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Jaykumar Thumar, Eva Giesen, Harriet M KlugerYale Cancer Center, Yale School of Medicine, New Haven, CT, USAAbstract: Melanoma is the leading cause of fatal skin cancer, and in the past few decades, there has been an increase in the incidence of and mortality from metastatic melanoma. Until recently, the therapeutic options for treatment of metastatic melanoma were limited. The approval of ipilimumab (an anti-CTLA-4 antibody) and vemurafenib (mutant B-RAFV600E kinase inhibitor) by the Federal Drug Administration has led to a new era in melanoma treatment, and additional promising drugs and drug combinations are currently being investigated. As the choices of treatment for melanoma have expanded, the need to identify predictive biomarkers to tailor treatment strategies to individual tumor or immune system characteristics has become necessary. Such strategies have the potential of maximizing antitumor effect while minimizing toxicity and improving clinical benefit. In this article, we review the currently approved targeted therapies in melanoma and discuss the future of personalized therapy for this disease.Keywords: vemurafenib, mutations, inhibitors, tumors

Variation in the apparent stiffness of cancellous bone is generally ascribed to variation in cancellous structure and density, while the bone tissue stiffness is assumed to be constant. The purpose of the present study was to examine whether the bone tissue stiffness is dependent on the direction and density of the cancellous structure. Bone tissue stiffness was estimated by combining mechanical testing and micro-finite element (micro-FE) modeling on cylindrical bone specimens obtained from the human mandibular condyle. One set of specimens was tested in the vertical direction of the condyle (n = 39) and another set in the transverse direction (n = 30). The cancellous structure of the specimens was characterized by micro-CT. The apparent bone stiffnesses predicted by the FE model correlated strongly (r2 = 0.91) with the measured apparent bone stiffnesses. Apparent bone stiffness in the transverse direction was considerably smaller than that in the vertical direction. In contrast, the predicted bone tissue stiffness was significantly larger in the transverse direction (E = 13.70 GPa) than in the vertical direction (E = 11.87 GPa). In addition, bone tissue stiffness correlated negatively with the bone volume fraction and directional sensitivity of the bone tissue stiffness increased with a decrease of bone volume fraction. The results suggest that the transversely oriented trabeculae in the mandibular condyle are stiffer and more mineralized than the vertically oriented trabeculae and that bone loss is compensated by an increase in the degree of mineralization. [ABSTRACT FROM AUTHOR]

Since edentate subjects have a reduced masticatory function, it can be expected that the morphology of the cancellous bone of their mandibular condyles has changed according to the altered mechanical environment. In the present study, the morphology of cylindrical cancellous bone specimens of the mandibular condyles of edentate subjects (n = 25) was compared with that of dentate subjects (n = 24) by means of micro-computed tomography and by the application of Archimedes' principle. Stiffness and strength were determined by destructive mechanical testing. Compared with dentate subjects, it appeared that, in edentate subjects, the bone was less dense and the trabecular structure was less plate-like. The regression models of stiffness and strength built from bone volume fraction and the trabecular orientation relative to the axis of the specimen were similar for both dentate and edentate subjects. This indicates that, under reduced mechanical load, the fundamental relationship between bone morphology and mechanical properties does not change. [ABSTRACT FROM AUTHOR]

The human mandibular condyle has a parasagittal plate-like trabecular structure. We tested the hypothesis that this structure reflects the mechanical loading of the condyle. We developed a finite element model of the condyle to analyze the strains occurring during static compressive loading. The principal strains in the trabecular bone were primarily oriented in the sagittal plane. The first component was compressive and oriented supero-inferiorly. The second component was negligibly small and oriented medio-laterally. The third component was tensile, oriented anteroposteriorly, and almost equal to the compressive strain. This tensile strain was caused by anteroposterior bulging of the cortex. This means that the trabecular structure is also subjected to significant tensile forces. The orientation of the parasagittal strains followed the direction of the applied load. It was concluded that the trabecular structure of the mandibular condyle is optimal in resisting the compressive and tensile strains to which it is subjected. [ABSTRACT FROM AUTHOR]

