Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand ...1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors’ outcomes in patients with R/M HNSCC.
NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes.
High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively).
Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression.
•PD-1/PD-L1 axis inhibitors have become the standard of care for R/M HNSCC.•Low response rates dictate the need to identify resistance mechanisms and develop biomarkers for patient selection.•The associations of immune cell density with treatment outcomes were investigated in nivolumab-treated R/M HNSCC cases.•Increased B-cell infiltration led to prolonged PFS and improved PD-L1-based patient selection.•The synchronous assessment of B-cell infiltration and PD-L1 expression could guide therapeutic decisions in R/M HNSCC.
•Anthracyclines remain the gold standard in first-line treatment challenged by molecular targets as mdm2 inhibitors.•PFS and OS endpoints have not been significantly raised with any of the approved ...second-line options.•Combinations of immunotherapy with TKIs show promising activity.
Well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) account for 60 % of all liposarcomas, reflecting the heterogeneity of this type of sarcoma. Genetically, both types of liposarcomas are characterized by the amplification of MDM2 and CDK4 genes, which indicates an important molecular event with diagnostic and therapeutic relevance. In both localized WDLPS and DDLPS of the retroperitoneum and the extremities, between 25 % and 30 % of patients have local or distant recurrence, even when perioperatively treated, with clear margins present. The systemic treatment of WDLPS and DDLPS remains a challenge, with anthracyclines as the gold standard for first-line treatment. Several regimens have been tested with modest results regarding their efficacy. Herein we discuss the systemic treatment options for WDLPS and DDLPS and review their reported clinical efficacy results.
Sarcomas are tumors that originate from mesenchymal cells. The variety of sarcomas’ response to chemotherapy and the wide range of prognosis reflect their heterogeneity. In order to improve the rates ...of response, the research has been orientated toward other forms of therapy, such as targeted therapies and immunotherapy or toward combinations of them. Immune checkpoint inhibitors (ICIs) have been the highlight of immunotherapy in the last decade. Although ICIs are already included in the guidelines of different malignancies, their clinical benefit in sarcomas is still under study. Alveolar soft part sarcomas, undifferentiated pleomorphic sarcomas and other subtypes of sarcoma with high presence of tertiary lymphoid structures tend to respond to ICIs, but further investigation is still needed. Furthermore, the search of predictive biomarkers to determine the type of sarcomas that are sensitive to ICIs is still very challenging. This review will focus on the results of clinical trials, which examine the effect of ICIs and their combination with chemotherapy, targeted therapies and other forms of immunotherapy in sarcomas.
•Sarcomas are rare mesenchymal tumors with wide heterogeneity and response to chemotherapy and radiotherapy.•Programmed death-ligand 1 expression in sarcomas does not follow the respective responses of this type of tumors in immunotherapy.•Monotherapies of immune checkpoint inhibitors do not show adequate responses in sarcomas.•Combination of TKIs and anti-CTLA-4 has shown satisfying responses in alveolar soft part sarcomas.•Atezolizumab is the only immune checkpoint inhibitor approved for the treatment of alveolar soft part sarcomas.
Background
The mechanism underlying remote ischemic conditioning (RIC) remains unclear. We investigated whether RIC protects the heart through the activation of the adenosine receptor and the ...PI3K-Akt pathway at the onset of myocardial reperfusion.
