Impact of adjuvant radiotherapy and chemotherapy on thymoma.

PURPOSE: Thymoma is a rare tumour. The most common treatment for thymoma is surgical resection, while the use of radiotherapy and chemotherapy remains controversial. PATIENTS AND METHODS: We conducted a monocentric observational study of 31 patients diagnosed with thymoma from June 2004 to July 2020 at cancer centre in Strasbourg, France. We analysed the outcomes of the patients. RESULTS: The 2- and 5- year locoregional relapse-free survival rates were 96.3% (95% confidence interval [CI]: 76.5-99.5%) and 68.0% (95% CI: 43.8-83.5%), respectively. Radiotherapy and chemotherapy significantly improved local tumour control (P=0.0008 and 0.04, respectively), while a larger initial tumour size significantly worsened local control rates (P=0.04). The 5- and 10-year overall survival rates were 87.1% (95% CI: 69.2-95%) and 81.7% (95% CI: 60.3-92.2%), respectively. The median overall survival was not reached, and no favourable factor was retrieved. For relapsed patients, the median overall survival after relapse was 115 months. CONCLUSION: Despite the inherent limitations of retrospective studies with a limited patient sample size, we demonstrated that chemotherapy and radiotherapy in addition to surgery were effective in achieving local control and contributed to improving patient outcomes in thymoma. Notably, an aggressive treatment strategy at the time of relapse resulted in favourable outcomes for retreated patients.

Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients.

BACKGROUND: Stereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT). MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created. RESULTS: 36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT. CONCLUSION: Repeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT): a retrospective study of 184 patients.

PURPOSE: Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs. METHODS AND MATERIALS: The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated. RESULTS: 184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range: 1-6), for a median of 4 BMs treated during all sessions (range: 2-19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p = 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r = 0.89; p < 0.001). CONCLUSION: Repeated SRT doesn't lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldn't be aborted, especially for patients developing more than twelve BMs annually.

Hemodynamic changes during conventional and daylight photodynamic therapy of actinic keratoses - a randomized controlled trial.

BACKGROUND: Photodynamic therapy (PDT) is an effective treatment for actinic keratosis (AK). However, pain and hypertension are important side effects of conventional PDT (c-PDT). Several studies have demonstrated that daylight PDT (dl-PDT) is less painful while being as effective as c-PDT. OBJECTIVE: To observe the effect of c-PDT and dl-PDT on different hemodynamic parameters (systolic blood pressure and diastolic blood pressure, pulse rate, and peripheral oxygen saturation). METHODS: Fifty patients with AK on the head were enrolled into this prospective, randomized, controlled study and treated with c-PDT or dl-PDT in a 1:1 ratio. Hemodynamic parameters were measured at four different time points during treatment. Pain was quantified using a visual analog scale. AK was counted before treatment and after one month. RESULTS: C-PDT is associated with significantly more pain, a significant increase in blood pressure and a higher rate of patients with grade 3 hypertension. Whereas dl-PDT is almost painless and does not lead to any changes in hemodynamic parameters. For both treatments, a similar lesion response rate was found after one month. CONCLUSIONS: dl-PDT has a better tolerability while being as effective as c-PDT and therefore may be the more favorable treatment option in certain patient groups.

Radionecrosis after repeated courses of radiotherapy under stereotactic conditions for brain metastases: Analysis of clinical and dosimetric data from a retrospective cohort of 184 patients.

PURPOSE: Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient. MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy). RESULTS: At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3-20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2-14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6-18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001). CONCLUSION: Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

Is Substantial Lymphovascular Space Invasion Prognostic for Clinical Outcomes in Type II Endometrial Cancer?