In the present study, we tested the hypothesis that the cancellous bone of the mandibular condyle is inhomogeneous and anisotropic. For this purpose, 11 mandibular condyles from embalmed human cadavers were scanned in a micro-CT system. Within each condyle, 9 volumes of interest were selected from different mediolateral and supero-inferior regions. Several bone parameters were calculated to describe the morphology. It appeared that the cancellous bone of the condyle could be approximated by parallel plates. These plates were almost vertically oriented at an angle of 17° relative to the sagittal plane, i.e., perpendicular to the condylar axis. In the superior regions of the condyle, the cancellous bone had the largest bone volume fraction (0.19), associated with the thickest trabeculae (0.1 1 mm), and the highest trabecular number (1.72 mm-1). The lowest bone volume fraction (0.15) was found more inferiorly. The degree of anisotropy increased from superior to inferior across the condyle. No mediolateral differences in bone morphology were found, but superiorly central regions contained more bone than peripheral regions. The plate-like trabeculae could indicate that the condyle is optimally adapted to sustain loads from all directions in a plane perpendicular to the condylar axis. The high bone mass and lower anisotropy in the superior regions could enable the condyle to sustain multiple load directions. Toward the collum, the trabeculae are more aligned. This could point to stresses acting predominantly in one direction. [ABSTRACT FROM AUTHOR]

In France, Inserm (National Institute of Health And Medical Research) puts considerable effort into scientific integrity and quality management since more than 10 yr. Quality managers are present in about one hundred of the three hundred Inserm Units (the “Unit” at Inserm is an individualized research laboratory, with a head which is nominated by the President of Inserm and a defined life span. Usually, Units are the result of partnerships of Inserm with universities, university hospitals and other research organizations). When Quality management audits are performed, various dysfunctions are noted. Some of these are related to scientific integrity and Questionable Research Practice. Since an increasing number of Inserm Units disposes of Quality management systems according to the ISO 9001 standard, Inserm promotes since several years ISO 9001 management concepts and tools to improve scientific integrity. “Scientific integrity” as used in the missions of the (American) Office of Research Integrity (ORI, https://ori.hhs.gov/policies-ori-mission) and materialized in the Singapore statement on Research integrity (https://wcrif.org/statement). The Singapore Statement is not a regulatory document and does not represent the official policies of the countries represented at the conference. Rather, the intent of the Singapore Statement is to provide ethical guidance which research organizations, governments, and scientists can use to develop policies, regulations, and codes of conduct (World Conference on Research Integrity, https://wcrif.org/statement). Inserm, like others (Bouter, Account. Res. 22, 148–161 (2015)), believes that ISO 9001 research management favors good quality and integrity of research. In this field study the degree of awareness and whether scientists in Inserm Units are ready to make specific efforts to foster integrity and quality of their research was investigated. This study shows that a majority of scientists considers integrity and quality as being necessary. However, it appears that knowledge and understanding of integrity and quality in research should be improved. An effort has to be made to increase this level, specific actions have to be taken but scientists at Inserm are willing to make this effort.

Preventive actions for scientific misconduct and questionable research practice must be taken at an institutional level but also by scientists themselves as part of their role of science managers. We have proposed the concept of “Ethical and Efficient Research Management” and a panoply of easy to use tools which are designed to favour ethical behaviour, sound data and robust methods. Through the example of the processes “Arrival” and “Departure of a co-worker”, we show here that flow charts can help visualize critical steps in an activity and how to manage these steps in an ethical and efficient way.

Scientific misconduct and questionable research practices occur on occasion because scientific research is performed by human beings. With growing pressure to produce results, competition for limited resources and in a well-informed society, however, the number of reported cases has increased more than 10 fold in 10 years. Moreover, the impact of cases of fraud, poor quality of data and unethical research management is high and scientists are concerned by this phenomenon. Codes of conduct and investigations for misconduct are in place in most fields. Preventive actions however are difficult to conduct because managerial tools are missing or unknown by scientists. Here we describe the concept of Ethical and efficient research management and its use for preventive measures against bad research practice. The concept is based on the belief that sustainable management of a research team, project or collaboration is not possible without ethical conduct of management. Ethical and efficient research and research management are thus intrinsically connected. The Inserm-Quality-Network (Riq), uses currently management tools for different purposes: organization, quality management, quality control, knowledge management, project management and so forth and has adapted them for purpose of good research practice (http://extranet.inserm.fr/demarche-qualite/reseau-inserm-qualite).

