The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma.

Background: The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood.

Methods: We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1-ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion.

The Influence of Gender and Age on the Outcomes of and Adherence to a Digital Interdisciplinary Mental Health Promotion Intervention in an Australasian Nonclinical Setting: Cohort Study.

Background: The global prevalence of mental health disorders is at a crisis point, particularly in the wake of COVID-19, prompting calls for the development of digital interdisciplinary mental health promotion interventions (MHPIs) for nonclinical cohorts. However, the influence of gender and age on the outcomes of and adherence to MHPIs is not well understood.

Objective: The aim of this study was to determine the influence of gender and age on the outcomes of and adherence to a 10-week digital interdisciplinary MHPI that integrates strategies from positive psychology and lifestyle medicine and utilizes persuasive systems design (PSD) principles in a nonclinical setting.

The Influence of Human Support on the Effectiveness of Digital Mental Health Promotion Interventions for the General Population.

Mental wellbeing amongst the general population is languishing-exacerbated by the Coronavirus Disease 2019 (COVID-19) pandemic. Digital mental health promotion interventions, that improve mental health literacy and encourage adoption of evidence-informed practical strategies are essential. However, attrition and non-adherence are problematic in digital interventions.

The effectiveness of an online interdisciplinary intervention for mental health promotion: a randomized controlled trial.

Background: There is an urgent need for efficacious interventions to combat the global mental health crisis, and mental health promotion and primary prevention approaches are paramount. The aim of this study is to examine whether an online interdisciplinary intervention that incorporates evidence-based strategies from the disciplines of Lifestyle Medicine and Positive Psychology improves measures of mental health and emotional wellness.

Methods: A randomized controlled trial with a wait-list control (N = 425, aged 46.

Participant Perceptions of Facilitators and Barriers to Adherence in a Digital Mental Health Intervention for a Nonclinical Cohort: Content Analysis.

Background: Digital mental health promotion interventions (MHPIs) present a scalable opportunity to attenuate the risk of mental health distress among nonclinical cohorts. However, adherence is frequently suboptimal, and little is known about participants' perspectives concerning facilitators and barriers to adherence in community-based settings.

Objective: This study aimed to examine participants' perceptions of facilitators and barriers to adherence in a web- and mobile app-based MHPI for a nonclinical cohort.

Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft.

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood-derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME).

The Influence of Three Modes of Human Support on Attrition and Adherence to a Web- and Mobile App-Based Mental Health Promotion Intervention in a Nonclinical Cohort: Randomized Comparative Study.

Background: The escalating prevalence of mental health disorders necessitates a greater focus on web- and mobile app-based mental health promotion initiatives for nonclinical groups. However, knowledge is scant regarding the influence of human support on attrition and adherence and participant preferences for support in nonclinical settings.

Objective: This study aimed to compare the influence of 3 modes of human support on attrition and adherence to a digital mental health intervention for a nonclinical cohort.

Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells.

Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying cross-talk between TAM and CSC in HNSCC remain largely unknown.

The humanized mouse: Emerging translational potential.

The humanized mouse (HM) has emerged as a valuable animal model in cancer research. Engrafted with components of a human immune system and subsequently implanted with tumor tissue from cell lines or in the form of patient-derived xenografts, the HM provides a unique platform in which the tumor microenvironment (TME) can be evaluated in vivo. This model may also be beneficial in the assessment of potential cancer treatments including immune checkpoint inhibitors.

Backshore nourishment of a beach degraded by off-road vehicles: Ecological impacts and benefits.

Worldwide, spoil from maintenance dredging of navigation channels is increasingly used to opportunistically nourish beaches. This is often justified on the presumption that nourishment will improve public beach amenity and restore sandy beach habitat. However, this is not necessarily the case, especially for beaches that do not have an immediate threat of significant erosion.

Inhibiting Translation Elongation with SVC112 Suppresses Cancer Stem Cells and Inhibits Growth in Head and Neck Squamous Carcinoma.

Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor.

A Web- and Mobile App-Based Mental Health Promotion Intervention Comparing Email, Short Message Service, and Videoconferencing Support for a Healthy Cohort: Randomized Comparative Study.

Background: The rapid increase in mental health disorders has prompted a call for greater focus on mental health promotion and primary prevention. Web- and mobile app-based interventions present a scalable opportunity. Little is known about the influence of human support on the outcomes of these interventions.

Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap.

Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highly immunodeficient mouse strains into which human immune systems can be engrafted can help bridge this gap.

Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2.

Background: We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus-positive (HPV-positive) and -negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown.

Methods: We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs).

An open source solution for an in-house built dynamic platform for the validation of stereotactic ablative body radiotherapy for VMAT and IMRT.