AIMS: Substantial lymphovascular space invasion (LVSI) compared with none or focal LVSI is predictive of lymph node involvement and worse clinical outcomes in endometrioid-type endometrial carcinoma. We aimed to quantify the incidence of substantial LVSI in type II (clear cell and serous) endometrial cancer and correlate the extent of LVSI with clinical outcomes. MATERIALS AND METHODS: A retrospective review was conducted on type II endometrial cancer patients who underwent surgical management from July 2017 to December 2019 using the three-tier LVSI scoring system. Binary logistic regression and Cox regression were used to analyse predictors of lymph node involvement or survival outcomes, respectively. The Kaplan-Meier method and Log-rank test were used to analyse differences in locoregional disease-free survival (LR-DFS), distant metastasis disease-free survival (DM-DFS) and overall survival between patients with substantial versus none/focal LVSI. RESULTS: In 79 patients with type II endometrial carcinoma, no LVSI, focal LVSI and substantial LVSI was present in 48.1%, 15.2% and 36.7% of patients, respectively. Lymph nodes were involved in 0.0% with no LVSI, 20.0% with focal LVSI and 60.0% with substantial LVSI (P < 0.001). The median follow-up was 22.2 months. In patients with none/focal versus substantial LVSI, the 2-year LR-DFS and DM-DFS rates were 91.5% versus 71.4% (P = 0.01) and 90.2% versus 63.8% (P = 0.005), respectively. On univariate analysis, myometrial invasion ≥50%, tumour size ≥3.6 cm, substantial versus none/focal LVSI, lymph node involvement and omission of adjuvant radiotherapy were significant predictors for worse LR-DFS and DM-DFS (P < 0.05). DISCUSSION: Substantial LVSI has a high incidence in type II pathology at our institution and predicts for lymph node involvement and worse clinical outcomes.

[Prognostic factors of acute radiodermatitis in breast cancer after adjuvant radiotherapy treated with RT3D or IMRT]. / Étude des facteurs pronostiques de radiodermite aiguë dans le cancer du sein traité par irradiation conformationnelle adjuvante avec ou sans modulation d'intensité.

PURPOSE: Real life study of prognostic factors of acute radiodermatitis in a monocentric cohort of 200 patients with breast cancer treated with RT3D or IMRT for adjuvant radiotherapy. PATIENTS AND METHODS: This study comprises 200 patients with breast cancer treated with adjuvant radiotherapy, included consecutively. For each patient, their clinical and tumoral characteristics and the irradiation schedule was retrospectively collected. The severity of acute radiodermatitis was also collected, during the treatment and 6weeks after the end of irradiation. The objective was to identify risk factors for acute radiodermatitis grade≥2. RESULTS: The univariate analysis found that a more important BMI (p<0.001), a more important volume of PTV (p<0.001) a normofractionated schedule (p=0.002) were statistically associated to a greater risk of occurrence of grade≥2 acute radiodermatitis. The multivariate analysis found BMI>30 (OR=9.31, p=0.04), light phototype (OR=0.04, p=0.02) and histology other than invasive breast carcinomas (OR=0.07, p=0.04) to be statistically associated to the occurrence of grade≥2 acute radiodermatitis. CONCLUSION: In this monocentric retrospective study, with a prospective collection of the severity of acute radiodermatitis, no grade 3 radiodermatitis has been observed and the frequency of occurrence of grade 2 radiodermatitis was lower than previously published. In contrast to previously published results, IMRT was not associated to a lower risk of grade≥2 acute radiodermatitis. Multivariate analysis found BMI, phototype, and histology to be risk factors of grade≥2 acute radiodermatitis.

Critical links between biodiversity and health in wild bee conservation.

Wild bee populations are declining due to human activities, such as land use change, which strongly affect the composition and diversity of available plants and food sources. The chemical composition of food (i.e., nutrition) in turn determines the health, resilience, and fitness of bees. For pollinators, however, the term 'health' is recent and is subject to debate, as is the interaction between nutrition and wild bee health. We define bee health as a multidimensional concept in a novel integrative framework linking bee biological traits (physiology, stoichiometry, and disease) and environmental factors (floral diversity and nutritional landscapes). Linking information on tolerated nutritional niches and health in different bee species will allow us to better predict their distribution and responses to environmental change, and thus support wild pollinator conservation.

Utility of Prophylactic Cranial Irradiation for Limited Stage Small Cell Lung Cancer in the Modern Era with Magnetic Resonance Imaging Surveillance.

