An improvement on the electrocatalytic performance of ZIF-67 byin situself-growing CNTs on surface.

Efficient and robust oxygen reduction reaction (ORR) catalysts are essential for the development of high-performance anion-exchange membrane fuel cells (AEMFC). To enhance the electrochemical performance of metal-organic frameworks of cobalt-based zeolite imidazolium skeleton (ZIF-67), this study reported a novel ZIF-67-4@CNT byin situgrowing carbon nanotubes (CNTs) on the surface of ZIF-67 via a mild two-step pyrolysis/oxidation treatment. The electrochemical results showed that the as-prepared ZIF-67-4@CNT after CTAB modification exhibited excellent catalytic activity with good stability, with Eonset, E1/2, and Ilimit, respectively were 0.98 V (versus RHE), 0.87 V (versus RHE) and 6.04 mA cm-2@1600 rpm, and a current retention rate of about 94.21% after polarized at 0.80 V for 10 000 s, which were all superior to that of the commercial 20 wt% Pt/C. The excellent ORR catalytic performance was mainly attributed to the large amount of thein situgrowing CNTs on the surface, encapsulated with a wide range of valence states of metallic cobalt.

Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling.

Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy-proved rejection, which confirmed the involvement of complement in IRI. Using FB-, C3-, C4-, C5-, C5aR1-, C5aR2-, and C6-deficient mice, we found that all components, except C5aR2 deficiency, significantly alleviated renal IRI to varying degrees. These gene deficiencies reduced local (deposition of C3d and membrane attack complex) and systemic (serum levels of C3a and C5a) complement activation, attenuated pathological damage, suppressed apoptosis, and restored the levels of multiple local cytokines (e.g., reduced IL-1ß, IL-9, and IL-12p40 and increased IL-4, IL-5, IL-10, and IL-13) in various gene-deficient mice, which resulted in the eventual recovery of renal function. In addition, we demonstrated that CRIg/FH, which is a targeted complement inhibitor for the classical and primarily alternative pathways, exerted a robust renoprotective effect that was comparable to gene deficiency using similar mechanisms. Further, we revealed that PI3K/AKT activation, predominantly in glomeruli that was remarkably inhibited by IRI, played an essential role in the CRIg/FH renoprotective effect. The specific PI3K antagonist duvelisib almost completely abrogated AKT phosphorylation, thus abolishing the renoprotective role of CRIg/FH. Our findings suggested that complement activation at multiple stages induced renal IRI, and CRIg/FH and/or PI3K/AKT agonists may hold the potential in ameliorating renal IRI.

HER2 assessment in locally advanced gastric cancer: comparing the results obtained with the use of two primary tumour blocks versus those obtained with the use of all primary tumour blocks.

AIMS: HER2 is currently the only biomarker used to select eligible patients with advanced gastric cancer (GC) for targeted therapy. The aims of this study were to verify the value of dual-block HER2 assessment and to explore whether increasing the block number is more beneficial by carrying out a randomized prospective cohort study in which dual-block and all-block HER2 assessment were compared in resected specimens of GC. METHODS AND RESULTS: Five hundred and forty-nine resected GC specimens were randomly enrolled into two cohorts: a dual-block group (n = 274) with two primary tumour blocks tested, and an all-block group (n = 275) with all primary tumour blocks tested. Immunohistochemical staining of HER2 was performed. For HER2-equivocal (2+) cases, fluorescence in-situ hybridization (FISH) was performed. As compared with single-block assessment, dual-block assessment increased the HER2 immunohistochemistry (IHC)-positive (3+) rate. The rate with dual-block assessment (11.3%) was significantly higher than that with block 1 assessment (8.8%) (P = 0.016) and block 2 assessment (9.1%) (P = 0.031). Similarly, all-block assessment demonstrated a higher HER2 3+ rate (12.4%) than single-block assessment (block 1, 6.5%; block 2, 6.2%; block 3, 7.2%; block 4, 8.7%) (P < 0.05). HER2 3+ rates of all-block and dual-block assessments showed no significant difference (P = 0.703). After IHC and FISH results had been combined, the HER2-positive rate with all-block assessment (13.5%) was slightly higher than that with dual-block assessment (12.0%), although the difference was not statistically significant (P = 0.62). CONCLUSIONS: Dual-block immunohistochemical assessment is an effective, practical and economic approach that is suitable for the preliminary screening of HER2. We recommend that dual-block HER2 assessment be routinely performed on resected specimens of GC. All-block assessment can be a supplement to dual-block assessment if necessary.

