Once- vs Twice-Daily Tacrolimus: Survival Rates and Side Effects: Single-Center Experience

BackgroundThis study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups.MethodsA total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients.ResultsBaseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P = .040).ConclusionThis study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.     

A retrospective analysis comparing set up errors from standard versus customised headrests for head and neck radiotherapy

IntroductionIn response to advice from The National Institute for Health and Care Excellence ⁽¹⁾ to reduce hospital visits during COVID-19, standard headrests were introduced for head and neck radiotherapy within Northern Centre for Cancer Care (NCCC). The standard headrest requires one mould room appointment compared to 3 appointments with customised headrests.MethodsTwo groups of 10 patients treated between December 2019 and June 2020 were retrospectively analysed by 1 observer. Groups were stratified according to age, sex and tumour site. One group had customised headrest and the other had standard headrest. Five hundred and forty seven cone beam computed tomography images were reviewed. A 6 Degree of Freedom match was performed then chin, shoulder and spine position were assessed using dosimetrist drawn structures. Structures out of the tolerance were recorded. A chi-squared test was used for statistical analysis.ResultsThe out of tolerance chin position count recorded was 21 for customised headrest and 36 for standard headrest, p-value 0.046. The shoulder position count was 13 for customised headrest and 77 for standard headrest p-value <0.001. The spine position count was 3 for CHR and 21 for standard headrest, p-value <0.001. This means the headrests compared are not equivalent in terms of set up reproducibility. Overall the standard headrest group had 10 set-up re-scans and no set up re-scans were recorded in the customised headrest group.ConclusionFewer hospital visits with SHR reduce patient exposure to COVID-19. However, CHR provided a more reliable level of immobilisation in this study.Implications for practiceThe radiotherapy service will be reviewed in line with these findings.     

miR-199-3p通过对FGF2的调控抑制肝癌细胞MHCC97H的增殖、迁移作用及机制

目的:探讨miR-199-3p通过靶向调控抑制靶基因FGF2从而抑制肝癌MHCC97H细胞的增殖和迁移及机制。方法:qRT-PCR检测癌旁正常组织及肝癌肿瘤组织中miR-199-3p的表达水平；Transwell细胞侵袭实验检测肝癌细胞株Huh7、MHCC-97L、SMMC7721、HepG2和MHCC97H株其侵袭能力；qRT-PCR检测miR-199-3p在5株肝癌细胞系中的表达量；通过生物信息软件预测靶基因FGF2 mRNA 3' UTR的碱基存在miR-199-3p可能互补结合的位点并用荧光报告基因法及WB进行验证；通过qRT-PCR、免疫组化及Western blot检测FGF2在肝癌肿瘤组织和癌旁正常组织及各类肝癌细胞株表达的影响；Transwell、划痕、CCK8及流式细胞法检测miR-199-3p与FGF2对肝癌MHCC97H细胞增殖、侵袭、迁移及周期S期聚集能力的调控；采用MHCC97H细胞构建肝癌肿瘤异种移植小鼠模型进行肿瘤观测及免疫组化实验验证miR-199-3p对肝癌的调控作用。结果:miR-199-3p的表达水平与肝癌细胞侵袭转移能力相关；miR-199-3p能够通过抑制FGF2的mRNA翻译，抑制FGF2蛋白水平表达；FGF2与肝癌细胞侵袭转移能力相关；miR-199-3p可以负调控FGF2抑制肝癌MHCC97H细胞的生物行为；miR-199-3p 可抑制肝癌细胞中阳性信号，细胞增殖水平显著降低。结论:miR-199-3p通过抑制FGF2抑制肝癌细胞MHCC97H的增殖和迁移。     

Thy-1 通过调控Notch1 通路促进肝癌细胞EMT进程

目的: 探索细胞表面抗原Thy-1 通过调控Notch1 通路促进肝癌HepG2 和MHCC-97 细胞上皮间质转化（EMT）。方法：选用具有高转移特性的MHCC-97 细胞和低转移特性的HepG2 细胞作为研究对象，WB检测细胞内Thy-1、Notch1 蛋白表达水平。用重组慢病毒转染MHCC-97 和HepG2 细胞，构建高表达与低表达Thy-1 蛋白的细胞，再分别用Notch1 激动剂rhNF-κB（1gsu/ml）和Notch1 抑制剂MW167（100 μmol/L）处理细胞24 h。Transwell 实验检测Thy-1 表达变化、rhNF-κB和MW167 处理对细胞侵袭能力的影响，qPCR检测对Notch1 mRNA表达的影响，WB实验检测细胞内EMT相关蛋白表达的影响。结果：MHCC-97细胞中Thy-1、Notch1 蛋白表达量均高于HepG2 细胞（P<0.05）。成功构建Thy-1 过表达的HepG2 细胞和Thy-1 低表达的MHCC-97 细胞。与亲本HepG2 细胞相比，Thy-1 过表达HepG2 细胞侵袭能力显著增强[ （475.78±80.37）vs（183.23±55.34）个，P<0.05）]、波形蛋白表达显著升高（P<0.05）、上皮钙黏素蛋白表达显著降低（P<0.05）、Notch1 mRNA表达水平显著升高（P<0.05）；与亲本MHCC-97 细胞相比，Thy-1 沉默的MHCC-97 细胞侵袭能力显著降低[ （237.44±62.18）vs（543.56±77.94）个，P<0.05）]、波形蛋白表达显著降低（P<0.05）、上皮钙黏素蛋白表达显著升高（P<0.05）、Notch1 mRNA表达水平显著降低（P<0.05）。而Notch1 激活剂或抑制剂处理上述肝癌细胞可逆转由于Thy-1 沉默或过表达所造成的改变。结论：Thy-1 可通过调控Notch1 表达影响肝癌HepG2和MHCC-97 细胞的EMT。     