AIMS: To retrospectively analyse the impact of prophylactic cranial irradiation (PCI) on survival and intracranial progression in patients with limited stage small cell lung cancer (LS-SCLC) in the modern era of widespread magnetic resonance imaging brain screening. MATERIALS AND METHODS: Patients with LS-SCLC treated within our network between 2009 and 2020 who responded to initial therapy were stratified by receipt of PCI and stage of disease. A propensity score match analysis was carried out for stage II-III patients. Overall and neurological survival were defined as time to death and presumed death due to uncontrolled intracranial disease, respectively. Brain metastasis-free survival and symptomatic brain metastasis-free survival were defined as freedom from intracranial progression and symptomatic intracranial progression, respectively. The effect of PCI on these outcomes was assessed using Kaplan-Meier and Cox proportional hazards models. RESULTS: In total, 243 (69.6%) of 349 patients received PCI. On multivariate analysis in the propensity matched stage II-III cohort, PCI was a significant predictor of improved neurological survival (hazard ratio 0.23, 95% confidence interval 0.08-0.65; P = 0.01), brain metastasis-free survival (hazard ratio 0.25, 95% confidence interval 0.12-0.51; P < 0.01) and symptomatic brain metastasis-free survival (hazard ratio 0.21, 95% confidence interval 0.08-0.55; P < 0.01), but not improved overall survival. Two-year neurological survival estimates within the propensity matched cohort were 96.8% (95% confidence interval 87.6-99.2%) with PCI and 77.2% (95% confidence interval 63.0-86.4%) without PCI and 1- and 2-year estimates of incidence of brain metastases were 3.9% (95% confidence interval 1.3-11.7%) and 11.7% (95% confidence interval 5.6-23.5%) in the PCI group and 31.6% (95% confidence interval 22.1-43.9%) and 40.4% (95% confidence interval 29.2-54.0%) in the no PCI group, respectively. CONCLUSIONS: In the modern era of magnetic resonance imaging screening, PCI was associated with reduced incidence of intracranial progression in patients with stage II-III LS-SCLC who respond to initial therapy. This, importantly, translated to a decreased risk of neurological death within our propensity matched cohort, without significant improvement in overall survival.

Sustained intrinsic WNT and BMP4 activation impairs hESC differentiation to definitive endoderm and drives the cells towards extra-embryonic mesoderm.

We identified a human embryonic stem cell subline that fails to respond to the differentiation cues needed to obtain endoderm derivatives, differentiating instead into extra-embryonic mesoderm. RNA-sequencing analysis showed that the subline has hyperactivation of the WNT and BMP4 signalling. Modulation of these pathways with small molecules confirmed them as the cause of the differentiation impairment. While activation of WNT and BMP4 in control cells resulted in a loss of endoderm differentiation and induction of extra-embryonic mesoderm markers, inhibition of these pathways in the subline restored its ability to differentiate. Karyotyping and exome sequencing analysis did not identify any changes in the genome that could account for the pathway deregulation. These findings add to the increasing evidence that different responses of stem cell lines to differentiation protocols are based on genetic and epigenetic factors, inherent to the line or acquired during cell culture.

Strain wave pathway to semiconductor-to-metal transition revealed by time-resolved X-ray powder diffraction.

One of the main challenges in ultrafast material science is to trigger phase transitions with short pulses of light. Here we show how strain waves, launched by electronic and structural precursor phenomena, determine a coherent macroscopic transformation pathway for the semiconducting-to-metal transition in bistable Ti3O5 nanocrystals. Employing femtosecond powder X-ray diffraction, we measure the lattice deformation in the phase transition as a function of time. We monitor the early intra-cell distortion around the light absorbing metal dimer and the long range deformations governed by acoustic waves propagating from the laser-exposed Ti3O5 surface. We developed a simplified elastic model demonstrating that picosecond switching in nanocrystals happens concomitantly with the propagating acoustic wavefront, several decades faster than thermal processes governed by heat diffusion.

[Overall survival and survival without local recurrence in case of radiotherapy of the tumor bed of ductal carcinomas in situ of the breast: Review of the literature]. / Survie globale et sans récidive locale en cas de radiothérapie du lit tumoral des carcinomes canalaires in situ du sein : revue de la littérature.

