Profiling the heterogeneity of colorectal cancer consensus molecular subtypes using spatial transcriptomics.

The consensus molecular subtypes (CMS) of colorectal cancer (CRC) is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signals, such as the potential regulation of the ETV4 transcriptional activity by DCN or the PLAU-PLAUR ligand-receptor interaction. Our study illustrates the potential of ST to resolve CRC molecular heterogeneity and thereby help advance personalized therapy.

The fibroblast growth factor receptor 1 (FGFR1), a marker of response to chemoradiotherapy in breast cancer?

The goal of the present study was to evaluate the role of the tyrosine kinase receptor fibroblast growth factor-1 (FGFR1) and its ligand, the fibroblast growth factor 2 (FGF2) in determining the response to chemoradiotherapy of breast cancers. S14 was a phase II neoadjuvant study carried out at the Institut Curie that recruited 59 patients between November 2001 and September 2003. This prospective study aimed to assess the pathological response after preoperative radiochemotherapy (5FU-Navelbine-radiotherapy) for large breast cancers. The expression of FGFR1 and FGF2 in tumor cells were assessed by immunohistochemistry. Tumors in which no staining was seen, were considered as negative for that protein. We used the Khi-2 test or the Fisher test to compare the qualitative variables and the Student t test or the non-parametric Wilcoxon test for the quantitative variables. We included in the present study all the 32 patients from the S14 cohort for whom the tissue blocks from the biopsy specimens were available with sufficient tumoral tissue. FGFR1 and FGF2 staining were observed respectively in 17 (56%) and 22 (68%) of the 32 tumoral biopsies. The expression of FGFR1 was associated with the hormone receptor positive status (p=0.0191). Only 11% (1/9) of the high grade tumors failed to respond to chemoradiotherapy compared to 68 % resistant tumors (15/22) among the low/intermediate grade tumors (p=0.0199). Among the low/intermediate grade tumors, FGFR1 negative tumors did not respond to chemoradiotherapy (0/9), compared with tumors expressing FGFR1 among which, almost one half had a good response (6/13) (p=0.0167). Among the low and intermediate grade breast cancers, the FGFR1 negative tumors were resistant to chemoradiotherapy. The expression of FGFR1 in patients' biopsies may serve as a marker of response to chemoradiotherapy.

Setting up an acupuncture knee clinic under Practice Based Commissioning.

This paper outlines the setting up of a new service in primary care offering acupuncture to patients with severe osteoarthritis of the knee. The high volume clinic is funded under the Practice Based Commissioning initiative and is the first of its type in the UK. It appears to offer a model for similar services elsewhere.

Sense of sight: part two. Seeing in colour, detail and depth.

This article is the second in a three-part series on the sense of sight. It forms part of a larger series on the special senses. The first article on sight examined the structures of the eye, the visual pathway and various disorders of the eye. This second article explores how the eye sees colour, detail and depth.

Exploring various methods for closing traumatic wounds.

This article describes the advantages and disadvantages of various methods used to close traumatic wounds.

Hearing and balance. Part 1--the outer and middle ear.

This article is the first in a four-part series on hearing and balance, continuing our exploration of the senses. It discusses the outer and middle chambers of the ear, whose primary function is to transmit sound to the auditory receptors in the inner ear (Allan, 2005).

The management of animal and human bite wounds.

Every year, large numbers of people are bitten by animals, and a smaller number by humans. The consequences can be serious. However, better health education to help prevent bites and teaching a bite-avoidance strategy when someone is being treated for a bite may help to reduce the problem. This article discusses treatment options and the possible complications of bite wounds.

Characterization of Breast Cancer Preclinical Models Reveals a Specific Pattern of Macrophage Polarization.

Drug discovery efforts have focused on the tumor microenvironment in recent years. However, few studies have characterized the stroma component in patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs). In this study, we characterized the stroma in various models of breast cancer tumors in mice. We performed transcriptomic and flow cytometry analyses on murine populations for a series of 25 PDXs and the two most commonly used GEMs (MMTV-PyMT and MMTV-erBb2). We sorted macrophages from five models. We then profiled gene expression in these cells, which were also subjected to flow cytometry for phenotypic characterization. Hematopoietic cell composition, mostly macrophages and granulocytes, differed between tumors. Macrophages had a specific polarization phenotype related to their M1/M2 classification and associated with the expression of genes involved in the recruitment, invasion and metastasis processes. The heterogeneity of the stroma component of the models studied suggests that tumor cells modify their microenvironment to satisfy their needs. Our observations suggest that such models are of relevance for preclinical studies.

A model for acupuncture training in primary care.

A recent innovation in acupuncture training at a clinic in a primary care practice is reported. The trainer is a General Practitioner within the practice and the trainee an academic nurse. The semi-structured training programme is outlined and benefits and challenges to both trainer and trainee are discussed. The patients generally welcomed the scheme. We consider that the programme could provide a model for similar-training initiatives in the future.

Introducing voluntary donations to fund primary care acupuncture--a user survey.

An acupuncture clinic has been running in general practice without any funding for nine years. However, reorganisation of the health service meant that it had to become self-funding. A scheme for voluntary donations was introduced, with a target of l15 per treatment. In the first six months, the scheme covered the clinic's costs. A user survey was undertaken to elicit patients' views on the scheme. The majority of patients thought that the scheme was a good idea, and the amount about right. However, a few patients found payment difficult, and stated that they would be less likely to use the service for that reason, or feel guilty about using it without paying. This information should be used to try to obtain public funding through public funds in the future.

