Immunocytes interact directly with cancer cells in the tumor microenvironment: one coin with two sides and future perspectives.

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.

Deep Learning-Based Stratification of Gastric Cancer Patients from Hematoxylin and Eosin-Stained Whole Slide Images by Predicting Molecular Features for Immunotherapy Response.

Determining the molecular characteristics of cancer patients is crucial for optimal immunotherapy decisions. The aim of this study was to screen immunotherapy beneficiaries by predicting key molecular features from hematoxylin and eosin-stained images based on deep learning models. An independent data set from Asian gastric cancer patients was included for external validation. In addition, a segmentation model (Horizontal-Vertical Network) was used to quantify the cellular composition of tumor stroma. The model performance was evaluated by measuring the area under the curve (AUC). The tumor extraction model achieved an AUC of 0.9386 and 0.9062 in the internal and external test sets, respectively. The stratification model could predict the immunotherapy-sensitive subtypes (AUC range, 0.8685 to 0.9461), the genetic mutations (AUC range, 0.8283 to 0.9225), and the pathway activity (AUC range, 0.7568 to 0.8612) fairly accurately. In external validation, the prediction performance of Epstein-Barr virus and programmed cell death ligand 1 expression status achieved AUCs of 0.7906 and 0.6384, respectively. The segmentation model identified a relatively high proportion of inflammatory cells and connective cells in some immunotherapy-sensitive subtypes. The deep learning-based models potentially may serve as a valuable tool to screen for the beneficiaries of immunotherapy in gastric cancer patients.

Neuroprotective effect of combined use of nicotine and celecoxib by inhibiting neuroinflammation in ischemic rats.

INTRODUCTION: The contribution of neuroinflammation in cognitive impairment is increasingly recognized. Non-steroidal anti-inflammatory drugs had been proven that it could improve cognitive impairment in large dose but with more side effect, which limited the application. The main objective of this study was to investigate whether the combined use of nicotine and celecoxib could obtain synergistic neuroprotective effect in ischemic rats. METHODS: Twenty adult Sprague-Dawley (SD) rats underwent ischemic model surgery by injecting endothelin-1 into the left thalamus, which were classified into four groups with different interventions: nicotine (1.5 mg/kg/d), celecoxib (15 mg/kg/d), nicotine (1.5 mg/kg/d) +celecoxib (15 mg/kg/d), or saline after surgery. The other five SD rats also underwent same surgery by injecting saline instead of endothelin-1, as the control group. Morris water maze (MWM) test was adopted to assess the cognition. Micro PET/CT with 2-[18F]-A-85380 were performed for α4ß2-nAChRs detection in vivo. Western blot, real-time PCR and immunohistochemical staining were adopted to detect the expression of α4ß2-nAChRs and inflammatory factors which included TNF-α, IL-1ß, IL-6 in brain tissue. Microglial activation in the brain was monitored by immunofluorescence with IBA1 staining. RESULTS: The MWM test showed rats given with nicotine or celecoxib alone showed much better memory than rats with saline, no difference was observed between nicotine and celecoxib. The rat memory was recovered most significant when the nicotine and celecoxib were combined (p < 0.05). Micro-PET/CT showed much more tracer uptake in the left thalamus and whole brain in rats given with nicotine, or nicotine + celecoxib (nico + cele group) than saline treated rats, whereas the rats given celecoxib did not. Compared with saline treated rats, we found the proteins of α4nAChR and ß2nAChR in rats given nicotine or nico + cele increased significantly, and mRNA/proteins of TNF-α, IL-1ß and IL-6 decreased at the same time. The α 4nAChR and ß 2nAChR proteins in rats given celecoxib is the same as saline treated rats, whereas the inflammatory factors decreased obviously compared with saline treated rats. Microglial activation was confirmed in saline treated rats, which was inhibited in rats give nicotine, celecoxib or both. CONCLUSIONS: The study revealed the combined use of nicotine and celecoxib may improve the cognitive function in ischemic rats, with a better effect than either alone. Both nicotine and celecoxib can inhibit inflammation, but through different mechanisms: nicotine can activate α4ß2-nAChRs while celecoxib is cyclooxygenase-2 inhibitor. Our findings suggest the combined application of two drugs with different anti-inflammation mechanism could attenuate cognitive impairment more effectively in ischemic rats, which may hold therapeutic potential in the clinical practice.

Atomic Force Microscopy in Mechanoimmunology Analysis: A New Perspective for Cancer Immunotherapy.

