Serological Antibodies against Kidney, Liver, and Spleen Membrane Antigens as Potential Biomarkers in Patients with Immune Disorders.

Immune disorders arise from complex genetic and environmental factors, which lead to dysregulation at the cellular and inflammatory levels and cause tissue damage. Recent research highlights the crucial role of reactive antibodies in autoimmune diseases and graft rejection, but their complex determination poses challenges for clinical use. Therefore, our study aimed to ascertain whether the presence of reactive antibodies against membrane antigens in tissues from both animal models and humans could serve as biomarkers in patients with autoimmune disorders. To address this issue, we examined the binding profile of serological antibodies against a diverse panel of cell membranes from the spleen, liver, and kidney tissues of monkeys, rats, and humans. After developing the cell membrane microarrays, human sera were immunologically assayed. The study was first conducted on sera from two groups, healthy subjects and patients with inflammatory and autoimmune disorders, and then optimized for kidney transplant patient sera. A significant increase in antibody reactivity against specific monkey kidney and spleen membranes was observed in the serum of patients with lupus nephritis, while kidney transplant patients showed a significant enhancement against human tissues and human embryonic kidney 293 cells. These results show the potential importance for clinical and basic research purposes of studying the presence of specific IgG against membrane antigens in patients' serum as potential biomarkers of immune disorders. However, it is important to note that these results need to be verified in further studies with a larger sample size to confirm their relevance.

Accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy compared with whole-breast irradiation with boost for early breast cancer: 10-year results of a GEC-ESTRO randomised, phase 3, non-inferiority trial.

BACKGROUND: Several randomised, phase 3 trials have investigated the value of different techniques of accelerated partial breast irradiation (APBI) for patients with early breast cancer after breast-conserving surgery compared with whole-breast irradiation. In a phase 3 randomised trial, we evaluated whether APBI using multicatheter brachytherapy is non-inferior compared with whole-breast irradiation. Here, we present the 10-year follow-up results. METHODS: We did a randomised, phase 3, non-inferiority trial at 16 hospitals and medical centres in Austria, Czech Republic, Germany, Hungary, Poland, Spain, and Switzerland. Patients aged 40 years or older with early invasive breast cancer or ductal carcinoma in situ treated with breast-conserving surgery were centrally randomly assigned (1:1) to receive either whole-breast irradiation or APBI using multicatheter brachytherapy. Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with a supplemental boost of 10 Gy to the tumour bed, and APBI was delivered as 30·1 Gy (seven fractions) and 32·0 Gy (eight fractions) of high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy over 5 treatment days. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was ipsilateral local recurrence, analysed in the as-treated population; the non-inferiority margin for the recurrence rate difference (defined for 5-year results) was 3 percentage points. The trial is registered with ClinicalTrials.gov, NCT00402519; the trial is complete. FINDINGS: Between April 20, 2004, and July 30, 2009, 1328 female patients were randomly assigned to whole breast irradiation (n=673) or APBI (n=655), of whom 551 in the whole-breast irradiation group and 633 in the APBI group were eligible for analysis. At a median follow-up of 10·36 years (IQR 9·12-11·28), the 10-year local recurrence rates were 1·58% (95% CI 0·37 to 2·8) in the whole-breast irradiation group and 3·51% (1·99 to 5·03) in the APBI group. The difference in 10-year rates between the groups was 1·93% (95% CI -0·018 to 3·87; p=0·074). Adverse events were mostly grade 1 and 2, in 234 (60%) of 393 participants in the whole-breast irradiation group and 314 (67%) of 470 participants in the APBI group, at 7·5-year or 10-year follow-up, or both. Patients in the APBI group had a significantly lower incidence of treatment-related grade 3 late side-effects than those in the whole-breast irradiation group (17 [4%] of 393 for whole-breast irradiation vs seven [1%] of 470 for APBI; p=0·021; at 7·5-year or 10-year follow-up, or both). At 10 years, the most common type of grade 3 adverse event in both treatment groups was fibrosis (six [2%] of 313 patients for whole-breast irradiation and three [1%] of 375 patients for APBI, p=0·56). No grade 4 adverse events or treatment-related deaths have been observed. INTERPRETATION: Postoperative APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is a valuable alternative to whole-breast irradiation in terms of treatment efficacy and is associated with fewer late side-effects. FUNDING: German Cancer Aid, Germany.

