The risk of treatment-related toxicities with PD-1/PD-L1 inhibitors in patients with lung cancer.

The risk of treatment-related toxicities with programmed cell death 1 and its ligand (PD-1/PD-L1) inhibitors in patients with lung cancer is unclear and inconclusive. PubMed, EMBASE, and the Cochrane Library databases were systematically searched without language restrictions from inception to May 31, 2024 to identify Phase 3 randomized controlled trials of lung cancer comparing PD-1/PD-L1 inhibitors versus placebo/best supportive care (alone or in combination with nontargeted chemotherapy) that had available data regarding treatment-related adverse events (TRAEs) or incidence and sample size. Random-effect models were employed to study the pooled relative risk (RR) and 95% confidence intervals (CIs). Finally, 36 trials, involving 19,693 participants, fulfilled the inclusion criteria. PD-1/PD-L1 inhibitors significantly augmented the likelihood of developing all-grade (RR, 1.03; 95% CI, 1.01-1.04, p < .01) and grade ≥3 TRAEs (RR, 1.16; 95% CI, 1.10 to 1.23, p < .01). PD-1/PD-L1 inhibitors substantially augmented the odds of developing treatment-related serious adverse events (SAEs) (RR, 1.48; 95% CI, 1.27-1.71, p < .01) and fatal adverse events (FAEs) (RR, 1.42; 95% CI, 1.11-1.82, p < .01). Subgroup analyses indicated that the RR of SAEs and FAEs were generally consistent, regardless of treatment type, tumor type, treatment setting, PD-1/PD-L1 inhibitors type and study design. The most common causes of FAEs were respiratory failure/insufficiency (33.3%), cardiac events (16.1%), and hematological disorders (10.1%). We demonstrated that PD-1/PD-L1 inhibitors were significantly correlated with higher possibility of developing treatment-related toxicities, especially SAEs and FAEs, compared with placebo/best supportive care controls.

Hydroxyl-Amide Alkaloids from Pepper Roots: Potential Sources of Natural Antioxidants and Tyrosinase Inhibitors.

Pepper (Piper nigrum L.) is a widely used spice plant known for its fruits and roots, which serve as flavor enhancers in culinary applications and hold significant economic value. Despite the popularity of pepper fruits, their roots remain relatively understudied, with limited research conducted on their bioactive components. This study focused on discovering and separating the primary bioactive amide alkaloids found in pepper roots. The process involved using the antioxidant activity of crude fractions and the Global Natural Products Social Molecular Networking analysis platform. The process led to the discovery of 23 previously unknown hydroxyl-amide alkaloids. Notably, compounds 11, 12, and 14 showed excellent antioxidant activity, while compound 11 exhibited significant inhibitory effects on mushroom tyrosinase. Theoretical exploration of enzyme-ligand interactions was conducted through molecular docking and molecular dynamics simulation. The findings of this study highlight the potential of hydroxyl-amide alkaloids as antioxidant products and natural food preservatives in the pharmaceutical and food cosmetic industries.

[Medium- and long-term effectiveness of hip revision with SL-PLUS MIA stem in patients with Paprosky type â - â ¢ femoral bone defect].

