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Abstract The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and the time scale at which such effects can occur following irradiation. To explore these phenomena, we exposed atheroprone ApoE(−/−) mice to a single dose of 0, 0.05, 0.5 or 1 Gy of 137Cs (γ) administered at a 10.35 mGy min−1 dose rate and evaluated short-term (1–10 days) and long-term consequences (100 days). Bone marrow-derived macrophages were derived from mice 1 day after exposure. Irradiation was associated with a significant skewing of M0 and M2 polarized macrophages towards the M2 phenotype, as demonstrated by an increased mRNA expression of Retnla, Arg1, and Chil3 in cells from mice exposed to 0.5 or 1 Gy compared with non-irradiated animals. Minimal effects were noted in M1 cells or M1 marker mRNA. Concurrently, we observed a reduced secretion of IL-1β but enhanced IL-10 release from M0 and M2 macrophages. Effects of irradiation on circulating monocytes were most marked at day 10 post-exposure, when the 1 Gy dose was associated with enhanced numbers of both Ly6CHigh and Ly6Low cells. By day 100, levels of circulating monocytes in irradiated and non-irradiated mice were equivalent, but anti-inflammatory Ly6CLow monocytes were significantly increased in the spleen of mice exposed to 0.05 or 1 Gy. Long term exposures did not affect atherosclerotic plaque size or lipid content, as determined by Oil red O staining, whatever the dose applied. Similarly, irradiation did not affect atherosclerotic plaque collagen or smooth muscle cell content. However, we found that lesion CD68+ cell content tended to decrease with rising doses of radioactivity exposure, culminating in a significant reduction of plaque macrophage content at 1 Gy. Taken together, our results show that short- and long-term exposures to low to moderate doses of ionizing radiation drive an anti-inflammatory response, skewing bone marrow-derived macrophages towards an IL-10-secreting M2 phenotype and decreasing plaque macrophage content. These results suggest a low-grade athero-protective effect of low and moderate doses of ionizing radiation.

Recent epidemiological studies have shown that patients with right-sided breast cancer (RBC) treated with X-ray irradiation (IR) are more susceptible to developing cardiovascular diseases, such as arrhythmias, atrial fibrillation, and conduction disturbances after radiotherapy (RT). Our aim was to investigate the mechanisms induced by low to moderate doses of IR and to evaluate changes in the cardiac sympathetic nervous system (CSNS), atrial remodeling, and calcium homeostasis involved in cardiac rhythm. To mimic the RT of the RBC, female C57Bl/6J mice were exposed to X-ray doses ranging from 0.25 to 2 Gy targeting 40% of the top of the heart. At 60 weeks after RI, Doppler ultrasound showed a significant reduction in myocardial strain, ejection fraction, and atrial function, with a significant accumulation of fibrosis in the epicardial layer and apoptosis at 0.5 mGy. Calcium transient protein expression levels, such as RYR2, NAK, Kir2.1, and SERCA2a, increased in the atrium only at 0.5 Gy and 2 Gy at 24 h, and persisted over time. Interestingly, 3D imaging of the cleaned hearts showed an early reduction of CSNS spines and dendrites in the ventricles and a late reorientation of nerve fibers, combined with a decrease in SEMA3a expression levels. Our results showed that local heart IR from 0.25 Gy induced late cardiac and atrial dysfunction and fibrosis development. After IR, ventricular CSNS and calcium transient protein expression levels were rearranged, which affected cardiac contractility. The results are very promising in terms of identifying pro-arrhythmic mechanisms and preventing arrhythmias during RT treatment in patients with RBC.

Objective: Our work is focused on tungsten, considered as an emerging contaminant. Its environmental dispersion is partly due to mining and military activities. Exposure scenario can also be occupational, in areas such as the hard metal industry and specific nuclear facilities. Our study investigated the cerebral effects induced by the inhalation of tungsten particles., Methods: Inhalation exposure campaigns were carried out at two different concentrations (5 and 80 mg/m 3 ) in single and repeated modes (4 consecutive days) in adult rats within a nose-only inhalation chamber. Processes involved in brain toxicity were investigated 24 h after exposure., Results and Discussion: Site-specific effects in terms of neuroanatomy and concentration-dependent changes in specific cellular actors were observed. Results obtained in the olfactory bulb suggest a potential early effect on the survival of microglial cells. Depending on the mode of exposure, these cells showed a decrease in density accompanied by an increase in an apoptotic marker. An abnormal phenotype of the nuclei of mature neurons, suggesting neuronal suffering, was also observed in the frontal cortex, and can be linked to the involvement of oxidative stress. The differential effects observed according to exposure patterns could involve two components: local (brain-specific) and/or systemic. Indeed, tungsten, in addition to being found in the lungs and kidneys, was present in the brain of animals exposed to the high concentration., Conclusion: Our data question the perceived innocuity of tungsten relative to other metals and raise hypotheses regarding possible adaptive or neurotoxic mechanisms that could ultimately alter neuronal integrity.

