A molecular perspective for the use of type IV tyrosine kinase inhibitors as anticancer therapeutics

Tyrosine kinases are enzymes that can transfer a phosphate group from ATP to a specific protein tyrosine, serine or threonine residue within a cell, operating as a switch that can turn ‘on’ and ‘off’ causing different physiological alterations in the body. Mutated kinases have been shown to display an equilibrium shift toward the activated state. Types I–III have been studied intensively leading to drugs like imatinib (type II), cobimetinib (type III), among others. It is the same scenario for types V–VII; however, there is a lacuna in information regarding type IV inhibitors, although recently some advances have surfaced. This review aims to accumulate the knowledge gained so far about type IV inhibitors.     

Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer

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Robust antibody response after a third BNT162b2 vaccine compared to the second among immunocompromised and healthy individuals,a prospective longitudinal cohort study

PurposeAs protection from COVID-19 following two doses of the BNT162b2 vaccine showed a time dependent waning, a third (booster) dose was administrated. This study aims to compare the antibody response following the third dose versus the second and to evaluate post-booster seroconversion.MethodsA prospective observational study conducted in Maccabi Healthcare Services. Serial SARS-CoV-2 Spike IgG tests, 1,2,3 and 6 months following the second vaccine dose and one month following the third were obtained. Neutralizing antibody levels were measured in a subset of participants. Per individual SARS-CoV-2 Spike IgG titer ratios were calculated one month after the booster administration compared to titers one month following the second dose and prior to booster.ResultsAmong 110 participants, 56 (51%) were women. Mean age was 61.7 ± 1.9 years and 66 (60%) were immunocompromised. One month after third dose, IgG titers were induced 7.83 (95 %CI 5.25–11.67) folds and 2.40 (95 %CI 1.90–3.03) folds compared to one month after the second, in the immunocompromised and immunocompetent groups, respectively. Of the 17 immunocompromised participants who were seronegative after the second dose, 4 (24%) became seropositive following the third. Comparing the titers prior to the third dose, an increase of 50.7 (95 %CI 32.5–79.1) fold in the immunocompromised group and 25.7 (95 %CI 19.1–34.7) fold in and immunocompetent group, was observed.ConclusionA third BNT162b2 vaccine elicited robust humoral response, superior to the response observed following the second, among immunocompetent and immunocompromised individuals.     

原发性肺鳞癌中EGFR和ALK基因突变的临床研究北大核心

目的:探讨赣南地区原发性肺鳞癌患者EGFR和ALK基因突变的特点,科学指导此类患者优选靶向用药。方法:入组73例原发性肺鳞癌病例,采用ARMS-PNA技术检测EGFR基因第18、19、20、21外显子突变,应用不平衡法检测其中60例病例的ALK融合基因,回顾性分析EGFR和ALK基因突变患者的临床病理特征。结果:EGFR基因突变8例,阳性率为10.96%(8/73),4例为L858R突变,3例为19del突变,1例为G719X突变。女性患者突变率(66.67%,2/3)明显高于男性患者(8.57%,6/70)(P=0.030),EGFR基因突变在高龄(≥60岁)、进展期(N_(1-3)、Ⅲ+Ⅳ期)患者中相对较高,但差异无统计学意义(P>0.05)。EGFR基因突变与吸烟史、T分期以及肿瘤分布位置均无相关性(P>0.05);ALK融合基因表达2例,阳性率3.33%(2/60),与患者性别、年龄、吸烟史、TNM分期及肿瘤分布类型等各临床病理特征均无相关性(P>0.05);未发现EGFR和ALK基因共存突变病例。结论:赣南地区原发性肺鳞癌患者EGFR和ALK基因突变率相对不高,EGFR基因突变以L858R和19del突变为主,且好发于女性患者,可能是患者病情进展的预测因子之一。     

The impact of the updated EORTC/MSG criteria on the classification of hematological patients with suspected invasive pulmonary aspergillosis