Objective: To investigate the medium- and long-term effectiveness of hip revision with SL-PLUS MIA stem in patients with Paprosky typeⅠ-Ⅲ femoral bone defect. Methods: Between June 2012 and December 2018, 44 patients with Paprosky typeⅠ-Ⅲ femoral bone defect received hip revision using SL-PLUS MIA stem. There were 28 males and 16 females, with an average age of 57.7 years (range, 31-76 years). Indications for revision comprised aseptic loosening (27 cases) and periprosthetic joint infection (17 cases). The Harris hip scores were 54 (48, 60) and 43 (37, 52) in patients with aseptic loosening and periprosthetic joint infection, respectively. The preoperative femoral bone defects were identified as Paprosky type Ⅰ in 32 cases, type Ⅱ in 9 cases, type ⅢA in 2 cases, and type ⅢB in 1 case. Operation time and intraoperative blood transfusion volume were recorded. During follow-up after operation, the hip joint function were evaluated by Harris hip score and X-ray films, the femoral stem survival was analyzed, and the surgical related complications were recorded. Results: The operation time of infected patients was 95-215 minutes, with an average of 125.0 minutes. The intraoperative blood transfusion volume was 400-1 800 mL, with an average of 790.0 mL. The operation time of patients with aseptic loosening was 70-200 minutes, with an average of 121.0 minutes. The intraoperative blood transfusion volume was 400-1 400 mL, with an average of 721.7 mL. All patients were followed up 5.3-10.0 years (mean, 7.4 years). At last follow-up, the Harris hip scores were 88 (85, 90) and 85 (80, 88) in patients with aseptic loosening and periprosthetic joint infection, respectively, both of which were significantly higher than those before operation ( P<0.05). Radiological examination results showed that the distal end of the newly implanted femoral stem did not cross the distal end of the original prosthesis in 25 cases, and all femoral stems obtained bone fixation. Two cases experienced femoral stem subsidence and 1 case had a translucent line on the lateral side of the proximal femoral stem. When aseptic loosening was defined as the end event, the 10-year survival rate of the SL-PLUS MIA stem was 100%. When treatment failure due to any reason was defined as the end event, the survival time of the prosthesis was (111.70±3.66) months, and the 7-year survival rate was 95.5%. The 7-year survival rates were 94.1% and 96.3% in patients with aseptic loosening and periprosthetic joint infection, respectively. The incidence of postoperative complications was 9.1% (4/44), among which the prosthesis related complications were 4.5% (2/44), 1 case of dislocation and 1 case of infection recurrence. Conclusion: Hip revision with SL-PLUS MIA stem has the advantages of simple operation and few postoperative complications in the patients with Paprosky type Ⅰ-Ⅲ femoral bone defect, and the medium- and long-term effectiveness is reliable.

Novel SERCA2 inhibitor Diphyllin displays anti-tumor effect in non-small cell lung cancer by promoting endoplasmic reticulum stress and mitochondrial dysfunction.

Abnormal calcium signaling is associated with non-small cell lung cancer (NSCLC) malignant progression, poor survival and chemotherapy resistance. Targeting endoplasmic reticulum (ER) Ca2+ channels or pumps to block calcium uptake in the ER induces ER stress and concomitantly promotes mitochondrial calcium uptake, leading to mitochondrial dysfunction and ultimately inducing cell death. Here, we identified Diphyllin was a potential specific inhibitor of endoplasmic reticulum (ER) calcium-importing protein sarco/endoplasmic-reticulum Ca2+ ATPase 2 (SERCA2). In vitro and in vivo studies showed that Diphyllin increased NSCLC cell apoptosis, along with inhibition of cell proliferation and migration. Mechanistically, Diphyllin promoted ER stress by directly inhibiting SERCA2 activity and decreasing ER Ca2+ levels. At the same time, the accumulated Ca2+ in cytoplasm flowed into mitochondria to increase reactive oxygen species (ROS) and decrease mitochondrial membrane potential (MMP), leading to cytochrome C (Cyto C) release and mitochondrial dysfunction. In addition, we found that Diphyllin combined with cisplatin could have a synergistic anti-tumor effect in vitro and in vivo. Taken together, our results suggested that Diphyllin, as a potential novel inhibitor of SERCA2, exerts anti-tumor effects by blocking ER Ca2+ uptake and thereby promoting ER stress and mitochondrial dysfunction.

Integrated analysis reveals critical cisplatin-resistance regulators E2F7 contributed to tumor progression and metastasis in lung adenocarcinoma.

