High Response Rate to Carboplatin-Paclitaxel-Cetuximab and Pembrolizumab in Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

The management of R/M HNSCC is rapidly evolving with new available treatment molecules and combination modalities. Anti-EGFR cetuximab (CTX) and immune checkpoint inhibitors (ICI) can be used either alone or in combination with conventional platinum-based doublet chemotherapy (with taxanes or fluorouracil). No data have been reported to date on the association of doublet chemotherapy concomitantly with both CTX and ICI. We present a case series of patients treated with 4 cycles of quadritherapy, every 3 weeks, including paclitaxel 175 mg/m2, carboplatin AUC 5, pembrolizumab 200 mg, and weekly 250 mg/m2 CTX. All patients achieved an objective response (6 complete responses, 2 partial responses). Clinical response was fast, so 1 patient avoided an emergency tracheostomy for laryngeal dyspnea. Four patients furtherly benefited from cisplatin-based chemoradiotherapy on residual tumor sites after the response to quadritherapy. Adverse events were manageable, except for an ICI-related liver toxicity in a patient. Overall, this short series indicates that a quadruple therapy with carboplatin-paclitaxel-CTX and pembrolizumab seems to be safe and active in patients with R/M HNSCC. This observation could be confirmed through further clinical trials.

Radiotherapy of the Primary Disease for Synchronous Metastatic Cancer: A Systematic Review.

In the case of synchronous metastatic disease, the local treatment of primary tumors by radiotherapy has long been reserved for palliative indications. The emergence of the concept of oligometastatic and oligopersistent diseases, the advent of new systemic therapies enabling longer overall survival with an enhanced quality of life, a better understanding of the biologic history of metastatic spread, and technical advances in radiation therapy are revolutionizing the management of patients with de novo metastatic cancer. The prognosis of these patients has been markedly improved and many studies have investigated the survival benefits from the local treatment of various primary tumors in cases of advanced disease at the time of diagnosis or in the case of oligopersistence. This article provides an update on the place of irradiation of the primary tumor in cancer with synchronous metastases, and discusses its interest through published or ongoing trials.

Current Standards in the Management of Early and Locally Advanced Cervical Cancer: Update on the Benefit of Neoadjuvant/Adjuvant Strategies.

Globally, cervical cancers continue to be one of the leading causes of cancer-related deaths. The primary treatment of patients with early-stage disease includes surgery or radiation therapy with or without chemotherapy. The main challenge in treating these patients is to maintain a curative approach and limit treatment-related morbidity. Traditionally, inoperable patients are treated with radiation therapy solely and operable patients undergo upfront surgery followed by adjuvant (chemo) radiotherapy in cases with poor histopathological prognostic features. Patients with locally advanced cervical cancers are treated with concurrent chemoradiotherapy followed by an image-guided brachytherapy boost. In these patients, the main pattern of failure is distant relapse, encouraging intensification of systemic treatments to improve disease control. Ongoing trials are evaluating immunotherapy in locally advanced tumours following its encouraging efficacy reported in the recurrent and metastatic settings. In this article, clinical evidence of neoadjuvant and adjuvant treatments in cervical cancer patients is reviewed, with a focus on potential strategies to improve patients' outcome and minimize treatment-related morbidity.

High-FOM Temperature Sensing Based on Hg-EIT-Like Liquid Metamaterial Unit.

High-performance temperature sensing is a key technique in modern Internet of Things. However, it is hard to attain a high precision while achieving a compact size for wireless sensing. Recently, metamaterials have been proposed to design a microwave, wireless temperature sensor, but precision is still an unsolved problem. By combining the high-quality factor (Q-factor) feature of a EIT-like metamaterial unit and the large temperature-sensing sensitivity performance of liquid metals, this paper designs and experimentally investigates an Hg-EIT-like metamaterial unit block for high figure-of-merit (FOM) temperature-sensing applications. A measured FOM of about 0.68 is realized, which is larger than most of the reported metamaterial-inspired temperature sensors.

Combined modality including novel sensitizers in gynecological cancers.

