MTBVAC is a live-attenuated Mycobacterium tuberculosis vaccine, currently under clinical development, that contains the major antigens ESAT6 and CFP10. These antigens are absent from the current ...tuberculosis vaccine, BCG. Here we compare the protection induced by BCG and MTBVAC in several mouse strains that naturally express different MHC haplotypes differentially recognizing ESAT6 and CFP10. MTBVAC induces improved protection in C3H mice, the only of the three tested strains reactive to both ESAT6 and CFP10. Deletion of both antigens in MTBVAC reduces its efficacy to BCG levels, supporting a link between greater efficacy and CFP10- and ESAT6-specific reactogenicity. In addition, MTBVAC (but not BCG) triggers a specific response in human vaccinees against ESAT6 and CFP10. Our results warrant further exploration of this response as potential biomarker of protection in MTBVAC clinical trials.
Abstract
Intravesical administration of Bacillus Calmette-Guérin (BCG) was one of the first FDA-approved immunotherapies and remains a standard treatment for bladder cancer. Previous studies have ...demonstrated that intravenous (IV) administration of BCG is well-tolerated and effective in preventing tuberculosis infection in animals. Here, we examine IV BCG in several preclinical lung tumor models. Our findings demonstrate that BCG inoculation reduced tumor growth and prolonged mouse survival in models of lung melanoma metastasis and orthotopic lung adenocarcinoma. Moreover, IV BCG treatment was well-tolerated with no apparent signs of acute toxicity. Mechanistically, IV BCG induced tumor-specific CD8
+
T cell responses, which were dependent on type 1 conventional dendritic cells, as well as NK cell-mediated immunity. Lastly, we also show that IV BCG has an additive effect on anti-PD-L1 checkpoint inhibitor treatment in mouse lung tumors that are otherwise resistant to anti-PD-L1 as monotherapy. Overall, our study demonstrates the potential of systemic IV BCG administration in the treatment of lung tumors, highlighting its ability to enhance immune responses and augment immune checkpoint blockade efficacy.
Previous studies have suggested a more frequent and severe course of novel coronavirus SARS-CoV-2 infection in cancer patients undergoing active oncologic treatment. Our aim was to describe the ...characteristics of the disease in this population and to determine predictive factors for poor outcome in terms of severe respiratory distress (acute respiratory distress syndrome ARDS) or death.
Patients consecutively admitted for SARS-CoV-2 infection were prospectively collected, and retrospective statistical analysis was performed. Univariate and multivariate analyses were performed to assess potential factors for poor outcomes defined as ARDS or death.
Sixty-three patients were analysed, and 34 of them developed respiratory failure (70% as ARDS). Lymphocytes/mm3 (412 versus 686; p = 0.001), serum albumin (2.84 versus 3.1); lactate dehydrogenase (LDH) (670 versus 359; p < 0.001) and C-reactive protein (CRP) levels (25.8 versus 9.9; p < 0.001) discriminate those that developed respiratory failure. Mortality rate was 25%, significantly higher among ARDS, neutropenic patients (p = 0.01) and in those with bilateral infiltrates (44% versus 0%; p < 0.001). Multivariate logistic analyses model confirmed the predictive value of severe neutropenia (odds ratio OR 16.54; 95% confidence interval CI 1.43–190.9, p 0.025), bilateral infiltrates (OR 32.83, CI 95% 3.51–307, p 0.002) and tumour lung involvement (OR 4.34, CI 95% 1.2–14.95, p 0.02).
Cancer patients under active treatment admitted for SARS-CoV-2 infection have worse outcomes in terms of mortality and respiratory failure rates compared with COVID-19 global population. Lymphopenia, LDH, CRP and albumin discriminate illness severity, whereas neutropenia, bilateral infiltrates and tumour pulmonary involvement are predictive of higher mortality.
•Cancer patients are supposed to be especially vulnerable for SARS-CoV-2 infection.•Active cancer treatment could be deleterious in case of simultaneous SARS-CoV-2 infection.•Outcomes of patients under treatment and admitted for SARS-CoV-2 infection are described.•Hospitalised SARS-CoV-2 cancer patients show similar death rate to non-cancer patients.
Silicon monoxide (SiO) is a structurally complex compound exhibiting differentiated oxide-rich and silicon-rich nano-phases at length scales covering nanoclusters to the bulk. Although nano-sized and ...nano-segregated SiO has great technological potential (e.g. nano-silicon for optical applications) and is of enormous astronomical interest (e.g. formation of silicate cosmic dust) an accurate general description of SiO nucleation is lacking. Avoiding the deficiencies of a bulk-averaged approach typified by classical nucleation theory (CNT) we employ a bottom-up kinetic model which fully takes into account the atomistic details involved in segregation. Specifically, we derive a new low energy benchmark set of segregated (SiO)
cluster ground state candidates for N ≤ 20 and use the accurately calculated properties of these isomers to calculate SiO nucleation rates. We thus provide a state-of-the art evaluation of the range of pressure and temperature conditions for which formation of SiO will or will not proceed. Our results, which match with available experiment, reveal significant deficiencies with CNT approaches. We employ our model to shed light on controversial issue of circumstellar silicate dust formation showing that, at variance with the predictions from CNT-based calculations, pure SiO nucleation under such conditions is not viable.
