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ObjectiveTo explore the independent risk factors that affect the overall survival (OS) of elderly patients with hepatocellular carcinoma (HCC, ≥60 years old) and build a nomogram prediction model. MethodsClinical data of all elderly patients with HCC from the SEER database from 2005 to 2020 were downloaded from SEER database. In accordance with the inclusion and exclusion criteria, the screened patients were randomly assigned to a training group (70%) and a validation group (30%). The independent risk factors of elderly patients with HCC were determined by univariate and multivariate Cox regression analyses and further validated by Kaplan-Meier survival analysis. On the basis of the determined variables, nomograms were developed and verified to predict the OS of elderly patients with HCC at 6, 12, and 24 months. The consistency index (C index), calibration curve, receiver’s operating characteristic (ROC) curve, and area under curve (AUC) were used to evaluate the prediction efficiency and discrimination ability of the prediction model, and decision curve analysis (DCA) was used to evaluate the potential clinical application value of the nomogram. ResultsA total of 1134 elderly patients with HCC were included, with 793 in the training group and 341 in the validation group. Seven variables, including age, clinical grade, clinical stage, M stage, tumor size classification, and radiotherapy, were identified as independent prognostic factors of this population. The constructed nomogram shows excellent prediction performance, with C indices of 0.745 in the training group and 0.704 in the validation group. The AUC values of the training group at 6, 12, and 24 months were 0.785, 0.788, and 0.798, respectively, and those of the validation group were 0.780, 0.725, and 0.607, respectively. The calibration curve shows good consistency from the predicted survival probability to the actual probability. The ROC curve and DCA show that the nomogram proposed in this study has good prediction ability. ConclusionAge, clinical grade, clinical stage, M stage, tumor size classification, and radiotherapy are important influencing factors for the survival of elderly patients with HCC. The prediction model of prognosis nomogram constructed in this study has good predictive value, and it can be used to predict the OS of elderly patients with HCC, which could be helpful for individualized survival assessment and clinical management of these patients.

Summary: Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B–E (GSDMB–GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress.

BackgroundOur study was designed to determine the incidence and risk factors of severe acute high-altitude illness (AHAI) in healthy adults first entering the northern Tibetan Plateau of over 5,000 m.MethodsIn our prospective observational study, we enrolled 500 people who were scheduled for fast ascension to the northern Tibetan Plateau. The primary outcome variable was severe AHAI, defined as the presence of serious symptoms that could not be ameliorated by general treatment and required evacuation to lower altitudes. According to the inclusion and exclusion criteria, a cohort of 383 healthy people was included in the statistical analysis. We calculated the incidence of severe AHAI, identified the risk factors, and the differences in the most severe symptoms experienced.ResultsSixty-eight people were diagnosed with severe AHAI, and the incidence was 17.8%. Compared to individuals without severe AHAI, those with severe AHAI were more likely to be over the age of 40 years, of Han Chinese nationality, and living at an altitude of

Abstract Esophagogastric variceal bleeding (EVB) is one of the common digestive system emergencies with poor prognosis and high rate of rebleeding after treatment. To explore the effects of endoscopic therapy and drug therapy on the prognosis and rebleeding of patients with EVB, and then select better treatment methods to effectively improve the prognosis. From January 2013 to December 2022, 965 patients with EVB who were hospitalized in gastroenterology Department of the 940 Hospital of Joint Logistic Support Forces of PLA were retrospectively analyzed. Patients were divided into endoscopic treatment group (ET, n = 586) and drug treatment group (DT, n = 379). Propensity score matching (PSM) analysis was performed in both groups, and the general information, efficacy and length of hospital stay were recorded. The patients were followed up for 3 months after bleeding control to determine whether rebleeding occurred. There were 286 cases in each group after PSM. Compared with DT group, ET had higher treatment success rate (P 0.05). Compared with drug therapy, endoscopic treatment of EVB has short-term efficacy advantages, and can effectively reduce the incidence of rebleeding and mortality within 3 months.

