Safety and efficacy of laparoscopic digestive tract nutrition reconstruction combined with conversion therapy for patients with unresectable and obstructive gastric cancer

BackgroundTo explore the safety, efficacy, and survival benefits of laparoscopic digestive tract nutrition reconstruction (LDTNR) combined with conversion therapy in patients with unresectable gastric cancer with obstruction.MethodsThe clinical data of patients with unresectable gastric cancer with obstruction who was treated in Fujian Provincial Hospital from January 2016 to December 2019, were analyzed. LDTNR was performed according to the type and degree of obstruction. All patients received the epirubicin + oxaliplatin + capecitabine regimen as conversion therapy.ResultsThirty-seven patients with unresectable obstructive gastric cancer underwent LDTNR, while thirty-three patients received chemotherapy only. In LDTNR group patients, the proportion of nutritional risks gradually decreased, the rate of severe malnutrition decreased, the proportion of neutrophil-lymphocyte ratio (NLR) <2.5 increased, the proportion of prognosis nutrition index (PNI) ≥45 increased, and the Spitzer QOL Index significantly increased at day 7 and 1 month postoperatively (P<0.05). One patient (6.3%) developed grade III anastomotic leakage and was discharged after the endoscopic intervention. The median chemotherapy cycle of patients in LDTNR group was 6 cycles (2-10 cycles), higher than that in Non-LDTNR group (P<0.001). Among those who received LDTNR therapy, 2 patients had a complete response, 17 had a partial response, 8 had stable disease, and 10 had progressive disease, which was significantly better than the response rate in Non-LDTNR group(P<0.001). The 1-year cumulative survival rates of the patients with or without LDTNR were 59.5% and 9.1%. The 3-year cumulative survival rate with or without LDTNR was 29.7% and 0%, respectively (P<0.001).ConclusionsLDTNR can improve the inflammatory and immune status, increase compliance with chemotherapy, and have potential benefits in improving the safety and effectiveness of and survival after conversion treatment

BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations

The breast cancer susceptibility gene BRCA1 encodes a protein that has been implicated in multiple nuclear functions, including transcription and DNA repair. The multifunctional nature of BRCA1 has raised the possibility that the polypeptide may regulate various nuclear processes via a common underlying mechanism such as chromatin remodeling. However, to date, no direct evidence exists in mammalian cells for BRCA1-mediated changes in either local or large-scale chromatin structure. Here we show that targeting BRCA1 to an amplified, lac operator–containing chromosome region in the mammalian genome results in large-scale chromatin decondensation. This unfolding activity is independently conferred by three subdomains within the transactivation domain of BRCA1, namely activation domain 1, and the two BRCA1 COOH terminus (BRCT) repeats. In addition, we demonstrate a similar chromatin unfolding activity associated with the transactivation domains of E2F1 and tumor suppressor p53. However, unlike E2F1 and p53, BRCT-mediated chromatin unfolding is not accompanied by histone hyperacetylation. Cancer-predisposing mutations of BRCA1 display an allele-specific effect on chromatin unfolding: 5′ mutations that result in gross truncation of the protein abolish the chromatin unfolding activity, whereas those in the 3′ region of the gene markedly enhance this activity. A novel cofactor of BRCA1 (COBRA1) is recruited to the chromosome site by the first BRCT repeat of BRCA1, and is itself sufficient to induce chromatin unfolding. BRCA1 mutations that enhance chromatin unfolding also increase its affinity for, and recruitment of, COBRA1. These results indicate that reorganization of higher levels of chromatin structure is an important regulated step in BRCA1-mediated nuclear functions

Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway

Supermassive Black Holes with High Accretion Rates in Active Galactic Nuclei. IV. Hβ\beta Time Lags and Implications for Super-Eddington Accretion

