Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab.

Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB.

The Temple Vie weight management and lifestyle programme: initial data and reflections on Covid-19.

During the first three months of the Temple Vie programme, average weight loss in 36 subjects exceeded 13 kg. There were associated improvements in Patient Reported Outcome Measures, blood pressure and serum lipids. The Covid-19 pandemic may focus attention on programmes that give rise to rapid weight loss and improvements in cardiovascular health parameters.

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases.

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants.

Wnt signaling dynamics in head and neck squamous cell cancer tumor-stroma interactions.

Wnt pathway activation maintains the cancer stem cell (CSC) phenotype and promotes tumor progression, making it an attractive target for anti-cancer therapy. Wnt signaling at the tumor and tumor microenvironment (TME) front have not been investigated in depth in head and neck squamous cell carcinoma (HNSCC). In a cohort of 48 HNSCCs, increased Wnt signaling, including Wnt genes (AXIN2, LGR6, WISP1) and stem cell factors (RET, SOX5, KIT), were associated with a more advanced clinical stage.

Prediction of acute myeloid leukaemia risk in healthy individuals.

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion.

Salivary Gland Cancer Patient-Derived Xenografts Enable Characterization of Cancer Stem Cells and New Gene Events Associated with Tumor Progression.

Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however, current models are limited both in their availability and suitability to characterize these rare cells. Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient. Patient and PDX samples were analyzed by RNA-seq and Exome-seq.

Patterns of facial trauma before and after legalization of marijuana in Denver, Colorado: A joint study between two Denver hospitals.

Introduction: The effect of marijuana on human health has been studied extensively. Marijuana intoxication has been shown to affect performance, attention span, and reaction time. The public health relationship between trauma and cannabis use has also been studied, with mixed conclusions.

Cobimetinib: inhibiting MEK1/2 in BRAF V600-mutant melanoma.

Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib.

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).

A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma.

Background: This phase 1, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), antitumor activity, and molecular correlates of IPI-926, a Hedgehog pathway (HhP) inhibitor, combined with cetuximab in patients with relapsed/metastatic squamous cell carcinoma of the head and neck.

Patients And Methods: Cetuximab was given with a 400mg/m(2) loading dose followed by 250mg/m(2) weekly. IPI-926 was given daily starting two weeks after cetuximab initiation.

Radiation dose uncertainty and correction for a mouse orthotopic and xenograft irradiation model.

Purpose: In animal irradiation models, reported dose can vary significantly from the actual doses delivered. We describe an effective method for in vivo dose verification.

Materials And Methods: Mice bearing commercially-available cell line or patient-derived tumor cell orthotopic or flank xenografts were irradiated using a 160 kVp, 25 mA X-ray source.

FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers.

Purpose: FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398.

Experimental Design: FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines.

An Inducible TGF-β2-TGFβR Pathway Modulates the Sensitivity of HNSCC Cells to Tyrosine Kinase Inhibitors Targeting Dominant Receptor Tyrosine Kinases.

The epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of head and neck squamous cell carcinomas (HNSCC), and molecularly targeted therapy against the EGFR with the monoclonal antibody cetuximab modestly increases overall survival in head and neck cancer patients. We hypothesize that co-signaling through additional pathways limits the efficacy of cetuximab and EGFR-specific tyrosine kinase inhibitors (TKIs) in the clinical treatment of HNSCC. Analysis of gene expression changes in HNSCC cell lines treated 4 days with TKIs targeting EGFR and/or fibroblast growth factor receptors (FGFRs) identified transforming growth factor beta 2 (TGF-β2) induction in the three cell lines tested.

XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer.

The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice).

Neural processes mediating the preparation and release of focal motor output are suppressed or absent during imagined movement.

Movements that are executed or imagined activate a similar subset of cortical regions, but the extent to which this activity represents functionally equivalent neural processes is unclear. During preparation for an executed movement, presentation of a startling acoustic stimulus (SAS) evokes a premature release of the planned movement with the spatial and temporal features of the tasks essentially intact. If imagined movement incorporates the same preparatory processes as executed movement, then a SAS should release the planned movement during preparation.

Transcranial direct current stimulation over the supplementary motor area modulates the preparatory activation level in the human motor system.

Transcranial direct current stimulation (tDCS) is a non-invasive stimulation method that can induce transient polarity-specific neuroplastic changes in cortical excitability lasting up to 1h post-stimulation. While excitability changes with stimulation over the primary motor cortex have been well documented, the functional effects of stimulation over premotor regions are less well understood. In the present experiment, we tested how cathodal and anodal tDCS applied over the region of the supplementary motor area (SMA) affected preparation and initiation of a voluntary movement.

Expressive and Instrumental Offending: Reconciling the Paradox of Specialisation and Versatility.

Although previous research into specialisation has been dominated by the debate over the existence of specialisation versus versatility, it is suggested that research needs to move beyond the restrictions of this dispute. The current study explores the criminal careers of 200 offenders based on their criminal records, obtained from a police database in the North West of England, aiming to understand the patterns and nature of specialisation by determining the presence of differentiation within their general offending behaviours and examining whether the framework of Expressive and Instrumental offending styles can account for any specialised tendencies that emerge. Fifty-eight offences were subjected to Smallest Space Analysis.

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.

Views of general practitioners in Grampian about undergraduate psychiatric teaching.

This paper reports the free-text responses of general practitioners (GPs) in the Grampian area to a questionnaire about their experiences of undergraduate psychiatry teaching. Most respondents were senior GPs whose undergraduate training had taken place a number of years ago. Respondents varied in their perceptions of the quality of their psychiatric teaching.

Pregnancy outcomes of women with and without a history of anorexia nervosa.

Background: When women have a history of anorexia nervosa (AN), the advice given about becoming pregnant, and about the management of pregnancies, has usually been cautious. This study compared the pregnancy outcomes of women with and without a history of AN.

Method: Women with a confirmed diagnosis of AN who had presented to psychiatric services in North East Scotland from 1965 to 2007 were identified.

Seasonal symptoms in bipolar and primary care patients.

Background: There is evidence of seasonality in bipolar affective disorder (BAD) and the preponderance of atypical symptoms in bipolar depressive episodes is also seen in winter type Seasonal Affective Disorder. Differences in seasonal symptoms between BAD and appropriate comparison populations have been scrutinised only in small studies.

Methods: Symptoms described on the Seasonal Pattern Assessment Questionnaire (SPAQ) were compared between 183 patients with BAD and 468 patients consulting their general practitioners.