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Background: The peculiarity and the lack of clinical studies of dual primary lung cancer (DPLC) led to limited knowledge about its clinical characteristics and prognosis. The current study performed a retrospective analysis and established a prognostic nomogram to assess the prognostic factors and clinical characteristics of DPLC.Methods: A total of 1419 DPLC patients with pathological confirmation from SEER were selected and analyzed by univariate and multivariable Cox regression analyses. The independent prognostic factors were included to establish a nomogram. The accuracy and reliability of prognostic model were evaluated by C-indexes, calibration plots, receiver operating characteristic (ROC) curves, decision curve analyses (DCA) and integrated discrimination improvement (IDI) scores. Chi-square test was used to assess the differences between DPLC and single primary lung cancer (SPLC) or synchronous DPLC (sDPLC) and metachronous DPLC (mDPLC).Results: Cox regression analysis showed that age, sex, histological type, stage, LN metastasis, surgery, chemotherapy were independent prognostic factors, we included these factors to establish a prognostic model. In the training cohort, the C-index was 0.690, and the area under curves (AUC) of 3- and 5-year survival time were 0.720 and 0.723. The calibration plots in training cohort and validation cohort were in excellent agreement. DCA and IDI showed that the predictive effect of the novel prognostic model was better than the model based on 8th AJCC TNM system. Chi-square test indicated that DPLC and SPLC had statistical differences on pathological and clinical features.Conclusions: The clinical and pathological characteristics of DPLC were different from the SPLC. The nomogram based on significant factors could provide accurate and individualized survival predictions for DPLC.

Background Lung cancer remains the leading cause of cancer death globally. In 2015, the cancer classification guidelines of the World Health Organization were updated. The term “invasive mucinous adenocarcinoma (IMA)” aroused people’s attention, while the clinicopathological factors that may influence survival were unclear. Methods Data of IMA patients was downloaded from SEER database. Kaplan-Meier methods and log-rank tests were used to compare the differences in OS and LCSS. The nomogram was developed based on the result of the multivariable analysis. The discrimination and accuracy were tested by Harrell’s concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve and decision curve analyses (DCA). Integrated discrimination improvement (IDI) index was used to evaluate the clinical efficacy. Results According to multivariate analysis, the prognosis of IMAs was associated with age, differentiation grade, TNM stage and treatments. Surgery might be the only way that would improve survival. Area under the curve (AUC) of the training cohort was 0.834and 0.830 for3-and 5-year OS, respectively. AUC for 3-and 5-year LCSS were separately 0.839 and 0.839. The new model was then evaluated by calibration curve, DCA and IDI index. Conclusion Based on this study, prognosis of IMAs was systematically reviewed, and a new nomogram was developed and validated. This model helps us understand IMA in depth and provides new ideas for IMA treatment.

Objectives The rarity of atypical carcinoid (AC) of lung and the lack of prospective clinical trials lead to limited knowledge of its biology, treatment information and prognosis. The current study analyzed AC patients from the Surveillance, Epidemiology, and End Results (SEER) database to better understand the clinical characteristics of this disease and build a prognostic nomogram for clinical practice. Materials and methods A total of 507 AC patients with pathological confirmation from SEER database were performed with univariate Cox regression analyses for both overall survival (OS) and lung cancer specific survival (LCSS) analyses. Of the 507 observations, 464 were used in the multivariable Cox proportional hazards model as training cohort of new nomogram. A new nomogram was constructed based on the training cohort and validated by an external validation cohort to predict the 3-, 5- and 10-year OS of ACs. The accuracy and clinical practicability were separately tested by Harrell's C-indexes, calibration plots and decision curve analyses (DCA). Results Lobectomy and segmental resection were found to be protective factors for AC patients. Age, primary tumor size, N stage, M stage, surgery and regional lymph nodes examination were shown as significant prognostic factors in Cox regression analyses and included in the nomogram as predictors. The C-index in the training cohort for 3-, 5-, and 10-year OS were 0.722, 0.737 and 0.712, respectively. The internal and external calibration plots for predictions of the 3-, 5-, and 10-year OS were in excellent agreement. An online webserver was built based on the proposed nomogram for convenient clinical use. Conclusion AC patients with lobectomy or segmental resection tended to have better OS and LCSS. A nomogram was constructed and validated to predict the OS for AC patients and to provide accurate and individualized survival predictions.

The bacterial messenger cyclic diguanylate monophosphate (c-di-GMP) binds to various effectors, the most common of which are single-domain PilZ proteins. These c-di-GMP effectors control various cellular functions and multicellular behaviors at the transcriptional or posttranslational level. We found that MapZ (methyltransferase-associated PilZ; formerly known as PA4608), a single-domain PilZ protein from the opportunistic pathogen Pseudomonas aeruginosa, directly interacted with the methyltransferase CheR1 and that this interaction was enhanced by c-di-GMP. In vitro assays indicated that, in the presence of c-di-GMP, MapZ inhibited CheR1 from methylating the chemoreceptor PctA, which would be expected to increase its affinity for chemoattractants and promote chemotaxis. MapZ localized to the poles of P. aeruginosa cells, where the flagellar motor and other chemotactic proteins, including PctA and CheR1, are also located. P. aeruginosa cells exhibit a random walk behavior by frequently switching the direction of flagellar rotation in a uniform solution. We showed that binding of c-di-GMP to MapZ decreased the frequency of flagellar motor switching and that MapZ was essential for generating the heterogeneous motility typical of P. aeruginosa cell populations and for efficient surface attachment during biofilm formation. Collectively, the studies revealed that c-di-GMP affects flagellar motor output by regulating the methylation of chemoreceptors through a single-domain PilZ adaptor protein.

