Pinpointing the tumor-specific T cells via TCR clusters.

Adoptive cell transfer (ACT) is a promising approach to cancer immunotherapy, but its efficiency fundamentally depends on the extent of tumor-specific T cell enrichment within the graft. This can be estimated via activation with identifiable neoantigens, tumor-associated antigens (TAAs), or living or lysed tumor cells, but these approaches remain laborious, time-consuming, and functionally limited, hampering clinical development of ACT. Here, we demonstrate that homology cluster analysis of T cell receptor (TCR) repertoires efficiently identifies tumor-reactive TCRs allowing to: (1) detect their presence within the pool of tumor-infiltrating lymphocytes (TILs); (2) optimize TIL culturing conditions, with IL-2/IL-21/anti-PD-1 combination showing increased efficiency; (3) investigate surface marker-based enrichment for tumor-targeting T cells in freshly isolated TILs (enrichment confirmed for CD4 and CD8 PD-1/CD39 subsets), or re-stimulated TILs (informs on enrichment in 4-1BB-sorted cells).

Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors.

BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target.

Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB-IVM1c melanoma.

Background: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response.

Methods: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response.

Results: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC.

Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial.

Background: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAF mutation-positive advanced or metastatic melanoma.

Methods: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAF mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group).

Contrast-enhanced ultrasound for diagnosis of an enlarged cervical lymph node in a patient with oropharyngeal cancer: a case report.

In oral and oropharyngeal cancer, the presence of regional neck metastasis strongly influences treatment planning and survival prognosis. A number of imaging techniques can be utilized in the clinic for diagnosis and staging. A patient with oropharyngeal cancer was staged T2 cN1 after clinical examination, computed tomography, and F-fluorodeoxyglucose positron emission tomography with computed tomography.

Epigenetics of Virus-Induced Tumors: Perspectives for Therapeutic Targeting.

About 15-20% of human cancers worldwide have viral etiology. Seven human DNA and RNA viruses are accepted to be oncogenic viruses or oncoviruses and contribute to the development of various cancer types. Human oncoviruses have developed multiple molecular mechanisms to interfere with specific cellular pathways to promote viral replication and viral life cycle maintenance in the host.

More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.

Background: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF).

Materials And Methods: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes.

A Novel Monoclonal Antibody Against Alpha-Methylacyl-CoA Racemase Applicable for Paraffin-Embedded Tissues and Diagnostics of Prostate Cancer.

AMACR (alpha-methylacyl-CoA racemase) has been recently described as a prostate cancer-specific gene that encodes a protein involved in the beta-oxidation of branched chain fatty acids. Expression of AMACR protein is found in prostatic adenocarcinoma, but not in benign prostatic tissue. Thus, monoclonal antibodies (mAbs) for AMACR detection are an important tool for the diagnosis of AMACR-positive cancers.

Contrast-enhanced ultrasound mapping of sentinel lymph nodes in oral tongue cancer-a pilot study.

Objectives: To assess the usefulness of contrast-enhanced ultrasound (CEUS) with peritumoral injection of microbubble contrast agent for detecting the sentinel lymph nodes for oral tongue carcinoma.

Methods: The study was carried out on 12 patients with T1-2cN0 oral tongue cancer. A radical resection of the primary disease was planned; a modified radical supraomohyoid neck dissection was reserved for patients with larger lesions (T2, n = 8).

Tumor Associated Macrophages in Kidney Cancer.

Tumor associated macrophages (TAMs) are an important element of tumor stroma. They originate from blood monocytes attracted by chemokines and cytokines produced by tumor cells and, being instructed by tumor microenvironment, develop into potent tumor-supporting cell population. TAMs were demonstrated to directly stimulate tumor cell proliferation and to promote angiogenesis.

Molecular mechanisms of the effect of TGF-β1 on U87 human glioblastoma cells.

Glioblastoma multiforme (GBM) is the most widespread and aggressive type of primary brain tumor. The prognosis following diagnosis with GBM is poor, with a median survival time of 14 months. Tumor cell invasion, metastasis and proliferation are the major causes of mortality in patients with GBM.

Genomic characterization of viral integration sites in HPV-related cancers.

Persistent infection with carcinogenic human papillomaviruses (HPV) causes the majority of anogenital cancers and a subset of head and neck cancers. The HPV genome is frequently found integrated into the host genome of invasive cancers. The mechanisms of how it may promote disease progression are not well understood.

Human papillomavirus types 16 E1 mRNA is transcribed from P14 early promoter in cervical neoplasms.

High-risk human papillomavirus (HR-HPV) persistent infection is responsible for the development of the majority of cervical cancers. The therapy against HPV-associated cancer requires knowledge of the viral gene expression mechanisms. In this study, the polyadenylated polycistronic transcripts containing full-size E1ORF and produced from the early P14 promoter were detected for the first time in cervical tumors with episomal forms of the HPV16 genome.

Pharmacoeconomic and clinical implications of sequential therapy for metastatic renal cell carcinoma patients in Central and Eastern Europe.

