[The influence of lung metastasis on prognosis of previously untreated gestational trophoblastic neoplasia patients].

Objective: To investigate the impact of lung metastases on the prognosis of patients with gestational trophoblastic neoplasia (GTN). Methods: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage Ⅰ-Ⅲ GTN receiving primary chemotherapy in Peking Union Medical College Hospital between July 2014 and December 2018 were retrospectively analyzed and divided into group 1 with lung metastasis and group 2 without lung metastasis. The baseline characteristics and treatment outcomes of the two groups were compared. The optimal cut-off values of the diameter of largest lung nodule associated with recurrence were identified by receiver operating characteristic (ROC) curves. Logistic regression analyses were performed to identify risk factors for prognosis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Results: Of the 381 GTN patients enrolled (216 with lung metastases and 165 without lung metastases), the pretreatment ß human chorionic gonadotrophin [median: 12 572 IU/L (1 832-51 594 IU/L) vs. 5 614 IU/L (559-26 140 IU/L), P=0.001] and FIGO score [median: 3 (1-6) vs. 2 (1-4), P=0.038] were significantly higher in patients with lung metastases than those without lung metastases. In patients with FIGO score≥5, the emergence of resistance (26.76% vs. 10.26%, P=0.036) and median number of chemotherapy courses to achieve complete remission [6 (6-8) vs. 5 (4-6), P<0.001] were significantly higher than patients with lung metastases. In patients with FIGO score 0-4, no significant difference was found in the treatment outcomes between the two groups(P=0.833). Among all patients with lung metastases, the ROC curve showed a sensitivity and specificity of 62.5% and 78.8%, respectively, for predicting recurrence when the length of the largest lung nodule was 1.6 cm, with an area under the curve (AUC) of 0.711 (95% CI: 0.550, 0.871, P=0.044). Multivariate logistic regression analysis suggested a significantly higher recurrence rate when the largest lung nodule was ≥1.6 cm (OR=7.394, 95% CI: 1.003, 54.520, P=0.049). The 1-year disease-free survival rate was significantly lower in patients with the largest lung nodule ≥1.6 cm than in patients with the nodule <1.6 cm (98.2% vs. 82.4%, P=0.001). Conclusions: Lung metastasis is associated with increased first-line chemotherapy resistance in patients with FIGO scores≥5. The diameter of the largest lung metastatic nodule ≥1.6 cm is an effective factor for predicting recurrence.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials. Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS. Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022. Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy. Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria. Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50). Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

The impact of bone mineral density screening on incident fractures and healthcare resource utilization among postmenopausal breast cancer survivors treated with aromatase inhibitors.

Bone mineral density screening prior to initiating aromatase inhibitor therapy was associated with lower incident bone fractures and healthcare resource utilization among postmenopausal breast cancer survivors. INTRODUCTION: Postmenopausal women with hormone receptor-positive breast cancer (BC) often receive aromatase inhibitor (AI) therapy. However, AIs induce bone loss and BC survivors are at an increased risk of bone fractures. This study determined whether receipt of baseline dual-energy x-ray absorptiometry (DXA) screening is associated with decreased incident fractures and lower healthcare resource utilization. METHODS: We retrospectively analyzed 22,713 stage 0-III primary BC survivors who received AI therapy ≤ 1 year prior to BC diagnosis from the Medicare-Linked Surveillance, Epidemiology, and End-Results database. We categorized DXA screening for those who had a procedural claim within 12 months prior through 6 months after first AI claim. We used propensity score methods to assess the association of DXA screening with bone fractures and health resource utilization. RESULTS: Of the study cohort, 62% received a DXA screening. Women with comorbid dementia, renal disease, and congestive heart failure were less likely to receive a DXA. After adjusting for confounders, BC survivors who received a DXA had a 32% decreased risk of any bone fracture compared to those who did not (hazard ratio (HR): 0.68, 95% confidence interval (CI): 0.60-0.76, p < 0.001). Similarly, those who received a DXA were less likely to be hospitalized (HR 0.73 (0.62-0.86)) or use outpatient services (HR 0.85 (0.74-0.97)). CONCLUSIONS: Bone density screening is associated with decreased incident bone fractures and a lower likelihood of utilizing healthcare resource for fracture-related events. Postmenopausal BC survivors treated with AIs should undergo appropriate bone density screening to reduce morbidity, mortality, and health care expenses.