Complement and complement regulatory proteins are upregulated in lungs of COVID-19 patients.

We explored the pathological changes and the activation of local complement system in COVID-19 pneumonia. Lung paraffin sections of COVID-19 infected patients were analyzed by HE (hematoxylin-eosin) staining. The deposition of complement C3, the deposition of C3b/iC3b/C3d and C5b-9, and the expression of complement regulatory proteins, CD59, CD46 and CD55 were detected by immunohistochemistry. In COVID-19 patients' lung tissues, fibrin exudation, mixed with erythrocyte, alveolar macrophage and shed pneumocyte are usually observed in the alveoli. The formation of an "alveolar emboli" structure may contribute to thrombosis and consolidation in lung tissue. In addition, we also found that compared to normal tissue, the lung tissues of COVID-19 patients displayed the hyper-activation of complement that is represented by extensive deposition of C3, C3b/iC3b/C3d and C5b-9, and the increased expression level of complement regulatory proteins CD55, and especially CD59 but not CD46. The thrombosis and consolidation in lung tissues may contribute to the pathogenesis of COVID-19. The increased expression of CD55 and CD59 may reflect a feedback of self-protection on the complement hyper-activation. Further, the increased C3 deposition and the strongly activated complement system in lung tissues may suggest the rationale of complement-targeted therapeutics in conquering COVID-19.

Spatial and temporal regeneration patterns within gaps in the primary forests vs. secondary forests of Northeast China.

Forest gaps play an important role during forest succession in temperate forest ecosystems. However, the differences in spatial distribution and replacement patterns of woody plants (trees and shrubs) between primary and secondary forests remain unclear during the gap-filling processes, especially for temperate forests in Northeast China. We recorded 45,619 regenerated trees and shrubs in young gaps (<10 years), old gaps (10~20 years), and closed forest stands (i.e., filled gaps) in the primary broadleaved Korean pine (Pinus koraiensis Sieb. Rt Zucc.) forests vs. secondary forests (degraded from primary forests). The gap-filling processes along horizontal (Cartesian coordinate system) and vertical (lower layer: 0~5 m, medium layer: 5~10 m, and upper layer: >10 m) dimensions were quantified by shade tolerance groups of trees and shrubs. We found that gap age, competition between species, and pre-existing regeneration status resulted in different species replacement patterns within gaps in primary vs. secondary forests. Gap formation in both primary and secondary forests increased species richness, with 33, 38, 39, and 41 in the primary closed stands, primary forest gaps, secondary closed stands, and secondary forest gaps, respectively. However, only 35.9% of species in primary forest gaps and 34.1% in secondary forest gaps successfully reached the upper layer. Based on the importance values (IVs) of tree species across different canopy heights, light-demanding trees in the upper layer of the secondary forests were gradually replaced by intermediate and shade-tolerant trees. In the primary forests, Korean pine exhibited intermittent growth patterns at different canopy heights, while it had continuous regeneration along vertical height gradients in the secondary forests. The differences in Korean pine regeneration between the primary and secondary forests existed before gap formation and continued during the gap-filling processes. The interspecific competition among different tree species gradually decreased with increasing vertical height, and compared to the primary forests, the secondary forests showed an earlier occurrence of competition exclusion within gaps. Our findings revealed the species replacement patterns within gaps and provided a further understanding of the competition dynamics among tree species during the gap-filling processes.

The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model.