BACKGROUND: Drug resistance poses a significant challenge in cancer treatment, particularly as a leading cause of therapy failure. Cisplatin, the primary drug for lung adenocarcinoma (LUAD) chemotherapy, shows effective treatment outcomes. However, the development of resistance against cisplatin is a major obstacle. Therefore, identifying genes resistant to cisplatin and adopting personalized treatment could significantly improve patient outcomes. METHODS: By examining transcriptome data of cisplatin-resistant LUAD cells from the GEO database, 181 genes associated with cisplatin resistance were identified. Using univariate regression analysis, random forest and multivariate regression analyses, two prognostic genes, E2F7 and FAM83A, were identified. This study developed a prognostic model utilizing E2F7 and FAM83A as key indicators. The Cell Counting Kit 8 assay, Transwell assay, and flow cytometry were used to detect the effects of E2F7 on the proliferation, migration, invasiveness and apoptosis of A549/PC9 cells. Western blotting was used to determine the effect of E2F7 on AKT/mTOR signaling pathway. RESULTS: This study has pinpointed two crucial genes associated with cisplatin resistance, E2F7 and FAM83A, and developed a comprehensive model to assist in the diagnosis, prognosis, and evaluation of relapse risk in LUAD. Analysis revealed that patients at higher risk, according to these genetic markers, had elevated levels of immune checkpoints (PD-L1 and PD-L2). The prognostic and diagnosis values of E2F7 and FAM83A were further confirmed in clinical data. Furthermore, inhibiting E2F7 in lung cancer cells markedly reduced their proliferation, migration, invasion, and increased apoptosis. In vivo experiments corroborated these findings, showing reduced tumor growth and lung metastasis upon E2F7 suppression in lung cancer models. CONCLUSION: Our study affirms the prognostic value of a model based on two DEGs, offering a reliable method for predicting the success of tumor immunotherapy in patients with LUAD. The diagnostic and predictive model based on these genes demonstrates excellent performance. In vitro, reducing E2F7 levels shows antitumor effects by blocking LUAD growth and progression. Further investigation into the molecular mechanisms has highlighted E2F7's effect on the AKT/mTOR signaling pathway, underscoring its therapeutic potential. In the era of personalized medicine, this DEG-based model promises to guide clinical practice.

Laser-activable murine ferritin nanocage for chemo-photothermal therapy of colorectal cancer.

Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.

CRISPR/Cas-based CAR-T cells: production and application.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment approach for cancer, autoimmune disease, and heart disease. The integration of CAR into T cells is typically facilitated by retroviral or lentiviral vectors. However, the random insertion of CARs can lead to issues like clonal expansion, oncogenic transformation, variegated transgene expression, and transcriptional silencing. The advent of precise gene editing technology, like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), allows for controlled and precise genome modification, facilitating the translation of CAR-T research to the clinical applications. This review aims to provide a comprehensive analysis of the application of CRISPR gene editing techniques in the context of precise deletion and insertion methodologies, with a specific focus on their potential for enhancing the development and utilization of CAR-T cell therapy.

Predicting the error magnitude in patient-specific QA during radiotherapy based on ResNet.

BACKGROUND: The error magnitude is closely related to patient-specific dosimetry and plays an important role in evaluating the delivery of the radiotherapy plan in QA. No previous study has investigated the feasibility of deep learning to predict error magnitude. OBJECTIVE: The purpose of this study was to predict the error magnitude of different delivery error types in radiotherapy based on ResNet. METHODS: A total of 34 chest cancer plans (172 fields) of intensity-modulated radiation therapy (IMRT) from Eclipse were selected, of which 30 plans (151 fields) were used for model training and validation, and 4 plans including 21 fields were used for external testing. The collimator misalignment (COLL), monitor unit variation (MU), random multi-leaf collimator shift (MLCR), and systematic MLC shift (MLCS) were introduced. These dose distributions of portal dose predictions for the original plans were defined as the reference dose distribution (RDD), while those for the error-introduced plans were defined as the error-introduced dose distribution (EDD). Different inputs were used in the ResNet for predicting the error magnitude. RESULTS: In the test set, the accuracy of error type prediction based on the dose difference, gamma distribution, and RDD + EDD was 98.36%, 98.91%, and 100%, respectively; the root mean squared error (RMSE) was 1.45-1.54, 0.58-0.90, 0.32-0.36, and 0.15-0.24; the mean absolute error (MAE) was 1.06-1.18, 0.32-0.78, 0.25-0.27, and 0.11-0.18, respectively, for COLL, MU, MLCR and MLCS. CONCLUSIONS: In this study, error magnitude prediction models with dose difference, gamma distribution, and RDD + EDD are established based on ResNet. The accurate prediction of the error magnitude under different error types can provide reference for error analysis in patient-specific QA.