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study.

BACKGROUND: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor. PATIENTS AND METHODS: Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy. RESULTS: Eleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual. CONCLUSIONS: Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

PAG1 stimulates proliferation and metastasis of nasopharyngeal carcinoma through downregulating PTEN.

OBJECTIVE: We aim to uncover the expression pattern and biological functions of PAG1 in the progression of nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: PAG1 levels in 28 paired NPC tissues and paracancerous tissues were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Then, the potential influences of PAG1 on proliferative, migratory and invasive abilities of SUNE2 and CNE2 cells were assessed by cell counting kit-8 (CCK-8) and transwell assay, respectively. Next, the interaction between PAG1 and its direct target gene of phosphate and tension homology deleted on chromosome ten (PTEN) was verified by Dual-Luciferase reporter gene assay. At last, rescue experiments were conducted to uncover the role of PAG1/PTEN axis in the malignant progression of NPC. RESULTS: PAG1 was highly expressed in NPC tissues and cell lines. Knockdown of PAG1 blocked NPC cells to proliferate, migrate, and invade. Dual-Luciferase reporter gene assay indicated the binding relationship between PAG1 and PTEN. In addition, both mRNA and protein levels of PTEN were negatively regulated by PAG1 in NPC cells. Notably, PTEN was responsible for PAG1-regulated malignant progression of NPC. CONCLUSIONS: PAG1 is upregulated in NPC tissues and cells and stimulates the proliferative and metastatic abilities in NPC by targeting PTEN, thus aggravating the malignant progression of NPC.

A study on protective effect of morphine against myocardial ischemia-reperfusion injury in rats via CAMP/PKA signaling pathway.

The purpose of this study was to explore the mitigating effect of morphine on the myocardial ischemia-reperfusion injury (MIRI) in rats through the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. A total of 30 male Wistar rats were assigned into sham group, MIRI group and morphine group using a random number table. The model of MIRI was routinely established. Then, the pathological changes in the morphology of myocardial tissues were observed via hematoxylin-eosin (HE) staining. The levels of the oxidative stress indicators superoxide dismutase (SOD) and malondialdehyde (MDA), the content of the inflammatory cytokine tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß) and IL-6 and the quantity of glutathione peroxidase (GSH-Px), lactate dehydrogenase (LDH), creatine kinase (CK), CK-MB and cardiac troponin I (cTnI) in the myocardial enzyme spectrum were determined and analyzed through enzyme-linked immunosorbent assay (ELISA). Moreover, the messenger ribonucleic acid (mRNA) and protein expressions of cAMP, PKA, cAMP-response element binding protein (CREB) and phosphorylated CREB (p-CREB) in the cAMP/PKA signaling pathway in the myocardial tissues were measured using real-time polymerase chain reaction (PCR) and Western blotting, respectively. The results manifested that compared with those in MIRI group, the levels of myocardial infarct size, LDH, CK, CK-MB, cTnI, MDA, TNF-α, IL-1ß, IL-6 and p-CREB were decreased, while the levels of GSH-Px, SOD, PKA and CREB were increased in the morphine group. In conclusion, morphine may mitigate MIRI in rats through the cAMP/PKA signaling pathway.

LncRNA WTAPP1 promotes proliferation of laryngeal carcinoma cells through regulating microRNA-592.

