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Background: The improvements in the treatment of colorectal cancer (CRC) and prolongation of survival time have improved the incidence of bone metastasis. Forkhead box D3 (FOXD3) is involved in the development of CRC. However, the role and mechanism of FOXD3 in CRC bone metastases development are unknown. Objective: Using the combined bioinformatics and cytology experimental analyses, this study aimed to explore the mechanistic role of FOXD3 in the bone metastasis of colon cancer, thereby aiding in the treatment of colon cancer bone metastasis and identification of drug-targeting markers. Methods: First, the changes in the expression levels of the FOXD3 gene and differentially expressed genes (DEGs) between the colon cancer samples and colon cancer metastases were obtained from The Cancer Genome Atlas (TCGA) database. Then, the correlations of the FOXD3 gene with the DEGs were identified. Next, the effects of the FOXD3 on the proliferation and invasion abilities of colon cancer bone metastatic cells were identified using Cell Counting Kit-8 (CCK8) and Transwell cell migration assays, respectively. In addition, Western blot analysis was used to identify the expression levels of the proteins related to the EGFR/Ras/Raf/MEK/ERK(EGFR/ERK) signaling pathway and epithelial-to-mesenchymal transition (EMT). Results: FOXD3 was downregulated in colon cancer and could interact with multiple DEGs in colon cancer bone metastases. FOXD3 gene knockdown could increase the proliferation of human colon cancer bone metastatic cells and their invasive ability. FOXD3 gene knockdown could activate the expression of EGFR/ERK signaling pathway-related proteins and inhibit/promote the expression of EMT-related proteins, which in turn promoted the proliferation and metastasis of LoVo cells from colon cancer bone metastases. Conclusion: Overall, this study demonstrated that the downregulation of the FOXD3 gene might promote the proliferation of colon cancer bone metastatic cell lines through the EGFR/ERK pathway and promote their migration through EMT, thereby serving as a promising therapeutic target.

Although the National Comprehensive Cancer Network (NCCN) guidelines include clear recommendations for the appropriate resection margins in non-acral cutaneous melanoma, the required margin for acral melanoma is controversial. In this retrospective study, we aimed to investigate whether narrow-margin excision is warranted for thick acral melanoma. Records from 277 melanoma patients with stage T3–T4 disease who underwent radical surgery in three centers in China from September 2010 to October 2018 were reviewed. Clinicopathologic data, including age, gender, excision margin (1–2 cm versus ≥ 2 cm), Clark level, Breslow thickness, ulceration, N stage and adjuvant therapy, were included for survival analysis. The patients were followed up until death or March 31, 2021. Log-rank and Cox regression analyses were used to identify prognostic factors for overall survival (OS), disease-free survival (DFS) and local and in-transit recurrence-free survival (LITRFS). Among all enrolled patients, 207 (74.7%) had acral melanoma, and 70 (25.3%) had non-acral cutaneous melanoma. No significant difference in baseline characteristics was identified between non-acral and acral melanoma, except for age (p = 0.004), gender (p = 0.009) and ulceration (p = 0.048). In non-acral melanoma, a resection margin of 1–2 cm was a poor independent prognostic factor for OS [p = 0.015; hazard ratio (HR) (95% CI), 0.26 (0.009–0.77)] and LITRFS [p = 0.013; HR (95% CI), 0.19 (0.05–0.71)] but not for DFS [p = 0.143; HR (95% CI), 0.51 (0.21–1.25)]. Forty-three (20.8%) patients in the acral melanoma group had a 1–2-cm resection margin. The resection margin was not correlated with patients’ OS (p = 0.196 by log-rank analysis, p = 0.865 by multivariate survival analysis), DFS (p = 0.080 by log-rank analysis, p = 0.758 by multivariate survival analysis) or LITRFS (p = 0.354 by log-rank analysis) in acral melanoma. As recommended in the NCCN guidelines, a resection margin ≥ 2 cm is required for non-acral cutaneous melanoma. Meanwhile, a narrow resection margin (1–2 cm) may be safe for patients with acral melanoma.

