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PurposeGenomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib.MethodsThis two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.ResultsTovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg.ConclusionsThe safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.ClinicaltrialsGov identifierNCT01425008.

Abstract Objective According to a seminal hypothesis stated by Crick and Koch in 1995, one is not aware of neural activity in primary visual cortex (V1) because this region lacks reciprocal connections with prefrontal cortex (PFC). Methods We provide here a neuropsychological illustration of this hypothesis in a patient with a very rare form of cortical blindness: ventral and dorsal cortical pathways were lesioned bilaterally while V1 areas were partially preserved. Results Visual stimuli escaped conscious perception but still activated V1 regions that were functionally disconnected from PFC. Interpretation These results are consistent with the hypothesis of a causal role of PFC in visual awareness.

Background: Inferior glenohumeral subluxation (GHS) can cause disabling pain in hemiplegics. Conservative treatments have not been proven to be effective or maintained over time. A few studies have shown the benefits of surgical treatment. The objective of our study was to evaluate the medium-term clinical and radiological results of arthroscopic glenohumeral suspensioplasty surgery by biceps tenodesis in the setting of painful GHS in hemiplegics. Methods: We conducted a retrospective study of patients who underwent arthroscopic glenohumeral suspensioplasty. The assessment, at a minimum of 1 year, included a clinical evaluation (pectoralis major spasticity, pain, range of motion, satisfaction) and a radiographic evaluation (Dursun classification, height of subacromial space). Results: Five patients with a mean age of 51 years (36-72 years) were included at a mean follow-up of 40 months (12-70). Satisfaction was good in 80% of patients. Pain decreased in all patients, but not significantly. Four patients (80%) would repeat the procedure if it were necessary. In all patients, a reduction in GHS over time was observed, with a reduction in subacromial height, except in 1 patient who suffered a tenodesis rupture during a fall. Conclusion: Our results suggest that arthroscopic glenohumeral suspensioplasty by biceps tenodesis may be a therapeutic option in hemiplegic patients with painful GHS.

Background: Scapulectomy is one of the surgical options in the case of malignant lesions in the scapula with an indication of surgical removal. Very few series in the literature have looked at postoperative quality of life and emotional acceptance, particularly in the case of scapulectomy without reconstruction. The objective is to assess the midterm results of scapulectomies in terms of function, quality of life, and acceptance for the patient. Methods: With a mean follow-up of 85 months (range 42 months-180 months), 11 scapulectomies for malignant tumors were performed with a mean age of 50 years: 5 partial scapulectomies, 4 total scapulectomies, and 2 subtotal scapulectomies. There were 6 chondrosarcomas, 2 high-grade osteosarcomas, 1 malignant peripheral nerve sheath tumor, and 1 low-grade atypical epithelioid sarcoma. The radio-clinical analysis was focused on functional results and mental health evaluation. Results: The mean Musculoskeletal Tumor Society score of 11 scapulectomies was 20 ± 5 at 66% of normal, with the Disabilities of the Arm, Shoulder and Hand (DASH) score of 35 ± 26, and the Toronto Extremity Salvage Score of 76%. Patients had controlled pain (mean visual analog scale 1/10). Mobilities of the 11 scapulectomies were correct: average active anterior elevation of 89.5 ± 43 degrees, average abduction of 81 ± 42 degrees, average external rotation of 30 ± 25 degrees, and average internal rotation was at L5. Scapulectomy results in impaired physical and mental health compared with the general population (PCS-12 = -9; MCS-12 = -7). Partial scapulectomy, compared to total scapulectomy, gave better results: Musculoskeletal Tumor Society score (14 ± 1 vs. 24 ± 1 P = .0175), acceptance (45 ± 9 vs. 92 ± 16, P = .0184), mental health (MCS-12: 29 ± 1 vs. 55 ± 4, P = .0175), and Toronto Extremity Salvage Score (84 ± 5 vs. 68 ± 7, P = .0195). Partial and subtotal scapulectomies were better accepted (45 ± 9 vs. 86 ± 23, P = .0323) and tolerated (MCS-12: 29 ± 1 vs. 52 ± 6, P = .0099) by the patient compared to total scapulectomy. Conclusion: Total or partial scapulectomies without scapula reconstruction remain a disabling procedure performed with consequences on the physical and mental health of the patients. Partial or subtotal scapulectomy should be performed whenever possible because it seems to be associated with a better functional prognosis as well as less poor mental health and emotional acceptance of the patients, even though total scapulectomy may be necessary to obtain a complete curative tumor resection, which is the main goal.