Review of Technological Challenges in Personalised Medicine and Early Diagnosis of Neurodegenerative Disorders.

Neurodegenerative disorders are characterised by progressive neuron loss in specific brain areas. The most common are Alzheimer's disease and Parkinson's disease; in both cases, diagnosis is based on clinical tests with limited capability to discriminate between similar neurodegenerative disorders and detect the early stages of the disease. It is common that by the time a patient is diagnosed with the disease, the level of neurodegeneration is already severe. Thus, it is critical to find new diagnostic methods that allow earlier and more accurate disease detection. This study reviews the methods available for the clinical diagnosis of neurodegenerative diseases and potentially interesting new technologies. Neuroimaging techniques are the most widely used in clinical practice, and new techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have significantly improved the diagnosis quality. Identifying biomarkers in peripheral samples such as blood or cerebrospinal fluid is a major focus of the current research on neurodegenerative diseases. The discovery of good markers could allow preventive screening to identify early or asymptomatic stages of the neurodegenerative process. These methods, in combination with artificial intelligence, could contribute to the generation of predictive models that will help clinicians in the early diagnosis, stratification, and prognostic assessment of patients, leading to improvements in patient treatment and quality of life.

Consensus statement from the Spanish Brachytherapy Group (GEB) on accelerated partial breast irradiation using multicatheter interstitial brachytherapy.

AIM: To establish consensus guidelines for a safe clinical practice of accelerated partial breast irradiation (APBI) interstitial multicatheter brachytherapy (BT). BACKGROUND: APBI with interstitial multicatheter BT has proved to be effective in the treatment of early stage breast cancer. This paradigm shift in the approach to early breast cancer conservative treatment, along with the existing controversies on the clinical practice of APBI, prompted the Spanish Brachytherapy Group (GEB) of the Spanish Societies of Radiation Oncology (SEOR) and Medical Physics (SEFM) to address BT APBI in a consensus meeting. MATERIALS AND METHODS: Prior to the meeting, a survey with 27 questions on indication, inclusion criteria, BT modality, implant technique, image guidance and simulation, CTV and OAR definition, dose prescription and fractionation, dose calculation, implant quality metrics and OAR dose constrains was distributed. Items not reaching a level of agreement of 70% were discussed and voted during the meeting. RESULTS: 26 Institutions completed the survey, 60% of them perform APBI procedures. The analysis of the survey showed consensus reached on approximately half the questions. An expert panel discussed the remaining items; thereafter, a voting established the definite consensus. CONCLUSIONS: This document summarizes the consensus guidelines agreed during the meeting of the Spanish Brachytherapy Group SEOR-SEFM. Institutions with BT facilities available should offer interstitial BT APBI as a treatment option to patients fulfilling the inclusion criteria. Institutions willing to implement interstitial BT APBI are encouraged to follow the consensus guidelines established herein.

Association between inflammatory bowel disease and uveal melanoma: case report of two young adults and a literature review.

INTRODUCTION: Uveal melanoma is a rare tumour caused by genetic factors and alterations in the immune response. Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disorder characterized by an inappropriate or excessive immune response. The two main types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). A diagnosis of IBD and the use of immunosuppressive drugs are both independently associated with an increased risk of developing skin melanoma. The association between IBD and uveal melanoma (UM) has not been previously described. CASES DESCRIPTION: Two young Caucasian men, aged 24 and 28, developed UM 3 and 15 years, respectively, after being diagnosed with IBD. Both received long-term treatment with immunomodulatory drugs, with periodic switching among the drugs due to the refractory nature of IBD. In both cases, melanoma was treated by brachytherapy with iodine-125 COMS plaque implant at a dose of 75 Gy. DISCUSSION: Chronic inflammation can promote cell proliferation and growth. The use of immunomodulatory drugs is associated with an increased risk of developing melanoma and non-melanoma skin cancer. The two patients described in this report both had long-standing IBD treated with immunomodulatory drugs. It seems reasonable to suggest that these two factors may have promoted the development of uveal melanoma. More studies are warranted to investigate and confirm this possible association.

Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial.

