First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Low-level laser therapy for carpal tunnel syndrome: systematic review and network meta-analysis.

BACKGROUND: Splinting is recommended by various organisations as a non-surgical first-line treatment for carpal tunnel syndrome (CTS), despite the limited evidence supporting its effectiveness. Previous studies on the effectiveness of low-level laser therapy (LLLT) have reported mixed results, and this systematic review aimed to resolve this controversy. OBJECTIVE: To perform a network meta-analysis (NMA) for evaluating the effectiveness of LLLT compared with other conservative treatments for CTS. METHODS: Eighteen electronic databases were searched for potential randomised controlled trials (RCTs). RCTs evaluating LLLT or other non-surgical treatments as an add-on to splinting were included. Included RCTs measured at least one of the following three outcomes with validated instruments: pain, symptom severity and functional status. RESULTS: Six RCTs (418 patients) were included. NMA suggested that LLLT plus splinting has the highest probability (75%) of pain reduction, compared with sham laser plus splinting (61%), ultrasound plus splinting (57%) and splinting alone (8%). However, while LLLT plus splinting is significantly more effective than sham laser plus splinting for pain reduction, the magnitude is not clinically significant (Visual Analogue Scale mean difference -0.53cm, 95% confidence interval -1.01 to -0.05cm; P=0.03, I2=25%). The effect of LLLT plus splinting on symptom severity and functional status was not superior to splinting alone. CONCLUSION: The use of LLLT in addition to splinting for the management of CTS is not recommended, as LLLT offers limited additional benefits over splining alone in terms of pain reduction, reduction of symptom severity or improved functional status. PROSPERO for systematic reviews and meta-analyses registration number CRD42017082650.

Technique and preliminary findings for in vivo quantification of brain motion during injurious head impacts.

Computational models of the human brain are widely used in the evaluation and development of helmets and other protective equipment. These models are often attempted to be validated using cadaver tissue displacements despite studies showing neural tissue degrades quickly after death. Addressing this limitation, this study aimed to develop a technique for quantifying living brain motion in vivo using a closed head impact animal model of traumatic brain injury (TBI) called CHIMERA. We implanted radiopaque markers within the brain of three adult ferrets and resealed the skull while the animals were anesthetized. We affixed additional markers to the skull to track skull kinematics. The CHIMERA device delivered controlled, repeatable head impacts to the head of the animals while the impacts were fluoroscopically stereo-visualized. We observed that 1.5 mm stainless steel fiducials (∼8 times the density of the brain) migrated from their implanted positions while neutral density targets remained in their implanted position post-impact. Brain motion relative to the skull was quantified in neutral density target tests and showed increasing relative motion at higher head impact severities. We observed the motion of the brain lagged behind that of the skull, similar to previous studies. This technique can be used to obtain a comprehensive dataset of in vivo brain motion to validate computational models reflecting the mechanical properties of the living brain. The technique would also allow the mechanical response of in vivo brain tissue to be compared to cadaveric preparations for investigating the fidelity of current human computational brain models.

Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

BACKGROUND: Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors. PATIENTS AND METHODS: Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression. RESULTS: We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted. CONCLUSION: We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Gonadotropin-releasing hormone agonist induces downregulation of tensin 1 in women with endometriosis.

INTRODUCTION: Many cell migration-related molecules are associated with endometriosis. Tensin 1 (TNS1), which has been implicated in cell migration, may play a role in endometriosis. The study goal was to evaluate the TNS1 expression in endometrial tissue and serum from women with endometriosis treated with gonadotropin-releasing hormone agonist (GnRHa). MATERIAL AND METHODS: Tissue and serum samples were collected from women with endometriosis who were treated (n = 29) with GnRHa or untreated (n = 30). TNS1 mRNA was examined using quantitative PCR. TNS1 protein levels in tissue and serum samples were investigated using Western blot, immunohistochemistry and ELISA. Eleven women with endometriosis participated in a follow-up investigation of serum TNS1 before and after GnRHa treatment. RESULTS: TNS1 mRNA (P = 0.006) and protein (P = 0.001) were significantly downregulated in endometriotic tissue from women with endometriosis who received GnRHa. Immunolocalization of TNS1 showed strong expression in the epithelial and stromal cells of endometriotic tissue from women untreated with GnRHa, whereas endometriotic tissue from GnRHa-treated women showed low TNS1 expression. Follow-up monitoring of serum TNS1 concentration in 11 women showed an average decrease in concentration of 53%, from 294.9 ± 66.69 to 140.3 ± 55.21 pg/mL, following GnRHa treatment (P = 0.003). CONCLUSIONS: GnRHa induces downregulation of TNS1 in tissue and serum in women with endometriosis. These results emphasize the importance TNS1 as a potential therapeutic molecular target for the treatment of endometriosis with GnRHa.