Inferior glenohumeral subluxation represents one of the causes of disabling pain in patients with hemiplegia after a stroke. In the case of failure of medical treatment by orthosis or electrical stimulation, surgical treatment of suspensionplasty has been described with good results. We describe here an arthroscopic technique of glenohumeral suspensionplasty by tenodesis of the biceps, proposed in the context of a painful glenohumeral subluxation in patients with hemiplegia.

Abstract Background Pupils in secondary schools do not meet the targets for physical activity levels during physical education (PE) sessions, and there is a lack of data on the vigorous physical activity domain (VPA) in PE known to be positively associated with cardio metabolic health While PE session intensity depends on a variety of factors, the large majority of studies investigating these factors have not taken into account the nested structure of this type of data set. Therefore, the aim of this study was to investigate the relationship between various factors (gender, activity type, class location and class composition) and various activity levels during PE classes in secondary schools, using a multi-level statistical approach. Methods Year eight (12–13 years old) adolescents (201 boys and 106 girls) from six schools were fitted with accelerometers during one PE session each, to determine the percentage (%) of the PE session time spent in sedentary (SPA), light (LPA), moderate (MPA), vigorous (VPA) and moderate-to-vigorous (MVPA) intensity levels. Two- and three-level (pupils, n = 307; classes, n = 13, schools, n = 6) mixed-effect models were used to assess the relationship between accelerometer-measured physical activity levels (% of class time spent in various activity levels) and gender, activity type, class location and composition. Results Participants engaged in MVPA and VPA for 30.7 ± 1.2% and 11.5 ± 0.8% of PE classes, respectively. Overall, no significant association between gender or class composition and PA was shown. A significant relationship between activity type and PA was observed, with Artistic classes significantly less active than Fitness classes for VPA (5.4 ± 4.5 vs. 12.5 ± 7.1%, p = 0.043, d:1.19). We also found a significant association between class location and PA, with significantly less time spent in SPA (24.8 ± 4.8% vs. 30.0 ± 3.4%, p = 0.042, d:0.77) and significantly more time spent in VPA (12.4 ± 3.7% vs. 7.6 ± 2.0%, p = 0.022, d:1.93) and MVPA (32.3 ± 6.7% vs.24.8 ± 3.8%, p = 0.024, d:1.33) in outdoors vs. indoors classes. Conclusions The results suggest that class location and activity type could be associated with the intensity of PA in PE. It is essential to take into account the clustered nature of this type of data in similar studies if the sample size allows it.

Melatonin (MLT) is a biological modulator of circadian and seasonal rhythms and reproduction. The photoperiodic information is detected by retinal photoreceptors and transmitted through nerve transmissions to the pineal gland, where MLT is synthesized and secreted at night into the blood. MLT interacts with two G protein-coupled receptors, MT1 and MT2. The aim of our work was to provide evidence for the presence of MLT receptors in the ovine pineal gland and define their involvement on melatonin secretion. For the first time, we identified the expression of MLT receptors with the specific 2-[125I]-MLT agonistic radioligand in ovin pinealocytes. The values of Kd and Bmax are 2.24 ± 1.1 nM and 20 ± 6.8 fmol/mg. MLT receptors are functional and inhibit cAMP production and activate ERK1/2 through pertussis toxin-sensitive Gi/o proteins. The MLT receptor antagonist/ inverse agonist luzindole increased cAMP production (189 ± 30%) and MLT secretion (866 ± 13%). The effect of luzindole on MLT secretion was additive with the effect of well-described activators of this pathway such as the β-adrenergic agonist isoproterenol and the α-adrenergic agonist phenylephrine. Co-incubation of all three compounds increased MLT secretion by 1236 ± 199%. These results suggest that MLT receptors are involved in the negative regulation of the synthesis of its own ligand in pinealocytes. While adrenergic receptors promote MLT secretion, MLT receptors mitigate this effect to limit the quantity of MLT secreted by the pineal gland.