Wound closure.

This article is to provide emergency nurses with a knowledge and understanding of the wound healing process and the appropriate choice of method in wound closure.

Selecting a treatment option in subungual haematoma management.

A subungual haematoma is a collection of blood beneath a finger or toe nail. It is often caused by a crush injury (Purcell, 2003) such as shutting a finger in a door or other types of trauma. Heim et al (2000) note that these haematomas can also be caused by repetitive trauma in athletes such as runners and dancers.

The management of allergic reaction to venomous insect stings.

Insects that sting play a vital role in our ecosystem by consuming crop pests and by pollinating plants (Earth-Life Web Productions, 2004). Some of these insects, particularly bees and wasps (hymenoptera), can also deliver a painful and venomous sting. Their bodies contain a sac of venom attached to a stinger which is forced through the skin. The painful sting occurs when the sac contracts and venom is deposited in the tissues (Prodigy, 2004). The venom contains allergens that typically produce an intense, burning pain followed by erythema (redness) and a small area of oedema (up to 1 cm) which usually subsides within a few hours (Ewan, 1998a). Some people suffer more serious localised or systemic reactions including anaphylaxis. Every year in the UK between two and nine people die as a consequence of a severe allergic reaction to a bee or wasp sting (The Anaphylaxis Campaign, 2004).

Acute wounds: an overview of the physiological healing process.

When an injury occurs and the skin is damaged, the process of tissue repair begins immediately, but some wounds can take up to two years or more to heal completely. Healing is usually categorised into stages to aid understanding of the complex physiological processes that are occurring. However, it is a continuous process and different parts of a wound may be at different stages of healing at any one time.

Procedures for cleansing, closing and covering acute wounds.

Every wound and patient is different so there is no single method for the management of acute wounds. However, there are some guiding principles that can assist in the decision-making process. Most wounds are suitable for primary closure, for example with sutures, while for other wounds closure is either delayed or not attempted (healing by secondary intention). Atiyeh et al (2002) provide a list of the principles of wound care that must always be observed in order to avoid sepsis and to achieve optimal wound healing (Box 1).

Understanding the structure and function of the skin.

The skin is the body's largest organ. It measures about 1.5-2 m2 in adults and weighs about 15 per cent of total body weight. It is home to up to three million micro-organisms per cm2, which feed on its scales and secretions. Understanding this fascinating organ's functions will help us to assess patients' skin and evaluate its potential for healing following injury or disease.

Causes and effective management of insect bites in the UK.

Insects play an important role in maintaining the world's ecosystem (Zhu and Stiller, 2002) but many of them feed on other animals. Humans are relatively hairless and provide an easy target, especially when partly clothed (Cohn, 2003). Biting insects common to the UK include midges, gnats, mosquitoes, flies, fleas, lice, mites, ticks, and bedbugs (Fig 1).

The physiology of mucus and sputum production in the respiratory system.

The main function of the respiratory system is to draw air into the lungs to allow the exchange of gases with blood circulating to the lungs. This blood supplies the cells of the body with oxygen and removes the waste products of metabolism. Tissues of the respiratory tract are thin and delicate, and become thinnest at the surfaces of the aveoli, where gaseous exchange occurs. The body has a number of mechanisms which protect these tissues and ensure that debris and bacteria do not reach them.

Physiology for practice: the mechanisms controlling respiration.

Breathing, or respiration, is something we do not have to think about--it just happens; indeed, if we do think about it, our breathing pattern changes. Nurses count and record patients' respirations every day with perhaps little thought as to the physiological mechanisms that maintain this vital function, or to the wealth of information available from careful assessment of a patient's breathing. Knowledge of these processes is important to be able to understand the symptoms, treatment and management of respiratory disease.

Predictive gene signature of response to the anti-TweakR mAb PDL192 in patient-derived breast cancer xenografts.

PURPOSE: (1) To determine TweakR expression in human breast cancers (BC), (2) evaluate the antitumor effect of the anti-TweakR antibody PDL192, used alone or after chemotherapy-induced complete remission (CR), on patient-derived BC xenografts (PDX) and (3) define predictive markers of response. EXPERIMENTAL DESIGN: TweakR expression was analyzed by IHC on patients and PDXs BC samples. In vivo antitumor effect of PDL192 was evaluated on eight TweakR-positive BC PDXs alone or after complete remission induced by a combination of doxorubicin and cyclophosphamide. Using both responding and resistant PDX tumors after PDL192 administration, RT-QPCR were performed on a wide list of selected candidate genes to identify predictive markers of response. RESULTS: TweakR protein was expressed in about half of human BC samples. In vivo PDL192 treatment had significantly anti-tumor activity in 4 of 8 TweakR-positive BC PDXs, but no correlation between the expression level of the Tweak receptor and response to therapy was observed. PDL192 also significantly delayed tumor relapse after CR. Finally, an 8 gene signature was defined from sensitive and resistant PDXs. CONCLUSIONS: PDL192 was highly efficient in some BC PDXs. We found 8 genes that were differentially expressed in responding and resistant tumors and could constitute a gene expression signature which would need to be extended to other xenograft models for confirmation. These data confirm the therapeutic potential of TweakR targeting in BC and the possibility of prospectively selecting patients who might benefit from therapy.