Introduction: Human papillomavirus (HPV) integration can induce gene expression dysregulation by destroying higher-order chromatin structure in cervical cancer. Objectives: We established a 13q22 site-specific HPV16 gene knock-in cell model to interrogate the changes in chromatin structure at the initial stages of host cell malignant transformation. Methods: We designed a CRISPR-Cas9 system with sgRNA targeting 13q22 site and constructed the HPV16 gene donor. Cells were cotransfected, screened, and fluorescence sorted. The whole genome sequencing (WGS) was used to confirm the precise HPV16 gene integration site. Western blot and qRT-PCR were used to measure gene expression. In vitro and in vivo analysis were performed to estimate the tumorigenic potential of the HPV16 knock-in cell model. Combined Hi-C, chromatin immunoprecipitation and RNA sequencing analyses revealed correlations between chromatin structure and gene expression. We performed a coimmunoprecipitation assay with anti-PIBF1 antibody to identify endogenous interacting proteins. In vivo analysis was used to determine the role of PIBF1 in the tumor growth of cervical cancer cells. Results: We successfully established a 13q22 site-specific HPV16 gene knock-in cell model. We found that HPV integration promoted cell proliferation, invasion and stratified growth in vitro, and monoclonal proliferation in vivo. HPV integration divided the affected topologically associated domain (TAD) into two smaller domains, and the progesterone-induced blocking factor 1 (PIBF1) gene near the integration site was upregulated, although PIBF1 was not enriched at the domain boundary by CUT-Tag signal analysis. Moreover, PIBF1 was found to interact with the cohesin complex off chromatin to reduce contact domain formation by disrupting the cohesin ring-shaped structure, causing dysregulation of tumorigenesis-related genes. Xenograft experiments determined the role of PIBF1 in the proliferation in cervical cancer cells. Conclusion: We highlight that PIBF1, a potential chromatin structure regulatory protein, is activated by HPV integration, which provides new insights into HPV integration-driven cervical carcinogenesis.

Additive manufacturing (AM) or 3D printing is a promising industrial technology that enables rapid prototyping of complex configurations. Powder Bed Fusion (PBF) is one of the most popular AM techniques for metallic materials. Until today, only a few metals and alloys are available for AM, e.g., titanium alloys, the most common of which is Ti-6Al-4V. After optimization of PBF parameters, with or without post processing such as heat treatment or hot isostatic pressing, the printed titanium alloy can easily reach tensile strengths of over 1100 MPa due to the quick cooling of the AM process. However, attributed to the unique features of metallurgical defects and microstructure introduced by this AM process, their fatigue strength has been low, often less than 30% of the tensile strength, especially in very-high-cycle regimes, i.e., failure life beyond 107 cycles. Here, based on our group’s research on the very-high-cycle fatigue (VHCF) of additively manufactured (AMed) Ti-6Al-4V alloys, we have refined the basic quantities of porosity, metallurgical defects, and the AMed microstructure, summarized the main factors limiting their VHCF strengths, and suggested possible ways to improve VHCF performance.