OBJECTIVE: The aim of this work was to investigate the mechanism by which long non-coding RNA (lncRNA) WTAPP1 promotes the malignant progression of laryngeal cancer. PATIENTS AND METHODS: In this study, quantitative real-time polymerase chain reaction (qRT-PCR) examined the expression of lncRNA WTAPP1 in 49 pairs of tumor tissue specimens and paracancerous normal ones collected from laryngeal cancer patients. Subsequently, in the laryngeal squamous cell carcinoma cell lines AMC-HN-8 and Hep-2, WTAPP1 overexpression and knockdown vectors were constructed using lentivirus, and cell counting kit-8 (CCK-8), cell colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays were carried out to analyze the impact of lncRNA WTAPP1 on the function of laryngeal cancer cells. Finally, Luciferase reporting assay and recovery experiments were carried out to further explore whether lncRNA WTAPP1 has an impact on the malignant progression of laryngeal cancer via modulating microRNA-592. RESULTS: QRT-PCR results revealed a significantly higher expression of lncRNA WTAPP1 in tumor tissues of patients with laryngeal cancer than that in adjacent normal ones. Compared with patients with low expression of WTAPP1, those with higher expression had a more advanced pathological stage. Meanwhile, the proliferation ability of cells in sh-WTAPP1 group was remarkably attenuated when compared with that in sh-NC group. In addition, microRNA-592 and WTAPP1 mRNA levels were found negatively correlated in laryngeal carcinoma tissue specimens. Luciferase reporter gene assay indicated that WTAPP1 can be targeted by microRNA-592 through certain binding sites. Moreover, we demonstrated through some recovery experiments that WTAPP1 can indeed serve as an oncogene accelerating the malignant progression of laryngeal cancer through the modulation of microRNA-592. CONCLUSIONS: LncRNA WTAPP was markedly highly expressed both in laryngeal carcinoma tissues and cell lines, which was also found to be closely relevant to the pathological stage of laryngeal cancer patients. Additionally, lncRNA WTAPP1 is able to enhance the proliferation capacity of laryngeal carcinoma cells via regulating microRNA-592.

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.

BACKGROUND: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. PATIENTS AND METHODS: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH. RESULTS: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. CONCLUSIONS: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

[Study of thermal injury effects on human HaCaT cells under simulated microgravity environment].