Faith in scientific publications is based on the reliability of scientific data, sound assessment of risk and its management and high quality of management of a research project. Different tools enable researchers to detect possible week points in their study set-up and their data, validation of methods and equipment, quality control of products and sub-products contribute to ensuring reliability. Quality management and project management can be used (and are useful) in bio-medical research.

Objective: Invasive motor cortex stimulation (iMCS) has been proposed as a treatment for intractable neuropathic pain syndromes. Although the mechanisms underlying the analgesic effect of iMCS remain largely elusive, several studies found iMCS-related changes in regional cerebral blood flow (rCBF) in neuropathic pain patients. The aim of this study was to meta-analyze the findings of neuroimaging studies on rCBF changes to iMCS., Methods: PubMed, Embase, MEDLINE, Google Scholar, and the Cochrane Library were systematically searched for retrieval of relevant scientific papers. After initial assessment of relevancy by screening title and abstract by two investigators, independently, predefined inclusion and exclusion criteria were used for final inclusion of papers. Descriptive results were statistically assessed, whereas coordinates were pooled and meta-analyzed in accordance with the activation likelihood estimation (ALE) methodology., Results: Six studies were included in the systematic narrative analysis, suggesting rCBF increases in the cingulate gyrus, thalamus, insula, and putamen after switching the MCS device "ON" as compared to the "OFF" situation. Decreases in rCBF were found in for example the precentral gyrus and different occipital regions. Two studies did not report stereotactic coordinates and were excluded from further analysis. ALE meta-analysis showed that, after switching the iMCS electrode "ON," increased rCBF occurred in the (1) anterior cingulate gyrus; (2) putamen; (3) cerebral peduncle; (4) precentral gyrus; (5) superior frontal gyrus; (6) red nucleus; (7) internal part of the globus pallidus; (8) ventral lateral nucleus of the thalamus; (9) medial frontal gyrus; (10) inferior frontal gyrus; and (11) claustrum, as compared to the "OFF" situation. Reductions in rCBF were found in the posterior cingulate gyrus when the iMCS electrode was turned "OFF.", Conclusions: These findings suggested that iMCS induces changes in principal components of the default mode-, the salience-, and sensorimotor network., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.)

Experimental treatments for treating neuropathic pain include transcranial magnetic stimulation (TMS) and invasive electric motor cortex stimulation (iMCS) of the primary motor cortex (M1). Mechanisms of action of both methods, however, remain largely elusive. Within this paper, we focus on animal-based experiments in order to investigate the biological mechanisms that are involved in alleviating pain by use of TMS and/or iMCS. Therefore, this paper systematically reviewed the animal-based evidence on these mechanisms. Multiple online databases were systematically searched and retrieved articles were assessed using predefined inclusion and exclusion criteria. Twenty-three suitable articles were included; six on TMS and seventeen on iMCS. In general, iMCS and TMS were found to impact the primary motor cortex structure and function in animals. Furthermore, structural and functional changes within the thalamus, striatum, periaqueductal grey, rostral ventromedial medulla and dorsal horn were reported to occur. Although widespread, all areas in which structural and functional changes occurred after TMS and iMCS have been found to be interconnected anatomically. This could provide a rationale for future investigations of treating neuropathic pain by use of neuromodulation., Competing Interests: Declaration of Competing Interest The authors declare that they have had no conflict of interest in the conduction of this research., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Novel immune therapies targeting tumor specific antigens are being developed. Our purpose was to determine expression of the cancer testes antigen NY-ESO-1 in renal cell carcinoma (RCC), as NY-ESO-1 targeting approaches, particularly adoptive cell therapy, have not been evaluated in this disease., Methods: We employed tissue microarrays containing >300 unique RCC cases and adjacent benign renal tissue to determine NY-ESO-1 expression using a quantitative immunofluorescence method. In addition, we studied NY-ESO-1 expression in 35 matched primary and metastatic RCC specimens to assess concordance between different tumor sites., Results: NY-ESO-1 was highly expressed in a subset of RCCs. Expression in primary RCC specimens was significantly higher than adjacent normal renal tissue (P<0.0001) and higher in clear cell carcinomas than papillary RCC (P<0.0001). Expression levels in metastatic specimens were higher than in matched primary samples (P=0.0018), and the correlation between the two sites was modest (χ2=3.5, p=0.06)., Conclusions: Aberrant NY-ESO-1 expression seen in clear cell RCC suggests that NY-ESO-1 targeting approaches should be studied in this disease. Expression is higher in metastatic sites, and discordance between primary and metastatic sites in some patients suggests that patient selection for these therapies should be based on expression in metastatic rather than nephrectomy specimens.