Background: Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification)., Methods: We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan-Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman's correlation coefficient. Analyses were conducted by tumor subtype., Results: 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8-6.2) for HR-/HER2 - subtype to 13.3 months (36% CI 12.7-14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR - /HER2 - mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies., Conclusions: Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates., (© 2023. The Author(s).)

Tumor blood vessels are an important emerging target for anticancer therapy. Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin polymerization. At low nM concentrations, EHT 6706 exhibits highly potent antiproliferative activity on more than 60 human tumor cell lines, even those described as being drug resistant. EHT 6706 also shows strong efficacy as a vascular-disrupting agent, since it prevents endothelial cell tube formation and disrupts pre-established vessels, changes the permeability of endothelial cell monolayers and inhibits endothelial cell migration. Genome-wide transcriptomic analysis of EHT 6706 effects on human endothelial cells shows that the antiangiogenic activity elicits gene deregulations of antiangiogenic pathways. These findings indicate that EHT 6706 is a promising tubulin-binding compound with potentially broad clinical antitumor efficacy.

The synthesis of a series of berberine, phenantridine and isoquinoline derivatives was realized to explore their Rho GTPase nucleotide inhibitory activity. The compounds were evaluated in a nucleotide binding competition assay against Rac1, Rac1b, Cdc42 and in a cellular Rac GTPase activation assay. The insertion of 19 AA in the splice variant Rac1b is shown to be sufficient to introduce a conformational difference that allows compounds 4, 21, 22, and 26 to exhibit selective inhibition of Rac 1b over Rac1.

beta-Amyloid peptides (Abeta) that form the senile plaques of Alzheimer disease consist mainly of 40- and 42-amino acid (Abeta 40 and Abeta 42) peptides generated from the cleavage of the amyloid precursor protein (APP). Generation of Abeta involves beta-secretase and gamma-secretase activities and is regulated by membrane trafficking of the proteins involved in Abeta production. Here we describe a new small molecule, EHT 1864, which blocks the Rac1 signaling pathways. In vitro, EHT 1864 blocks Abeta 40 and Abeta 42 production but does not impact sAPPalpha levels and does not inhibit beta-secretase. Rather, EHT 1864 modulates APP processing at the level of gamma-secretase to prevent Abeta 40 and Abeta 42 generation. This effect does not result from a direct inhibition of the gamma-secretase activity and is specific for APP cleavage, since EHT 1864 does not affect Notch cleavage. In vivo, EHT 1864 significantly reduces Abeta 40 and Abeta 42 levels in guinea pig brains at a threshold that is compatible with delaying plaque accumulation and/or clearing the existing plaque in brain. EHT 1864 is the first derivative of a new chemical series that consists of candidates for inhibiting Abeta formation in the brain of AD patients. Our findings represent the first pharmacological validation of Rac1 signaling as a target for developing novel therapies for Alzheimer disease.

Context: Breast cancer is one of the major causes of premature death for women. Its cost management is important for both the national health insurance and the individual health care providers., Objective: The objective of this study was to assess the global medical cost of breast cancer from diagnosis to follow up in one French medical centre: centre René-Huguenin, Saint-Cloud (92)., Method: Duration of medical activities and other medical resources utilisations were collected from a retrospective cohort of 120 patients followed from January 1995 to February 2000. Unit costs were obtained from cost accounts of the Centre., Results: The mean medical cost per patient was FF 66,067 [60,318-7,815] (USD $ 10,744 [9,809-11,679]). The mean cost varied from FF 41,875 (UDS $ 6,810) to FF 81,020 (UDS $ 13,175) depending on choice of type of therapy. The initial treatment phase was the most expensive, costing FF 48,397 [46,176-50,617] (USD $ 7,870 [7,509-8,231]) which represented 73.3% of the global cost., Conclusion: This study has provided an estimate of the real global cost of managing patients with breast cancer in a single French Comprehensive Cancer Centre (CLCC). The study method used is readily transposable to other treatment contexts and to other types of cancer.

Trilostane and aminoglutethimide, both given with a physiological replacement dose of hydrocortisone, were randomly allocated to 112 eligible patients with postmenopausal advanced breast cancer. Following treatment failure on either drug the patient continued with the other, if they were in a suitable clinical condition. Sixty-three patients initially received trilostane, of whom 33 subsequently received aminoglutethimide; 49 patients initially had aminoglutethimide and 14 of these then received trilostane. Both groups of patients were comparable in all respects. There was no difference in the response rate to either drug or in the average time to disease progression for the two drugs. Of the 47 patients who received both drugs, nine (19%) showed a response to both, indicating no cross-resistance. Side effects were seen to both drugs in approximately half the patients; these were mainly gastrointestinal symptoms with trilostane and rashes and drowsiness with aminoglutethimide. There was no evidence of cross-over patient susceptibility to side effects.

