Chromosomal radiosensitivity in two cell lineages derived from clinically radiosensitive cancer patients.

PURPOSE: Despite its prominent contribution to cancer cure and palliation, around 1% to 5% of cancer patients suffer serious side effects from radiotherapy. A cardinal goal in the fields of radiobiology and oncology is to predict normal tissue radiosensitivity of a cancer patient before radiotherapy. Higher tumor control rates are likely if radiotherapy individualization could be achieved by applying predictive approaches. EXPERIMENTAL DESIGN: Here, we make use of the cytokinesis block micronucleus assay to assess radiosensitivity in cell lines derived from two different cell lineages obtained from clinically radiosensitive patients. We determined the micronucleus frequency after graded doses of ionizing radiation to primary fibroblasts and lymphoblast cell lines derived from 36 highly radiosensitive cancer patients. RESULTS: Many cell lines, following exposure to ionizing radiation, from patients with severe clinical reactions to radiotherapy showed statistically significantly higher frequencies of micronuclei than those from patients who had normal reactions to radiotherapy. One individual revealed significantly higher micronucleus frequencies in both cell lineages. Interestingly, lymphoblast cell lines from one patient showed micronucleus frequencies similar to ataxia telangiectasia mutated-deficient cells. CONCLUSIONS: These results indicate that the micronucleus assay may have use for identifying predisposition to clinical radiosensitivity, at least in a subset of patients as a component of a pretreatment radiosensitivity assay for use in the clinic.     

Perceived future career prospects in general practice: quantitative results from questionnaire surveys of UK doctors

BackgroundThere are more studies of current job satisfaction among GPs than of their views about their future career prospects, although both are relevant to commitment to careers in general practice.AimTo report on the views of GPs compared with clinicians in other specialties about their future career prospects.MethodQuestionnaires were sent to the doctors at different times after graduation, ranging from 3 to 24 years.ResultsBased on the latest survey of each graduation year of the 20 940 responders, 66.2% of GPs and 74.2% of hospital doctors were positive about their prospects and 9.7% and 8.3%, respectively, were negative. However, with increasing time since graduation and increasing levels of seniority, GPs became less positive about their prospects; by contrast, over time, surgeons became more positive. Three to 5 years after graduation, 86.3% of those training in general practice were positive about their prospects compared with 52.9% of surgical trainees: in surveys conducted 12–24 years after graduation, 60.2% of GPs and 76.6% of surgeons were positive about their prospects.ConclusionGPs held broadly positive views of their career prospects, as did other doctors. However, there was an increase in negativity with increasing time since graduation that was not seen in hospital doctors. Research into the causes of this negativity and policy measures to ameliorate it would contribute to the continued commitment of GPs and may help to reduce attrition.     

Service Based Internship Training to Prepare Workers to Support the Recovery of People with Co-Occurring Substance Abuse and Mental Health Disorders

A repeated measures design was used to evaluate a 12 month on-site counsellor internship programme aimed at training staff to support the recovery needs of people with co-occurring substance use and mental health disorders. Fifty-four interns completed measures of recovery knowledge, attitudes, confidence/competence, as well as identifying significant learning events. Statistically significant improvements were found in terms of attitudes and confidence/competence, and only one recovery knowledge factor, ‘roles of self-definition and peers in recovery’. Recovery knowledge at the end of the internship was positively associated with increases in interns’ confidence/competence but was not associated with changes in the interns’ attitudes. The mentoring, training/feedback and observational elements of the internship programme were highly valued by interns. Competency based learning events were most frequently identified as significant. Strategies to increase self-directed and interpersonally focused learning, and specific personal recovery knowledge in training are discussed.     