Background: Cisplatin-based therapy is associated with acute and late toxicities. Therefore, a potentially less toxic carboplatin-based regimen was evaluated in patients with advanced seminoma., Patients and Methods: Eighteen patients with advanced seminoma were treated on outpatient basis with carboplatin (AUC5) at day 1, etoposide (100 mgm(-2)) at days 1-5, and bleomycin (30 IU) at day 2 (CEB). Treatment was 3-weekly for a total of 4 cycles. Outcome and toxicities were analyzed., Results: Median follow-up was 4 years and 7.5 months. Five-year progression-free survival was 86.6% (95% confidence interval (CI), 70.6%-100%), 5-year overall survival 100%, and 10-year overall survival 85% (95% CI, 63.3%-100%); 39% of all patients reached complete remission. Two patients underwent adjuvant treatment. Two patients relapsed; 1 is in ongoing remission 4 years after salvage therapy, the other died almost 6 years after CEB-therapy, despite multiple lines of salvage therapy. The main acute toxicity observed was hematologic. No late cardiovascular events or secondary malignancies were noted., Conclusion: CEB treatment is effective in advanced seminoma, showing minor toxicity. Progression-free and overall survival rates at 5 and 10 years are comparable to those achieved with cisplatin-based therapy. This indicates that carboplatin-combination therapy might be a good alternative to cisplatin-based therapy in the treatment of advanced seminomas., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Bone loss may affect the structure of cancellous bone. But its effect on trabeculae with different characteristics, like rods and plates, is not accurately known. This study analyzes the effect of bone loss on individual rod-like and plate-like trabeculae. 94 specimens were obtained from mandibular condyles from both dentate and edentate humans and scanned with a micro-CT scanner. The bone volume fraction (BV/TV) of these specimens ranged from 7% to 30%. Next, the rod-like and plate-like trabeculae were identified with an especially developed algorithm. Plate volume fraction (PV/TV), rod volume fraction (RV/TV), plate thickness, rod thickness, number of plates, and number of rods were determined. In individual specimens, the thickness of the rods ranged from 40 mum to 180 mum, while the thickness of the plates ranged from 40 mum to 300 mum. In every specimen, the thickness of the plates was larger than the thickness of the rods. Statistical analysis revealed that PV/TV was proportional (r = 0.98, P < 0.001) and RV/TV inversely proportional (r = -0.45, P < 0.001) to BV/TV. Also the thickness of the plates correlated with BV/TV (r = 0.62, P < 0.001), while the thickness of the rods (mean = 90 mum, SD = 7 mum) remained constant (r = -0.09, P = 0.378). A four-fold reduction of the bone volume fraction was accompanied by a three-fold reduction of the number of plates and a 40% reduction of their thickness, but also by a three-fold increase in the number of rods and RV/TV. It was concluded that the effect of bone loss on plate-like trabeculae was opposite to its effect on rod-like trabeculae. Remarkably, the thickness of the rods (90 mum) was independent of the bone volume fraction. This suggests that there is a minimal thickness for trabeculae.

The mechanical properties of cancellous bone depend on the bone structure. The present study examined the extent to which the apparent stiffness of the cancellous bone of the human mandibular condyle can be predicted from its structure. Two models were compared. The first, a structure model, used structural parameters such as bone volume fraction and anisotropy to estimate the apparent stiffness. The second was a finite element model (FEM) of the cancellous bone. The bone structure was characterized by micro-computed tomography. The calculated stiffnesses of 24 bone samples were compared with measured stiffnesses. Both models could predict 89% of the variation in the measured stiffnesses. From the stiffness approximated by FEM in combination with the measured stiffness, the stiffness of the bone tissue was estimated to be 11.1 +/- 3.2 GPa. It was concluded that both models could predict the stiffness of cancellous bone with adequate accuracy.