Improvement of Prediction Performance for Radiation Pneumonitis by Using 3-Dimensional Dosiomic Features.

INTRODUCTION: Patients with early non-small-cell lung cancer (NSCLC) have a relatively long survival time after stereotactic body radiation therapy (SBRT). Predicting radiation-induced pneumonia (RP) has important clinical and social implications for improving the quality of life of such patients. This study developed an RP prediction model by using 3-dimensional (3D) dosiomic features. The model can be used to guide radiation therapy to reduce toxicity. METHODS: Radiomic features were extracted from pre-treatment CT, dose-volume histogram (DVH) parameters and dosiomic features were extracted from the 3D dose distribution of 140 lung cancer patients. Four predictive models: (1) CT; (2) CT + DVH; (3) CT + Rtdose; and (4) Hybrid, CT + DVH + Rtdose, were trained to predict symptomatic RP by extremely randomized trees. Accuracy, sensitivity, specificity, and area under the receiver operator characteristic curve were evaluated. RESULT: Results showed that the fraction regimen was correlated with symptomatic RP (P < .001). The proposed model achieved promising prediction results. The performance metrics for CT, CT + DVH, CT + Rtdose, and Hybrid were as follows: accuracy: 0.786, 0.821, 0.821, and 0.857; sensitivity: 0.625, 1, 0.875, and 1; specificity: 0.8, 0.565, 0.5, and 0.875; and area under the receiver operator characteristic curve: 0.791, 0.809, 0.907, and 0.920, respectively. CONCLUSION: Dosiomic features can improve the performance of the predictive model for symptomatic RP compared with that obtained with the CT + DVH model. The model proposed in this study can help radiation oncologists individually predict the incidence rate of RP.

Dosimetry and treatment efficiency of SBRT using TaiChiB radiotherapy system for two-lung lesions with one overlapping organs at risk.

Purpose: This study aims to assess the dosimetry and treatment efficiency of TaiChiB-based Stereotactic Body Radiotherapy (SBRT) plans applying to treat two-lung lesions with one overlapping organs at risk. Methods: For four retrospective patients diagnosed with two-lung lesions each patient, four treatment plans were designed including Plan Edge, TaiChiB linac-based, RGS-based, and a linac-RGS hybrid (Plan TCLinac, Plan TCRGS, and Plan TCHybrid). Dosimetric metrics and beam-on time were employed to evaluate and compare the TaiChiB-based plans against Plan Edge. Results: For Conformity Index (CI), Plan TCRGS outperformed all other plans with an average CI of 1.06, as opposed to Plan Edge's 1.33. Similarly, for R50 %, Plan TCRGS was superior with an average R50 % of 3.79, better than Plan Edge's 4.28. In terms of D2 cm, Plan TCRGS also led with an average of 48.48%, compared to Plan Edge's 56.25%. For organ at risk (OAR) sparing, Plan TCRGS often displayed the lowest dosimetric values, notably for the spinal cord (Dmax 5.92 Gy) and lungs (D1500cc 1.00 Gy, D1000cc 2.61 Gy, V10 Gy 15.14%). However, its high Dmax values for the heart and great vessels sometimes exceeded safety thresholds. Plan TCHybrid presented a balanced approach, showing doses comparable to or better than Plan Edge without crossing safety limits. In terms of beam-on time, Plan TCLinac emerged as the most efficient treatment option in three out of four cases, followed closely by Plan Edge in one case. Plan TCRGS, despite its dosimetric advantages, was the least efficient, recording notably longer beam-on times, with a peak at 33.28 minutes in Case 2. Conclusion: For patients with two-lung lesions treated by SBRT whose one lesion overlaps with OARs, the Plan TCHybrid delivered by TaiChiB digital radiotherapy system can be recommended as a clinical option.