Background: The unplanned excision of synovial sarcomas in centers that do not specialize in sarcoma treatment necessitates extensive wide re-excision to maintain adequate margins. The present study was developed to examine the efficacy in SS patients with and without residual tumor tissue following unplanned surgical excision, and to compare differences in prognostic outcomes between individuals with residual tumor tissue and those that experienced local recurrence. Method: Synovial sarcoma patients that underwent re-excision in our center between 2009 and 2019 were included in unplanned excision and local recurrence groups, with patients in the unplanned excision group being further stratified into those with and without residual tumor tissue. Analyzed endpoints included overall survival (OS), local recurrence-free survival (LRFS), and distant relapse-free survival (DRFS). Prognostic factors associated with these three different survival outcomes were analyzed through the use of Kaplan-Meier curves and Cox regression approaches. Result: In total, this study incorporated 121 synovial sarcoma patients (68 female, 53 male; median age: 36 years), including 33 (27.3%) with no residual tumor tissue, 31 (25.6%) with residual tumor tissue, and 57 (47.1%) in the local recurrence group. Patients were assessed over a median 51-month follow-up period. The respective median intervals to definitive surgery in the unplanned excision and local recurrence groups were 35 days and 60 days. The respective 5-year OS, 5-year LRFS, and 5-year DRFS were 76.9%, 80.6%, and 59.6% for the non-residual group, 73.0%, 80.4%, and Not Available (NA) for the residual tumor tissue group, and 75.2%, 77.3%, and NA in the local recurrence group. Conclusion: In synovial sarcoma patients with positive margins or residual tumor tissue following unplanned surgical excision, re-excision procedures can yield improved local control and OS to levels similar to those observed in patients without residual tumor. Relative to patients with local recurrence, significantly improved local control and OS are observed for patients with residual tumor following immediate extensive R0 resection. These results thus suggest that following initial incomplete tumor excision, patients should be promptly transferred to centers specializing in the treatment of sarcomas for adequate re-excision.

In this paper, we use a stochastic dynamic programming model to evaluate the impacts of uncertainties on the abatement planning process. By involving the endogenous emission path, we differentiate two types of uncertainties during the planning process, which come from the volatility of the abatement cost and the ambiguity of emission rate. Results suggest that the considered uncertainties influence the decision-making process in several aspects by shaping the abatement path as well as emission path. (1) The impacts vary with the expected value and the level of variance of the uncertainty effects. Uncertainties caused by abatement costs from 0.02 to 0.06 and emission factors from 0.01 to 0.03 increase the total abatement costs around 7% and 5% respectively. (2) Both of these uncertainties can generate precautionary abatement in short-term. Especially during the early stages, the abatement task will be increased by 1% around in each period due to the uncertainties. However such an action will be diminishing as the duration elapses. (3) Both of these uncertainties influence the long-term abatement performances, however, with different forms and mechanisms. With small volatility, the emission rate changes the priority sequence of abatement actions more substantially in the short-term than the emission rate does. (4) The combined uncertainties can behave in a compound way to improve the uncertainty performance in the model. The difference between the emission peaks of conservative and extreme cases is significant with the gap being about 5 million metric ton. These results have potentially important policy implications and can provide a rationale for abatement actions.

The DeGroot model is one of the most classical models in the field of opinion dynamics. The standard DeGroot model assumes that agents are homogeneous and update their opinions in the direction of a weighted average of their neighbors’ opinions. One natural question is whether a second type of agents could significantly change the main properties of the model. The authors address this question by introducing rebels, who update their opinions toward the opposite of their neighbors’ weighted average. The authors find that the existence of rebels remarkably affects the opinion dynamics. Under certain mild conditions, the existence of a few rebels will lead the group opinion to the golden mean, regardless of the initial opinions of the agents and the structure of the learning network. This result is completely different from that of the standard DeGroot model, where the final consensus opinion is determined by both the initial opinions and the learning topology. The study then provides new insights into understanding how heterogeneous individuals in a group reach consensus and why the golden mean is so common in human society.

Guanylate binding protein 5 (GBP5) belongs to the GTPase subfamily, which is mainly induced by interferon gamma (IFN-γ) and is involved in many important cellular processes, including inflammasome activation and innate immunity against a wide variety of microbial pathogens. However, it is unknown whether GBP5 inhibits respiratory syncytial virus (RSV) infection. In this study, we identified GBP5 as an effector of the anti-RSV activity of IFN-γ and found that in children, the weaker immune response, especially the weaker IFN-γ response and the decreased GBP5 expression, leads to RSV susceptibility. Furthermore, we revealed that GBP5 reduced the cell-associated levels of the RSV small hydrophobic (SH) protein, which was identified as a viroporin. In contrast, overexpression of the SH protein rescued RSV replication in the presence of GBP5. The GBP5-induced decrease in intracellular SH protein levels is because GBP5 promotes the release of the SH protein into the cell culture. Moreover, the GBP5 C583A mutants with changes at the C terminus or the GBP5 ΔC mutant lacking the C-terminal region, which impairs GBP5 localization in the Golgi, could not inhibit RSV infection, whereas the GTPase-defective GBP5 maintained RSV inhibition, suggesting that Golgi localization but not the GTPase activity of GBP5 is required for RSV inhibition. Interestingly, we found that RSV infection or RSV G protein downregulates GBP5 expression by upregulating DZIP3, an E3 ligase, which induces GBP5 degradation through the K48 ubiquitination and proteasomal pathways. Thus, this study reveals a complicated interplay between host restrictive factor GBP5 and RSV infection and provides important information for understanding the pathogenesis of RSV. IMPORTANCE RSV is a highly contagious virus that causes multiple infections in infants within their first year of life. It can also easily cause infection in elderly or immunocompromised individuals, suggesting that individual differences in immunity play an important role in RSV infection. Therefore, exploring the pathogenic mechanisms of RSV and identifying essential genes which inhibit RSV infection are necessary to develop an effective strategy to control RSV infection. Here, we report that the IFN-inducible gene GBP5 potently inhibits RSV replication by reducing the cell-associated levels of the RSV small hydrophobic (SH) protein, which is a viroporin. In contrast, the RSV G protein was shown to upregulate the expression of the DZIP3 protein, an E3 ligase that degrades GBP5 through the proteasomal pathway. Our study provides important information for the understanding of the pathogenic mechanisms of RSV and host immunity as well as the complicated interplay between the virus and host.