Pulmonary arterial hypertension (PAH) is suspected to be a strong mortality determinant of hemolytic disorders. However, direct contribution of acute intravascular hemolysis to fatal PAH has not been investigated. The roles of nitric oxide (NO) insufficiency and platelet activation in hemolysis-associated fatal PAH have been suspected but not been experimentally studied. We recently generated a unique intravascular hemolysis mouse model in which the membrane toxin, intermedilysin (ILY), exclusively lyses the erythrocytes of transgenically expressing human CD59 mice (ThCD59(RBC)), thereby inducing ILY-dose-dependent massive hemolysis. Using this murine hemolysis model, we found that the acute increase in pulmonary arterial pressure leading to right ventricle failure caused sudden death. Reduced NO bioavailability and massive platelet activation/aggregation leading to the formation of massive thrombosis specifically in the pulmonary microvasculature played the critical roles in pathogenesis of acute hemolysis-associated fatal PAH. Therapeutic interventions enhancing NO bioactivity or inhibiting platelet activation prevented sudden death or prolonged survival time via the suppression of the acute increase in pulmonary arterial pressure and improvement of right ventricle function. These findings further highlight the importance of the inhibition of platelet activation and the enhancement of NO bioavailability for the treatment and prevention of hemolysis-associated (fatal) PAH.

Vascular endothelial growth factor receptor 2 (VEGFR2, Flk-1/KDR) protects HEK293 cells against CoCl(2) -induced hypoxic toxicity.

Vascular endothelial growth factor (VEGF) is an endothelium-specific mitogen and a promising inducer of angiogenesis and lymphangiogenesis. The VEGF receptors on endothelial cell membrane include the tyrosine kinases VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR) and VEGFR-3 (Flt-4). KDR is a major mediator of mitogenic, angiogenic and permeability-enhancing effects of VEGF. KDR is upregulated in response to hypoxia, a major inducer of VEGF gene transcription. A HEK293 cell line overexpressing KDR was established under cell hypoxic stress to explore the function of KDR. A hypoxia-inducing agent, cobalt chloride (CoCl(2)) was applied to detect whether KDR was able to prevent against chemical hypoxic toxicity. The results indicate that KDR attenuated CoCl(2)-induced cell injury in HEK293 cells. Furthermore, the underlying mechanisms may be explained by the increased expression of Bcl-2, AKT1 and phosphorylated AKT, key members of cell survival pathway, and decreased expression of pro-apoptosis protein Bax.

Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis.

BACKGROUND: Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin's lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression. METHODS: Immunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The in vitro and in vivo experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH. RESULTS: We demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues. CONCLUSIONS: Our findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy.

SOX2 amplification and chromosome 3 gain significantly impact prognosis in esophageal squamous cell carcinoma.

BACKGROUND: We aimed to investigate the prevalence and prognostic role of Sex determining region Y-box 2 (SOX2) amplification and expression in surgically resected esophageal squamous cell carcinoma (ESCC). METHODS: We evaluated 450 ESCC samples using fluorescence in-situ hybridization and immunohistochemistry for SOX2 gene amplification and protein expression, respectively. The relationships of gene status with various clinicopathological characteristics and patient survival were statistically analyzed. RESULTS: SOX2 amplifications and chromosome 3 gain were observed in 4.4% and 12.9% of patients with ESCC. SOX2 amplification was associated with later clinical stage, and chromosome 3 gain was associated with earlier clinical stage (P=0.025). Low and high SOX2 expression were found in 28.9% and 24.7% of cases, respectively. SOX2 expression was significantly associated with gene copy number variation (P=0.007). SOX2 amplification was associated with a significantly shorter disease-free survival (DFS) or overall survival (OS). However, chromosome 3 gain was associated with a significantly longer DFS or OS (P<0.001). Multivariate analysis using the Cox proportional hazard model indicated that SOX2 amplification was an independently poorer prognostic factor (DFS, P<0.001, HR 2.638, 95% CI, 1.581-4.403; OS, P<0.001, HR 2.608, 95% CI, 1.562-4.355), along with pathology tumor-node-metastasis (pTNM) stage, whereas chromosome 3 gain was an independently better prognostic factor (DFS, P=0.003, HR 0.486, 95% CI, 0.300-0.789; OS, P=0.003, HR 0.474, 95% CI, 0.289-0.779) for ESCC. CONCLUSIONS: This is the first study wherein SOX2 amplification and chromosome 3 gain in a large cohort of ESCC were evaluated. SOX2 amplification is an independently poorer prognostic factor, whereas chromosome 3 gain is an independently favorable prognostic factor. Our results suggest that SOX2 amplification and chromosome 3 gain are potential biomarkers related to tumor progression and risk stratification in ESCC.