Exposure frequency and radiation dose from CT examinations in Huaian.

This study quantified the exposure frequency and established the local diagnostic reference levels (DRLs) for the most common computed tomography (CT) examinations. A combined method census and sampling survey was used to quantify both frequency and radiation dose of CT examinations. Data were acquired through Picture Archiving and Communication System (PACS) or Radiology Information System (RIS). The annual frequency of CT examinations was 239.8 per 1000 inhabitants. The P75 of volume CT dose index (CTDIvol) to adult patients from CT scanning for head, chest, abdomen and lumbar spine examinations were 63.0, 12.4, 20.0 and 24.0 mGy, respectively. The P75 of dose-length product were 858.6, 416.0, 620.7 and 559.2 mGy·cm, respectively. This dose audit of CT practice can act as a starting point for establishing Huaian local DRLs and could be a reference for dose optimisation in China. This study compared DRLs in different countries and analysed some reasons for the rapid growth of CT examination frequency in Huaian.

AS-NeSt: A Novel 3D Deep Learning Model for Radiation Therapy Dose Distribution Prediction in Esophageal Cancer Treatment With Multiple Prescriptions.

PURPOSE: Implementing artificial intelligence technologies allows for the accurate prediction of radiation therapy dose distributions, enhancing treatment planning efficiency. However, esophageal cancers present unique challenges because of tumor complexity and diverse prescription types. Additionally, limited data availability hampers the effectiveness of existing artificial intelligence models. This study developed a deep learning model, trained on a diverse data set of esophageal cancer prescriptions, to improve dose prediction accuracy. METHODS AND MATERIALS: We retrospectively collected data from 530 patients with esophageal cancer, including single-target and simultaneous integrated boost prescriptions, for model building. The proposed Asymmetric ResNeSt (AS-NeSt) model features novel 3-dimensional (3D) ResNeSt blocks and an asymmetrical architecture. We constructed a loss function targeting global and local doses and validated the model's performance against existing alternatives. Model-assisted experiments were used to validate its clinical benefits. RESULTS: The AS-NeSt model maintained an absolute prediction error below 5% for each dosimetric metric. The average Dice similarity coefficient for isodose volumes was 0.93. The model achieved an average relative prediction error of 2.02%, statistically lower than Hierarchically Densely Connected U-net (4.17%), DoseNet (2.35%), and Densely Connected Network (3.65%). It also demonstrated significantly fewer parameters and shorter prediction times. Clinically, the AS-NeSt model raised physicians' ability to accurately preassess appropriate treatment methods before planning from 95.24% to 100%, reduced planning time by over 61% for junior dosimetrists and 52% for senior dosimetrists, and decreased both inter- and intra-dosimetrist discrepancies by more than 50%. CONCLUSIONS: The AS-NeSt model, developed with innovative 3D ResNeSt blocks and an asymmetrical encoder-decoder structure, has been validated using clinical esophageal cancer patient data. It accurately predicts 3D dose distributions for various prescriptions, including simultaneous integrated boost, showing potential to improve the management of esophageal cancer treatment in a clinical setting.

PDZ and LIM Domain-Encoding Genes: Their Role in Cancer Development.