Abstract Background Recurrent or metastatic cervical cancer (r/m CC) often has poor prognosis owing to its limited treatment options. The development of novel therapeutic strategies has been hindered by the lack of preclinical models that accurately reflect the biological and genomic heterogeneity of cervical cancer (CC). Herein, we aimed to establish a large patient-derived xenograft (PDX) biobank for CC, evaluate the consistency of the biologic indicators between PDX and primary tumor tissues of patients, and explore its utility for assessing patient’s response to conventional and novel therapies. Methods Sixty-nine fresh CC tumor tissues were implanted directly into immunodeficient mice to establish PDX models. The concordance of the PDX models with their corresponding primary tumors (PTs) was compared based on the clinical pathological features, protein biomarker levels, and genomic features through hematoxylin & eosin staining, immunohistochemistry, and whole exome sequencing, respectively. Moreover, the clinical information of CC patients, RNA transcriptome and immune phenotyping of primary tumors were integrated to identify the potential parameters that could affect the success of xenograft engraftment. Subsequently, PDX model was evaluated for its capacity to mirror patient’s response to chemotherapy. Finally, PDX model and PDX-derived organoid (PDXO) were utilized to evaluate the therapeutic efficacy of neratinib and adoptive cell therapy (ACT) combination strategy for CC patients with human epidermal growth factor receptor 2 (HER2) mutation. Results We established a PDX biobank for CC with a success rate of 63.8% (44/69). The primary features of established PDX tumors, including clinicopathological features, the expression levels of protein biomarkers including Ki67, α-smooth muscle actin, and p16, and genomics, were highly consistent with their PTs. Furthermore, xenograft engraftment was likely influenced by the primary tumor size, the presence of follicular helper T cells and the expression of cell adhesion-related genes in primary tumor tissue. The CC derived PDX models were capable of recapitulating the patient’s response to chemotherapy. In a PDX model, a novel therapeutic strategy, the combination of ACT and neratinib, was shown to effectively inhibit the growth of PDX tumors derived from CC patients with HER2-mutation. Conclusions We established by far the largest PDX biobank with a high engraftment rate for CC that preserves the histopathological and genetic characteristics of patient’s biopsy samples, recapitulates patient’s response to conventional therapy, and is capable of evaluating the efficacy of novel therapeutic modalities for CC.

Abstract Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers, best exemplified by loss-of-function mutations in genes encoding components of the TGF-β signaling pathway in colorectal and pancreatic cancers. Alternatively, gain-of-function oncogene mutations can also disrupt antiproliferative TGF-β signaling. However, the molecular mechanisms underlying oncogene-induced modulation of TGF-β signaling have not been extensively investigated. Here, we show that the oncogenic BCR-ABL1 of chronic myelogenous leukemia (CML) and the cellular ABL1 tyrosine kinases phosphorylate and inactivate Smad4 to block antiproliferative TGF-β signaling. Mechanistically, phosphorylation of Smad4 at Tyr195, Tyr301, and Tyr322 in the linker region interferes with its binding to the transcription co-activator p300/CBP, thereby blocking the ability of Smad4 to activate the expression of cyclin-dependent kinase (CDK) inhibitors and induce cell cycle arrest. In contrast, the inhibition of BCR-ABL1 kinase with Imatinib prevented Smad4 tyrosine phosphorylation and re-sensitized CML cells to TGF-β-induced antiproliferative and pro-apoptotic responses. Furthermore, expression of phosphorylation-site-mutated Y195F/Y301F/Y322F mutant of Smad4 in Smad4-null CML cells enhanced antiproliferative responses to TGF-β, whereas the phosphorylation-mimicking Y195E/Y301E/Y322E mutant interfered with TGF-β signaling and enhanced the in vivo growth of CML cells. These findings demonstrate the direct role of BCR-ABL1 tyrosine kinase in suppressing TGF-β signaling in CML and explain how Imatinib-targeted therapy restored beneficial TGF-β anti-growth responses.

BackgroundPostoperative recurrence is associated with poor prognosis in patients with gastric cancer. This study aimed to explore predictive factors contributing to recurrence in patients with stage II/III gastric cancer after laparoscopic D2 gastrectomy.MethodsThis retrospective study was conducted at a single tertiary referral hospital. Patients diagnosed with gastric cancer who met the inclusion criteria were included in the study. The clinicopathological characteristics of the patients were collected. The patients were divided into recurrence and non-recurrence groups. The predictive factors were investigated using univariate and multivariate analyses.ResultsIn total, 462 patients were included. The incidence of recurrence was 26.4% (122/462) in all patients. The most common recurrence pattern was haematogenous recurrence. In the multivariate analysis, the independent predictive factors for recurrence were serum prealbumin level (p < 0.001), prognostic nutritional index (p = 0.001), carbohydrate antigen 19-9 (CA19-9) (p < 0.001), number of lymph node metastases (p < 0.001), signet-ring cell carcinoma (p = 0.001), tumor deposit (p = 0.001), and no/incomplete adjuvant chemotherapy (p < 0.001).ConclusionsOur findings revealed that nutritional status was an independent predictive factor for recurrence in patients with gastric cancer after D2 gastrectomy. We suggest that patients with risk factors for recurrence receive both nutritional support and intense surveillance.