Introduction: The incidence and mortality rates of kidney cancer in the Central and Eastern European (CEE) region are among the highest in the world. Access to second and subsequent lines of metastatic renal cell carcinoma (mRCC) therapies is highly varied in the region. Despite the increasing body of evidence supporting the clinical benefit of multiple lines of treatment, access to treatment beyond first line is restricted in many of these countries.

Tudor staphylococcal nuclease drives chemoresistance of non-small cell lung carcinoma cells by regulating S100A11.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC), the major lung cancer subtype, is characterized by high resistance to chemotherapy. Here we demonstrate that Tudor staphylococcal nuclease (SND1 or TSN) is overexpressed in NSCLC cell lines and tissues, and is important for maintaining NSCLC chemoresistance.

DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix.

Mechanisms that regulate attachment of the scaffold/matrix attachment regions (S/MARs) to the nuclear matrix remain largely unknown. We have studied the effect of simple sequence length polymorphism (SSLP), DNA methylation and chromatin organization in an S/MAR implicated in facioscapulohumeral dystrophy (FSHD), a hereditary disease linked to a partial deletion of the D4Z4 repeat array on chromosome 4q. This FSHD-related nuclear matrix attachment region (FR-MAR) loses its efficiency in myoblasts from FSHD patients.

Arf6 promotes cell proliferation via the PLD-mTORC1 and p38MAPK pathways.

The small G-protein ADP-ribosylation factor 6 (Arf6) belongs to the Ras GTPases superfamily and is mostly known for its actin remodeling functions and involvement in the processes of plasma membrane reorganization and vesicular transport. The majority of data indicates that Arf6 contributes to cancer progression through activation of cell motility and invasion. Alternatively, we found that the expression of a wild-type or a constitutively active Arf6 does not influence tumor cell motility and invasion but instead significantly stimulates cell proliferation and activates phospholipase D (PLD).

Paclitaxel+BEP (T-BEP) regimen as induction chemotherapy in poor prognosis patients with nonseminomatous germ cell tumors: a phase II study.

Objectives: To evaluate paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) in patients with poor-prognosis nonseminomatous germ cell tumor (NSGCT). Paclitaxel is an active treatment of nonseminomatous germ cell tumors.

Methods: The present study was an open-label, single-center, Phase II study.

Gemcitabine combined with cisplatin as neoadjuvant chemotherapy in stage IB-IIIA non-small cell lung cancer.

This single-arm, multicenter, phase II study examined the objective response rate and toxicity after neoadjuvant chemotherapy with gemcitabine and cisplatin in patients with stage IB-IIIA non-small cell lung cancer. Treatment consisted of three 21-day cycles of gemcitabine (1000 mg/m(2)) on days 1 and 8 and cisplatin (75 mg/m(2)) on day 1 of each cycle. Surgery was performed 4-5 weeks after day 1 of the last cycle of study therapy.

Melanoma vasculogenic mimicry capillary-like structure formation depends on integrin and calcium signaling.

Objective: We recently demonstrated that the formation of CLSs in vitro, which are thought to be a reconstitution of VM, is controlled by VEGFA. CLS formation also requires the extracellular matrix signals, presumably transduced by integrins. Both pathways are affected by Ca(2+).

Deregulation of hepatocyte nuclear factor 4 (HNF4)as a marker of epithelial tumors progression.

Tissue-specific transcription factors forming the regulatory cascades which determine the specification and differentiation of epithelial cells during embryogenesis, play the central role in the control of functional and morphological properties of different cell types. Hepatocyte nuclear factors (HNFs) network is one of the most investigated tissue-specific regulatory systems which controls the specification and maintenance of differentiation of several epithelial cell types. Nuclear receptor HNF4α is one of the central elements of this regulatory network in the liver.

Is it necessary to deplete the lymphokine activated killers' populations of CD4+CD25+ lymphocytes? Regulatory Foxp3-positive T cells within lymphokine activated killers.

LAKs are used in cancer therapy. A common argument against LAK therapy is the probability of the activation of Tregs by IL-2 alongside with NK cells. In order to evaluate negative impact of Tregs, contents of Foxp3(+)CD4(+)CD25(+) Tregs and their influence on LAKs' cytotoxic activity in the samples of healthy volunteers' PBMCs cultured with or without IL-2 were determined.

Melanoma vasculogenic mimicry is strongly related to reactive oxygen species level.

The concept of 'vasculogenic mimicry' (VM) was introduced to describe the unique ability of highly invasive tumor cells to form capillary-like structures (CLS) and matrix-rich patterned network in three-dimensional culture that mimic embryonic vasculogenic network. Recently, we have shown that CLS formation requires apoptotic cell death through activation of caspase-3-dependent mechanism. In this study, to identify some molecular determinants driving aggressive melanoma cells to express a latent 'angiogenic program' that recapitulates the early events of CLS formation, we focused on the involvement of antioxidants (AOs) in the process of melanoma VM.