Evidence-Based Strategies for the Treatment of Peritoneal Malignancies during Health Care Resource Restriction: The COVID-19 Pandemic

Background: The COVID-19 pandemic has put enormous pressure on hospital resources, and has affected all aspects of patient care. As operative volumes decrease, cancer surgeries must be triaged and prioritized with careful thought and attention to ensure maximal benefit for the maximum number of patients. Peritoneal malignancies present a unique challenge, as surgical management can be resource intensive, but patients have limited non-surgical treatment options. This review summarizes current data on outcomes and resource utilization to help inform decision-making and case prioritization in times of constrained health care resources. Methods: A rapid literature review was performed, examining surgical and non-surgical outcomes data for peritoneal malignancies. Narrative data synthesis was cross-referenced with relevant societal guidelines. Peritoneal malignancy surgeons and medical oncologists reviewed recommendations to establish a national perspective on case triage and mitigating treatment strategies. Results and Conclusions: Triage of peritoneal malignancies during this time of restricted health care resource is nuanced and requires multidisciplinary discussion with consideration of individual patient factors. Prioritization should be given to patients where delay may compromise resectability of disease, and where alternative treatment options are lacking. Mitigating strategies such as systemic chemotherapy and/or surgical deferral may be utilized with close surveillance for disease stability or progression, which may affect surgical urgency. Unique hospital capacity, and ability to manage the complex post-operative course for these patients must also be considered to ensure patient and system needs are aligned.     

CCL2 recruits T cells into the brain in a CCR2‐independent manner

CCL2 is a chemokine that can be induced during neuroinflammation to recruit immune cells, but its role in the central nervous system (CNS) is unclear. Our aim was to better understand its role. We induced CCL2 in CNS of naive CCL2‐deficient mice using intrathecally administered replication‐defective adenovirus and examined cell infiltration by flow cytometry. CCL2 expression induced pronounced and unexpected recruitment of regulatory and IFNγ‐producing T cells to CNS from blood, possibly related to defective egress of monocytes from CCL2‐deficient bone marrow. Infiltration also occurred in mice lacking CCR2, a receptor for CCL2. Expression of another receptor for CCL2, CCR4, and CXCR3, a receptor for CXCL10, which was also induced, were both increased in CCL2‐treated CNS. CCR4 was expressed by neurons and astrocytes as well as CD4 T cells, and CXCR3 was expressed by CD4 and CD8 T cells. Chemokine‐recruited T cells did not lead to CNS pathology. Our findings show a role for CCL2 in recruitment of CD4 T cells to the CNS and show that redundancy among chemokine receptors ensures optimal response.     

Metastasis-associated protein S100A4 induces a network of inflammatory cytokines that activate stromal cells to acquire pro-tumorigenic properties

Tumor cells have the ability to exploit stromal cells to facilitate metastasis. By using malignant melanoma as a model, we show that the stroma adjacent to metastatic lesions is enriched in the known metastasis-promoting protein S100A4. S100A4 stimulates cancer cells to secrete paracrine factors, such as inflammatory cytokines IL8, CCL2 and SAA, which activate stromal cells (endothelial cells and monocytes) so that they acquire tumor-supportive properties. Our data establishes S100A4 as an inducer of a cytokine network enabling tumor cells to engage angiogenic and inflammatory stromal cells, which might contribute to pro-metastatic activity of S100A4.     

Overexpression of the pp32r1 (ANP32C) oncogene or its functional mutant pp32r1Y140H confers enhanced resistance to FTY720 (Finguimod)

pp32r1 (ANP32C) is oncogenic and has been shown to be overexpressed in tumors of the breast, prostate, and pancreas. In this work we show that pp32 family proteins are able to bind to the sphingosine analog FTY720 (Finguimod). Molecular docking studies highlight that a conserved residue F136 is likely to be a key determinant of the FTY720 binding site on the pp32 leucine-rich repeat domain. Transduction of the renal carcinoma cell line ACHN or cervical cancer cell line HeLa with lentivirus expressing the oncogenic family member pp32r1 or a pp32r1Y140H functional mutant illustrated an enhanced resistance to FTY720 induced apoptosis. These findings highlight that certain cancers overexpressing pp32r1 or pp32r1 mutants are likely to demonstrate enhanced resistance to FTY720 treatment.