Effectiveness of smartphone technologies on glycaemic control in patients with type 2 diabetes: systematic review with meta-analysis of 17 trials.

Patient education and behavioural interventions for self-management of type 2 diabetes mellitus (T2DM) are effective but place demands on manpower resources. This systematic review aimed to investigate the effectiveness of smartphone technologies (STs) for improving glycaemic control among T2DM patients. CENTRAL, MEDLINE, Embase, CINAHL and ScienceDirect were searched through December 2016. Randomized controlled trials comparing STs with usual diabetes care among T2DM patients and reporting change in glycated haemoglobin (HbA1c) level were included. Seventeen trials (2,225 participants) were included. There was a significant reduction in HbA1c (pooled weighted mean difference: -0.51%; 95% confidence interval: -0.71% to -0.30%; p < 0.001), favouring ST intervention. The pooled weighted mean difference was -0.83% in patients with T2DM <8.5 years and -0.22% in patients with T2DM ≥8.5 years, with significant subgroup difference (p = 0.007). No subgroup differences were found among different follow-up durations, trial locations, patients' age, healthcare provider contract time, baseline body mass index and baseline HbA1c. Compared with usual diabetes care, STs improved glycaemic control among T2DM patients, especially for patients at earlier disease stages (duration of diagnosis <8.5 years). STs could be a complement or alternative to labour-intensive patient education and behavioural interventions, but more studies on up-to-date technologies are needed.

Methodological quality of systematic reviews on treatments for depression: a cross-sectional study.

AIMS: Depression is one of the most common mental disorders and identifying effective treatment strategies is crucial for the control of depression. Well-conducted systematic reviews (SRs) and meta-analyses can provide the best evidence for supporting treatment decision-making. Nevertheless, the trustworthiness of conclusions can be limited by lack of methodological rigour. This study aims to assess the methodological quality of a representative sample of SRs on depression treatments. METHODS: A cross-sectional study on the bibliographical and methodological characteristics of SRs published on depression treatments trials was conducted. Two electronic databases (the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects) were searched for potential SRs. SRs with at least one meta-analysis on the effects of depression treatments were considered eligible. The methodological quality of included SRs was assessed using the validated AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool. The associations between bibliographical characteristics and scoring on AMSTAR items were analysed using logistic regression analysis. RESULTS: A total of 358 SRs were included and appraised. Over half of included SRs (n = 195) focused on non-pharmacological treatments and harms were reported in 45.5% (n = 163) of all studies. Studies varied in methods and reporting practices: only 112 (31.3%) took the risk of bias among primary studies into account when formulating conclusions; 245 (68.4%) did not fully declare conflict of interests; 93 (26.0%) reported an 'a priori' design and 104 (29.1%) provided lists of both included and excluded studies. Results from regression analyses showed: more recent publications were more likely to report 'a priori' designs [adjusted odds ratio (AOR) 1.31, 95% confidence interval (CI) 1.09-1.57], to describe study characteristics fully (AOR 1.16, 95% CI 1.06-1.28), and to assess presence of publication bias (AOR 1.13, 95% CI 1.06-1.19), but were less likely to list both included and excluded studies (AOR 0.86, 95% CI 0.81-0.92). SRs published in journals with higher impact factor (AOR 1.14, 95% CI 1.04-1.25), completed by more review authors (AOR 1.12, 95% CI 1.01-1.24) and SRs on non-pharmacological treatments (AOR 1.62, 95% CI 1.01-2.59) were associated with better performance in publication bias assessment. CONCLUSION: The methodological quality of included SRs is disappointing. Future SRs should strive to improve rigour by considering of risk of bias when formulating conclusions, reporting conflict of interests and authors should explicitly describe harms. SR authors should also use appropriate methods to combine the results, prevent language and publication biases, and ensure timely updates.