PDZ-LIM family proteins (PDLIMs) are a kind of scaffolding proteins that contain PDZ and LIM interaction domains. As protein-protein interacting molecules, PDZ and LIM domains function as scaffolds to bind to a variety of proteins. The PDLIMs are composed of evolutionarily conserved proteins found throughout different species. They can participate in cell signal transduction by mediating the interaction of signal molecules. They are involved in many important physiological processes, such as cell differentiation, proliferation, migration, and the maintenance of cellular structural integrity. Studies have shown that dysregulation of the PDLIMs leads to tumor formation and development. In this paper, we review and integrate the current knowledge on PDLIMs. The structure and function of the PDZ and LIM structural domains and the role of the PDLIMs in tumor development are described.

Novel in-house knowledge-based automated planning system for lung cancer treated with intensity-modulated radiotherapy.

PURPOSE: The goal of this study was to propose a knowledge-based planning system which could automatically design plans for lung cancer patients treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: From May 2018 to June 2020, 612 IMRT treatment plans of lung cancer patients were retrospectively selected to construct a planning database. Knowledge-based planning (KBP) architecture named αDiar was proposed in this study. It consisted of two parts separated by a firewall. One was the in-hospital workstation, and the other was the search engine in the cloud. Based on our previous study, A­Net in the in-hospital workstation was used to generate predicted virtual dose images. A search engine including a three-dimensional convolutional neural network (3D CNN) was constructed to derive the feature vectors of dose images. By comparing the similarity of the features between virtual dose images and the clinical dose images in the database, the most similar feature was found. The optimization parameters (OPs) of the treatment plan corresponding to the most similar feature were assigned to the new plan, and the design of a new treatment plan was automatically completed. After αDiar was developed, we performed two studies. The first retrospective study was conducted to validate whether this architecture was qualified for clinical practice and involved 96 patients. The second comparative study was performed to investigate whether αDiar could assist dosimetrists in improving the quality of planning for the patients. Two dosimetrists were involved and designed plans for only one trial with and without αDiar; 26 patients were involved in this study. RESULTS: The first study showed that about 54% (52/96) of the automatically generated plans would achieve the dosimetric constraints of the Radiation Therapy Oncology Group (RTOG) and about 93% (89/96) of the automatically generated plans would achieve the dosimetric constraints of the National Comprehensive Cancer Network (NCCN). The second study showed that the quality of treatment planning designed by junior dosimetrists was improved with the help of αDiar. CONCLUSIONS: Our results showed that αDiar was an effective tool to improve planning quality. Over half of the patients' plans could be designed automatically. For the remaining patients, although the automatically designed plans did not fully meet the clinical requirements, their quality was also better than that of manual plans.

A planning strategy may reduce the risk of heart diseases and radiation pneumonia: Avoiding the specific heart substructures.

BACKGROUND: Dose to heart substructures is a better predictor for major adverse cardiac events (MACE) than mean heart dose (MHD). We propose an avoidance planning strategy for important cardiac substructures. MATERIAL AND METHODS: Two plans, clinical and cardiac substructure-avoidance plan, were generated for twenty patients. Five dose-sensitive substructures, including left ventricle, pulmonary artery, left anterior descending branch, left circumflex branch and the coronary artery were chosen. The avoidance plan aims to meet the target criteria and organ-at-risk (OARs) constraints while minimizing the dose parameters of the above five substructures. The dosimetric assessments included the mean dose and the maximum dose of cardiac substructures and several volume parameters. In addition, we also evaluated the relative risk of coronary artery disease (CAD), chronic heart failure (CHF), and radiation pneumonia (RP). RESULTS: Pearson correlation coefficient and R2 value of linear regression fitting demonstrated that MHD had poor prediction ability for the mean dose of the cardiac substructures. Compared to clinical plans, an avoidance plan is able to statistically significantly decrease the dose to key substructures. Meanwhile, the dose to OARs and the coverage of the target are comparable in the two plans. In addition, it can be observed that the avoidance plan statistically decreases the relative risks of CAD, CHF, and RP. CONCLUSIONS: The substructure-avoidance planning strategy that incorporates the cardiac substructures into optimization process, can protect the important heart substructures, such as left ventricle, left anterior descending branch and pulmonary artery, achieving the substantive sparing of dose-sensitive cardiac structures, and have the potential to decrease the relative risks of CAD, CHF, and RP.