Immunotherapy has remarkable success outcomes against hematological malignancies with high rates of complete remission. To date, many studies have been conducted to increase its effectiveness in other types of cancer. However, it still yields unsatisfying results in solid tumor therapy. This limitation is partly attributed to the lack of understanding of how immunotherapy works in cancer from other perspectives. The traditional studies focus on the biological and chemical perspectives to determine which molecular substrates are involved in the immune system that can eradicate cancer cells. In the last decades, accumulating evidence has shown that physical properties also play important roles in the immune system to combat cancer, which is studied in mechanoimmunology. Mechanoimmunology analysis requires special tools; and herein, atomic force microscopy (AFM) appears as a versatile tool to determine and quantify the mechanical properties of a sample in nanometer precisions. Owing to its multifunctional capabilities, AFM can be used to explore immune system function from the physical perspective. This review paper explains the mechanoimmunology of how immune systems work through AFM, which includes mechanosignaling, mechanosensing, and mechanotransduction, with the aim to deepen the understanding of the mechanistic role of immunotherapy for further development in cancer treatment.

Transforming stealthy to sticky nanocarriers: a potential application for tumor therapy.

Nanomedicine has shown remarkable progress in preclinical studies of tumor treatment. Over the past decade, scientists have developed various nanocarriers (NCs) for delivering drugs into the tumor area. However, the average amount of accumulated drugs in tumor sites is far from satisfactory. This limitation is strongly related to the corona formation during blood circulation. To overcome this issue, NCs should be designed to become highly stealthy by modifying their surface charge. However, at the same time, stealthy effects not only prevent protein formation but also alleviate the cellular uptake of NCs. Therefore, it is necessary to develop NCs with switchable properties, which are stealthy in the circulation system and sticky when arriving at tumor sites. In this review, we discuss the recent strategies to develop passive and active charge-switchable NCs, known as chameleon-like drug delivery systems, which can reversibly transform their surface from stealthy to sticky and have various designs.

Chinese Data of Efficacy of Low- and High-Dose Iodine-131 for the Ablation of Thyroid Remnant.

BACKGROUND: Chinese data on the efficacy of low- and high-dose radioiodine for thyroid remnant are still absent. The aim of the study was to investigate whether a low dose of radioiodine is as effective as a high dose for remnant ablation in Chinese patients. METHODS: Patients presenting for radioiodine ablation in the authors' department were included. Inclusion criteria were aged ≥16 years, total or near-total thyroidectomy, tumor-node-metastasis (TNM) stage of pT1-3, any N stage, and M0. All patients were randomly allocated to either the high-dose group of 3700 MBq or the low-dose group of 1850 MBq for remnant ablation. The response to treatment was defined as successful or unsuccessful after a six- to nine-month interval. Ablation was considered to be successful if patients fulfilled the following criteria: no tracer uptake in the thyroid bed on diagnosis whole-body scanning and a negative level of serum thyroglobulin. RESULTS: There were 327 patients enrolled between January 2013 and December 2014. More than 95% had papillary thyroid cancer. Data could be analyzed for 278 cases (Mage = 44 years; 71.6% women), 155 in the low-dose group and 123 in the high-dose group. The rate of initial successful ablation was 84.2% in all patients, 82.6% in the low-dose group, and 86.2% in the high-dose group. There was no difference between the two groups (p = 0.509). CONCLUSIONS: In Chinese patients with differentiated thyroid carcinoma, the low dose of 1850 MBq radioiodine activity is as effective as a high dose of 3700 MBq for thyroid remnant ablation.

The efficacy of radioiodine remnant ablation for differentiated thyroid carcinoma patients with an incomplete thyroidectomy.