A possible link between cellular cyclic AMP content and Na+K+ATPase activity was investigated in homogenates of rat kidney. Enzyme kinetics of Mg2+ and Na+K+ATPase were run in the presence of cyclic AMP, dibutyryl cAMP and compounds expected to elevate cyclic AMP levels such as forskolin, a potent adenylate cyclase activator, IBMX, an inhibitor of phosphodiesterases, and the beta-agonist isoproterenol. Medullary Na+K+ATPase is strongly inhibited by cyclic AMP whereas cortical Na+K+ATPase was stimulated in the same conditions. The correlation between ATPase activity and cellular cyclic AMP content supports the concept of a possible regulation of the enzyme by cyclic AMP.

The renal vascular effects of dopaminomimetics were studied in the isolated perfused rat kidney after pretreatment with 10(-5) M phenoxybenzamine and 10(-5) M sotalol and after contraction of the vascular bed with prostaglandin F2 alpha (10(-7) to 3 x 10(-6) M). Under these conditions, our criterion for vascular dopaminomimetic activity was renal vasodilation, competitively inhibited by d-butaclamol (10(-8) M) but not by 1-butaclamol (3 x 10(-8) M). Dopamine is active at micromolar concentrations (ED50 = 2.53 +/- 0.34 x 10(-6) M). The N-alkylated analogues of dopamine preserve this activity if the alkyl group is a methyl group (epinine) or two n-propyl groups (di-n-propyl-dopamine). The catechol nucleus appears essential for renal vascular dopaminomimetic activity (SK&F 38393, active; p-tyramine, di-n-propyl-m-tyramine and RU 24926, inactive). Bromocriptine reproduces renal dopaminergic vasodilation with an ED50 of 1.3 +/- 0.14 x 10(-6) M. The study of structure-activity relationships of dopaminomimetics relates the vascular dopamine receptor, associated with renal vasodilation, to the dopamine receptor, associated with stimulation of dopamine-sensitive adenylate cyclase.

The effects of several antagonists of glucocorticoid action on a line of hepatoma cells (HTC strain) have been studied in order to determine their mechanisms of action. The induction of tyrosine aminotransferase by dexamethasone can be partially or totally inhibited if an antagonist is added simultaneously with dexamethasone or some time later. Antagonists, even if they have as much affinity for the cytoplasmic receptor as dexamethasone, must be administered at a 100-fold excess as compared to dexamethasone. Their receptor binding kinetics are not identical to those of inducer steroids: moreover there is no correlation between relative binding affinities and anti-inducing capacities. A short contact between the cells and the antagonist is sufficient to obtain a full antagonistic effect, but the antagonist is inactive if administered and removed from the cells before induction. An interpretation if suggested, considering these results which do not find a satisfactory explanation in the classical theory of receptor action.

We studied the renal vascular effects of flupenthixol and sulpiride isomers in the isolated perfused rat kidney in the presence of phenoxybenzamine (10(-5) M) and sotalol (10(-5) M). The vascular bed was contracted with prostaglandin F2 alpha (10(-7) -3 X 10(-6) M) and dose-dependently relaxed with dopamine. Cis-flupenthixol (10(-9)-10(-7) M) antagonized competitively the response to dopamine (apparent pA2 = 8.34 +/- 0.09; mean +/- SD) without affecting papaverine-induced relaxation. Trans-flupenthixol was without effect at 10(-7) M. The dopamine receptor antagonist activities of the sulpiride isomers are low and d-sulpiride is twice as active as 1-sulpiride. Thus, the renal vascular dopamine receptor can be further characterized by the relative antagonist activities of cis-flupenthixol and sulpiride and by a rather low stereospecificity in favor of d-sulpiride.