We have completed two years of photometric and spectroscopic monitoring of a large number of active galactic nuclei (AGNs) with very high accretion rates. In this paper, we report on the result of the second phase of the campaign, during 2013--2014, and the measurements of five new H$\beta$ time lags out of eight monitored AGNs. All five objects were identified as super-Eddington accreting massive black holes (SEAMBHs). The highest measured accretion rates for the objects in this campaign are $\dot{\mathscr{M}}\gtrsim 200$, where $\dot{\mathscr{M}}= \dot{M}_{\bullet}/L_{\rm Edd}c^{-2}$, $\dot{M}_{\bullet}$ is the mass accretion rates, $L_{\rm Edd}$ is the Eddington luminosity and $c$ is the speed of light. We find that the H$\beta$ time lags in SEAMBHs are significantly shorter than those measured in sub-Eddington AGNs, and the deviations increase with increasing accretion rates. Thus, the relationship between broad-line region size ($R_{_{\rm H\beta}}$) and optical luminosity at 5100\AA, $R_{_{\rm H\beta}}-L_{5100}$, requires accretion rate as an additional parameter. We propose that much of the effect may be due to the strong anisotropy of the emitted slim-disk radiation. Scaling $R_{_{\rm H\beta}}$ by the gravitational radius of the black hole, we define a new radius-mass parameter ($Y$) and show that it saturates at a critical accretion rate of $\dot{\mathscr{M}}_c=6\sim 30$, indicating a transition from thin to slim accretion disk and a saturated luminosity of the slim disks. The parameter $Y$ is a very useful probe for understanding the various types of accretion onto massive black holes. We briefly comment on implications to the general population of super-Eddington AGNs in the universe and applications to cosmology.Comment: 53 pages, 12 figures, 7 tables, accepted for publication in The Astrophysical Journa

Anti-proliferation effects of Sirolimus sustained delivery film in rabbit glaucoma filtration surgery

Purpose: To investigate the efficacy, safety, and mechanisms of Sirolimus sustained delivery film on prevention of scar formation in a rabbit model of glaucoma filtration surgery. Methods: Sixty-four New Zealand white rabbits who underwent trabeculectomy in the right eye were randomly allocated to one of the four treatment regimens: Sirolimus sustained delivery film treatment group (Group A), or drug-free film treatment group (Group B), or 30 ng/ml Sirolimus-soaked sponge treatment group (Group C), or no adjunctive treatment group (Group D), and each group consists of 16 rabbits. Intraocular pressure (IOP), morphologic changes of bleb, anterior chamber flare, and corneal endothelial cell count and complications were evaluated over a 28-day period follow-up time. Aqueous humor samples were gathered from Group A, and the concentration of Sirolimus was measured regularly post-operation. Rabbits were sacrificed on the 7th, 14th, and 28th day post-operation separately, and the fibroblast hypertrophy, infiltration of inflammatory, and proliferation of new collagen fiber formation in each group were evaluated with HE and Masson staining. Proliferative cell nuclear antigen (PCNA) and fibroblast apoptosis were evaluated by immunohistochemistry and terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) assay at the 28th day post-operation. Results: Both Sirolimus sustained delivery film (Group A) and Sirolimus alone (Group C) were well tolerated in this model, and significantly prolonged bleb survival compared with no drug treatment group (Group B and D; p<0.001). Group A had the longest bleb survival time in comparison with other groups (p<0.001). There were significant differences in IOP readings between Group A and other groups at the last follow-up (p<0.05). The concentration of Group A maintained stable for over 2 weeks, drops from (10.56 +/- 0.05) ng/ml at day 3 to (7.74 +/- 0.05) ng/ml at day 14. The number of corneal endothelial cells of Group A was not statistically significant between pre and post-operation. Histologic examination demonstrated that eyes treated with Sirolimus, especially the Sirolimus sustained delivery film, showed an obvious reduction in subconjunctival fibroblast scar tissue formation compared with no drug treatment groups, and had minimal evidence of inflammatory cell infiltration and new collagen deposition in the subconjunctiva. Immunohistochemistry assay showed that PCNA-expression was lower in the Group A (16.25 +/- 3.24%) compared to other groups (p<0.01). TUNEL assay showed a significant increase in the number of apoptotic fibroblasts around the surgical area in Group A and Group C (9.75 +/- 1.71% and 8.50 +/- 1.92%) compared to the Group B and D (p<0.01). Conclusions: Sirolimus drug sustained delivery film can inhibit inflammatory cell activity, impede fibroblast proliferation activity, and induce fibroblast apoptosis in the filtration surgery sites in rabbit. The results indicate a safe and effective treatment strategy in anti-scaring treatment in glaucoma surgery.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000295289900001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Biochemistry & Molecular BiologyOphthalmologySCI(E)9ARTICLE270-712495-25061