotherapy, 20 underwent complete resection. The disease control rate was 96.7% (95% CI: 90.3%-99.99%), with an ORR of 55% (95% CI: 37.2%-72.8%) and a downstaging rate of 80% (95% CI: 65.7%-94.3%). In the subgroup of 20 patients who underwent surgery, the MPR rate was 65% (95% CI: 43.3%-82.9%), and the pCR rate was 40% (95% CI: 21.2%-46.3%). The 2-year DFS rate in the surgical group was 75% (95% CI 56%-94%). Notably, the MPR group demonstrated significantly prolonged DFS compared with the non-MPR group (p = 0.00024). A significant increase in pretreatment CD8 expression correlated with improved DFS (p = 0.00019). Three patients (10%) experienced grade 3 or higher immune-related AEs-one case of grade 3 elevated myocardial enzymes, one case of grade 3 interstitial pneumonia, and one case of grade 5 bronchopleural fistula. Interpretation: Neoadjuvant immunotherapy markedly enhanced the rate of pathological response and 2-year DFS in patients with potentially resectable IIIA/IIIB NSCLC. Overexpression of CD8 before treatment (H score≥3) may serve as a potential predictive biomarker for DFS. Consequently, the treatment landscape for potentially resectable IIIA/IIIB NSCLC could undergo changes. Funding: This study did not receive any financial support.

[Retracted] miR­154 suppresses non­small cell lung cancer growth in vitro and in vivo.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that certain of the western blotting data shown in Fig. 5 were strikingly similar to data appearing in different form in other articles by different authors, some of which have been retracted. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, elsewhere when it was submitted to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 33: 3053­3060, 2015; DOI: 10.3892/or.2015.3895].

Torrefaction characteristics of cellulose loaded with boric acid.

To explore the catalytic effect of boric acid on biomass, cellulose loaded with boric acid was roasted by a tubular furnace. The gaseous products were adsorbed by activated carbon and then analyzed by GC-MS. Boric acid was shown to improve the selectivity of the product levoglucosenone (LGO). The effects of the parameters such as boric acid loading, nitrogen flow, and temperature on the torrefaction behavior of cellulose were investigated. In the studied temperature range of 240-420 °C, the yield of LGO first increases and then decreases. In addition, its yield increases directly with increasing nitrogen flow rate. The results show that the highest LGO yield of 6.64% (analytical value) can be obtained under 10% (w/w) boric acid loading, 380 °C and nitrogen flow rate of 65 ml/min conditions.

ARID1A mutations in lung cancer: biology, prognostic role, and therapeutic implications.

Mutations in the AT-interacting domain-rich protein 1A (ARID1A) gene, a critical component of the switch/sucrose nonfermentable (SWI/SNF) complex, are frequently found in most human cancers. Approximately 5-10% of lung cancers carry ARID1A mutations. ARID1A loss in lung cancer correlates with clinicopathological features and poor prognosis. Co-mutation of ARID1A and epidermal growth factor receptor (EGFR) results in the limited efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) but increases the clinical benefit of immune checkpoint inhibitors (ICIs). ARID1A gene mutation plays a role in cell cycle regulation, metabolic reprogramming, and epithelial-mesenchymal transition. We present the first comprehensive review of the relationship between ARID1A gene mutations and lung cancer and discuss the potential of ARID1A as a new molecular target.

Interim analysis of the efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy (nab-paclitaxel and carboplatin) in potentially resectable stage IIIA/IIIB non-small cell lung cancer: a single-arm, phase 2 trial.

INTRODUCTION: While some clinical studies have shown that PD-1 and PD-L1 can also be an effective neoadjuvant treatment for early-stage non-small cell lung cancer (NSCLC), no evidence has been available for the use of the PD-1 inhibitor sintilimab combined with chemotherapy as a neoadjuvant treatment for potentially resectable NSCLC in the Chinese population. METHODS: This prospective, single-center, single-arm, phase 2 clinical trial (registration number: NCT04326153) included treatment-naive patients with potentially resectable NSCLC (stage IIIA/IIIB) who received sintilimab plus nab-paclitaxel and carboplatin for two to three cycles before systematic nodal dissection 30 to 45 days after neoadjuvant treatment. After surgery, patients needed to complete two cycles of adjuvant chemoimmunotherapy (sintilimab + nab-paclitaxel + carboplatin). The primary endpoint was disease-free survival rate at 24 months, whereas secondary endpoints included major pathological response (MPR) and pathologic complete response (pCR) rates, the proportion of patients who achieved tumor downstaging, overall survival, objective response rate (ORR), and adverse effects. PD-L1 status before and after treatment was also determined. RESULTS: Among the 20 patients who received neoadjuvant chemoimmunotherapy, 16 underwent radical resection. The disease control rate and ORR were 90% and 70%, respectively. Among the 16 patients who underwent surgery, 10 (62.5%) and 5 (31.25%) achieved MPR and pCR, respectively. Squamous cell NSCLC exhibited superior response rates compared to adenocarcinoma (pCR 35.7% vs. 0%). Moreover, 14 patients (70%) experienced grade 1 or 2 neoadjuvant treatment-related adverse events (TRAEs), whereas 6 (30%) experienced grade 3 TRAEs. Bronchopleural fistula (BPF) was found in the current study as an adverse reaction of concern. The rate of BPF was 20% (4/20), of which three patients were in grade 1-2, and one patient died. The occurrence of BPF had no significant correlation with basic disease history, nutritional status, anemia, hypoalbuminemia, surgical procedure, pathological remission, and PD-L1 expression. However, during neoadjuvant treatment, no adverse events prompted dose reduction, treatment discontinuation, surgery delay, or death. Although PD-L1 expression may change after chemoimmunotherapy, no regular pattern was noted. PD-L1 expression, neither at baseline nor after neoadjuvant chemoimmunotherapy, was associated with pathological remission. CONCLUSIONS: The current study found similar ORR, slightly lower MPR and pCR rates, and lower grade 3 TRAEs among patients with potentially resectable stage IIIA/IIIB NSCLC compared to the NADIM trial, as well as a greater ORR, MPR rate, pCR rate, and grade 3 TRAEs compared to Gao's study involving sintilimab for Chinese patients with resectable stage IA-IIIB NSCLC. Though neoadjuvant chemoimmunotherapy had been found to promote a high risk of BPF for patients with stage IIIA/IIIB disease, it offered greater potential for radical cure. Therefore, the current study suggests that neoadjuvant chemoimmunotherapy can be a safe approach in increasing the efficiency of treatment and hopefully improving the prognosis of patients with potentially resectable locally advanced NSCLC.