Standard treatment of locally advanced gynecological cancers relies mainly on platinum-based concurrent chemoradiotherapy followed by brachytherapy. Current chemotherapeutic drugs are only transiently effective and patients with advanced disease often develop resistance and subsequently, distant metastases despite significant initial responses of the primary tumor. In addition, some patients still develop local failure or progression, suggesting that there is still a place for increasing the anti-tumor radiation effect. Several strategies are being developed to increase the probability of curing patients. Vaginal cancer and vulva cancer are rare diseases, which resemble cervical cancer in their histology and pathogenesis. These gynecological cancers are predominantly associated with human papilloma virus infection. Treatment strategies in other unresectable gynecologic cancers are usually derived from evidence in locally advanced cervical cancers. In this review, we discuss mechanisms by which novel therapies could work synergistically with conventional chemoradiotherapy, from pre-clinical and ongoing clinical data. Trimodal, even quadrimodal treatment are currently being tested in clinical trials. Novel combinations derived from a metastatic setting, and being tested in locally advanced tumors, include anti-angiogenic agents, immunotherapy, tumor-infiltrating lymphocytes therapy, adoptive T-cell therapy and apoptosis inducers to enhance chemoradiotherapy efficacy through complementary molecular pathways. In parallel, radiosensitizers, such as nanoparticles and radiosensitizers of hypoxia aim to maximize the effect of radiotherapy locally.

Research on the reflection-type ELC-based optomechanical metamaterial.

In this paper, we propose a new kind of optomechanical metamaterial based on a planar ELC-type absorbing structure fabricated on the low-loss flexible substrate. The nonlinear coupling mechanism and nonlinear response phenomenon of the proposed optomechanical metamaterial driven by electromagnetic induced force are analyzed theoretically. The mechanical deformation/displacement and the mechanical resonance frequency shift of the metamaterial unit deposed on the flexible substrate are also numerically and experimentally demonstrated to reveal the coupling phenomenon of electromagnetic field and mechanical field. These results will help researchers to further understand the multi-physics interactions of optomechanical metamaterials and will promote the developments of new type of metasurface for high-efficiency dynamic electromagnetic wave controlling and formatting.

Thermally tunable high-Q metamaterial and sensing application based on liquid metals.

Achieving a high Q-factor metamaterial unit for a precision sensing application is highly demanded in recent years, and most of the developed high-performance sensors based on the high-Q metamaterial units are due to the dielectric/magnetic property changes of the substrate/superstrate. In this paper, we propose a completely different sensing metamaterial unit configuration, with good sensing sensitivity and precision properties, based on the thermally tunable liquid metals. Specifically, a basic thermally tunable metamaterial unit, the mercury-inspired split ring resonator (SRR), is firstly presented to theoretically show the magnetic resonance and negative permeability frequency band shift properties under different background temperatures. Then, considering the radiation loss mechanism of the conventional SRR metamaterial unit and based on the physically reliable ability of liquid metals, the modified mercury-inspired Fano and toroidal resonators with a large frequency tuning range and high Q-factor are developed and discussed. The numerical demonstrations have shown that the designed Fano and toroidal resonators have much better sensing precision performances compared to the conventional SRR for the temperature sensing application. The experimental demonstrations have also been used to verify the proposed mercury-based toroidal resonators, and good agreements are achieved.

The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells.

The transcription factor TCF7L2 remains the most important diabetes gene identified to date and genetic risk carriers exhibit lower insulin secretion. We show that Tcf7l2 regulates the auxiliary subunit of voltage-gated Ca2+ channels, Cacna2d1 gene/α2δ-1 protein levels. Furthermore, suppression of α2δ-1 decreased voltage-gated Ca2+ currents and high glucose/depolarization-evoked Ca2+ signaling which mimicked the effect of silencing of Tcf7l2. This appears to be the result of impaired voltage-gated Ca2+ channel trafficking to the plasma membrane, as Cav1.2 channels accumulated in the recycling endosomes after α2δ-1 suppression, in clonal as well as primary rodent beta-cells. This impaired the capacity for glucose-induced insulin secretion in Cacna2d1-silenced cells. Overexpression of α2δ-1 increased high-glucose/K+-stimulated insulin secretion. Furthermore, overexpression of α2δ-1 in Tcf7l2-silenced cells rescued the Tcf7l2-dependent impairment of Ca2+ signaling, but not the reduced insulin secretion. Taken together, these data clarify the connection between Tcf7l2, α2δ-1 in Ca2+-dependent insulin secretion.

N1-methylnicotinamide is a signalling molecule produced in skeletal muscle coordinating energy metabolism.