INTRODUCTION: Carcinomas in situ represent more than 15 to 20% of breast cancers. Radiotherapy of whole breast is part of the therapeutic standard and follows surgery. However, the indication of tumor bed irradiation is still controversial and heterogeneous according to international practice even though it is a very frequent clinical situation. The aim of this study is to define the indications of tumor bed irradiation in the context of ductal carcinomas in situ and to discuss accelerated partial irradiation of the breast. METHOD: The selected papers were published between 2015 and 2020 and included as MeSH terms "ductal carcinoma in situ" and "boost" for the analysis of tumor bed irradiation, and "ductal carcinoma in situ" and "accelerated partial breast irradiation" for the analysis of accelerated partial irradiation. RESULTS: Boost was more often performed when risk factors for local recurrence were present, such as age less than 40 or 50 years old, clinical mode of detection, tumor size greater than 15 to 20mm, high nuclear grade, presence of necrosis, positive or insufficient surgical margins, associated atypical hyperplastic lesions, and lobular carcinoma in situ. Accelerated partial irradiation is an option for favorable or intermediate prognosis CCIS, further studies involving more patients are required. CONCLUSION: Radiotherapy of the mammary gland in the context of DCIS has shown its effectiveness in terms of local and locoregional control of the disease, thus reducing in situ and infiltrating recurrences. However, the indication of operating bed irradiation is still debated, and the practice is very heterogeneous depending on the country. Another possible alternative for patients with a favorable prognosis and a small tumor bed volume would be IPA.

Early outcomes after definitive chemoradiation therapy with Vienna/Venezia hybrid high-dose rate brachytherapy applicators for cervical cancer: A single-institution experience.

PURPOSE: The Vienna and Venezia (Elekta) are hybrid intracavitary/interstitial brachytherapy (BT) applicators for cervical cancers unsuitable for intracavitary BT alone to improve target coverage or reduce critical organ dose. There is limited outcome data with the use of these applicators outside published experience of the EMBRACE group. We report feasibility and early outcomes with the use of these hybrid applicators at our institution. METHODS AND MATERIALS: Hybrid applicators were used to treat 61 patients with cervical cancer from November 2011 to December 2019. Indications for hybrid applicator use were involvement of the vagina in 10 patients (16%), residual central or parametrial disease in 46 patients (75%), and a narrow introitus in 5 patients (9%). Toxicities were graded using the CTCAE v4.0. Outcomes were assessed with the Kaplan-Meier method. RESULTS: Median follow-up was 16 months (IQR 9-32 mos). Median HRCTV volume was 31.6 cm3 (IQR 25-48 cm3). Median HRCTV D90 was 86.1 Gy (IQR 84.3-88.0 Gy). In 54 patients with follow-up PET/CT at 3 months, complete initial imaging response locally was seen in 46 patients.Estimated 12-month Kaplan-Meier overall survival, locoregional control, distant control, and recurrence-free survival estimates were 86.9%, 80.6%, 73.8%, and 65.9%, respectively. The 12-month incidence of Grade 3+ GI/GU chronic toxicities was 5.7%, consisting of vesicovaginal fistula, rectovaginal fistula, and ureterovesical fistula. CONCLUSIONS: Our single-institution data support the use of the hybrid applicators, as an alternative to traditional BT applicators when clinically warranted. Use of hybrid applicators is feasible with adequate coverage of disease in the vagina and parametrium.

Abnormal neovascular and proliferative conjunctival phenotype in limbal stem cell deficiency is associated with altered microRNA and gene expression modulated by PAX6 mutational status in congenital aniridia.