Objective: To investigate the thermal injury effects on human HaCaT cells under simulated microgravity environment. Methods: The human HaCaT cells were collected and divided into simulated microgravity thermal injury (SMGTI) group, normal gravity thermal injury (NGTI) group, and normal gravity false injury (NGFI) group according to the random number table. Cells in NGTI and NGFI groups were cultured routinely in culture bottle, and cells in SMGTI group were cultured in the rotary cell culture system to simulate microgravity environment. Cells in SMGTI and NGTI groups were bathed in hot water of 45 ℃ for 10 minutes to make thermal injury model, and cells in NGFI group were bathed in warm water of 37 ℃ for 10 minutes to simulate thermal injury. At post injury hour (PIH) 12, cell morphology of 3 groups was observed under inverted phase contrast electron microscope. At PIH 2, 6, and 12, single cell suspension in the 3 groups was collected to detect the cell cycle by flow cytometer and the mRNA expressions of heat shock protein 70 (HSP70), matrix metalloproteinase 9 (MMP-9), and cysteine-aspartic protease 3 (caspase-3) by real time fluorescence quantitative reverse transcription polymerase chain reaction, and the experiments were repeated for 3 times. At PIH 2, 6, and 12, cell culture supernatant in the 3 groups was collected to detect the concentration of heparin-binding epidermal growth factor (HB-EGF) by enzyme linked immunosorbent assay method, the experiment was repeated for 3 times. The sample in each group and each time point was 3. Data were statistically analyzed with analysis of variance for factorial design, one-way analysis of variance, least significant difference test, Kruskal-Wallis H test, and Mann-Whitney U test. Results: (1) At PIH 12, cells in NGFI group showed regular shape and regular arrangement, with no cell debris. The cell shape in NGTI group was generally regular, with fewer cell debris and closer arrangement than that in NGFI group. The cells in SMGTI group showed more irregular shapes, different sizes, and dead cell debris. (2) The percentage of G1 phase cells in NGTI group was significantly higher than that in NGFI group and SMGTI group at PIH 2, respectively (P<0.05), and the percentage of G1 phase cells in NGTI group was significantly lower than that in NGFI group and SMGTI group at PIH 6 and 12, respectively (P<0.05). The percentage of G2/M phase cells in NGTI group was significantly lower than that in SMGTI group at PIH 2 (P<0.05), and the percentage of G2/M phase cells in NGTI group was significantly higher than that in NGFI group and SMGTI group at PIH 6 and 12, respectively (P<0.05). The percentage of S phase cells in NGTI group at PIH 2, 6, and 12 was significantly higher than that in SMGTI group (P<0.05), and the percentage of S phase cells in NGTI group at PIH 2 and 6 was significantly lower than that in NGFI group (P<0.05). (3) The HSP70 mRNA expressions of cells in NGTI group were 2.50±0.30 and 3.99±0.35 at PIH 2 and 6, which were significantly higher than 1.14±0.15 and 0.82±0.27 in NGFI group (P<0.05), and 1.17±0.53 and 1.65±0.59 in SMGTI group (P<0.05). The MMP-9 mRNA expression of cells in SMGTI group was significantly higher than that in NGTI group at PIH 2, 6, and 12, respectively (Z=-2.319, -2.882, -2.908, P<0.05). At each time point after injury, the mRNA expression of caspase-3 of cells in NGTI group was similar to that in NGFI group and SMGTI group, respectively (P>0.05). (4) The concentration of HB-EGF in cell culture supernatant of NGTI group was significantly lower than that in NGFI group at PIH 2, 6 and 12 (P<0.05), and the concentration of HB-EGF in cell culture supernatant of SMGTI group was significantly higher than that in NGTI group at PIH 2 and 6 (P<0.05). Conclusions: The proliferation and secretion functions and expression of wound repair related protein of human HaCaT cells inflicted with thermal injury in simulated microgravity environment showed complex and diversified changes, which provide theoretical basis for further research on damage repair under weightlessness.

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

This corrects the article DOI: 10.1038/onc.2017.8.

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

GATA binding protein 3 (GATA3) is indispensable in development of human organs. However, the role of GATA3 in cancers remains elusive. Hypoxia inducible factor (HIF)-1 plays an important role in pathogenesis of human cancers. Regulation of HIF-1α degradation is orchestrated through collaboration of its interacting proteins. In this study, we discover that GATA3 is upregulated in head and neck squamous cell carcinoma (HNSCC) and is an independent predictor for poor disease-free survival. GATA3 promotes invasive behaviours of HNSCC and melanoma cells in vitro and in immunodeficient mice. Mechanistically, GATA3 physically associates with HIF-1α under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1α, which is independent of HIF-1α prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1α complex binds to and regulates HIF-1 target genes, which is also supported by the microarray analysis. Notably, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown, suggesting a critical role of HIF-1α in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1α to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1α axis as a potential therapeutic target for cancer treatment.

[The correlation between CT score of lung injury and oxygenation index in patients with acute hydrogen sulphide poisoning].