PI3K/AKT inhibition reverses R-CHOP resistance by destabilizing SOX2 in diffuse large B cell lymphoma.

Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen, while the remaining therapeutic options are limited. Thus, understanding the underlying mechanisms and developing therapeutic approaches are urgently needed. Methods: We generated two germinal center B cell-like (GCB) and activated B cell-like (ABC) subtype R-CHO resistant DLBCL cell lines, of which the tumor-initiating capacity was evaluated by serial-transplantation and stemness-associated features including CD34 and CD133 expression, side population and ALDH1 activity were detected by flow cytometry or immunoblotting. Expression profiles of these resistant cells were characterized by RNA sequencing. The susceptibility of resistant cells to different treatments was evaluated by in vitro CytoTox-glo assay and in tumor-bearing mice. The expression levels of SOX2, phos-AKT, CDK6 and FGFR1/2 were detected in 12 R-CHOP-resistant DLBCL clinical specimens by IHC. Results: The stem-like CSC proportion significantly increased in both resistant DLBCL subtypes. SOX2 expression level remarkably elevated in both resistant cell lines due to its phosphorylation by activated PI3K/AKT signaling, thus preventing ubiquitin-mediated degradation. Further, multiple factors, including BCR, integrins, chemokines and FGFR1/2 signaling, regulated PI3K/AKT activation. CDK6 in GCB subtype and FGFR1/2 in ABC subtype were SOX2 targets, whose inhibition potently re-sensitized resistant cells to R-CHOP treatment. More importantly, addition of PI3K inhibitor to R-CHOP completely suppressed the tumor growth of R-CHO-resistant DLBCL cells, most likely by converting CSCs to chemo-sensitive differentiated cells. Conclusions: The PI3K/AKT/SOX2 axis plays a critical role in R-CHOP resistance development and the pro-differentiation therapy against CSCs proposed in this study warrants further study in clinical trials for the treatment of resistant DLBCL.

Late stage gastric cancer patients with extra gained HER2 positivity by dual block assessment may not show compromised efficacy to trastuzumab treatment.

Dual block HER2 assessment can effectively increase the HER2 positive rate in resected specimens of gastric cancer (GC). The aim of this study is to explore whether GC patients with extra gained HER2 positivity by dual block assessment can benefit from trastuzumab therapy. Twenty-eight GC patients receiving gastrectomy prior to trastuzumab treatment were retrospectively analyzed. All the cases routinely accepted dual block HER2 assessment. The cases were divided into 2 cohorts based on HER2 status: cohort A with concordant HER2 results and cohort B with discordant HER2 results between the two blocks (cases with extra gained HER2 positivity). Response rate (RR), progress free survival (PFS) and overall survival (OS) were compared between the two cohorts. The results showed that no significant differences were found between the two cohorts in main clinicopathologic characteristics. No statistical difference was found in response rate (47.6% vs 57.1%) (P=1.0), either. The two cohorts did not demonstrate statistical differences in the PFS (10.5 months (95%CI 6.4-14.6) vs 8.0 months (95%CI 3.2-12.8), P=0.686) and the OS (23.3 months (95%CI 12.1-34.5) vs 20.0 months (95%CI 10.1-29.9), P=0.776). In conclusion, our study suggests that patients with extra gained HER2 positivity may not show compromised efficacy to trastuzumab treatment.

Immunostaining by dual tumor tissue paraffin blocks increases the sensitivity of c-Met detection in gastric cancer.