[Clinical application of neurovascular staghorn flap for repairing of defects in fingertips].

Objective: To evaluate the effectiveness of neurovascular staghorn flap for repairing defects in fingertips. Methods: Between August 2019 and October 2021, a total of 15 fingertips defects were repaired with neurovascular staghorn flap. There were 8 males and 7 females with an average age of 44 years (range, 28-65 years). The causes of injury included 8 cases of machine crush injury, 4 cases of heavy object crush injury, and 3 cases of cutting injury. There were 1 case of thumb, 5 cases of index finger, 6 cases of middle finger, 2 cases of ring finger, and 1 case of little finger. There were 12 cases in emergency, and 3 cases with finger tip necrosis after trauma suture. Bone and tendon exposed in all cases. The range of fingertip defect was 1.2 cm×0.8 cm to 1.8 cm×1.5 cm, and the range of skin flap was 2.0 cm×1.5 cm to 2.5 cm×2.0 cm. The donor site was sutured directly. Results: All flaps survived without infection or necrosis, and the incisions healed by first intention. All patients were followed up 6-12 months, with an average of 10 months. At last follow-up, the appearance of the flap was satisfactory, the wear resistance was good, the color was similar to the skin of the finger pulp, and there was no swelling; the two-point discrimination of the flap was 3-5 mm. One patient had linear scar contracture on the palmar side with slight limitation of flexion and extension, which had little effect on the function; the other patients had no obvious scar contracture, good flexion and extension of the fingers, and no dysfunction. The finger function was evaluated according to the total range of motion (TAM) system of the Hand Surgery Society of Chinese Medical Association, and excellent results were obtained in 13 cases and good results in 2 cases. Conclusion: The neurovascular staghorn flap is a simple and reliable method to repair fingertip defect. The flap has a good fit with the wound without wasting skin. The appearance and function of the finger are satisfactory after operation.

Cinchonine exerts anti-tumor and immunotherapy sensitizing effects in lung cancer by impairing autophagic-lysosomal degradation.

Currently, there are several treatments approaches available for lung cancer; however, patients who develop drug resistance or have poor survival rates urgently require new therapeutic strategies for lung cancer. In autophagy, damaged proteins or organelles are enclosed within autophagic vesicles with a bilayer membrane structure and transported to the lysosomes for degradation and recirculation. Autophagy is a crucial pathway involved in the clearance of reactive oxygen species (ROS) and damaged mitochondria. Meanwhile, inhibiting autophagy is a promising strategy for cancer treatment. In this study, we found for the first time that Cinchonine (Cin) can act as an autophagy suppressor and exert anti-tumor effects. Cin significantly inhibited the proliferation, migration, and invasion of cancer cells in vitro and the tumor growth and metastasis in vivo, without obvious toxic effects. We found that Cin suppressed the autophagic process by blocking autophagosome degradation through the inhibition of the maturation of lysosomal hydrolases. Cin-mediated autophagy inhibition resulted in the elevated ROS level and the accumulation of damaged mitochondria, which in turn promoted apoptosis. N-acetylcysteine, a potential ROS scavenger, significantly suppressed Cin-induced apoptosis. Additionally, Cin upregulated programmed death-ligand 1 (PD-L1) expression in lung cancer cells by inhibiting autophagy. Compared with monotherapy and control group, the combined administration of anti-PD-L1 antibody and Cin significantly reduced tumor growth. These results suggest that Cin exerts anti-tumor effects by inhibiting autophagy, and that the combination of Cin and PD-L1 blockade has synergistic anti-tumor effects. The data demonstrates the significant clinical potential of Cin in lung cancer treatment.

Optimization of isocenter position for multiple brain metastases single-isocenter stereotactic radiosurgery to minimize dosimetric variations due to rotational uncertainty.