Objective: To explore correlation between chest CT score and oxygenation index in patients with acute hydrogen sulphide poisoning, whether CT score can be applied to assess acute lung injury after acute hydrogen sulfide poisoning and provide basis and reference. Methods: The clinic and a series of CT datas of 32 acute hydrogen sulphide poisoning cases were retrospectively analysed and compared, According to GBZ31-2002 (the diagnostic standard of occupational H(2)S acute poisoning) , these patients were divided into 2 grouds including moderate groud and severe groud; The CT score were improved, referenceing the scoring criteria of the chest X-ray; The difference of the CT score and the oxygenation index were analyzed between moderate and severe group in the acute phase and the disperse phase; The correlation between CT score and oxygenation index were analyzed. Results: The CT score in moderate poisoning group were lower than severe group (2.26±1.37 vs 10.44±2.55, 1.34±0.65 vs 4.55±2.45, all P<0.05) in the acute phase and the dissipation phase.The oxygen index of the 19 cases in the acute phase were 307.55±28.29, and the oxygen index of the 8 cases in the dissipation phase was 435.75±37.00; The oxygen index of the 9 cases in the acute phase and the dissipation phase were respectively 193.17±36.41, 347.67±44.49. The oxygen partial pressure and oxygenation index in severe group were significantly lower than those in moderate group (all P<0.01) in the acute phase and the dissipation phase. Pearman correlation analysis showed that the CT score were negatively correlated to the oxygen index in the acute phase and the dissipation phase, respectively (r=-0.97、-0.75, all P<0.01) . Conclusions: The CT score of lung injury and oxygenation index is negatively correlated. The CT score can be used to evaluate the degree of lung injury, and can be used in the evaluation of acute lung injury after acute hydrogen sulfide poisoning.

Effects of autologous bone marrow mononuclear cells implantation on cholangiocytes apoptosis in model of intrahepatic ischemic type biliary lesion in rabbits.

AIM: To investigate the effects of autologous bone marrow mononuclear cells (BM-MNCs) implantation on regulation of cholangiocyte apoptosis in a model of intrahepatic ischemic type biliary lesion (ITBL) in rabbits. MATERIALS AND METHODS: Thirty Japanese white rabbits were divided randomly into 3 groups (10 per group) including controls (group A), ITBL model (group B), and BM-MNCs implantation groups (group C). All rabbits underwent the same surgical procedure to prepare the liver for graft removal during transplantation. Subsequently, no additional vascular intervention was performed in group A. In group B, the hepatic artery and common bile duct were clamped with microvascular clips for 2 hours, where after the clips were removed to recover the blood supply. Group C received, BM-MNCs (10(8) cells per rabbit) injected through the hepatic artery after removing the clips. The animals were killed 4 weeks after operation. The survival rate, histopathologic examination, cholangiocyte apoptosis with terminal uridine nick-end labeling (TUNEL) staining and expressions of Bcl-2 and Bax proteins were examined using immunohistochemical staining. RESULTS: Group A animals showed a survival of 100%; the rates in groups B and C were both 90%. Histopathologic examination revealed normal intrahepatic cholangiocytes in group A, obviously damaged ones in group B, and alleviated damage in group C. TUNEL staining indicated apoptosis of cholangiocytes in group B was more serious than that in group A or group C. Immunohistochemical staining demonstrated significantly decreased Bcl-2 expression in group B compared with that in group A; Bcl-2 expression in group C returned to the level of group A. Simultaneously, the Bax expression presented adverse results; the ratios of Bcl-2/Bax were ranked as group A > group C > group B. CONCLUSION: Implantation of autologous BM-MNCs significantly reduced apoptosis of intrahepatic cholangiocytes and prevented or abated intrahepatic ITBL.

Hand-assisted laparoscopic surgery versus the open approach in curative resection of rectal cancer.

This prospective, randomized study compared the outcomes of hand-assisted laparoscopic surgery (HALS) with open surgery for the resection of rectal cancer. The main outcome measures were procedure time, blood loss, post-operative pain, time to oral intake, return of bowel function, length of hospital stay, morbidity and functional recovery. Patients in each group were similar with regard to general status, procedure types and the histopathological features of tumours. Procedure times were significantly longer with HALS versus open surgery. Analgesic requirements, surgical blood loss, time to first passing flatus, time to first oral fluids and post-operative hospital stay length were all significantly shorter in the HALS group. At a median follow-up of 16.3 months, local recurrence of tumour was not observed in either group. In this study, the HALS approach for curative resection of rectal cancer was safe and effective and may offer several potential advantages to patients in their post-operative recovery.