BackgroundGestational diabetes mellitus (GDM) is a common endocrine metabolic disease, involving a carbohydrate intolerance of variable severity during pregnancy. The incidence of GDM-related complications and adverse pregnancy outcomes has declined, in part, due to early screening. Machine learning (ML) models are increasingly used to identify risk factors and enable the early prediction of GDM. ObjectiveThe aim of this study was to perform a meta-analysis and comparison of published prognostic models for predicting the risk of GDM and identify predictors applicable to the models. MethodsFour reliable electronic databases were searched for studies that developed ML prediction models for GDM in the general population instead of among high-risk groups only. The novel Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to assess the risk of bias of the ML models. The Meta-DiSc software program (version 1.4) was used to perform the meta-analysis and determination of heterogeneity. To limit the influence of heterogeneity, we also performed sensitivity analyses, a meta-regression, and subgroup analysis. ResultsA total of 25 studies that included women older than 18 years without a history of vital disease were analyzed. The pooled area under the receiver operating characteristic curve (AUROC) for ML models predicting GDM was 0.8492; the pooled sensitivity was 0.69 (95% CI 0.68-0.69; P

BackgroundThe aim of this study is to explore the clinical feasibility of detecting folate receptor-positive circulating tumor cells (FR+ CTCs) for predicting peritoneal metastasis and short-term outcome in gastric cancer patients.MethodsThis is a prospective, single-center, observational study. We applied ligand-targeted enzyme-linked polymerization method to detect preoperative FR+ CTC levels in peripheral blood. We evaluated the diagnostic value of FR+ CTCs and other biomarkers in predicting peritoneal metastasis. Prognostic factors for recurrence-free survival (RFS) were investigated in univariate and multivariate analyses.ResultsA total of 132 patients with gastric cancer and 9 patients with benign disease were recruited. Gastric cancer patients had a significantly higher CTC level compared to that of patients with benign disease (p < 0.01). Combined model including CTC level and other biomarkers presented high sensitivity (100%) and moderate specificity (59.3%) in predicting peritoneal metastasis. Univariate analysis revealed that decreased serum prealbumin, decreased peripheral lymphocyte count, FR+ CTCs, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and lymph node metastasis were significantly associated with shorter RFS. FR+ CTC level [≥12.6 folate units (FU)/3 ml, hazard ratio (HR) = 6.957, p = 0.005] and CA19-9 (>34 ng/ml, HR = 3.855, p = 0.037) were independent prognostic factors in multivariate analysis.ConclusionsOur findings for the first time suggested the diagnostic value of preoperative CTC levels in predicting peritoneal metastasis in gastric cancer. Moreover, the FR+ CTC level could be a novel and promising prognostic factor for the recurrence of gastric cancer in patients who underwent surgery.Clinical Trial RegistrationChinese Clinic Trial Registry, identifier ChiCTR2100050514.

Background: Although enhanced recovery after surgery (ERAS) has been proven to be beneficial after laparoscopic colorectal surgery, some of the patients may fail to complete the ERAS program during hospitalization. This prospective study aims to evaluate the risk factors associated with ERAS failure after laparoscopic colorectal cancer surgery.Methods: This is a prospective study from a single tertiary referral hospital. Patients diagnosed with colorectal cancer who met the inclusion criteria were included in this study. Demographic and clinicopathological characteristics were collected. Post-operative activity time and 6-min walking distance (6MWD) were measured. Patients were divided into ERAS failure group and ERAS success according to decreased post-operative activity and 6MWD. Factors associated with ERAS failure were investigated by univariate and multivariate analysis.Results: A total of 91 patients with colorectal cancer were included. The incidence of ERAS failure is 28.6% among all patients. Patients in ERAS failure group experienced higher rate of post-operative ileus and prolonged hospital stay (p < 0.001). Multivariate analysis revealed that older age (p = 0.006), body mass index ≥25.5 kg/m2 (p = 0.037), smoking (p = 0.002), operative time (p = 0.048), and post-operative energy intake