We study the DeGroot model for continuous opinion dynamics under the influence of innovations. In the original model, individuals’ opinions, after given their initial values, evolve merely according to the given learning topology. The main contribution of this paper is that external innovation effects are introduced: each individual is given the opportunity to change her opinion to a randomly selected opinion according to a given distribution on the opinion space and then the external opinion is either adapted by the individual, or combined into her learning process. It turns out that all the classical results of the DeGroot model are violated in this new model. We prove that convergence can still be guaranteed in the expectation sense, regardless of the learning topology. We also study the steady distributions of opinions among the society and the time spent to reach a steady state by means of Monte-Carlo simulations.

Recent studies show that conditional dissociation, a.k.a. post-interaction partner-refusal, can promote the emergence and stability of cooperation. However, in most of these studies, players’ strategies are restricted to pure ones, which is obviously inconsistent with many biological and economic situations. Another concern with line of these studies is that conditional dissociation is often combined with other mechanisms. These mechanisms may favor cooperation per se, leaving it unclear whether conditional dissociation is indeed a key factor. In this paper, we study a clean model, pruning all the factors other than conditional dissociation that may favor cooperation. We find that conditional dissociation, which could be viewed as a variant of peer punishment, does promote cooperation, no matter whether mixed strategies are allowed or not. This confirms the previous findings in the literature. In addition, compared with the pure strategy scenario, cooperators are less competitive when mixed strategies are allowed. Our main finding is supported by both the numerical simulations and the theoretical analysis of Neutrally Stable Strategy. We also find that cooperative behavior is favored when waiting time and/or the population’s lifespan are longer.

This study aimed to summarise the clinical experience of peritoneal tuberculosis (TB). Clinical data of 26 patients admitted and diagnosed with peritoneal TB mimicking advanced ovarian cancer or peritoneal carcinoma between June 2008 and June 2017, was evaluated. The mean age was 35.92 ±15.30 years. The most common findings were abdominal mass (n=21, 80.77%) and elevated CA 125 levels (n=19, 73.08%). One patient underwent PET-CT and was diagnosed with peritoneal TB. Laparotomy was performed in 14 patients (70%) and laparoscopy in six patients (30%), out of whom two patients were converted to laparotomy due to severe adhesions. Meanwhile, mass puncture biopsy or small incision biopsy was the preferred method for diagnosing peritoneal TB, while PET-CT was considered as a good diagnostic method.

BACKGROUND The aim of this study was to investigate the expression of a novel long noncoding RNA (lncRNA), LL22NC03-N64E9.1, and its effect on the phenotype of lung cancer cells and tissues using The Cancer Genome Atlas (TCGA) RNA sequencing data and other publicly available profiling data. MATERIAL AND METHODS The lung cancer dataset GSE30219 was downloaded from the Gene Expression Omnibus (GEO) repository. Differentially expressed lncRNA, LL22NC03-N64E9.1, in 48 lung cancer tissue samples and adjacent normal lung tissues, normal lung cell lines BEAS-2B and A549, and lung cancer cell lines, H1703, and H292, were detected by quantitative reverse transcription polymerase chain reaction (PCR) (qRT-PCR). Interference efficiency was performed using small interfering RNA (siRNA). Tumor levels of lncRNA, LL22NC03-N64E9.1, and clinicopathological parameters were statistically analyzed. RESULTS Analysis of the GSE30219 test cohort showed that lncRNA, LL22NC03-N64E9.1 expression was significantly increased in lung cancer. In clinical tissue samples, the level of LL22NC03-N64E9.1 in patients with lung cancer was significantly increased compared with adjacent normal lung tissues (P0.001). The level of LL22NC03-N64E9.1 in patients with lung cancer was significantly correlated with tumor size and TNM stage (P0.05), but not with age, sex and the presence of lymph node metastasis (P0.05). In the H292 cells, following knockdown of LL22NC03-N64E9.1, cell proliferation and cloning were reduced. CONCLUSIONS Expression of lncRNA, LL22NC03-N64E9.1, promoted proliferation of lung cancer cells in vitro, was highly expressed in lung cancer tissues and was associated with increased overall survival (OS), tumor size, and tumor stage in patients with lung cancer.