Radiomics signatures for predicting the Ki-67 level and HER-2 status based on bone metastasis from primary breast cancer.

This study explores the potential of radiomics to predict the proliferation marker protein Ki-67 levels and human epidermal growth factor receptor 2 (HER-2) status based on MRI images of patients with spinal metastasis from primary breast cancer. A total of 110 patients with pathologically confirmed spinal metastases from primary breast cancer were enrolled between Dec. 2017 and Dec. 2021. All patients underwent T1-weighted contrast-enhanced MRI scans. The PyRadiomics package was used to extract features from the MRI images based on the intraclass correlation coefficient and least absolute shrinkage and selection operator. The most predictive features were used to develop the radiomics signature. The Chi-Square test, Fisher's exact test, Student's t-test, and Mann-Whitney U test were used to evaluate the clinical and pathological characteristics between the high- and low-level Ki-67 groups and the HER-2 positive/negative groups. The radiomics models were compared using receiver operating characteristic curve analysis. The area under the receiver operating characteristic curve (AUC), sensitivity (SEN), and specificity (SPE) were generated as comparison metrics. From the spinal MRI scans, five and two features were identified as the most predictive for the Ki-67 level and HER-2 status, respectively. The developed radiomics signatures generated good prediction performance for the Ki-67 level in the training (AUC = 0.812, 95% CI: 0.710-0.914, SEN = 0.667, SPE = 0.846) and validation (AUC = 0.799, 95% CI: 0.652-0.947, SEN = 0.722, SPE = 0.833) cohorts. Good prediction performance for the HER-2 status was also achieved in the training (AUC = 0.796, 95% CI: 0.686-0.906, SEN = 0.720, SPE = 0.776) and validation (AUC = 0.705, 95% CI: 0.506-0.904, SEN = 0.733, SPE = 0.762) cohorts. The results of this study provide a better understanding of the potential clinical implications of spinal MRI-based radiomics on the prediction of Ki-67 levels and HER-2 status in breast cancer.

Reciprocal costimulatory molecules control the activation of mucosal type 3 innate lymphoid cells during engagement with B cells.

Innate lymphoid cells (ILCs) are the counterpart of T helper cells in the innate immune system and share multiple phenotypes with T helper cells. Inducible T-cell costimulator (ICOS) is recognized on T cells and participates in T-cell activation and T and B-cell engagement in lymphoid tissues. However, the role of ICOS in ILC3s and ILC3-involved interactions with the immune microenvironment remains unclear. Here, we found that ICOS expression on human ILC3s was correlated with the activated state of ILC3s. ICOS costimulation enhanced the survival, proliferation, and capacity of ILC3s to produce cytokines (IL-22, IL-17A, IFN-γ, TNF, and GM-CSF). Via synergistic effects of ICOS and CD40 signaling, B cells promoted ILC3 functions, and ILC3-induced T-cell-independent B-cell IgA and IgM secretion primarily required CD40 signaling. Hence, ICOS is essential for the nonredundant role of ILC3s and their interaction with adjacent B cells.

A DFT study on the structure activity relationship of the natural xanthotoxin-based pharmaceutical cocrystals.

In this work, the pharmaceutical cocrystals xanthotoxin-para-aminobenzoic acid (XT-PABA) and xanthotoxin-oxalic acid (XT-OA) were systematically investigated in the gas and water phases by using the quantum chemical approach. The weak intermolecular interactions have been estimated and the O1…H4 (O1…H5) intermolecular hydrogen bond (IHB) with moderate intensity and partial covalent natures was confirmed based on the computed structural parameters, topology analysis, and reduced density gradient (RDG) isosurfaces. The electrophilic and nucleophilic reactivities of different positions associated with intermolecular interactions in XT, PABA, and OA were predicted by plotting the molecular electrostatic potential (MESP) diagrams. The calculated natural bond orbital (NBO) population analysis has quantitatively unveiled the intrinsic reason for the variations in weak intermolecular interactions within XT-PABA and XT-OA cocrystals, from the gas phase to the water phase. Besides, the frontier molecular orbitals (FMOs), Fukui function, and various global reactivity descriptors were computed to measure the chemical reactivity of all the investigated molecular systems. The XT-PABA and XT-OA cocrystals explored in this work could be regarded as valuable exemplar systems to design and synthesize the high-efficiency pharmaceutical cocrystals in the experiment.