PURPOSE: This paper studied a novel calculation framework that can determine the optimal value isocenter position of single isocenter SRS treatment plan for multiple brain metastases, in order to minimize the dosimetric variations caused by rotational uncertainty. MATERIALS AND METHODS: 21 patients with 2-4 GTVswho received SRS treatment for multiple brain metastases in our institution were selected for the retrospective study. The PTVwas obtained by expanding GTV 1 mm isotropic margin. We studied a stochastic optimization framework, which determined the optimal value isocenter location by maximizing the average target dose coverageCtarget,meanwith a rotation error of no more than 1°. We evaluated the performance of the optimal isocenter by comparing theCtarget,meanand average dice similarity coefficient (DSC)with the optimal value and the center of mass (CM) respectively as the treatment isocenter. The extra PTV margin to achieve 100% target dose coverage was calculated by our framework. RESULTS: Compared to the CM method, the optimal value isocenter method increased the averageCtarget,meanof all targets from 97.0% to 97.7%and the average DSC from 0.794to 0.799. Throughout all the cases, the average extra PTV margin to obtain full target dose coverage was 0.7 mmwhen using the optimal value isocenter as the treatment isocenter. CONCLUSION: We studied a novel computational framework using stochastic optimization to determine the optimal isocenter position of SRS treatment plan for multiple brain metastases. At the same time, our framework gave the extra PTV margin to obtain full target dose coverage.

Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy.

Unprecedented breakthroughs have been made in cancer immunotherapy in recent years. Particularly immune checkpoint inhibitors have fostered hope for patients with cancer. However, immunotherapy still exhibits certain limitations, such as a low response rate, limited efficacy in certain populations, and adverse events in certain tumors. Therefore, exploring strategies that can improve clinical response rates in patients is crucial. Tumor-associated macrophages (TAMs) are the predominant immune cells that infiltrate the tumor microenvironment and express a variety of immune checkpoints that impact immune functions. Mounting evidence indicates that immune checkpoints in TAMs are closely associated with the prognosis of patients with tumors receiving immunotherapy. This review centers on the regulatory mechanisms governing immune checkpoint expression in macrophages and strategies aimed at improving immune checkpoint therapies. Our review provides insights into potential therapeutic targets to improve the efficacy of immune checkpoint blockade and key clues to developing novel tumor immunotherapies.

Identification of m7G-Related miRNA Signatures Associated with Prognosis, Oxidative Stress, and Immune Landscape in Lung Adenocarcinoma.

The role of N7-methylguanosine(m7G)-related miRNAs in lung adenocarcinoma (LUAD) remains unclear. We used LUAD data from The Cancer Genome Atlas (TCGA) to establish a risk model based on the m7G-related miRNAs, and divided patients into high-risk or low-risk subgroups. A nomogram for predicting overall survival (OS) was then constructed based on the independent risk factors. In addition, we performed a functional enrichment analysis and defined the oxidative stress-related genes, immune landscape as well as a drug response profile in the high-risk and low-risk subgroups. This study incorporated 28 m7G-related miRNAs into the risk model. The data showed a significant difference in the OS between the high-risk and low-risk subgroups. The receiver operating characteristic curve (ROC) predicted that the area under the curve (AUC) of one-year, three-year and five-year OS was 0.781, 0.804 and 0.853, respectively. The C-index of the prognostic nomogram for predicting OS was 0.739. We then analyzed the oxidative stress-related genes and immune landscape in the high-risk and low-risk subgroups. The data demonstrated significant differences in the expression of albumin (ALB), estimated score, immune score, stromal score, immune cell infiltration and functions between the high-risk and low-risk subgroups. In addition, the drug response analysis showed that low-risk subgroups may be more sensitive to tyrosine kinase inhibitor (TKI) and histone deacetylase (HDAC) inhibitors. We successfully developed a novel risk model based on m7G-related miRNAs in this study. The model can predict clinical prognosis and guide therapeutic regimens in patients with LUAD. Our data also provided new insights into the molecular mechanisms of m7G in LUAD.