Anti-obesity effects of seaweeds of Jeju Island on the differentiation of 3T3-L1 preadipocytes and obese mice fed a high-fat diet

The seaweeds were collected from the coast of Jeju Island, South Korea. We investigated ethanol extracts from seaweed as potential antiobesity agents by testing their effect on adipogenic differentiation in 3T3-L1 cells. Among the red algae extracts tested, the Plocamium telfairiae extract (PTE) showed the highest inhibitory effect on lipogenesis in adipocytes and, thus, was selected as a potential antiobesity agent. PTE treatment significantly decreased the expression of the adipogenic-specific proteins peroxisome proliferator-activated receptor-γ, CCAAT/enhancer-binding protein-α, sterol regulatory element-binding protein 1, and fatty acid-binding protein 4 compared with that in the untreated 3T3-L1 cells. PTE also inhibited high-fat diet (HFD)-induced obesity in male C57BL/6 mice. Oral administration of PTE significantly reduced the body weight, fatty liver, amount of white adipose tissue, and levels of triglyceride and glucose in the tested animals. Taken together, these data demonstrate that PTE can be developed as a therapeutic agent for obesity.     

Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

p97/VCP is an endoplasmic reticulum (ER)‐associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC₅₀, 100‐500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. IC₅₀ of OSSL_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of DBeQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell‐free ATPase assays, OSSL_325096 showed dose‐dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti‐myeloma activity, at least in part through p97/VCP inhibition.     

Broad neutralization against SARS-CoV-2 variants induced by ancestral and B.1.351 AS03-Adjuvanted recombinant Plant-Derived Virus-Like particle vaccines

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the coronavirus disease 2019 (COVID-19) has afflicted hundreds of millions of people in a worldwide pandemic. Several safe and effective COVID-19 vaccines are now available. However, the rapid emergence of variants and risk of viral escape from vaccine-induced immunity emphasize the need to develop broadly protective vaccines. A recombinant plant-derived virus-like particle vaccine for the ancestral COVID-19 (CoVLP) recently authorized by Canadian Health Authorities and a modified CoVLP.B1351 targeting the B.1.351 variant (both formulated with the adjuvant AS03) were assessed in homologous and heterologous prime-boost regimen in mice. Both strategies induced strong and broadly cross-reactive neutralizing antibody (NAb) responses against several Variants of Concern (VOCs), including B.1.351/Beta, B.1.1.7/Alpha, P.1/Gamma, B.1.617.2/Delta and B.1.1.529/Omicron strains. The neutralizing antibody (NAb) response was robust with both primary vaccination strategies and tended to be higher for almost all VOCs following the heterologous prime-boost regimen.     

The sigma-2 (σ-2) receptor: a review of recent patent applications: 2013–2018

Introduction: The discovery of the sigma-2 receptor and the analogous sigma-1 receptor led to a decade-long quest to determine the true nature of this protein and novel ligands capable of modulating its activity. Despite this challenge, the sigma-2 receptor has been linked to several disease states, and multiple classes of sigma-2 ligands have been published in the 40+ years since its initial discovery.

Areas covered: This review covers newly published patent applications that describe sigma-2 receptor ligands capable of modulating disease states. The aforementioned documents entered the public domain as PCT patent applications between 2013 and 2018.

Expert opinion: In 2017, the sigma-2 receptor was positively identified as TMEM97 (transmembrane protein 97). The resolution of this ‘identity crisis’ will facilitate a greater understanding of the pharmacological role of sigma-2 receptor as well as support the identification of novel sigma-2 receptor ligands with potential utility as disease-modifying therapies.     

人参二醇诱导3T3-L1脂肪前体细胞凋亡及其作用机制

探讨人参二醇（PD）诱导3T3-L1脂肪前体细胞凋亡作用,并阐明其可能的作用机制。