Methods and results
Domestic pigs (27–35 kg) were subjected to in situ left anterior descending coronary artery ischemia (60 min) followed by reperfusion (180 min) and randomised to the following: (1) Control- No additional intervention; (2) Remote ischemic preconditioning (RIPC)- Four-5 min cycles of lower limb ischemia/reperfusion were administered prior to myocardial ischemia; (3) RIPC + Wort or 8-SPT: Wortmannin (Wort 20 μg/kg, a PI3K inhibitor) or 8-sulfophenyltheophylline (8-SPT 10 mg/kg, an adenosine receptor inhibitor) were administered intravenously 30 s before myocardial reperfusion to RIPC-treated animals; (4) Remote ischemic perconditioning (RIPerC)- Four-5 min cycles of lower limb ischemia/reperfusion were applied 1 min before myocardial reperfusion; (5) RIPerC + Wort or 8-SPT: Wort or 8-SPT were given 30 s before myocardial reperfusion to RIPerC-treated animals. Both RIPC and RIPerC reduced myocardial infarct size (13.3 ± 2.2% with RIPC, 18.2 ± 2.0% with RIPerC versus 48.8 ± 4.2% in control:P < 0.05:
N
≥ 5/group). Wortmannin abolished the infarct-limiting effects of RIPC (33.2 ± 6% with RIPC + Wort versus 13.3 ± 2.2% with RIPC:P < 0.05:
N
≥ 5/group) but not RIPerC (18.0 ± 3.4% with RIPerC + Wort versus 18.2 ± 2.0% with RIPerC:
P
> 0.05:
N
≥ 5/group). 8-SPT did not influence the infarct-limiting effects of either RIPC or RIPerC. Western blot analysis confirmed Wortmannin-sensitive PI3K and Akt activation at myocardial reperfusion in RIPC-treated hearts.
Conclusions
In the porcine heart, both RIPC and RIPerC both reduce myocardial infarct size and with RIPC but not RIPerC this cardioprotective effect is associated with the activation of the PI3K-Akt pathway at reperfusion.
The cross sections of nuclear reactions between the radioisotope Be7 and deuterium, a possible mechanism of reducing the production of mass-7 nuclides in big-bang nucleosynthesis, were measured at ...center-of-mass energies between 0.2 and 1.5 MeV. The measured cross sections are dominated by the (d,α) reaction channel, towards which prior experiments were mostly insensitive. A new resonance at 0.36(5) MeV with a strength of ωγ=1.7(5) keV was observed inside the relevant Gamow window. Calculations of nucleosynthesis outcomes based on the experimental cross section show that the resonance reduces the predicted abundance of primordial Li7, but not sufficiently to solve the primordial lithium problem.
We sought to determine whether DNA damage response (DDR)-related aberrations predict therapeutic benefit in cisplatin-treated head and neck squamous cell carcinoma (HNSCC) patients and how DDR ...pathways are modulated after treatment with olaparib alone or in combination with cisplatin or durvalumab.
Oxidative stress, abasic sites and DDR-related parameters, including endogenous DNA damage, DNA repair mechanisms and apoptosis rates, were evaluated in HNSCC cell lines and peripheral blood mononuclear cells from 46 healthy controls (HC) and 70 HNSCC patients at baseline and following treatment with cisplatin-containing chemoradiation or nivolumab or enrolled in the OPHELIA phase II trial (NCT02882308; olaparib alone, olaparib plus cisplatin, olaparib plus durvalumab).
HNSCC patients at diagnosis exhibited deregulated DDR-related parameters and higher levels of oxidative stress and abasic sites compared with HC (all P < 0.05). Accordingly, nucleotide excision repair (NER; ERCC1, ERCC2/XPD, XPA, XPC) and base excision repair (APEX1, XRCC1) genes were downregulated in patients versus HC whereas double-strand breaks repair (MRE11A, RAD50, RAD51, XRCC2) and mismatch repair (MLH1, MSH2, MSH3) genes were overexpressed. Corresponding results were obtained in cell lines (all P < 0.001). Excellent correlations were observed between individual ex vivo and in vivo/therapeutic results, with cisplatin non-responders showing higher levels of endogenous DNA damage, augmented oxidative stress and abasic sites, increased NER capacities and reduced apoptosis than responders (all P < 0.05). Also, longer progression-free survival correlated with lower NER capacity (P = 0.037) and increased apoptosis (P = 0.029). Interestingly, treatment with olaparib-containing regimens results in the accumulation of cytotoxic DNA damage and exerts an extra antitumor effect by elevating oxidative stress (all P < 0.05). Nivolumab induced no significant changes in the DDR parameters examined.
Aberrations in DDR signals are implicated in the response to HNSCC chemotherapy and can be exploited as novel therapeutic targets, sensitive/effective non-invasive biomarkers as well as for the design of novel clinical trials.