BACKGROUND: Previous results from the GEC-ESTRO trial showed that accelerated partial breast irradiation (APBI) using multicatheter brachytherapy in the treatment of early breast cancer after breast-conserving surgery was non-inferior to whole-breast irradiation in terms of local control and overall survival. Here, we present 5-year results of patient-reported quality of life. METHODS: We did this randomised controlled phase 3 trial at 16 hospitals and medical centres in seven European countries. Patients aged 40 years or older with 0-IIA breast cancer were randomly assigned (1:1) after breast-conserving surgery (resection margins ≥2 mm) to receive either whole-breast irradiation of 50 Gy with a boost of 10 Gy or APBI using multicatheter brachytherapy. Randomisation was stratified by study centre, tumour type, and menopausal status, with a block size of ten and an automated dynamic algorithm. There was no masking of patients or investigators. The primary endpoint of the trial was ipsilateral local recurrence. Here, we present 5-year results of quality of life (a prespecified secondary endpoint). Quality-of-life questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30, breast cancer module QLQ-BR23) were completed before radiotherapy (baseline 1), immediately after radiotherapy (baseline 2), and during follow-up. We analysed the data according to treatment received (as-treated population). Recruitment was completed in 2009, and long-term follow-up is continuing. The trial is registered at ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 633 patients had accelerated partial breast irradiation and 551 patients had whole-breast irradiation. Quality-of-life questionnaires at baseline 1 were available for 334 (53%) of 663 patients in the APBI group and 314 (57%) of 551 patients in the whole-breast irradiation group; the response rate was similar during follow-up. Global health status (range 0-100) was stable in both groups: at baseline 1, APBI group mean score 65·5 (SD 20·6) versus whole-breast irradiation group 64·6 (19·6), p=0·37; at 5 years, APBI group 66·2 (22·2) versus whole-breast irradiation group 66·0 (21·8), p=0·94. The only moderate, significant difference (difference of 10-20 points) between the groups was found in the breast symptoms scale. Breast symptom scores were significantly higher (ie, worse) after whole-breast irradiation than after APBI at baseline 2 (difference of means 13·6, 95% CI 9·7-17·5; p<0·0001) and at 3-month follow-up (difference of means 12·7, 95% CI 9·8-15·6; p<0·0001). INTERPRETATION: APBI with multicatheter brachytherapy was not associated with worse quality of life compared with whole-breast irradiation. This finding supports APBI as an alternative treatment option after breast-conserving surgery for patients with early breast cancer. FUNDING: German Cancer Aid.

Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial.

BACKGROUND: We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial. METHODS: We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast-conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6·6 years (IQR 5·8-7·6), no patients had any grade 4 toxities, and three (<1%) of 484 patients in the APBI group and seven (2%) of 393 in the whole-breast irradiation group had grade 3 late skin toxicity (p=0·16). No patients in the APBI group and two (<1%) in the whole-breast irradiation group developed grade 3 late subcutaneous tissue toxicity (p=0·10). The cumulative incidence of any late side-effect of grade 2 or worse at 5 years was 27·0% (95% CI 23·0-30·9) in the whole-breast irradiation group versus 23·3% (19·9-26·8) in the APBI group (p=0·12). The cumulative incidence of grade 2-3 late skin toxicity at 5 years was 10·7% (95% CI 8·0-13·4) in the whole-breast irradiation group versus 6·9% (4·8-9·0) in the APBI group (difference -3·8%, 95% CI -7·2 to 0·4; p=0·020). The cumulative risk of grade 2-3 late subcutaneous tissue side-effects at 5 years was 9·7% (95% CI 7·1-12·3) in the whole-breast irradiation group versus 12·0% (9·4-14·7) in the APBI group (difference 2·4%; 95% CI -1·4 to 6·1; p=0·28). The cumulative incidence of grade 2-3 breast pain was 11·9% (95% CI 9·0-14·7) after whole-breast irradiation versus 8·4% (6·1-10·6) after APBI (difference -3·5%; 95% CI -7·1 to 0·1; p=0·074). At 5 years' follow-up, according to the patients' view, 413 (91%) of 454 patients had excellent to good cosmetic results in the whole-breast irradiation group versus 498 (92%) of 541 patients in the APBI group (p=0·62); when judged by the physicians, 408 (90%) of 454 patients and 503 (93%) of 542 patients, respectively, had excellent to good cosmetic results (p=0·12). No treatment-related deaths occurred, but six (15%) of 41 patients (three in each group) died from breast cancer, and 35 (85%) deaths (21 in the whole-breast irradiation group and 14 in the APBI group) were unrelated. INTERPRETATION: 5-year toxicity profiles and cosmetic results were similar in patients treated with breast-conserving surgery followed by either APBI with interstitial brachytherapy or conventional whole-breast irradiation, with significantly fewer grade 2-3 late skin side-effects after APBI with interstitial brachytherapy. These findings provide further clinical evidence for the routine use of interstitial multicatheter brachytherapy-based APBI in the treatment of patients with low-risk breast cancer who opt for breast conservation. FUNDING: German Cancer Aid.