Human papillomavirus (HPV) integration in the human genome is suggested to be an important cause of cervical cancer. With the development of sequencing technologies, an increasing number of integration “hotspots” have been identified. However, this HPV integration information was derived from analysis of whole cervical cancer tissue, and we know very little about the integration in different cancer cell subgroups or individual cancer cells. This study optimized the preparation of probes and provided a dual-color fluorescence in situ hybridization (FISH) method to detect HPV integration sites in paraffin-embedded cervical cancer samples. We used both HPV probes and site-specific probes: 3p14 (FHIT), 8q24 (MYC), 13q22 (KLF5/KLF12), 3q28 (TP63), and 5p15 (TERT). We detected HPV signals in 75 of the 96 cases of cervical cancer; 62 cases showed punctate signals, and 13 cases showed diffuse punctate signals. We identified 3p14 as a high-frequency HPV integration site in 4 cervical cancer cases. HPV integration at 8p14 occurred in 2 cases of cervical cancer. In the same cervical cancer tissue of sample No.1321, two distinct subgroups of cells were observed based on the HPV probe but showed no difference in cell and nucleus morphology. Our study provides a new method to investigate the frequent HPV integration sites in cervical cancer and reports the heterogeneity within cervical cancer from the perspective of HPV integration.

Cervical squamous cell carcinoma (CSCC) is the major pathological type of cervical cancer (CC), the second most prevalent reproductive system malignant tumor threatening the health of women worldwide. The prognosis of CSCC patients is largely affected by the tumor immune microenvironment (TIME); however, the biomarker landscape related to the immune microenvironment of CSCC and patient prognosis is less characterized. Here, we analyzed RNA-seq data of CSCC patients from The Cancer Genome Atlas (TCGA) database by dividing it into high- and low-immune infiltration groups with the MCP-counter and ESTIMATE R packages. After combining weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis, we found that PLA2G2D, a metabolism-associated gene, is the top gene positively associated with immune infiltration and patient survival. This finding was validated using data from The Cancer Genome Characterization Initiative (CGCI) database and further confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, multiplex immunohistochemistry (mIHC) was performed to confirm the differential infiltration of immune cells between PLA2G2D-high and PLA2G2D-low tumors at the protein level. Our results demonstrated that PLA2G2D expression was significantly correlated with the infiltration of immune cells, especially T cells and macrophages. More importantly, PLA2G2D-high tumors also exhibited higher infiltration of CD8+ T cells inside the tumor region than PLA2G2D-low tumors. In addition, PLA2G2D expression was found to be positively correlated with the expression of multiple immune checkpoint genes (ICPs). Moreover, based on other immunotherapy cohort data, PLA2G2D high expression is correlated with increased cytotoxicity and favorable response to immune checkpoint blockade (ICB) therapy. Hence, PLA2G2D could be a novel potential biomarker for immune cell infiltration, patient survival, and the response to ICB therapy in CSCC and may represent a promising target for the treatment of CSCC patients.

BackgroundDry eye is often the first presenting manifestation of primary Sjögren’s syndrome (pSS). Because of the high prevalence of dry eye disease in normal population, ophthalmologists urgently need a non-invasive and reliable screening test to diagnose dry eye associated SS patients, other than ocular symptoms and signs. Currently, there is no single test available. The correlation of serum IL-14α with pSS has been found in pSS mouse model.PurposeTo evaluate whether IL-14α can serve as a biomarker to stratify dry eye in primary Sjögren’s syndrome and its correlation to BAFF in a cohort of patients with non-SS dry eye (NSDE), pSS with dry eye disease, rheumatoid arthritis (RA), and healthy controls (HC).MethodsRetrospective study based on serum levels of IL-14α (defined by Western Blot) and BAFF (measured by ELISA) were evaluated among pSS with dry eye disease, NSDE, RA, and HC groups. Serum levels of SS related autoantibodies (Ro, La, SP1, PSP, and CA6) were also measured by ELISA.ResultsOne hundred and eighty patients were included for the current study, patients were separated into four groups as defined by pSS (n=65), NSDE (n=20), RA (n=50) and HC (n=45). The level of serum IL-14α in pSS was significantly higher compared to NSDE, RA, and HC (p=0.0011, p=0.0052 and p