BACKGROUND: Gastric cancer (GC) is the second most frequent cause of cancer deaths worldwide. c-Met, a receptor tyrosine kinase, transduces signals from extracellular growth factors. c-Met-targeted therapeutics hold a great potential in treating gastric and related cancers, and a precise evaluation of c-Met expression is a prerequisite for subsequent treatment. METHODS: We compared the sensitivity between one and two paraffin blocks in evaluating c-Met expression in GC subjects by immunohistochemistry (IHC). A total of 365 GC patients were divided into cohort 1 (n = 206) for the one tumor tissue paraffin block test and cohort 2 (n = 159) for the dual tumor tissue paraffin block test. In the dual blocks group, we investigated the results from two different paraffin blocks, then we used the higher one as the final score. RESULTS: Inconsistent c-Met expression in the dual paraffin blocks group occurred in 29 (18.2%) cases. The pooled data in cohort 1 and cohort 2 indicate that when using results from dual paraffin blocks, the c-Met positive (3+) rate of GC testing could be promoted. CONCLUSION: In GC, using dual tumor tissue paraffin blocks instead of one tumor tissue paraffin block is an efficient, economical and practical method of minimizing the false-negative rate of c-Met status assessment by IHC.

A case report of nodal CD4-positive T-cell lymphoproliferative disorder with an indolent course.

RATIONALE: Primary nodal CD4-positive T-cell lymophoproliferative disorder with a relatively indolent process is a rare kind of lymphoproliferative disease. Here we report the first case of a 49 year-old man developed indolent nodal CD4-positive T-cell lymophoproliferative disorder. To our knowledge, based on a careful search of PubMed, it is the first case of primary nodal CD4-positive T-cell lymophoproliferative disorder. PATIENT CONCERNS: A 49-year-old Chinese man presented to our hospital with fever, enlargement of multiple superficial lymphonodes more than 14 years and splenomegaly. Clinical and pathological data were collected under treatment. This case was diagnosed based on histologically characteristic, immunohistochemical staining, and lymphoid clonality testing. On immunohistochemical staining, the abnormal T-cells were CD4 positive and CD8 negative. The lymphoid clonality testing showed positive results. The patient also has enlarged spleen. DIAGNOSES: The patient was diagnosed with nodal CD4-positive T-cell lymophoproliferative disorder. INTERVENTIONS: A watch-and-wait stratagem was performed without any chemotherapy or radiation therapy. OUTCOMES: During 17 years of follow-up, this case presented an indolent course without evidence of systemic dissemination. LESSONS: This report presents the first case of indolent nodal CD4-positive T-cell lymophoproliferative disorder. In this case, the proliferated T-cell in the paracortex of lymph node showed T-cell receptor gene rearrangement, which indicated a clonal proliferation. There are several kinds of nodal CD4-positive T-cell lymphoma, which have a relatively aggressive course; however, this case has a relatively indolent course.

Midostaurin potentiates rituximab antitumor activity in Burkitt's lymphoma by inducing apoptosis.

An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt's lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells. The PI3K/AKT inhibitor IPI-145 failed to reverse the resistance. In contrast, the pan-PKC inhibitor midostaurin exhibited potent antitumor activity in both original and resistant cells, alone or in combination with rituximab. Notably, midostaurin promoted apoptosis by reducing the phosphorylation of PKC and consequently of downstream Bad, Bcl-2 and NF-κB. Therefore, midostaurin improved rituximab activity by supplementing pro-apoptotic effects. In vivo, midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments. Addition of midostaurin to rituximab led to dramatically improved survival compared to rituximab but not midostaurin monotherapy. Our findings call for further evaluation of midostaurin alone or in combination with rituximab in treating resistant BL in particular.

Complement activation in the arteries of patients with severe atherosclerosis.