Obesity is a major health problem, and although caloric restriction and exercise are successful strategies to lose adipose tissue in obese individuals, a simultaneous decrease in skeletal muscle mass, negatively effects metabolism and muscle function. To deeper understand molecular events occurring in muscle during weight-loss, we measured the expressional change in human skeletal muscle following a combination of severe caloric restriction and exercise over 4 days in 15 Swedish men. Key metabolic genes were regulated after the intervention, indicating a shift from carbohydrate to fat metabolism. Nicotinamide N-methyltransferase (NNMT) was the most consistently upregulated gene following the energy-deficit exercise. Circulating levels of N1-methylnicotinamide (MNA), the product of NNMT activity, were doubled after the intervention. The fasting-fed state was an important determinant of plasma MNA levels, peaking at ~18 h of fasting and being lowest ~3 h after a meal. In culture, MNA was secreted by isolated human myotubes and stimulated lipolysis directly, with no effect on glucagon or insulin secretion. We propose that MNA is a novel myokine that enhances the utilization of energy stores in response to low muscle energy availability. Future research should focus on applying MNA as a biomarker to identify individuals with metabolic disturbances at an early stage.

Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals: implications for insulin signalling and glucose uptake in human adipocytes.

AIMS/HYPOTHESIS: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes. METHODS: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables. SIK2 and SIK3 expression and phosphorylation were analysed in adipocytes treated with TNF-α. Glucose uptake, GLUT protein levels and localisation, phosphorylation of protein kinase B (PKB/Akt) and the SIK substrate histone deacetylase 4 (HDAC4) were analysed after the SIKs had been silenced using small interfering RNA (siRNA) or inhibited using a pan-SIK-inhibitor (HG-9-91-01). RESULTS: We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. Moreover, SIK2 protein levels and specific kinase activity display a negative correlation to BMI in human adipocytes. Furthermore, SIK2 and SIK3 are downregulated by TNF-α in adipocytes. Silencing or inhibiting SIK1-3 in adipocytes results in reduced phosphorylation of HDAC4 and PKB/Akt, less GLUT4 at the plasma membrane, and lower basal and insulin-stimulated glucose uptake in adipocytes. CONCLUSION/INTERPRETATION: This is the first study to describe the expression and function of SIKs in human adipocytes. Our data suggest that SIKs might be protective in the development of obesity-induced insulin resistance, with implications for future treatment strategies.

Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified more than 65 genetic loci associated with risk of type 2 diabetes. However, the contribution of distorted parental transmission of alleles to risk of type 2 diabetes has been mostly unexplored. Our goal was therefore to search for parent-of-origin effects (POE) among type 2 diabetes loci in families. METHODS: Families from the Botnia study (n = 4,211, 1,083 families) were genotyped for 72 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and assessed for POE on type 2 diabetes. The family-based Hungarian Transdanubian Biobank (HTB) (n = 1,463, >135 families) was used to replicate SNPs showing POE. Association of type 2 diabetes loci within families was also tested. RESULTS: Three loci showed nominal POE, including the previously reported variants in KCNQ1, for type 2 diabetes in families from Botnia (rs2237895: p POE = 0.037), which can be considered positive controls. The strongest POE was seen for rs7578597 SNP in the THADA gene, showing excess transmission of the maternal risk allele T to diabetic offspring (Botnia: p POE = 0.01; HTB p POE = 0.045). These data are consistent with previous evidence of allelic imbalance for expression in islets, suggesting that the THADA gene can be imprinted in a POE-specific fashion. Five CpG sites, including those flanking rs7578597, showed differential methylation between diabetic and non-diabetic donor islets. CONCLUSIONS/INTERPRETATION: Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.

HMGB1 binds to the rs7903146 locus in TCF7L2 in human pancreatic islets.