An in-house solution for the verification of dose delivered to a moving phantom as required for the clinical implementation of lung stereotactic ablative body radiation therapy was developed. The superior-inferior movement required to simulate tumour motion during a normal breathing cycle was achieved via the novel use of an Arduino Uno™, a low-cost open-source microcontroller board connected to a high torque servo motor. Slow CT imaging was used to acquire the image set and a 4D cone beam CT (4D-CBCT) verified the efficacy of contoured margins before treatment on the moving phantom.

Post-upgrade testing on a radiotherapy oncology information system with an embedded record and verify system following the IAEA Human Health Report No. 7 recommendations.

Record and verify (R&V) systems have proven that their application in radiotherapy clinics leads to a significant reduction in mis-treatments of patients. The purpose of this technical note is to share our experience of acceptance testing, commissioning and setting up a quality assurance programme for the MOSAIQ® oncology information system and R&V system after upgrading from software version 2.41 to 2.

Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers.

Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition, and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here, we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradiation, where it contributes to therapeutic inhibition.

1,1-Olefin-bridged bis-(2-indenyl) metallocenes of titanium and zirconium.

Tetrasubstituted alkenes bearing geminal 2-indenyl substituents--9-[bis(1H-inden-2-yl)methylidene]-9H-fluorene (6), 2,2'-(2,2-diphenylethene-1,1-diyl)-bis(1H-indene) (7), and 2,2'-(2-propylpent-1-ene-1,1-diyl)-bis(1H-indene) (8) have been synthesized and metallated to form a new class of ansa titanium and zirconium metallocene complexes containing a single sp(2)-hybridized carbon bridge. The synthesis of the tetramethylated bis-indenyl Zr-analog is described. In addition, the 1,1-bis-indenyl ethylene is prepared and the Zr complex is modified by olefin metathesis.

The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas.

The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from eight patients with HNSCC [four HPV-serotype16 (HPV16)-positive].

The transcription start site landscape of C. elegans.

More than half of Caenorhabditis elegans pre-mRNAs lose their original 5' ends in a process termed "trans-splicing" in which the RNA extending from the transcription start site (TSS) to the site of trans-splicing of the primary transcript, termed the "outron," is replaced with a 22-nt spliced leader. This complicates the mapping of TSSs, leading to a lack of available TSS mapping data for these genes. We used growth at low temperature and nuclear isolation to enrich for transcripts still containing outrons, applying a modified SAGE capture procedure and high-throughput sequencing to characterize 5' termini in this transcript population.

A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins.

Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies.

Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer.

The EGF receptor (EGFR)-directed monoclonal antibody cetuximab is the only targeted therapy approved for the treatment of squamous cell carcinoma of the head and neck (HNSCC) but is only effective in a minority of patients. Epithelial-to-mesenchymal transition (EMT) has been implicated as a drug resistance mechanism in multiple cancers, and the EGFR and Hedgehog pathways (HhP) are relevant to this process, but the interplay between the two pathways has not been defined in HNSCC. Here, we show that HNSCC cells that were naturally sensitive to EGFR inhibition over time developed increased expression of the HhP transcription factor GLI1 as they became resistant after long-term EGFR inhibitor exposure.

RNA processing in C. elegans.

In Caenorhabditis elegans, newly transcribed RNA is processed in several novel ways. Although introns are removed by a canonical spliceosome, they have evolved several specialized features that reflect the differences in the way they are recognized and the way they are spliced. C.

Titanium "constrained geometry" complexes with pendant arene groups.

The synthesis of the proligands C(5)Me(4)HSiMe(2)N(H)R) (R = CMe(2)Ph 1, 2-C(6)H(4)Ph 2) was accomplished via a straightforward salt metathesis reaction of the appropriate lithium amide and ClSiMe(2)(C(5)Me(5)H). Generation of the dilithio salt and reaction with TiCl(3)·(THF)(3) followed by oxidation gave C(5)Me(4)SiMe(2)N(C(6)H(4)Ph)TiCl(2) (3) in low yield. In contrast, deprotonation of 1 and 2 and reaction with (Me(2)N)(2)TiCl(2) afforded C(5)Me(4)(SiMe(2)NR)Ti(NMe(2))(2) (R = CMe(2)Ph 4, 2-C(6)H(4)Ph 5), respectively, in good yields Treatment with MeI gave the analogs C(5)Me(4)(SiMe(2)NR)TiI(2) (R = CMe(2)Ph 6, 2-C(6)H(4)Ph 7).

Identification of transcription start sites of trans-spliced genes: uncovering unusual operon arrangements.

In Caenorhabditis elegans, the transcripts of many genes are trans-spliced to an SL1 spliced leader, a process that removes the RNA extending from the transcription start site to the trans-splice site, thereby making it difficult to determine the position of the promoter. Here we use RT-PCR to identify promoters of trans-spliced genes. Many genes in C.