•HNSCC patients at diagnosis show defective DDR network and higher levels of oxidative stress compared with HC.•DDR aberrations and oxidative stress status in PBMCs appear to correlate with the response to cisplatin-based therapy.•Olaparib treatment modulates DDR network and exerts extra antitumor effect by elevating oxidative stress in HNSCC patients.•DDR aberrations in PBMCs may potentially be exploited as novel therapeutic targets and non-invasive predictive biomarkers.
The effectiveness of postconditioning (POC) in hypercholesterolaemia is in dispute. We investigated the effects of 3-day lipophilc (simvastatin) or hydrophilic (pravastatin) statin treatment, without ...or with POC in normocholesterolaemic (Norm) and hypercholesterolaemic (Chol) rabbits.
Norm or Chol rabbits were subjected to 30 min ischaemia and randomized in two series of 12 groups each: control, simvastatin (Sim), pravastatin (Prav), POC, Sim-POC, Prav-POC, Chol, Sim-Chol, Prav-Chol, POC-Chol, Sim-POC-Chol, Prav-POC-Chol. After ischaemia, rabbits of the first series underwent 3 h reperfusion, followed by infarct size, total cholesterol, and low density lipoprotein plasma level evaluation; animals of the second series underwent 10 min reperfusion followed by tissue sampling for nitrotyrosine (NT), malondialdehyde, endothelial nitric oxide synthase (eNOS), and Akt analyses. N-nitro-l-arginine methylester (L-NAME) was given in two additional groups (POC-L-NAME and Prav-Chol-L-NAME) for infarct size assessment. All interventions reduced infarction in Norm (24.3 ± 1.3, 25.9 ± 2.8, 27.9 ± 3.1, 23.3 ± 2.3, and 33.4 ± 2.5%, in POC, Sim, Prav, Sim-POC, and Prav-POC groups, respectively, vs. 49.3 ± 1.9% in control, P < 0.05), but only Prav did so in Chol animals (25.7 ± 3.3 and 25.3 ± 3.9% in Prav-Chol and Prav-POC-Chol vs. 50.9 ± 1.7, 44.8 ± 4.3, 41.5 ± 3.5, and 49.3 ± 5.5% in Chol, Sim-Chol, POC-Chol, and Sim-POC-Chol, respectively, P < 0.05). L-NAME abolished the infarct size-limiting effect of POC and Prav-Chol. Prav induced the greatest reduction in NT, while it was the only intervention that increased myocardial eNOS and Akt in Chol rabbits (P < 0.05 vs. all others).
Prav, in contrast to same-dose Sim or POC, reduces infarction in Chol rabbits independently of lipid lowering, potentially through eNOS activation and nitro-oxidative stress attenuation.
The Antikythera Mechanism, the technologically advanced Greek computer of around 150–100B.C., was found in 1900. In the almost 110years since his recovery, the Mechanism has been largely ...investigated. It is now known that 30 gears have survived and that others are still missing. The construction of a working model of the Antikythera Mechanism would serve to investigate the accuracy of its predictions. Such a construction would though need determination with high precision of the geometrical characteristics of its gears. In this paper the geometrical dimensions of the gears needed for an operational model of the Antikythera Mechanism are being investigated.
► We investigate the Antikythera Mechanism. ► We determined the geometrical characteristics for the construction of a working model. ► We used the measurements of all gears found in the fragments of the Mechanism. ► We determined the root angle, the module and the chord length of all gears. ► We calculated the axial distances of all cooperating gears.
The main dials of the back face of the Antikythera Mechanism have partially survived together with the pointer of the upper dial and a few remains of the mechanism that supported and rotated it. The ...reconstruction of this mechanism, described in this article, fits perfectly its description in the Mechanism’s inscriptions. Our results also show that both spirals were Half Circles spirals, drawn from two different centres. The unwanted eccentricity that would be produced from the pointer’s being placed at one of the centres is proven to have been ingeniously avoided with the appropriate drawing of the cell divisions.
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