5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial.

BACKGROUND: In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS: We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1.44% (95% CI 0.51-2.38) with APBI and 0.92% (0.12-1.73) with whole-breast irradiation (difference 0.52%, 95% CI -0.72 to 1.75; p=0.42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3.2% with APBI versus 5.7% with whole-breast irradiation (p=0.08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7.6% versus 6.3% (p=0.53). The risk of severe (grade 3) fibrosis at 5 years was 0.2% with whole-breast irradiation and 0% with APBI (p=0.46). INTERPRETATION: The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING: German Cancer Aid.

Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to Pain-Related Anxiety in Arthritic Male Rats.

Background: There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety. Methods: Using the complete Freund's adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction. Results: The manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered. Conclusion: As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-related anxiety.

Cystine/glutamate antiporter blockage induces myelin degeneration.

The cystine/glutamate antiporter is a membrane transport system responsible for the uptake of extracellular cystine and release of intracellular glutamate. It is the major source of cystine in most cells, and a key regulator of extrasynaptic glutamate in the CNS. Because cystine is the limiting factor in the biosynthesis of glutathione, and glutamate is the most abundant neurotransmitter, the cystine/glutamate antiporter is a central player both in antioxidant defense and glutamatergic signaling, two events critical to brain function. However, distribution of cystine/glutamate antiporter in CNS has not been well characterized. Here, we analyzed expression of the catalytic subunit of the cystine/glutamate antiporter, xCT, by immunohistochemistry in histological sections of the forebrain and spinal cord. We detected labeling in neurons, oligodendrocytes, microglia, and oligodendrocyte precursor cells, but not in GFAP(+) astrocytes. In addition, we examined xCT expression and function by qPCR and cystine uptake in primary rat cultures of CNS, detecting higher levels of antiporter expression in neurons and oligodendrocytes. Chronic inhibition of cystine/glutamate antiporter caused high toxicity to cultured oligodendrocytes. In accordance, chronic blockage of cystine/glutamate antiporter as well as glutathione depletion caused myelin disruption in organotypic cerebellar slices. Finally, mice chronically treated with sulfasalazine, a cystine/glutamate antiporter inhibitor, showed a reduction in the levels of myelin and an increase in the myelinated fiber g-ratio. Together, these results reveal that cystine/glutamate antiporter is expressed in oligodendrocytes, where it is a key factor to the maintenance of cell homeostasis. GLIA 2016. GLIA 2016;64:1381-1395.

Dopamine-dependent long-term depression at subthalamo-nigral synapses is lost in experimental parkinsonism.

Impairments of synaptic plasticity are a hallmark of several neurological disorders, including Parkinson's disease (PD) which results from the progressive loss of dopaminergic neurons of the substantia nigra pars compacta leading to abnormal activity within the basal ganglia (BG) network and pathological motor symptoms. Indeed, disrupted plasticity at corticostriatal glutamatergic synapses, the gateway of the BG, is correlated to the onset of PD-related movement disorders and thus has been proposed to be a key neural substrate regulating information flow and motor function in BG circuits. However, a critical question is whether similar plasticity impairments could occur at other glutamatergic connections within the BG that would also affect the inhibitory influence of the network on the motor thalamus. Here, we show that long-term plasticity at subthalamo-nigral glutamatergic synapses (STN-SNr) sculpting the activity patterns of nigral neurons, the main output of the network, is also affected in experimental parkinsonism. Using whole-cell patch-clamp in acute rat brain slices, we describe a molecular pathway supporting an activity-dependent long-term depression of STN-SNr synapses through an NMDAR-and D1/5 dopamine receptor-mediated endocytosis of synaptic AMPA glutamate receptors. We also show that this plastic property is lost in an experimental rat model of PD but can be restored through the recruitment of dopamine D1/5 receptors. Altogether, our findings suggest that pathological impairments of subthalamo-nigral plasticity may enhance BG outputs and thereby contribute to PD-related motor dysfunctions.

Hype or hope? A review of challenges in balancing tumor control and treatment toxicity in breast cancer from the perspective of the radiation oncologist.