BACKGROUND: Excessive complement activation plays an important role in the pathogenesis of atherosclerosis (AS). We therefore wanted to investigate whether complement is activated in areas of AS by detecting the deposition of C3b/iC3b and membrane attack complex (MAC). We also analyzed the relationships between C3b/iC3b and MAC levels and the clinicopathological features of patients with AS. METHODS: The sample comprised 79 patients who had been diagnosed with AS. Their levels of C3b/iC3b and MAC deposition were evaluated by immunohistochemistry (IHC). The results were translated into scores, and the patients' clinical features were recorded. RESULTS: Compared with normal arteries, significantly greater deposits of C3b/iC3b and MAC were found in AS arteries. In the group with more C3b/iC3b deposition, the ratio of patients with hypertension was higher. Moreover, in the group with more MAC deposition, the ratio of patients with hypertriglyceridemia was higher. CONCLUSIONS: The finding of C3b/iC3b and MAC deposition in atherosclerotic arteries points to the activation of complement. Greater amounts of C3b/iC3b and MAC deposition imply excessive complement activation, which can lead to the development of AS. Hypertension and hypertriglyceridemia may, respectively, contribute to the activation of complement C3 or the formation of MAC.

Deficiency of the complement regulatory protein CD59 accelerates the development of diabetes-induced atherosclerosis in mice.

AIMS: Clinical and experimental evidence supports a strong link between the complement system, complement regulatory proteins and the pathogenesis of diabetes vascular complications. We previously reported that the complement regulatory protein CD59 is inactivated by glycation in humans with diabetes. Our objective for this study is to assess experimentally how the deficiency of CD59 impacts the development of diabetic atherosclerosis in vivo. METHODS: We crossed mCD59 sufficient and deficient mice into the ApoE-/- background to generate mCd59ab+/+/ApoE-/- and mCd59ab-/-/ApoE-/- mice, and induced diabetes by multiple low dose injections of streptozotocin. Atherosclerosis was detected by hematoxylin and eosin (H&E) and oil red-O staining. Membrane attack complex (MAC) deposition and macrophage infiltration were detected by immunostaining. RESULTS: Diabetic mCD59 deficient (mCD59ab-/-/ApoE-/-) mice developed nearly 100% larger atherosclerotic lesion areas in the aorta (7.5%±0.6 vs 3.6%±0.7; p<0.005) and in the aortic roots (H&E: 26.2%±1.9 vs. 14.3%±1.1; p<0.005), in both cases associated with increased lipid (Oil red-O: 14.9%±1.1 vs. 7.8%±1.1; p<0.05) and MAC deposition (6.8%±0.8 vs. 3.0%±0.7; p<0.005) and macrophage infiltration (31.5%±3.7 vs. 16.4%±3.0; p<0.05) in the aortic roots as compared to their diabetic mCD59 sufficient (mCD59ab+/+/ApoE-/-) counterpart. CONCLUSIONS: The deficiency of CD59 accelerates the development of diabetic atherosclerosis.

Tumor containing fragment number influences immunohistochemistry positive rate of HER2 in biopsy specimens of gastric cancer.

BACKGROUND: HER2 assessment in biopsy specimens of gastric cancer (GC) is challenging because of the intratumoral heterogeneity. False negative results may be get because of limited biopsy material. The aim of this study is to explore how tumor-containing fragment number and biopsy specimen number affect HER2 immunohistochemistry (IHC) positive rate. METHODS: Eight hundred and ninety biopsy specimens and 459 paired resected specimens were collected. IHC staining of HER2 was performed. HER2 IHC positive (scored 3+) rate was compared based on tumor-containing fragment number, biopsy specimen number, average size and tumor tissue proportion of tumor-containing fragments. The positive predictability of biopsy specimens to resected specimens was analyzed based on tumor fragment number. RESULTS: HER2 IHC positive rates were 2.0, 3.5, 7.0, 13.2, 17.1, and 15.9% when tumor fragment numbers were 1, 2, 3, 4, 5 and 6 respectively. The rate rose with the increase of tumor fragment number (P = 0.004). ROC curve analysis showed that biopsy specimens exhibited positive predictability when tumor fragment number reached 3, but showed better performance when the number was ≥4 (P < 0.05). After fragment number reached 4, no statistic differences were reached in either HER2 IHC positive rate or positive predictability with further increase of the number (P > 0.05). HER2 IHC positive rate was not associated with biopsy number (P = 0.127), average size of tumor fragments (P = 0.397), and tumor tissue proportion of tumor fragments (P = 0.825) directly. CONCLUSIONS: The number of tumor-containing fragments influences HER2 IHC positive (scored 3+) rate. Greater than or equal to 4 (≥4) tumor fragments give better results in the positive rate as well as positive predictability. We recommend the number of tumor containing fragments be described in the HER2 IHC pathology reports for clinical reference in endoscopic biopsy specimens of GC.