The intronic SNP rs7903146 in the T-cell factor 7-like 2 gene (TCF7L2) is the common genetic variant most highly associated with Type 2 diabetes known to date. The risk T-allele is located in an open chromatin region specific to human pancreatic islets of Langerhans, thereby accessible for binding of regulatory proteins. The risk T-allele locus exhibits stronger enhancer activity compared to the non-risk C-allele. The aim of this study was to identify transcriptional regulators that bind the open chromatin region in the rs7903146 locus and thereby potentially regulate TCF7L2 expression and activity. Using affinity chromatography followed by Edman sequencing, we identified one candidate regulatory protein, i.e. high-mobility group protein B1 (HMGB1). The binding of HMGB1 to the rs7903146 locus was confirmed in pancreatic islets from human deceased donors, in HCT116 and in HEK293 cell lines using: (i) protein purification on affinity columns followed by Western blot, (ii) chromatin immunoprecipitation followed by qPCR and (iii) electrophoretic mobility shift assay. The results also suggested that HMGB1 might have higher binding affinity to the C-allele of rs7903146 compared to the T-allele, which was supported in vitro using Dynamic Light Scattering, possibly in a tissue-specific manner. The functional consequence of HMGB1 depletion in HCT116 and INS1 cells was reduced insulin and TCF7L2 mRNA expression, TCF7L2 transcriptional activity and glucose stimulated insulin secretion. These findings suggest that the rs7903146 locus might exert its enhancer function by interacting with HMGB1 in an allele dependent manner.

TCF7L2 is a master regulator of insulin production and processing.

Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.

Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes.

A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly overexpressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1ß. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca(2+) channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.

A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets.

Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Using 48 genes located near T2D risk variants, we identified gene coexpression and protein-protein interaction networks that were strongly associated with islet insulin secretion and HbA(1c). We integrated our data to form a rank list of putative T2D genes, of which CHL1, LRFN2, RASGRP1, and PPM1K were validated in INS-1 cells to influence insulin secretion, whereas GPR120 affected apoptosis in islets. Expression variation of the top 20 genes explained 24% of the variance in HbA(1c) with no claim of the direction. The data present a global map of genes associated with islet dysfunction and demonstrate the value of systems genetics for the identification of genes potentially involved in T2D.

Survival of pancreatic beta cells is partly controlled by a TCF7L2-p53-p53INP1-dependent pathway.

The transcription factor T-cell factor 7-like 2 (TCF7L2) confers type 2 diabetes risk mainly through impaired insulin secretion, perturbed incretin effect and reduced beta-cell survival. The aim of this study was to identify the molecular mechanism through which TCF7L2 influences beta-cell survival. TCF7L2 target genes in INS-1 cells were identified using Chromatin Immunoprecipitation. Validation of targets was obtained by: siRNA silencing, real-time quantitative polymerase chain reaction, electrophoretic mobility shift assay, luciferase reporter assays and western blot. Apoptosis rate was measured by DNA degradation and caspase-3 content. Islet viability was estimated by measuring metabolic rate. TCF7L2 binds to 3646 gene promoters in INS-1 cells in high or low glucose, including Tp53, Pten, Uggt1, Adamts9 and Fto. SiRNA-mediated reduction in TCF7L2 activity resulted in increased apoptosis and increased expression of Tp53, which resulted in elevated p53 protein activity and an increased expression of the p53 target gene Tp53inp1 (encoding p53-induced-nuclear-protein 1). Reversing the increase in p53INP1 protein expression, seen after Tcf7l2 silencing, protected INS-1 cells from Tcf7l2 depletion-induced apoptosis. This result was replicated in primary rat islets. The risk T-allele of rs7903146 is associated with increased TCF7L2 mRNA expression and transcriptional activity. On the other hand, in vitro silencing of TCF7L2 lead to increased apoptosis. One possibility is that the risk T-allele increases expression of an inhibitory TCF7L2 isoform with lower transcriptional activity. These results identify the p53-p53INP1 pathway as a molecular mechanism through which TCF7L2 may affect beta-cell survival and established a molecular link between Tcf7l2 and two type 2 diabetes-associated genes, Tp53inp1 and Adamts9.

Molecular function of TCF7L2: Consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes.

TCF7L2 harbors the variant with the strongest effect on type 2 diabetes (T2D) identified to date, yet the molecular mechanism as to how variation in the gene increases the risk for developing T2D remains elusive. The phenotypic changes associated with the risk genotype suggest that T2D arises as a consequence of reduced islet mass and/or impaired function, and it has become clear that TCF7L2 plays an important role for several vital functions in the pancreatic islet. TCF7L2 comprises 17 exons, five of which are alternative (ie, exons 4 and 13-16). In pancreatic islets four splice variants of TCF7L2 are predominantly expressed. The regulation of these variants and the functional consequences at the protein level are still poorly understood. A clear picture of the molecular mechanism will be necessary to understand how an intronic variation in TCF7L2 can influence islet function.