The aim of this article is to discuss the challenges and new strategies in managing breast cancer patients, with a specific focus on radiation oncology and the importance of balancing oncologic outcomes with quality of life and post-treatment morbidity. A comprehensive literature review was conducted to identify advances in the management of breast cancer, exploring de-escalation strategies, hypofractionation schemes, predictors and tools for reducing toxicity (radiation-induced lymphocyte apoptosis, deep inspiration breath-hold, adaptive radiotherapy), enhancer treatments (hyperthermia, immunotherapy) and innovative diagnostic modalities (PET-MRI, omics). Balancing oncologic outcomes with quality of life and post-treatment morbidity is crucial in the era of personalized medicine. Radiotherapy plays a critical role in the management of breast cancer patients. Large randomized trials are necessary to generalize some practices and cost remains the main obstacle for many innovations that are already applicable.

Targeting parvalbumin-expressing neurons in the substantia nigra pars reticulata restores motor function in parkinsonian mice.

The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure of basal ganglia, is altered in Parkinson's disease (PD). However, neither the underlying mechanisms nor the type of neurons responsible for PD-related motor dysfunctions have been elucidated yet. Here, we show that parvalbumin-expressing SNr neurons (SNr-PV+) occupy dorsolateral parts and possess specific electrophysiological properties compared with other SNr cells. We also report that only SNr-PV+ neurons' intrinsic excitability is reduced by downregulation of sodium leak channels in a PD mouse model. Interestingly, in anesthetized parkinsonian mice in vivo, SNr-PV+ neurons display a bursty pattern of activity dependent on glutamatergic tone. Finally, we demonstrate that chemogenetic inhibition of SNr-PV+ neurons is sufficient to alleviate motor impairments in parkinsonian mice. Overall, our findings establish cell-type-specific dysfunction in experimental parkinsonism in the SNr and provide a potential cellular therapeutic target to alleviate motor symptoms in PD.

Sexual differences in locus coeruleus neurons and related behavior in C57BL/6J mice.

BACKGROUND: In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying these differences remains unclear. Interestingly, the Locus Coeruleus (LC), a noradrenergic nucleus that exhibits sexual dimorphism, integrates signals that are related to diverse activities, including emotions, cognition and pain. Therefore, we set-out to evaluate sex differences in behaviors related to LC nucleus, and subsequently, to assess the sex differences in LC morphology and function. METHODS: Female and male C57BL/6J mice were studied to explore the role of the LC in anxiety, depressive-like behavior, well-being, pain, and learning and memory. We also explored the number of noradrenergic LC cells, their somatodendritic volume, as well as the electrophysiological properties of LC neurons in each sex. RESULTS: While both male and female mice displayed similar depressive-like behavior, female mice exhibited more anxiety-related behaviors. Interestingly, females outperformed males in memory tasks that involved distinguishing objects with small differences and they also showed greater thermal pain sensitivity. Immunohistological analysis revealed that females had fewer noradrenergic cells yet they showed a larger dendritic volume than males. Patch clamp electrophysiology studies demonstrated that LC neurons in female mice had a lower capacitance and that they were more excitable than male LC neurons, albeit with similar action potential properties. CONCLUSIONS: Overall, this study provides new insights into the sex differences related to LC nucleus and associated behaviors, which may explain the heightened emotional arousal response observed in females.

Exploring sex differences in the brain is important to understand the impact of such differences in pathological conditions characterized by gender bias, as well as their therapeutic implications. In this manuscript, we examined sex differences in the mouse locus coeruleus (LC) and how this might affect related behaviours. The LC is a sexually dimorphic nucleus that integrates signals associated with attention, anxiety, stress, arousal, pain, memory and learning. Our findings reveal that female mice exhibit more intense anxiety-related behaviors but that they perform better than males in recognizing small differences between objects. Additionally, we found pronounced sex differences in the LC, which contained fewer noradrenergic cells in females, with a larger dendritic volume and displaying enhanced cell excitability. These differences in the LC, a nucleus that fulfils a pivotal role in stress and pain, could be important for understanding the higher prevalence of stress-related disorders in women, such as anxiety and depression, but also of chronic pain. Hence, it is clearly important to consider sex differences in both preclinical and clinical research studies that attempt to understand pathologies related to these phenomena.

Recommendations of the Spanish brachytherapy group of the Spanish Society of Radiation Oncology and the Spanish Society of Medical Physics for interstitial high-dose-rate brachytherapy for gynaecologic malignancies.