Interplay of hot electrons from localized and propagating plasmons.

Plasmon-induced hot-electron generation has recently received considerable interest and has been studied to develop novel applications in optoelectronics, photovoltaics and green chemistry. Such hot electrons are typically generated from either localized plasmons in metal nanoparticles or propagating plasmons in patterned metal nanostructures. Here we simultaneously generate these heterogeneous plasmon-induced hot electrons and exploit their cooperative interplay in a single metal-semiconductor device to demonstrate, as an example, wavelength-controlled polarity-switchable photoconductivity. Specifically, the dual-plasmon device produces a net photocurrent whose polarity is determined by the balance in population and directionality between the hot electrons from localized and propagating plasmons. The current responsivity and polarity-switching wavelength of the device can be varied over the entire visible spectrum by tailoring the hot-electron interplay in various ways. This phenomenon may provide flexibility to manipulate the electrical output from light-matter interaction and offer opportunities for biosensors, long-distance communications, and photoconversion applications.Plasmon-induced hot electrons have potential applications spanning photodetection and photocatalysis. Here, Hoang et al. study the interplay between hot electrons generated by localized and propagating plasmons, and demonstrate wavelength-controlled polarity-switchable photoconductivity.

Receipt of thyroid hormone deficiency treatment and risk of herpes zoster.

OBJECTIVE: Thyroid hormone (TH) has been suggested to control herpes virus gene expression and replication in neurons via epigenetics through its nuclear receptors. It has previously been shown that patients with hypothyroidism are predisposed to herpes zoster (HZ), suggesting that the TH deficiency may be a risk factor for varicella zoster virus (VZV) reactivation. The aim of this study was to test the hypothesis that TH treatment will ameliorate the complication of HZ. METHODS: This study investigated the hypothesis by enquiring into a comprehensive medical database at Kaiser Permanente Southern California (KPSC) to verify whether patients taking TH medication experience a reduction in HZ occurrence. RESULTS: It was shown by Kaplan-Meier analysis that hypothyroidism patients taking TH medicines had a lower risk of HZ. The fully adjusted analysis indicated that patients receiving medication for the treatment of TH deficiency exhibited a reduced risk of HZ (hazard ratio 0.60, 95% confidence interval 0.51-0.71). This lower risk of HZ was significant in all age groups except the 18-39 years cohort. In addition, female patients taking TH treatment exhibited a lower risk than their male counterparts. CONCLUSIONS: Together these findings support the hypothesis that a constant level of TH will provide a degree of protection from contracting HZ. More studies are underway to evaluate the laboratory data for an analysis of hormonal effects on individuals.

Discovery and preliminary structure-activity relationship of the marine natural product manzamines as herpes simplex virus type-1 inhibitors.

Herpes simplex virus type-1 (HSV-1) is a member of alpha-herpesviridae family and is known to cause contagious human infections. The marine habitat is a rich source of structurally unique bioactive secondary metabolites. A small library of marine natural product classes 1-10 has been screened to discover a new hit entity active against HSV-1. Manzamine A showed potent activity against HSV-1 via targeting the viral gene ICP0. Manzamine A is a ß-carboline alkaloid isolated from the Indo-Pacific sponge Acanthostrongylophora species. Currently, acyclovir is the drug of choice for HSV-1 infections. Compared with 50 µM acyclovir, manzamine A at 1 µM concentration produced potent repressive effects on viral replication and release of infectious viruses in SIRC cells in recent studies. The potent anti-HSV-1 activity of manzamine A prompted a preliminary structure-activity relationship study by testing targeted manzamines. These included 8-hydroxymanzamine A (11), to test the effect of the C-8 hydroxy substitution at the ß-carboline moiety; manzamine E (12), to assess the importance of substitution at the azacyclooctane ring; and ircinal A (13), to determine whether the ß-carboline ring is required for the activity. Manzamine A was chemically transformed to its salt forms, manzamine A monohydrochloride (14) and manzamine A monotartrate (15), to test whether improving water solubility and hydrophilicity will positively affect the activity. Compounds were tested for activity against HSV-1 using fluorescent microscopy and plaque assay. The results showed the reduced anti-HSV-1 activity of 11, suggesting that C-8 hydroxy substitution might adversely affect the activity. Similarly, manzamines 12 and 13 showed no activity against HSV-1, indicating the preference of the unsubstituted azacylcooctane and ß-carboline rings to the activity. Anti-HSV-1 activity was significantly improved for the manzamine A salts 14 and 15, suggesting that improving the overall water solubility as salt forms can significantly enhance the activity. Manzamines have significant potential for future development as anti-HSV-1 entity.