BackgroundIt is controversial to evaluate the function of hydronephrotic kidneys by renal dynamic imaging (RDI). Our aim was to study the features of renal dynamic imaging (RDI) at different stages after unilateral ureteral obstruction (UUO) and to investigate a method that could be reasonably used to evaluate renal function and predict renal functional recoverability.MethodsWe made UUO models using fifteen adult New Zealand white rabbits and systematically observed the changes in kidney morphology, blood flow, radiotracer distribution and function by RDI. We then compared the differences in terms of imaging features between different periods and analyzed the relationship between blood flow and function in obstructed kidneys.Results1) Obstructed kidneys gradually became larger than preoperative kidneys and contralateral kidneys (PConclusionIn different periods of severe UUO, the imaged features of obstructed kidneys were different. These features are beneficial for determining the degree of hydronephrosis and renal function and predicting renal functional recoverability.

Abstract Age-related macular degeneration (AMD), a leading contributor of vision loss, currently lacks comprehensive treatment. While AMD histopathology involves retinal pigment epithelium (RPE) injury associated with immune cell infiltration, the nature of immune cell responses to RPE injury remains undefined. We induced RPE injury pharmacologically and genetically in transgenic mouse models in which microglia and systemic monocytes were separately tagged, enabling a spatial and temporal dissection of the relative contributions of microglia vs. monocytes to post-injury changes. We found that myeloid cell responses to RPE injury occur in stages: (1) an early mobilization of endogenous microglia from the inner retina to the RPE layer, followed by (2) subsequent monocyte infiltration from the retinal vasculature into the inner retina that replenishes the local myeloid cell population in a CCR2-regulated manner. These altered distributions of myeloid cells post-injury were long-lived, with recruited monocytes acquiring the distribution, markers, and morphologies of neighboring endogenous microglia in a durable manner. These findings indicate the role played by infiltrating monocytes in maintaining myeloid cell homeostasis in the retina following AMD-relevant RPE injury and provide a foundation for understanding and therapeutically modulating immune aspects in retinal disease.

Eleven species of Ctenopelma Holmgren, 1857 are reported from China. Five species are new to science: C. labiatum Sheng, Sun & Li sp. nov., from Ningxia Hui Autonomous Region, C. lii Sheng, Sun & Li sp. nov., from Liaoning province, C. rufofasciatum Sheng, Sun & Li sp. nov., reared from Cephalcia lariciphila (Wachtl, 1898) from Beijing, C. pineatum Sheng, Sun & Li sp. nov., reared from Acantholyda posticalis (Matsumura, 1912) and Cephalcia lariciphila from Beijing and Henan, Shanxi, Shan’xi, Liaoning, Jilin and Heilongjiang provinces, and C. spiraculare Sheng, Sun & Li sp. nov., reared from Cephalcia lariciphila from Henan and Shanxi provinces. One species, C. nigrum Holmgren, 1857, reared from Cephalcia lariciphila in Beijing, is a new record for China. Ctenopelma tomentosum (Desvignes, 1856) was reared from Neurotoma sibirica Gussakovskij, 1935 (new host record) in Liaoning province. A key to species of Ctenopelma known in China is provided.

Despite the overall success of using R-CHOP for the care for non-Hodgkin’s lymphoma patients, it is clear that the disease is quite complex and new insight is needed to further stratify the patient for a better personized treatment. In current study, based on previous studies from animal model, new panels combining well-established cytokine (BAFF) and autoantibodies (anti-SSA/Ro) with newly identified cytokine (IL14) and autoantibodies (TSA) were used to evaluate the association between B cell growth factor and Sjögren’s related autoantibodies in NHL patients. The result clearly indicates that there was a unique difference between BAFF and IL14 in association with autoantibodies. While serum BAFF was negatively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in GI lymphoma patient, IL14 was positively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in non-GI lymphoma patient. Long-term follow-ups on these patients and evaluation of their response to the R-CHOP treatment and recurrence rate will be very interesting. Our result provides a solid evidence to support using novel diagnostic panel to better stratify the NHL patients.