PURPOSE: To evaluate conjunctival cell microRNA (miRNAs) and mRNA expression in relation to observed phenotype of progressive limbal stem cell deficiency in a cohort of subjects with congenital aniridia with known genetic status. METHODS: Using impression cytology, bulbar conjunctival cells were sampled from 20 subjects with congenital aniridia and 20 age and sex-matched healthy control subjects. RNA was extracted and miRNA and mRNA analyses were performed using microarrays. Results were related to severity of keratopathy and genetic cause of aniridia. RESULTS: Of 2549 miRNAs, 21 were differentially expressed in aniridia relative to controls (fold change ≤ -1.5 or ≥ +1.5). Among these miR-204-5p, an inhibitor of corneal neovascularization, was downregulated 26.8-fold in severely vascularized corneas. At the mRNA level, 539 transcripts were differentially expressed (fold change ≤ -2 or ≥ +2), among these FOSB and FOS were upregulated 17.5 and 9.7-fold respectively, and JUN by 2.9-fold, all being components of the AP-1 transcription factor complex. Pathway analysis revealed enrichment of PI3K-Akt, MAPK, and Ras signaling pathways in aniridia. For several miRNAs and transcripts regulating retinoic acid metabolism, expression levels correlated with keratopathy severity and genetic status. CONCLUSION: Strong dysregulation of key factors at the miRNA and mRNA level suggests that the conjunctiva in aniridia is abnormally maintained in a pro-angiogenic and proliferative state, and these changes are expressed in a PAX6 mutation-dependent manner. Additionally, retinoic acid metabolism is disrupted in severe, but not mild forms of the limbal stem cell deficiency in aniridia.

[The role of the gut microbiome in idiopathic Parkinson's disease]. / Die Rolle des Darmmikrobioms beim idiopathischen Parkinson-Syndrom.

BACKGROUND: In recent years studies have provided increasing evidence suggesting an association between the (gut) microbiome and idiopathic Parkinson's disease (IPD). OBJECTIVE: The aim of this article is to summarize and evaluate existing evidence with respect to the relevance of the (gut) microbiome for IPD. MATERIAL AND METHODS: An analysis and critical review of studies in the field of IPD and (gut) microbiome were carried out. The resulting potential perspectives and therapeutic strategies are discussed. RESULTS: Despite partially divergent results between different studies (potentially due to the applied methods and variance in the composition of the investigated cohorts), there is an overlap between studies indicating an association between IPD, the microbiome and microbial metabolites. Nevertheless, the cause-effect relationship between IPD and the microbiome has still not been clarified. Taken together, existing evidence supports a potentially relevant role for the microbiome with respect to typical disease symptoms and pathogenesis of the disease. CONCLUSION: Over the past 5 years there has been an enormous increase in the evidence with respect to the relevance of the microbiome for IPD. While early work in this field was mainly descriptive, new diagnostic methods provide evidence for the underlying mechanisms and the complex interactions between man as the host, the human immune system, the enteric nervous system, gut microbiota and microbial metabolites. A relatively novel and clinically relevant field of research is how the gut microbiome can influence the success of oral pharmacotherapy and whether substitution of specific microbiome components might be used either for future therapeutic or prophylactic strategies.

Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl/6 mice: Relevance to inflammatory markers in human bronchial epithelial cells.

COPD is a prevalent lung disease with significant impacts on public health. Affected airways exhibit pulmonary neutrophilia and consequent secretion of pro-inflammatory cytokines and proteases, which result in lung emphysema. Probiotics act as nonspecific modulators of the innate immune system that improve several inflammatory responses. To investigate the effect of Lactobacillus rhamnosus (Lr) on cigarette smoke (CS)-induced COPD C57Bl/6 mice were treated with Lr during the week before COPD induction and three times/week until euthanasia. For in vitro assays, murine bronchial epithelial cells as well as human bronchial epithelial cells exposed to cigarette smoke extract during 24 hours were treated with Lr 1 hour before CSE addition. Lr treatment attenuated the inflammatory response both in the airways and lung parenchyma, reducing inflammatory cells infiltration and the production of pro-inflammatory cytokines and chemokines. Also, Lr-treated mice presented with lower metalloproteases in lung tissue and lung remodeling. In parallel to the reduction in the expression of TLR2, TLR4, TLR9, STAT3, and NF-κB in lung tissue, Lr increased the levels of IL-10 as well as SOCS3 and TIMP1/2, indicating the induction of an anti-inflammatory environment. Similarly, murine bronchial epithelial cells as well as human bronchial epithelial cells (BEAS) exposed to CSE produced pro-inflammatory cytokines and chemokines, which were inhibited by Lr treatment in association with the production of anti-inflammatory molecules. Moreover, the presence of Lr also modulated the expression of COPD-associated transcription found into BALF of COPD mice group, i.e., Lr downregulated expression of NF-κB and STAT3, and inversely upregulated increased expression of SOCS3. Thus, our findings indicate that Lr modulates the balance between pro- and anti-inflammatory cytokines in human bronchial epithelial cells upon CS exposure and it can be a useful tool to improve the lung inflammatory response associated with COPD.