Expression and distribution of S-100 protein, CD83 and apoptosis-related proteins (Fas, FasL and Bcl-2) in thyroid tissues of autoimmune thyroid diseases.

Previous studies have shown that dendritic cells (DCs) and apoptosis-related proteins play a critical role in the pathogenesis of autoimmune thyroid diseases (ATD). This study was designed to investigate the expression and distribution of S-100 protein, CD83 and apoptosis-related proteins (Fas, FasL and Bcl-2) in the thyroid tissues of ATD and their role in ATD pathogenesis as determined by immunochemical staing techniques and other methods. Pathological tissues of 30 patients with Hashimoto's thyroiditis (HT), 30 patients with Graves' disease (GD) and 30 cases of thyroid follicular adenoma (TFA, as control) were used for this study. A higher expression of S-100 in HT (4.2+/-3.1%) and GD (3.9+/-2.8%) vs TFA (0.95+/-0.64%) (p<0.001). was observed as well as a higher expression of CD83 in HT (22.58+/-13.96% and GD (29.92+/-14.43%) vs TFA (5.19+/-8.08%) (p<0.001). HT thyrocytes adjacent to thyroid infiltrating lymphocytes (TILs) showed greater increases in the levels of Fas and FasL than did the GD thyrocytes while HT TILs exhibited lower expression of Fas and FasL than did the GD TILs. GD thyrocytes expressed increased levels of the antiapoptotic protein Bcl-2 as compared to the low levels detected in HT thyrocytes. An opposite pattern was observed in the TILs in GD (low expression of Bcl-2) and HT (high expression of Bcl-2). The findings suggest that the high expression of DC markers is related to the pathogenesis of HT and GD. Up-regulation of both the number and matured functions of DCs may lead to the presentation of more antigens to lymphocytes which are related to the development of autoimmune thyroid diseases. The regulation of Fas/FasL/Bcl-2 in GD favors apoptosis of infiltrating lymphocytes and thyrocyte survival. The regulation of Fas/FasL/Bcl-2 in HT may promote thyrocyte apoptosis leading to hypothyroidism.

A ropivacaine-lidocaine combination for caudal blockade in haemorrhoidectomy.

A single dose of caudal lidocaine does not provide a sufficiently long anaesthetic duration and is not generally used for complicated anorectal surgery. This study evaluated the safety and efficacy of a ropivacaine-lidocaine combination for caudal anaesthesia in patients undergoing haemorrhoidectomy. A total of 287 haemorrhoid patients with successful initial caudal anaesthesia were randomized to receive either a mixture of 0.375% ropivacaine and 1.0% lidocaine (ropi-lido group; n=146) or 1.0% lidocaine alone (placebo-lido group; n=141). Significantly fewer patients in the ropi-lido group required intra-operative supplemental anaesthesia than in the placebo-lido group. Patients treated with the ropivacaine-lidocaine combination had significantly lower scores for pain at each post-operative time point, and a longer mean time to the first requirement for post-operative analgesic than patients in the placebo-lido group. These results suggest that caudal anaesthesia with a combination of ropivacaine and lidocaine is a safe and effective method of inducing anaesthesia during haemorrhoidectomy.

Three-dimensional preoperative maps of hippocampal atrophy predict surgical outcomes in temporal lobe epilepsy.

The authors used surface-based anatomic mapping to detect features of hippocampal anatomy that correlated with surgical outcomes in patients undergoing surgery for mesial temporal lobe epilepsy with hippocampal sclerosis. Compared with a seizure-free group, hippocampal profiles for the non-seizure-free group had greater diffuse ipsilateral atrophy and more region-specific contralateral atrophy in the anterior, lateral hippocampus. These atrophic regions may indicate areas of increased epileptogenicity, contributing to poorer surgical outcomes.