Summary: Microtubule actin crosslinking factor 1 (MACF1) plays a role in the coordination of microtubules and actin in multiple cellular processes. Here, we show that MACF1 is also critical for ciliogenesis in multiple cell types. Ablation of Macf1 in the developing retina abolishes ciliogenesis, and basal bodies fail to dock to ciliary vesicles or migrate apically. Photoreceptor polarity is randomized, while inner retinal cells laminate correctly, suggesting that photoreceptor maturation is guided by polarity cues provided by cilia. Deletion of MACF1 in adult photoreceptors causes reversal of basal body docking and loss of outer segments, reflecting a continuous requirement for MACF1 function. MACF1 also interacts with the ciliary proteins MKKS and TALPID3. We propose that a disruption of trafficking across microtubles to actin filaments underlies the ciliogenesis defect in cells lacking MACF1 and that MKKS and TALPID3 are involved in the coordination of microtubule and actin interactions. : May-Simera et al. find that MACF1, a giant protein that mediates microtubule and actin interactions, is essential for ciliogenesis and maintenance. In the developing retina, MACF1 is required for establishing apicobasal polarity in photoreceptors, thus highlighting the importance of cilia in providing the correct positional cues. Keywords: retina, cilia, ciliogenesis, ciliopathy, polarity, retinal degeneration, basal body, centrosome, microtubule, actin

The Hippo pathway regulates intrinsic organ sizes by regulating apoptosis and cell proliferation. YAP1 (yes-associated protein 1) is a transcriptional effector of the Hippo pathway. YAP1 expression is reported to be associated with gastric cancer carcinogenesis and malignancy. In this study, we compared the expression of YAP1 in gastric cancer and normal stomach tissues. Tissue microarray analysis was performed in 156 gastric cancer samples, 8 adjacent normal stomach tissues, and 4 normal stomach tissues. We also analyzed the association between YAP1 protein expression and clinicopathological features, such as age, gender, histological differentiation, and clinical stages. We used the ONCOMINE database and the Kaplan–Meier plotter to analyze YAP1 expression status in different clinicopathological parameters of gastric cancer. We also used the Kaplan–Meier plotter to summarize the survival information of YAP1 from a total of 631 gastric cancer patients. YAP1 expression was found to be elevated in gastric cancer tissues compared to normal stomach tissues. YAP1 messenger RNA was found to be upregulated in gastric intestinal-type adenocarcinoma and gastric mixed adenocarcinoma compared to gastric mucosa. YAP1 high expression was found to be correlated to worse overall survival for all gastric cancer patients followed for 20 years. These results indicate that YAP1 can be used to predict the prognosis of gastric cancer. And YAP1 maybe a potential drug target for gastric cancer patients.

Cervical cancer is the second most common cancer and the third leading cause of cancer death in females worldwide, especially in developing countries. High risk human papillomavirus (HR-HPV) infection causes cervical cancer and precancerous cervical intraepithelial neoplasia (CIN). Integration of the HR-HPV genome into the host chromatin is an important step in cervical carcinogenesis. The detection of integrated papillomavirus sequences-PCR (DIPS-PCR) allowed us to explore HPV integration in the human genome and to determine the pattern of this integration. We performed DIPS-PCR for 4 cell lines including 3 cervical cancer cell lines and 40 tissue samples. Overall, 32 HR-HPV integration loci were detected in the clinical samples and the HeLa and SiHa cell lines. Among all the integration loci, we identified three recurrent integration loci: 3p14.2 (3 samples), 13q22.1 (2 samples and a SiHa cell line) and 8q24 (1 sample and a HeLa cell line). To further explore the effect of HR-HPV integration in the 3p14.2 locus, we used fluorescence in situ hybridization (FISH) to determine the copy number of the 3p14.2 locus and immunohistochemistry (IHC) to determine the protein expression levels of the related FHIT gene in the clinical samples. Both the 3p14.2 locus copy number and FHIT protein expression levels showed significant decreases when CIN transitioned to cervical cancer. HPV copy number was also evaluated in these clinical samples, and the copy number of HPV increased significantly between CIN and cervical cancer samples. Finally, we employed receiver operating characteristic curve (ROC curve) analysis to evaluate the potential of all these indexes in distinguishing CIN and cervical cancer, and the HPV copy number, FHIT copy number and FHIT protein expression levels have good diagnostic efficiencies.