The inflammation is the protective response of the body against various harmful stimuli; however, the aberrant and inappropriate activation tends to become harmful. The acute inflammatory response tends to resolved once the offending agent is subside but this acute response becomes chronic in nature when the body is unable to successfully neutralized the noxious stimuli. This chronic inflammatory microenvironment is associated with the release of various pro-inflammatory and oncogenic mediators such as nitric oxide (NO), cytokines [IL-1β, IL-2, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)], growth factor, and chemokines. These mediators make the inflammatory microenvironment more vulnerable toward tumorigenesis. The pro-inflammatory mediators released during the chronic inflammation tends to induce several molecular signaling cascades such as nuclear factor kappa B, MAPKinase, nuclear factor erythroid 2-related factor 2, phosphoinositide-3-kinase, Janus kinases/STAT, Wnt/B-catenin, and cyclic AMP response element binding protein. The immune system and its components have a pleiotropic effect on inflammation and cancer progression. Immune components such as T cells, natural killer cells, macrophages, and neutrophils either inhibit or enhance tumor initiation depending on the type of tumor and immune cells involved. Tumor-associated macrophages and tumor-associated neutrophils are pro-tumorigenic cells highly prevalent in inflammation-mediated tumors. Similarly, presence of T regulatory (Treg) cells in an inflammatory and tumor setting suppresses the immune system, thus paving the way for oncogenesis. However, Treg cells also inhibit autoimmune inflammation. By contrast, cytotoxic T cells and T helper cells confer antitumor immunity and are associated with better prognosis in patients with cancer. Cytotoxic T cells inflict a direct cytotoxic effect on cells expressing oncogenic markers. Currently, several anti-inflammatory and antitumor therapies are under trials in which these immune cells are exploited. Adoptive cell transfer composed of tumor-infiltrating lymphocytes has been tried for the treatment of tumors after their ex vivo expansion. Mediators released by cells in a tumorigenic and inflammatory microenvironment cross talk with nearby cells, either promoting or inhibiting inflammation and cancer. Recently, several cytokine-based therapies are either being developed or are under trial to treat such types of manifestations. Monoclonal antibodies directed against TNF-α, VEGF, and IL-6 has shown promising results to ameliorate inflammation and cancer, while direct administration of IL-2 has been shown to cause tumor regression.

We study the Stackleberg variant of the repeated Sequential Prisoner's Dilemma (SPD). The game goes in two stages, and the two players, the leader and the follower, are asymmetric in both stages. In the first stage of the game, the leader chooses a strategy (for the repeated SPD of the second stage), which is immediately known to the follower. In the second stage, they play repeated SPD: In each round the follower moves after observing the leader's action. Assuming complete rationality, we find some extraordinary properties of this model. (i) The (subgame perfect) equilibrium payoff profile is unique, which lies on the corner of the region predicted by classical folk theorems: It is best for the leader and at the same time worst for the follower, (ii) the leader has simple optimal strategies that are one-step memory and stationary. These features are in great contrast with classical results, where either uniqueness cannot be guaranteed and equilibrium strategies are often quite complicated, or bounded rationality is required. Although full cooperation, i.e., the outcome is always (cooperate, cooperate), is not attainable in our model, at least a half of the optimal social welfare can be guaranteed. We also do a non-equilibrium analysis which makes the usual equilibrium analysis more convincing.

Leaving is usually an option for individuals if they cannot tolerate their defective partners. In a two-player game, when a player chooses to leave, both she and her opponent become single players. However, in a multi-player game, the same decision may have different consequences depending on whether group cohesion exists. Players who choose not to leave would still be united together rather than be separated into singletons if there is cohesion among them. Considering this difference, we study two leaving mechanisms in public goods games. In the first mechanism, every player would be single once any of the group members leaves. In the second, we assume group cohesion exists that members who don't leave form a union. In our model, each player adopts a trigger strategy characterized by a threshold: she leaves if the number of defectors in her group exceeds the threshold. We find that under both mechanisms, when the expected lifespan of individuals is long enough, cooperators with zero tolerance toward defection succeed in the evolution. Moreover, when cohesion exists in groups, cooperation is better promoted because the cooperators have a higher chance to play together. That is, group cohesion facilitates positive assortment and therefore promotes cooperation.