Background
HER2‐positive gastric cancer (GC) affects 7%–34% of patients with GC. Trastuzumab‐based first‐line treatment has become the standard of care for HER2‐positive advanced gastric cancer ...(AGC). However, there are no clinically validated biomarkers for resistance to HER2‐targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2‐positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2‐positive AGC treated with trastuzumab.
Patients and Methods
Forty‐two HER2‐positive GC samples from patients treated with trastuzumab‐based first‐line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed.
Results
Concurrent genetic alterations were detected in 97.1% of HER2‐positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression‐free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab‐based chemotherapy in terms of OS and PFS.
Conclusion
Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2‐positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab.
Implications for Practice
This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2‐positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression‐free survival in AGC treated with trastuzumab‐based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2‐positive AGC.
摘要
背景。HER2阳性胃癌(GC)占所有胃癌的7%‐34% 。基于曲妥珠单抗的一线疗法已经成为HER2阳性晚期胃癌 (AGC)的标准治疗方法。然而,关于HER2靶向治疗耐药性,尚无经过临床验证的生物标志物。上调PI3K信号通路和酪氨酸激酶受体(TKR)改变已经被视为乳腺癌耐药性的分子机制。我们的研究旨在揭示HER2阳性AGC的分子特征,探索PI3K/Akt/mTOR信号通路激活和TKR基因拷贝数(GCN)增加作为预测性生物标志物在曲妥珠单抗经治HER2阳性AGC患者中的作用。
患者和方法。从接受基于曲妥珠单抗一线化疗方案治疗的患者中选取42份HER2阳性胃癌样本。DNA样本测序。实施PTEN和MET免疫组化。
结果。在97.1%的HER2阳性AGC样本中检测出并发的基因改变。我们在52.4%的患者中发现PI3K/Akt/mTOR信号通路激活,在38.1%的患者中发现TKR GCN增加。TKR GCN增加与总生存期(OS)或无进展生存期(PFS)无关。多变量Cox模型显示,PI3K/Akt/mTOR激活对基于曲妥珠单抗化疗的有效性(在OS和PFS方面)产生不利影响。
结论。我们的结果首次提供了HER2阳性AGC并发基因改变的详细分子谱。PI3K信号通路激活可作为此类患者人群预后不良的预测性标志物。此外,此类亚组人群中其它TKR基因拷贝数的增加也可能影响曲妥珠单抗治疗的生存益处。
实践意义:本文首次报告了HER2阳性晚期胃癌(AGC)患者基因改变的详细分子谱。PI3K/Akt/mTOR信号通路激活看起来对接受基于曲妥珠单抗化疗方案治疗的AGC患者的总生存期和无进展生存期产生了不同的不利作用。不同靶向药物的联合应用可能是改善HER2阳性AGC预后的成功治疗策略。
This article describes genomic profiling of patients with HER2‐positive advanced gastric cancer who were treated with first‐line trastuzumab‐based chemotherapy, focusing on whether PI3K/Akt/mTOR pathway status could be relevant in selecting suitable patients for targeted therapies.
Highlights • HER2 positive gastric cancer is associated with a specific phenotype. • Reliable HER2 testing is mandatory for the correct use of anti-HER2 treatment. • We review present HER2 diagnosis ...and directed therapies in gastric cancer. • Future strategies for HER2 gastric cancer treatment are discussed.
Abstract Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver and is the third cause of cancer-related death worldwide. Surveillance with abdominal ultrasound should be ...offered to individuals at high risk for developing HCC. Accurate diagnosis, staging, and liver function are crucial when determining the optimal therapeutic approach. The BCLC staging system is widely endorsed in Western countries. Managing this pathology requires a multidisciplinary, personalized approach, generally with a multimodal strategy. Surgery remains the only curative option, albeit local and systemic therapy may also increase survival when surgery is not suitable. In advanced disease, systemic treatment should be offered to patients with ECOG/PS 0-1 and Child–Pugh class A.
Retinoblastoma (RB, MIM 180200) is the paradigm of hereditary cancer. Individuals harboring a constitutional mutation in one allele of the RB1 gene have a high predisposition to develop RB. Here, we ...present the first case of familial RB caused by a de novo insertion of a full-length long interspersed element-1 (LINE-1) into intron 14 of the RB1 gene that caused a highly heterogeneous splicing pattern of RB1 mRNA. LINE-1 insertion was inferred by mRNA studies and full-length sequenced by massive parallel sequencing. Some of the aberrant mRNAs were produced by noncanonical acceptor splice sites, a new finding that up to date has not been described to occur upon LINE-1 retrotransposition. Our results clearly show that RNA-based strategies have the potential to detect disease-causing transposon insertions. It also confirms that the incorporation of new genetic approaches, such as massive parallel sequencing, contributes to characterize at the sequence level these unique and exceptional genetic alterations.
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