ObjectivesOur aim was to evaluate the effect of the updated European Organization for Research and Treatment of Cancer (EORTC) and Mycoses Study Group 2019 definitions for invasive pulmonary aspergillosis (IPA) on patient classification and the related all-cause 12-week mortality.MethodsIn this retrospective cohort study from our tertiary care centre, we reclassified patients with haematological malignancy who underwent bronchoalveolar lavage between 2014 and 2019 for suspected IPA using the novel EORTC 2019 criteria. We performed receiver operating characteristic curve analysis to define the optimal cut-off for positive PCR and galactomannan and present survival analyses and their possible association with these diagnostic criteria through post hoc comparisons with log rank and Cox regression.ResultsFrom 323 episodes of suspected IPA in 282 patients, 73 were reclassified: 31 (42.5%) from possible to probable IPA, 5 (6.8%) from EORTC criteria not met to probable IPA, and 37 (50.7%) from EORTC criteria not met to possible IPA. Probable IPA increased therefore 11.1% (64/323, 19.8% to 100/323, 30.9%), mostly due to positive PCR (31/36, 86.1%). There was no difference in mortality between newly defined possible and probable IPA (log rank p = 0.950). Mortality was higher in probable cases with lower cycle thresholds (Ct values) versus higher Ct values (p = 0.004). Receiver operating characteristic curve analysis showed an optimal Ct value cut-off of 36.8 with a sensitivity of 75% (95% CI 64.9%–85.1%) and a specificity of 61.7% (95% CI 53.5–69.9) for 12-week mortality.DiscussionThe new EORTC criteria led to 11.1% more probable IPA diagnoses, mostly due to Aspergillus PCR. Restricting positive PCR to below a certain threshold might improve the discrimination of the new EORTC IPA categories for mortality.     

基于规律成簇的间隔短回文重复序列及其相关蛋白技术检测乙型肝炎病毒共价闭合环状DNA方法的建立

目的建立一种基于规律成簇的间隔短回文重复序列及其相关蛋白(CRISPR/Cas13a)的乙型肝炎病毒(HBV)共价闭合环状DNA(HBV cccDNA)检测方法。方法提取2017年6月至2020年10月于首都医科大学附属北京佑安医院就诊的4例乙型肝炎患者肝脏总DNA后,使用HindⅢ内切酶和质粒安全性ATP依赖DNA酶(PSAD)分别进行酶切;根据松弛环状DNA(rcDNA)和cccDNA的结构差异,设计特异性扩增HBV cccDNA的引物,对酶切后的产物进行滚环扩增(RCA)和PCR扩增;并筛选crRNA,建立基于CRISPR/Cas13a技术的HBV cccDNA检测新方法。结果利用α-1-抗胰蛋白酶(A1AT)和HBV表面抗原(HBsAg)引物对双重酶切后的产物进行扩增,验证产物中HBV基因组的存在;利用HBV cccDNA和HBV rcDNA引物对PSDA酶切后的产物扩增,验证了产物中只存在HBV cccDNA;利用RCA后的阳性样本作为模板梯度稀释,然后进行PCR扩增转录后使用CRISPR/Cas13a检测,计算出检测下限为10拷贝/μl。结论本研究建立了RCA-PCR-CRISPR-Cas13a的新型检测方法,可对HBV cccDNA进行高灵敏度和高特异性检测,为乙型肝炎患者抗病毒治疗评估、治疗终点的确定以及调整治疗方案提供了有效的监测手段。     

Inverse correlation between the expression of AMPK/SIRT1 and NAMPT in psoriatic skin: A pilot study

PurposeEpidermal hyperplasia and the involvement of immune cells characterize the clinical picture of psoriasis. Among the several factors involved, attention has been focused on sirtuin 1 (SIRT1) - a deacetylase endowed with a variety of functions including the control of metabolic and inflammatory processes-, and on nicotinamide phosphoribosyltransferase (NAMPT), important for SIRT1 activation and involved in inflammatory events. The aim of the study was to analyze changes of SIRT1 and NAMPT expression in psoriatic skin.Patients and methodsSamples from healthy controls and psoriatic patients were subjected to immunohistochemical analysis.ResultsA strong downregulation of SIRT1 expression was observed in skin samples from psoriatic patients compared to healthy controls. This was accompanied by a parallel reduction of adenosine monophosphate-activated kinase (AMPK) expression and, more strikingly, by the disappearance of cells immunolabeled for its active, phosphorylated form (pAMPK). In both cases, analysis of the distribution of immunopositive cells revealed a shift towards reduced intensity of staining. In contrast, NAMPT expression was upregulated in psoriatic samples in line with its pro-inflammatory role. This was again more visible with an intensity-based distribution analysis that evidenced a shift towards more intensely immunostained cell populations.ConclusionsThe present data correlate in the same samples the expression of SIRT1, pAMPK/AMPK and NAMPT in psoriasis and open the way for novel pharmacological targets in the treatment of the disease.     

Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.