For nearly 40 years, a multidisciplinary team working in a private clinic has used a conservative approach to breast cancer for small tumours, i.e. T1-T2. Treatment is based on tumorectomy and radiotherapy. Good results, comparable to those obtained with mastectomy have been obtained and continue to improve with developments in therapeutic methods. The rate of recurrence remains below 7% and 95% of the women were able to keep their breast without any supplementary danger. There are satisfied.

A retrospective multicentric analysis of the results of irradiation of 1676 carcinomas of the skin of the nose and nasal vestibule was performed by the Groupe Européen de Curiethérapie (Tunis, May 1986). Overall local control was 93% with a minimum follow-up of 2 years. Local control is dependent on the tumor size (diameter less than 2 cm: 96%, 2-3.9 cm: 88%, greater than or equal to 4 cm: 81%), and tumor site (external surface of the nose: 94%, vestibule: 75%). Local control was independent of histology for smaller tumors, but for those larger than 4 cm, basal cell carcinomas were more frequently controlled than squamous cell carcinomas. Recurrent tumors are less frequently controlled than those being treated for the first time (88 vs. 95%). There were few complications and cosmetic results were generally satisfactory. The results of implantation, orthovoltage and megavoltage irradiation are compared with respect to local control, complication rate and cosmesis. Implantation is usually the treatment of choice for vestibular tumors but for those of the external surface the choice depends on the tumor diameter. Implantation and orthovoltage irradiation are equivalent for tumors less than 2 cm. For those from 2 to 3.9 cm, the results of orthovoltage irradiation may be satisfactory in a selected population but implantation is usually more suitable for tumors with rapidly changing contour.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of radiation therapy following breast-conserving surgery were analyzed for 410 patients with clinical Stage I-II mammary carcinoma having a minimum and median follow-up time of 5 years and 11 years, respectively. Crude survival rates were 82.2% at 5 years, 62.5% at 10 years, and 45.4% at 15 years. Local-regional recurrence was observed in 9.7% of patients. Seventy-five percent of these recurrences could be controlled locally by further treatment. Both local recurrences and metastatic deaths were more frequent in patients in clinical Stage II and in patients 40 years of age or younger. The cosmetic result was judged good to excellent in 77% of patients, with unacceptable results in 6.7%. The majority of poor results were seen in patients receiving 60 Gy or more to the entire breast. Arm edema occurred in 25% of patients having had axillary dissection, and in 3.4% of patients without axillary surgery. Edema was confined mainly to patients having had axillary doses of 60 Gy or more, and was never disabling. This study demonstrates that excellent long-term results are obtainable with breast-conserving techniques in early breast cancer. Satisfactory cosmetic results and a very low complication rate can be expected if extensive axillary surgery is avoided in conjunction with axillary radiation, and if the radiation dose applied to large treatment volumes is restricted to 50 Gy.

This study was aimed at determining the influence of time factor in local radiotherapy in patients with spindle cell neoplasms of the skin or basal cell carcinomas of the face, treatable in a single plane. These neoplasma were treated using identical doses (6,000 rads distributed over the envelope isodose), but divided at random into two groups corresponsing to two different spreads (60 +/- 12 hours and 156 +/- 12 hours). The biological effects observed (rate of disappearance of the lesion, intensity of skin reaction, duration of skin reaction) showed no difference between the two types of treatment. This results is unexpected considering the important influence of time factor in the case of fractionated irradiation. In fact, if it is accepted that between 60 and 156 hours, cellular multiplication phenomena are equivalent to approximately 30 rads per day, the difference in spread the two types of treatment is not sufficient to give a significant result.

The authors report on their experience with high energy radiation therapy in early-stage (I/II) carcinomas of the prostate. Among 191 cases of biopsy-proved carcinomas of the prostate, there were 111 stage I and II tumors, including 83 T1, T2 intracapsular tumors. 78 of the 111 patients received curative radiation therapy. Delivered doses did not exceed 65 to 70 grays to the prostate and 50 grays to the pelvis. High energy radiation was used. Extension of the lesions was determined using lymphography, abdominal and pelvic CT, and surgical removal of lymph nodes. Among the 78 irradiated patients, success rates at five years were 65% for the 52 T1-T2 tumors and 38% for the 26 T3 N0 tumors. Selection of patients, technical conditions and long term results are discussed, as well as the problems met in determining the stage of the tumor accurately. High energy radiation therapy can control localized carcinomas with a satisfactory quality of survival.