The present document includes consensus-based recommendations from the Brachytherapy Group (GEB) of the Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for interstitial high-dose-rate (HDR) brachytherapy (BT) for gynaecologic malignancies. A nine-item survey-which included questions on experience with interstitial BT; indications and technique; applicator type; magnetic resonance imaging (MRI)-based planning; dose; fractionation schedule; and treatment planning-was sent to all radiation oncology departments (n = 174) in Spain in 2021. Responses were received from 36 centres (50% of all centres [n = 72] with a BT unit). The consensus-based recommendations presented here are based on a review of the available literature, professional experience among the group of experts, and in-person discussions held during the annual meeting of these two societies. We describe the results of the survey and the following: indications; contraindications; patient selection; description of applicators; role of imaging in planning; contouring; dose prescription; dosimetric reconstruction; optimisation; and dose indications for cancers of the cervix, vagina, and vulva. The various clinical scenarios in which interstitial BT is used in the treatment of gynaecological tumours are described in detail, including cervix intracavitary/interstitial hybrid HDR-BT; cervix perineal templates/freehand implants; primary vaginal malignancies/vaginal recurrences; and vulvar interstitial implants.

Efficacy of invasive and non-invasive methods for the treatment of Parkinson's disease: Nanodelivery and enriched environment.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta and the subsequent motor disability. The most frequently used treatments in clinics, such as L-DOPA, restore dopaminergic neurotransmission in the brain. However, these treatments are only symptomatic, have temporary efficacy, and produce side effects. Part of the side effects are related to the route of administration as the consumption of oral tablets leads to unspecific pulsatile activation of dopaminergic receptors. For this reason, it is necessary to not only find alternative treatments, but also to develop new administration systems with better security profiles. Nanoparticle delivery systems are new administration forms designed to reach the pharmacological target in a highly specific way, leading to better drug bioavailability, efficacy and safety. Some of these delivery systems have shown promising results in animal models of PD not only when dopaminergic drugs are administered, but even more when neurotrophic factors are released. These latter compounds promote maturation and survival of dopaminergic neurons and can be exogenously administered in the form of pharmacological therapy or endogenously generated by non-pharmacological methods. In this sense, experimental exposure to enriched environments, a non-invasive strategy based on the combination of social and inanimate stimuli, enhances the production of neurotrophic factors and produces a neuroprotective effect in parkinsonian animals. In this review, we will discuss new nanodelivery systems in PD with a special focus on therapies that increase the release of neurotrophic factors.

Altered pallido-pallidal synaptic transmission leads to aberrant firing of globus pallidus neurons in a rat model of Parkinson's disease.

The pattern of activity of globus pallidus (GP) neurons is tightly regulated by GABAergic inhibition. In addition to extrinsic inputs from the striatum (STR-GP) the other source of GABA to GP neurons arises from intrinsic intranuclear axon collaterals (GP-GP). While the contribution of striatal inputs has been studied, notably its hyperactivity in Parkinson's disease (PD), the properties and function of intranuclear inhibition remain poorly understood. Our objective was therefore to test the impact of chronic dopamine depletion on pallido-pallidal transmission. Using patch-clamp whole-cell recordings in rat brain slices, we combined electrical and optogenetic stimulations with pharmacology to differentiate basic synaptic properties of STR-GP and GP-GP GABAergic synapses. GP-GP synapses were characterized by activity-dependent depression and insensitivity to the D(2) receptor specific agonist quinpirole and STR-GP synapses by frequency-dependent facilitation and quinpirole modulation. Chronic dopamine deprivation obtained in 6-OHDA lesioned animals boosted the amplitude of GP-GP IPSCs but did not modify STR-GP transmission and increased the amplitude of miniature IPSCs. Replacement of calcium by strontium confirmed that the quantal amplitude was increased at GP-GP synapses. Finally, we demonstrated that boosted GP-GP transmission promotes resetting of autonomous activity and rebound-burst firing after dopamine depletion. These results suggest that GP-GP synaptic transmission (but not STR-GP) is augmented by chronic dopamine depletion which could contribute to the aberrant GP neuronal activity observed in PD.

Motor cortico-nigral and cortico-entopeduncular information transmission and its modulation by buspirone in control and after dopaminergic denervation.