[Stereotactic radiotherapy of brain metastases in complex situations]. / La radiothérapie en conditions stéréotaxiques des métastases cérébrales en situation complexe.

Stereotactic radiation therapy of brain metastases is a treatment recognized as effective, well tolerated, applicable for therapeutic indications codified and validated by national and international guidelines. However, the effectiveness of this irradiation, the evolution of patient care and the technical improvements enabling its implementation make it possible to consider it in more complex situations: proximity of brain metastases to organs at risk; large, cystic, haemorrhagic or multiple brain metastases, combination with targeted therapies and immunotherapy, stereotactic radiotherapy in patients with a pacemaker. This article aims to put forward the arguments available to date in the literature and those resulting from clinical practice to provide decision support for the radiation oncologists.

Oral feeding of Lactobacillus bulgaricus N45.10 inhibits the lung inflammation and airway remodeling in murine allergic asthma: Relevance to the Th1/Th2 cytokines and STAT6/T-bet.

Asthma is a chronic disease with impacts on public health. It affects the airways causing pulmonary inflammation mediated by CD4 T cells type Th2, eosinophilia, mucus hypersecretion, and elevated IgE. The unbalance between cytokines and transcription factors is an important feature in asthma. Probiotics has gaining highlight as a therapy for chronic diseases. Thus, we investigate the Lactobacillus bulgaricus (Lb) effect in murine allergic asthma. BALB/c-mice were sensitized to ovalbumin (OA) on days 0 and 7 and were challenged from day 14-28 with OA. Mice received Lb seven days prior to sensitization and it was kept until day 28. The Lb attenuated the eosinophils infiltration, mucus and collagen secretion, IgE production, pro-inflammatory cytokines, TLR4 expression, GATA3, STAT6 and RORγt in lung. Otherwise, Lb increased the anti-inflammatory cytokines, the T-bet and foxp3. Finally, Lb attenuated the allergic asthma-induced inflammation and airway remodeling by interfering on Th1/Th2 cytokines and STAT6/T-bet transcription factors.

Gain of 20q11.21 in Human Pluripotent Stem Cells Impairs TGF-ß-Dependent Neuroectodermal Commitment.

Gain of 20q11.21 is one of the most common recurrent genomic aberrations in human pluripotent stem cells. Although it is known that overexpression of the antiapoptotic gene Bcl-xL confers a survival advantage to the abnormal cells, their differentiation capacity has not been fully investigated. RNA sequencing of mutant and control hESC lines, and a line transgenically overexpressing Bcl-xL, shows that overexpression of Bcl-xL is sufficient to cause most transcriptional changes induced by the gain of 20q11.21. Moreover, the differentially expressed genes in mutant and Bcl-xL overexpressing lines are enriched for genes involved in TGF-ß- and SMAD-mediated signaling, and neuron differentiation. Finally, we show that this altered signaling has a dramatic negative effect on neuroectodermal differentiation, while the cells maintain their ability to differentiate to mesendoderm derivatives. These findings stress the importance of thorough genetic testing of the lines before their use in research or the clinic.

Genetic variation across the human olfactory receptor repertoire alters odor perception.

Humans use a family of more than 400 olfactory receptors (ORs) to detect odors, but there is currently no model that can predict olfactory perception from receptor activity patterns. Genetic variation in human ORs is abundant and alters receptor function, allowing us to examine the relationship between receptor function and perception. We sequenced the OR repertoire in 332 individuals and examined how genetic variation affected 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR was frequently associated with changes in odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. In 8 of these 10 cases, reduced receptor function was associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age, and gender, we can explain between 10% and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in the variation of olfactory perception.