BACKGROUND: The aim of this study was to evaluate the efficacy of radioiodine remnant ablation (RRA) for differentiated thyroid carcinoma (DTC) patients with an incomplete thyroidectomy. METHODS: The medical histories of postsurgical DTC patients who accepted RRA between 2010 and 2012 were retrospectively reviewed. Among them, 113 patients who had undergone a total or near-total thyroidectomy comprised the complete thyroidectomy group (CT group) and the remaining 40 patients who had undergone a lobectomy or sub-total thyroidectomy comprised the incomplete thyroidectomy group (ICT group). The difference in the patients' age, gender, histology, serum TSH level and 24hr radioactive iodine uptake (RIU) between the two groups was analyzed by χ2 Test or ANOVA. The efficacy of RRA in ICT group was evaluated by comparing its rate of complete ablation after the first RRA and its cumulative rate of complete ablation after the second RRA to the rate of complete ablation after the first RRA in CT group respectively by χ2 Test. RESULTS: Of all the clinical characteristics, only serum TSH level and 24hr RIU have significant difference between two groups (P<0.01 for both). The rate of complete ablation after the first RRA was 67.26% in CT group. The rate of complete ablation after the first RRA and the cumulative rate of complete ablation after the second RRA was 27.50% and 67.50% respectively in ICT group. The ablative rate of the first RRA between the two groups was compared by χ2 Test and the difference was significant (P<0.01). The ablative rate of the first RRA in CT group was compared with the cumulative rate of the second RRA in ICT group and the difference was not significant (P=0.978). CONCLUSIONS: Although the efficacy of RRA in DTC patients with an incomplete thyroidectomy is not as good as that of patients with a complete thyroidectomy after the first RRA, a higher ablative rate can still be achieved after the second or third RRA.

(18)F-FDG Uptake Characteristics in Differentiating Benign from Malignant Nasopharyngeal Lesions in Children.

The characteristics of FDG uptake in the physiologic and malignant nasopharynx were investigated in the paper which was correlated with either pathologic findings or clinical follow-up. Three patients had pathologically established nasopharyngeal malignancy. In the 3 nasopharyngeal malignancies, 2 had diffusely and expansively increased FDG uptake, and one had asymmetric uptake. Our results indicated that the difference between adenoid hypertrophy and malignancy is asymmetric or diffusely expansive (18)F-FDG uptake with or without correlating morphologic lesion on diagnostic CT in children under 10 years of age. The typical characteristics of physiologic and inflammatory (18)F-FDG uptake in nasopharynx are symmetrically trapezoid. Diffusely increased nasopharyngeal FDG uptake can be considered physiologic if SUVmax is less than 7.6 but should be carefully assessed by pharyngorhinoscopy if SUVmax is greater than 11 and there is no correlating morphologic lesion on diagnostic CT. The diffusely, expansively increased uptake, and asymmetric uptake in particular, should be considered as malignancy. Further biopsy is especially indicated in patients with retropharyngeal space and bilateral cervical lymph node abnormality but no history of malignancy.

Comparison of 18F-AIF-NOTA-PRGD2 and 18F-FDG uptake in lymph node metastasis of differentiated thyroid cancer.

UNLABELLED: A widespread application of integrin αvß3 imaging has been emerging in both pre-clinical and clinical studies. But few studies reported its value as compared with 18F-FDG PET, especially for differentiated thyroid cancer (DTC). In this study, we compared the tracer uptake of 18F-AIF-NOTA-PRGD2 and 18F-FDG in lymph node metastasis of DTC to evaluate 18F-AIF-NOTA-PRGD2 as compared with 18F-FDG. METHODS: 20 DTC patients with presumptive lymph node metastasis were examined with 18F-AIF-NOTA-PRGD2 and 18F-FDG PET/CT. 16 patients undergoing fine needle aspiration biopsy (FNAB) were evaluated by cytology results. For lesions without FNAB, the findings of clinical staging procedures served as the standard of reference (including neck ultrasound and serum thyroglobulin). RESULTS: A total of 39 presumptive lymph node metastases were visualized on PET/CT images. 35 lesions were confirmed as malignant by FNAB and other clinical findings. The mean 18F-AIF-NOTA-PRGD2 in radioactive iodine-refractory (RAIR) lesions and benign lesions were 2.5±0.9 and 2.8±0.9 respectively. The mean SUV for 18F-FDG in all malignant lesions was 4.5±1.6 while in benign lesions it was 3.3±1.2. For all malignant lesions, the mean SUV for 18F-FDG was significantly higher than that for 18F-AIF-NOTA-PRGD2 (P<0.05). No significant correlation was found between the SUVs of 18F-AIF-NOTA-PRGD2 and 18F-FDG for 35 lesions (r = 0.114, P = 0.515). Moreover, 15 lesions of which the diameter larger than 1.5 cm had higher 18F-AIF-NOTA-PRGD2 uptake as compared with the lesions smaller than 1.5 cm. CONCLUSION: Although most lymph node metastases of DTC showed abnormal uptake of 18F-AIF-NOTA-PRGD2, its diagnostic value was inferior to 18F-FDG. No correlation was found between the uptake of 18F-AIF-NOTA-PRGD2 and 18F-FDG, which may suggest the two tracers provide complementary information in DTC lesions.