Circular dorsal ruffles (CDRs) are transient actin-rich ring-like structures which form on the dorsal surface of growth-factor stimulated cells. However, the dynamics and mechanism of formation of CDRs are still unknown. It has been observed that CDR formation leads to stress fibers disappearing near the CDRs. Since stress fiber formation can be modified by substrate stiffness, we examined the effect of substrate stiffness on CDR formation by seeding NIH 3T3 fibroblasts on glass and polydimethylsiloxane (PDMS) substrates of varying stiffnesses from 20 kPa to 1800 kPa. We found that increasing substrate stiffness increased the lifetime of the CDRs. We developed a mathematical model of the signaling pathways involved in CDR formation to provide insight into this lifetime and size dependence which is linked to substrate stiffness via Rac-Rho antagonism. From the model, increasing stiffness raised mDia1-nucleated stress fiber formation due to Rho activation. The increased stress fibers present increased replenishment of the G-actin pool, therefore prolonging Arp2/3-nucleated CDR formation due to Rac activation. Negative feedback by WAVE-related RacGAP on Rac explained how CDR actin propagates as an excitable wave, much like wave propagation in other excitable medium, e.g., nerve signal transmission. Accepted version

Circular dorsal ruffles (CDRs) are transient actin structures which have been linked to cell motility but the exact mechanism is still unclear. CDRs appear and grow in size after cells are stimulated with growth factors, such as the platelet-derived growth factor, eventually disappearing tens of minutes after stimulation. The role of CDR formation in cell motility is investigated for NIH 3T3 fibroblasts seeded on compliant polyacrylamide substrates. We found that CDR formation increases cell migration directional persistency but did not affect the migration speed. Furthermore, an increase in the localization of lamellipodial protrusion at the cell edge in the vicinity of the CDRs was observed. Relocalization of lamellipodia occured 1 to 6 min after CDR formation at the cell edge closest to the site of CDR formation. The time lag between peak CDR formation and the peak lamellipodial protrusion is then correlated with the spatial distance between the CDR and the lamellipodia; this time scale is consistent with the diffusive time scale of cytosolic globular actin (G actin). Using green to red photoswitchable Dendra2-conjugated actin, we photoconverted CDR actin from green to red and observed the subsequent appearance of red fluorescent actin in the lamellipodia at the cell leading edge. These findings help shed light on the interconversions between mesoscopic actin structures in cell behavior.

We have developed a three-dimensional random network model of the intracellular actin cytoskeleton and have used it to study the role of the cytoskeleton in mechanotransduction and nucleus deformation. We use the model to predict the deformation of the nucleus when mechanical stresses applied on the plasma membrane are propagated through the random cytoskeletal network to the nucleus membrane. We found that our results agree with previous experiments utilizing micropipette pulling. Therefore, we propose that stress propagation through the random cytoskeletal network can be a mechanism to effect nucleus deformation, without invoking any biochemical signaling activity. Using our model, we also predict how nucleus strain and its relative displacement within the cytosol vary with varying concentrations of actin filaments and actin-binding proteins. We find that nucleus strain varies in a sigmoidal manner with actin filament concentration, while there exists an optimal concentration of actin-binding proteins that maximize nucleus displacement. We provide a theoretical analysis for these nonlinearities in terms of the connectivity of the random cytoskeletal network. Finally, we discuss laser ablation experiments that can be performed to validate these results in order to advance our understanding of the role of the cytoskeleton in mechanotransduction.

Circular dorsal ruffles (CDRs) are actin rich structures formed in mammalian cells in response to stimulation with growth factors, such as platelet-derived growth factor (PDGF). CDR formation is a possible mechanism by which the actin cytoskeleton in cells is remodeled relating to migration. We have found that CDRs form immediately after PDGF stimulation, before persisting and disappearing after tens of minutes in fibroblast cells seeded on underlying polydimethylsiloxane (PDMS) substrates coated with fibronectin. Increasing the PDMS stiffness with the same PDGF stimulation in NIH 3T3 fibroblasts increases the percentage of cells in a population which contain CDRs. Increasing PDMS substrate stiffness also results in a biphasic response of the average persistence time of CDRs formed in a cell population. This biphasic response reveals that the percentage of cells with CDRs increases at low stiffnesses while decreasing at higher stiffnesses. Not only does the substrate stiffness affect the CDRs, but by applying biaxial stresses to the cells through stretching the PDMS substrates, we observe an increase in the average persistence time of CDRs formed in a cell population with similar PDGF stimulation. Our results suggest that the functionality of CDRs in cells after stimulation with PDGF is linked to substrate stiffness and also the mechanical environment of the cells. We believe that this work is of interest to a wide variety of fields including physics, biology, material science, and mechanics.