Planar cell polarity (PCP) signaling plays a critical role in tissue morphogenesis. In mammals, disruption of three of the six “core PCP” components results in polarity-dependent defects with rotated cochlear hair cell stereocilia and open neural tube. We recently demonstrated a role of Prickle1, a core PCP molecule in Drosophila, in mammalian neuronal development. To examine Prickle1 function along a broader developmental window, we generated three mutant alleles in mice. We show that the complete loss of Prickle1 leads to systemic tissue outgrowth defects, aberrant cell organization and disruption of polarity machinery. Curiously, Prickle1 mutants recapitulate the characteristic features of human Robinow syndrome and phenocopy mouse mutants with Wnt5a or Ror2 gene defects, prompting us to explore an association of Prickle1 with the Wnt pathway. We show that Prickle1 is a proteasomal target of Wnt5a signaling and that Dvl2, a target of Wnt5a signaling, is misregulated in Prickle1 mutants. Our studies implicate Prickle1 as a key component of the Wnt-signaling pathway and suggest that Prickle1 mediates some of the WNT5A-associated genetic defects in Robinow syndrome.

Gastric cancer is the second leading cause of cancer death worldwide. Here, we propose a novel type of tumor metastasis designated as Metastasis V in gastric cancer. Metastasis V is defined as the appearance of cancer cells in the mesogastrium with perigastric adipose tissue. To detect its incidence and characterize its clinic pathological features, large cross sectional tissue analysis of mesogastrium from 74 patients were used. Metastasis V was detected in 1 of 40 (2.5%) patients with early gastric cancer, 8 of 34 (24%) patients with advanced gastric cancer. The mean distance of Metastasis V from gastric wall was approximately 2.6 cm. Metastasis V was closely associated with tumor invasion depth, along with a number of positive lymph node metastasis. The prognosis of patients with Metastasis V was significantly (P

Previous epidemiologic studies have reported that a history of allergy is associated with reduced risk of colorectal cancer and other malignancies. However, no information is available for the association between allergy and the risk of lymph node metastasis. Our study was designed to determine this association in rectal cancer.Patients who were treated at our hospital in the period from January 2003 to June 2011, and with a pathologically hospital discharge diagnosis of rectal adencarcinoma, were included. The clinical, laboratory, and pathologic parameters were analyzed. A multivariate logistic regression model was used to determine the association. Moreover, for type of allergic drug, sub-group analysis was performed.469 patients were included, including 231 with pathological lymph node metastasis (pLNM) (49.3%) and 238 without pLNM. Univariate analysis showed, compared with patients without pLNM, patients with pLNM had a younger age (60.6 ± 12.8 yr vs. 63.6 ± 12.2 yr, P = 0.012), a lower percentage of drug allergy (8.7% vs. 16.0%, P = 0.016), an increased CEA (median/interquartile-range 5.40/2.40-13.95 vs. 3.50/2.08-8.67, P = 0.009), and a lower serum sodium (141 ± 3.1 mmol/L vs. 142 ± 2.9 mmol/L, P = 0.028). Multivariate analysis showed that drug allergy was associated with a reduced risk of pLNM (OR = 0.553; 95% CI, 0.308-0.994; P = 0.048). In addition, our results showed that: (1) for tumor classification, patients with drug allergy had a higher percentage of group patients with pT1/pT2; and (2) for type of allergic drug, this inverse association was found for penicillins, not for other allergic drugs.Drug allergy is associated with a reduced risk of pLNM in rectal cancer.