Sodium butyrate in a 5 mM concentration prevents the induction of tyrosine aminotransferase in hepatoma culture cells, without affecting the basal level of the enzyme. This effect is reversible immediately after the removal of butyrate, or after a lag, if butyrate was present for more than 2 h. Neither the amount of cellular RNA nor the rate of total RNA synthesis were affected by sodium butyrate. Furthermore, butyrate does not inhibit protein synthesis: [35S]methionine incorporation into proteins, measured in a reticulocyte lysate system, shows no significant difference between the translation capacity of the RNAs from butyrate-treated cells and from dexamethasone-induced or uninduced cells. Nevertheless, when tyrosine aminotransferase was isolated from the translation products by its specific antiserum and analyzed by gel electrophoresis, we observed that the amount of the enzyme synthetized in the presence of RNAs from dexamethasone/butyrate-treated cells was strongly diminished relative to that synthesized in the presence of RNA from dexamethasone-induced cells. These experiments indicate that the treatment of the cells with butyrate decreases the activity of the specific messenger RNA for tyrosine aminotransferase to a level close to the basal level.

The induction of tyrosine aminotransferase by a variety of steroids was studied in cells from a hepatoma tissue culture (HTC). We have defined a class of steroids that induce TAT synthesis to a higher level than optimal inducers described earlier; these are called supra-inducers. When TAT induction is compared with the binding of the steroids to the cytoplasmic receptor or to their binding in the whole cell, a good correlation between binding in vivo of the hormone and its induction capacity can be established, whereas such a correlation was not systematically observed in vitro. A very short exposure of HTC cells to either dexamethasone or corticosterone is sufficient to induce TAT. When the inducer is removed from the culture medium a few minutes after its administration, the intracellular hormone concentration decreases very rapidly but TAT will be synthesized at its maximal rate. Thus the hormones behave as a starting signal for the optimal synthesis of the enzyme, and their presence in the culture medium is not necessary throughout the entire induction period.

Hepatoma tissue culture cells, grown in the presence of D-galactosamine and 6-azauridine, demonstrate a strong reduction of the intracellular UTP pool that can be replenished by formation of UTP from uridine and FUTP from 5-fluorouridine within 2 h. Concomitantly with the UTP deficiency, a decrease of dexamethasone-induced tyrosine aminotransferase activity occurs. 5-Fluorouridine, as compared to uridine, is even more efficient in restoring the activity of tyrosine aminotransferase. Treatment of the cells with D-galactosamine alone results in a minor lowering of UTP that is not followed by the inhibition of the enzyme induction. However, the administration of D-galactosamine, simultaneously or at any time up to 5 h before or after dexamethasone, leads to a 1.5- to 2-fold higher induction (superinduction) which appears 24 h later.

The induction of tyrosine aminotransferase (TAT) in the HTC hepatoma cell line is observed after a single administration of an active steroid. A few minutes of contact between the cells and dexamethasone or corticosterone is sufficient to induce TAT synthesis to its maximal level. When radiolabeled hormones are used, no radioactivity is found in the cell one hour after removal of the hormone from the culture medium, whereas TAT activity remains optimal. Thus, the hormone behaves like a start signal for the optimal synthesis of the enzyme and its continuous presence in the medium is not necessary during the whole induction cycle.

Renin release elicited by i.v. injection of loop-diuretics was used to study the effects of angiotensin II (AII) on intrarenal hemodynamics. The vasoconstrictive action of intrarenally synthesized AII predominates in the efferent glomerular arteriole. Such a vasoconstrictive effect could affect blood flow in the vasa recta which stem from efferent arterioles of juxtamedullary glomeruli. Renin secretion and renal inner medullary blood flow (tissue clearance of 133Xe) were simultaneously measured before and after frusemide-induced renin release. The relationship between renin secretion and renal inner medullary blood flow was inverse. Changes in renal medullary blood flow may be physiological determinants of medullary osmolality and renal concentration ability. The intrarenal role of AII in urinary concentration recovery after frusemide was examined. Inhibition of renin release by propranolol or AII-blockade (by saralasin or Hoe 409) delayed recovery of urinary osmolality. In the conscious rat, propranolol slowed down recovery of the cortico-papillary gradient for sodium. Its vasoconstrictive action on the efferent glomerular arteriole might enable the renin-angiotensin system to participate in the control of renal excretion of salt and water.