Dedifferentiation of differentiated thyroid carcinoma cell line FTC-133 is enhanced by 131I pretreatment.

INTRODUCTION: Differentiated thyroid carcinoma (DTC) usually has a high iodine uptake. However, dedifferentiation of DTC with decreased or no radioiodine ((131)I) uptake is observed in clinical practice, with poor prognosis. The aim of this study was to investigate the effects of (131)I radiation on radioiodine uptake (RAIU) and the expression of thyroid-specific molecules. METHODS: FTC-133 cells were treated with (131)I, the dosage dictated by methylthiazol tetrazolium test results and preliminary experiments. The experimental cell group was incubated with (131)I for 48 h and then cultured for 3 months in (131)I-free medium. The control group was set without (131)I. Primary cells were defined as the blank group. Following treatment, RAIU was measured with a gamma counter as the counts/cell number. Na(+)/I(-) symporter (NIS), thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO) and thyroglobulin (Tg) levels were detected by Western blotting and radioimmunoassay, and their mRNAs were detected by real-time polymerase chain reaction. RESULTS: RAIU of FTC-133 cells decreased gradually after coincubation with (131)I and did not recover even if (131)I was removed. The relative RAIU of the control and experimental groups was 0.567 and 0.182, respectively, a statistically significant difference (P<.01). Expression of NIS, TSHR, TPO and Tg decreased in the experimental group to a statistically significant degree compared to that of controls (P<.05). CONCLUSION: Changes in the mRNA levels were in accordance with the expression of thyroid-specific proteins. Thus, FTC-133 cells undergo dedifferentiation during long-term culture in vitro, and (131)I may promote this progress.

The study of influence factors on (131)I treatment of differentiated thyroid carcinoma with lymph node metastases.

OBJECTIVE: Thyroid carcinoma is the most common malignant endocrine tumor, which comprises 1% in all human tumors. As for differentiated thyroid carcinoma (DTC), lymph nodes are the most common metastatic site for which the major treatment is (131)I therapy. This retrospective study aimed to investigate the therapeutic effect and analyze the influence factors on (131)I treatment of DTC with lymph node metastases. METHODS: Collecting clinical data of 66 DTC patients with lymph node metastases at the Department of Nuclear Medicine, Xin Hua Hospital from January 1996 to January 2006. Investigating the therapeutic effect firstly and then dividing 66 patients into an eliminated group and an uneliminated group according to the evaluation criteria of the therapeutic effect. Finally, observing the differences between the two groups. The significant differences in the following 10 influence factors were determined: gender, age, pathological type, the periods from the thyroidectomy to the first (131)I therapy, when the metastases were found, the history of resection of the lymph node metastases, the uptake of (18)F-FDG in the lymph node metastases, remnant thyroid, multiple metastases, and the cumulative dose of (131)I. This retrospective study was analyzed by Student t test, chi(2) test, and Fisher's exact test. RESULTS: Of all 66 patients with lymph node metastatic DTC treated by (131)I therapy, 31 patients (46.97%) had complete elimination. Twenty-seven patients were improved or controlled, and the overall effective rate reached 87.88%. The elimination rate of lymph node metastases in patients with resection was significantly higher than in those without resection (chi(2)=5.561, P=.018<0.05). The elimination rate of lymph node metastases in patients with (18)F-FDG uptake was significantly higher than in those without (18)F-FDG uptake (chi(2)=4.014, P=.045<.05). There was no significant difference in the elimination rate among the patients with various values in the other eight factors. CONCLUSIONS: (131)I Therapy is an effective treatment of lymph node metastatic DTC. The history of resection of the lymph node metastases and the uptake of (18)F-FDG in the lymph node metastases were the influence factors on the therapeutic effect, whereas the other eight factors were probably not.

[Measuring rupture forces of P-selectin/PSGL-1 bonds using an optical trap assay].

Selectin/ligand interaction plays an important role in such biological processes as inflammatory reaction, tumor metastasis, etc. External forces affect dissociation of receptor-ligand bonds. A novel approach, upon optical trap technique, was developed in this study to investigate the dissociation of P-selectin/PSGL-1 (P-Selectin Glycoprotein Ligand 1) bindings. Stiffness of optical trap was calibrated with laser power using a viscous drag method. While P-selectin and PSGL-1 molecules were functionally coated on surfaces of glass beads, respectively, the dissociation of interacting molecule bond was studied by measuring the rupture force distribution. It was found that most probable rupture force increased with loading rate at < 25 pN/s. These results complemented and validated the current theory at low loading rates.