Spinal commissural axon navigation across the midline in the floor plate requires repulsive forces from local Slit repellents. The long-held view is that Slits push growth cones forward and prevent them from turning back once they became sensitized to these cues after midline crossing. We analyzed with fluorescent reporters Slits distribution and FP glia morphology. We observed clusters of Slit-N and Slit-C fragments decorating a complex architecture of glial basal process ramifications. We found that PC2 proprotein convertase activity contributes to this pattern of ligands. Next, we studied Slit-C acting via PlexinA1 receptor shared with another FP repellent, the Semaphorin3B, through generation of a mouse model baring PlexinA1Y1815F mutation abrogating SlitC but not Sema3B responsiveness, manipulations in the chicken embryo, and ex vivo live imaging. This revealed a guidance mechanism by which SlitC constantly limits growth cone exploration, imposing ordered and forward-directed progression through aligned corridors formed by FP basal ramifications.

Loss of Heterozygosity (LOH) typically refers to a phenomenon in which diploid cells that are heterozygous for a mutant allele lose their wild type allele through mutations. LOH is implicated in oncogenesis when it affects the remaining wild type copy of a tumor suppressor. Drosophila has been a useful model to identify genes that regulate the incidence of LOH, but most of these studies use adult phenotypic markers such as multiple wing hair (mwh). Here, we describe a cell-autonomous fluorescence-based system that relies on the QF/QS transcriptional module to detect LOH, which may be used in larval, pupal and adult stages and in conjunction with the GAL4/UAS system. Using the QF/QS system, we were able to detect the induction of cells with LOH by X-rays in a dose-dependent manner in the larval wing discs, and to monitor their fate through subsequent development in pupa and adult stages. We tested the genetic requirement for changes in LOH, using both classical mutants and GAL4/UAS-mediated RNAi. Our results identify two distinct culling phases that eliminate cells with LOH, one in late larval stages and another in the pupa. The two culling phases are genetically separable, showing differential requirement for pro-apoptotic genes of the H99 locus and transcription factor Srp. A direct comparison of mwh LOH and QF/QS LOH suggests that cells with different LOH events are distinguished from each other in a p53-dependent manner and are retained to different degrees in the final adult structure. These studies reveal previously unknown mechanisms for the elimination of cells with chromosome aberrations.

BackgroundCTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.MethodsPeripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4+/CD8+ cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis.ResultsThree of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8+ cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup.ConclusionAdministration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood.Clinical trial registration numberNCT00086489.

Objective: According to a seminal hypothesis stated by Crick and Koch in 1995, one is not aware of neural activity in primary visual cortex (V1) because this region lacks reciprocal connections with prefrontal cortex (PFC). Methods: We provide here a neuropsychological illustration of this hypothesis in a patient with a very rare form of cortical blindness: ventral and dorsal cortical pathways were lesioned bilaterally while V1 areas were partially preserved. Results: Visual stimuli escaped conscious perception but still activated V1 regions that were functionally disconnected from PFC. Interpretation: These results are consistent with the hypothesis of a causal role of PFC in visual awareness. [ABSTRACT FROM AUTHOR]

Knowledge on G protein-coupled receptor (GPCRs) structure and mechanism of activation has profoundly evolved over the past years. The way drugs targeting this family of receptors are discovered and used has also changed. Ligands appear to bind a growing number of GPCRs in a competitive or allosteric manner to elicit balanced signaling or biased signaling (i.e., differential efficacy in activating or inhibiting selective signaling pathway(s) compared to the reference ligand). These novel concepts and developments transform our understanding of the follicle-stimulating hormone (FSH) receptor (FSHR) biology and the way it could be pharmacologically modulated in the future. The FSHR is expressed in somatic cells of the gonads and plays a major role in reproduction. When compared to classical GPCRs, the FSHR exhibits intrinsic peculiarities, such as a very large NH2-terminal extracellular domain that binds a naturally heterogeneous, large heterodimeric glycoprotein, namely FSH. Once activated, the FSHR couples to Gαs and, in some instances, to other Gα subunits. G protein-coupled receptor kinases and β-arrestins are also recruited to this receptor and account for its desensitization, trafficking, and intracellular signaling. Different classes of pharmacological tools capable of biasing FSHR signaling have been reported and open promising prospects both in basic research and for therapeutic applications. Here we provide an updated review of the most salient peculiarities of FSHR signaling and its selective modulation.