Cortical information is transferred to the substantia nigra pars reticulata (SNr) and the entopeduncular nucleus (EP), the output structures of the basal ganglia (BG), through three different pathways: the hyperdirect trans-subthalamic and the direct and indirect trans-striatal pathways. The nigrostriatal dopamine (DA) and the activation of 5-HT1A receptors, distributed all along the BG, may modulate cortical information transmission. We aimed to investigate the effect of buspirone (5-HT1A receptor partial agonist) and WAY-100635 (5-HT1A receptor antagonist) on cortico-nigral and cortico-entopeduncular transmission in normal and DA loss conditions. Herein, simultaneous electrical stimulation of the motor cortex and single-unit extracellular recordings of SNr or EP neurons were conducted in urethane-anesthetized sham and 6-hydroxydopamine (6-OHDA)-lesioned rats before and after drug administrations. Motor cortex stimulation evoked monophasic, biphasic, or triphasic responses, combination of an early excitation, an inhibition, and a late excitation in both the SNr and EP, while an altered pattern of evoked response was observed in the SNr after 6-OHDA lesion. Systemic buspirone potentiated the direct cortico-SNr and cortico-EP transmission in sham animals since increased duration of the inhibitory response was observed. In DA denervated animals, buspirone administration enhanced early excitation amplitude in the cortico-SNr transmission. In both cases, the observed effects were mediated via a 5-HT1A-dependent mechanism as WAY-100635 administration blocked buspirone's effect. These findings suggest that in control condition, buspirone potentiates direct pathway transmission and DA loss modulates responses related to the hyperdirect pathway. Overall, the results may contribute to understanding the role of 5-HT1A receptors and DA in motor cortico-BG circuitry functionality.

The Role of Interstitial Brachytherapy for Breast Cancer Treatment: An Overview of Indications, Applications, and Technical Notes.

Breast cancer represents the second leading cause of cancer-related death in the female population, despite continuing advances in treatment options that have significantly accelerated in recent years. Conservative treatments have radically changed the concept of healing, also focusing on the psychological aspect of oncological treatments. In this scenario, radiotherapy plays a key role. Brachytherapy is an extremely versatile radiation technique that can be used in various settings for breast cancer treatment. Although it is invasive, technically complex, and requires a long learning curve, the dosimetric advantages and sparing of organs at risk are unequivocal. Literature data support muticatheter interstitial brachytherapy as the only method with strong scientific evidence to perform partial breast irradiation and reirradiation after previous conservative surgery and external beam radiotherapy, with longer follow-up than new, emerging radiation techniques, whose effectiveness is proven by over 20 years of experience. The aim of our work is to provide a comprehensive view of the use of interstitial brachytherapy to perform breast lumpectomy boost, breast-conserving accelerated partial breast irradiation, and salvage reirradiation for ipsilateral breast recurrence, with particular focus on the implant description, limits, and advantages of the technique.

Locus coeruleus and dorsal raphe neuron activity and response to acute antidepressant administration in a rat model of Parkinson's disease.

In addition to noradrenergic and serotonergic systems, dopaminergic neurotransmission seems to play an important role in the aetiopathogenesis of, and recovery from, depression. Moreover, the incidence of depression is higher in patients affected by diseases where the dopaminergic system is highly impaired, such us Parkinson's disease. Here, we investigated the effects of dopamine degeneration on the activity and response to antidepressants of locus coeruleus (LC) noradrenergic and dorsal raphe nucleus (DRN) serotonergic neurons. To this end, single-unit extracellular recordings were performed in control and 6-hydroxydopamine (6-OHDA)-lesioned animals. In this latter group, LC neurons showed a lower basal firing rate as well as less sensitivity to the administration of the serotonin reuptake inhibitor, fluoxetine. The rest of electrophysiological parameters and the response to the administration of the α2-adrenoceptor agonist, clonidine and the noradrenaline reuptake inhibitor, reboxetine remained unaltered. In the DRN, dopamine depletion did not modify the basal electrophysiological characteristics and the response to clonidine or fluoxetine administration. In contrast, the administration of reboxetine more efficiently induced an inhibitory effect in the lesioned group. In additional analyses it was observed that while in control animals, LC and DRN basal firing rate was significantly correlated, this relationship was lost after the 6-OHDA lesion. In conclusion, dopaminergic degeneration alters LC neuron basal activity, the relationship/synteny between both nuclei, and their response to antidepressants. These findings shed fresh light on our understanding of the role of dopamine in depression and the mechanism action of antidepressants.