Poor efficacy response to trastuzumab therapy in advanced gastric cancer with homogeneous HER2 positive and non-intestinal type.

INTRODUCTION: Factors affecting trastuzumab efficacy in advanced gastric cancer (GC) are largely unknown. Heterogeneity is a notable feature of HER2 in GC. Whether the heterogeneity influences trastuzumab efficacy is still unknown. RESULTS: The HER2homogeneous group and HER2heterogeneous group showed no statistical difference in RR (46.4% vs 55.0%, P = 0.558), PFS (5.80 vs 6.30 months, P = 0.804) and OS (16.00 vs 16.00 months, P = 0.787). The Laurenintestinal group and Laurennon-intestinal group demonstrated no discrepancy in PFS (6.00 vs 6.00 months, P = 0.912) and OS (16.50 vs 14.00 months, P = 0.227). However, by combining HER2 heterogeneity and Lauren classification, PFS and OS of HER2homogeneous/Laurennon-intestinal subgroup was the shortest among the 4 subgroups (P = 0.012 and P = 0.037), which was much shorter than the other patients (PFS:3.00 vs 6.30 months, P = 0.003; OS: 4.50 vs 16.50 months, P = 0.004). Univariate and multivariate analysis showed that HER2 heterogeneity combined with Lauren classification was an independent prognostic factor in both PFS (P = 0.031 and P = 0.002) and OS (P = 0.039 and P = 0.013). MATERIALS AND METHODS: 48 patients with HER2 positive advanced GCs accepting trastuzumab treatment were retrospectively analyzed. Based on HER2 heterogeneity, the patients were divided into a HER2homogeneous group and a HER2heterogeneous group. Response rate (RR), progression free survival (PFS), and overall survival (OS) were compared. Main clinicopathological factors including Lauren classification were subjected to subgroup analysis. CONCLUSIONS: HER2 heterogeneity alone may not correlate with trastuzumab efficacy in HER2 positive advanced GCs. HER2 heterogeneity combined with Lauren classification may help to identify a subgroup with poor response to trastuzumabx which is homogeneous HER2 positive and non-intestinal type.

[Tree uprooting of coniferous-broad leaved Korean pine mixed forest in Lesser Khingan Mountains, China].

The morphological parameters, root wad indexes and site conditions of 127 uprooting trees from 76 plots (20 mx20 m) in Lesser Khingan coniferous-broad leaved Korean pine mixed forest were measured. Then the influencing factors of uprooting differences and the relationship between uprooting trees and disturbed soil were analyzed. Results showed that the number of uprooting trees varied significantly among species. Abies nephrolepis suffered the most serious uprooting damage, then Pinus koraiensis, and Ulmus spp. the least. Deciduous species had a stronger uprooting-resistant capacity than broad-leaved species. With the increase of tree DBH and height, tree' s uprooting resistance declined rapidly first and then was gradually enhanced, and finally reached the minimum at diameter class of 20 cm and height class of 14 m, respectively. The smaller the taper degree and projected area of crown were, the stronger the uprooting resistance was. Uprooting rate was negatively correlated with stand density. Trees lying in wet ground, flat terrain, medium low altitude area and windward slope had a greater risk of uprooting. There were significant positive correlation between the depth, area and volume of disturbed soil and the DBH, height, volume of uprooting trees.