An epithelial marker promoter induction screen identifies histone deacetylase inhibitors to restore epithelial differentiation and abolishes anchorage independence growth in cancers.

Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin. An expanded screen on 41 HDACi further identifies 28 compounds, such as class I-specific HDACi Mocetinosat, Entinostat and CI994, to restore E-cadherin and ErbB3 expressions in ovarian, pancreatic and bladder carcinoma cells. Mocetinostat is the most potent HDACi to restore epithelial differentiation with the lowest concentration required for 50% induction of epithelial promoter activity (EpIC-50).The HDACi exerts paradoxical effects on EMT transcriptional factors such as SNAI and ZEB family and the effects are context-dependent in epithelial- and mesenchymal-like cells. In vitro functional studies further show that HDACi induced significant increase in anoikis and decrease in spheroid formation in ovarian and bladder carcinoma cells with mesenchymal features. This study demonstrates a robust drug screening pipeline for the discovery of compounds capable of restoring epithelial differentiation that lead to significant functional lethality.

Metamaterial-enhanced vibrational absorption spectroscopy for the detection of protein molecules.

From visible to mid-infrared frequencies, molecular sensing has been a major successful application of plasmonics because of the enormous enhancement of the surface electromagnetic nearfield associated with the induced collective motion of surface free carriers excited by the probe light. However, in the lower-energy terahertz (THz) region, sensing by detecting molecular vibrations is still challenging because of low sensitivity, complicated spectral features, and relatively little accumulated knowledge of molecules. Here, we report the use of a micron-scale thin-slab metamaterial (MM) architecture, which functions as an amplifier for enhancing the absorption signal of the THz vibration of an ultrathin adsorbed layer of large organic molecules. We examined bovine serum albumin (BSA) as a prototype large protein molecule and Rhodamine 6G (Rh6G) and 3,3'-diethylthiatricarbocyanine iodide (DTTCI) as examples of small molecules. Among them, our MM significantly magnified only the signal strength of bulky BSA. On the other hand, DTTCI and Rh6G are inactive, as they lack low-frequency vibrational modes in this frequency region. The results obtained here clearly demonstrate the promise of MM-enhanced absorption spectroscopy in the THz region for detection and structural monitoring of large biomolecules such as proteins or pathogenic enzymes.

Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.

An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530).

The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

Monitoring the presence of ionic mercury in environmental water by plasmon-enhanced infrared spectroscopy.

We demonstrate the ppt-level single-step selective monitoring of the presence of mercury ions (Hg²âº) dissolved in environmental water by plasmon-enhanced vibrational spectroscopy. We combined a nanogap-optimized mid-infrared plasmonic structure with mercury-binding DNA aptamers to monitor in-situ the spectral evolution of the vibrational signal of the DNA induced by the mercury binding. Here, we adopted single-stranded thiolated 15-base DNA oligonucleotides that are immobilized on the Au surface and show strong specificity to Hg²âº. The mercury-associated distinct signal is located apart from the biomolecule-associated broad signals and is selectively characterized. For example, with natural water from Lake Kasumigaura (Ibaraki Prefecture, Japan), direct detection of Hg²âº with a concentration as low as 37 ppt (37 × 10⁻¹°%) was readily demonstrated, indicating the high potential of this simple method for environmental and chemical sensing of metallic species in aqueous solution.