The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development.

BACKGROUND: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. METHODS: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. RESULTS: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. CONCLUSION: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted.

Luminescence and Electronic Spectral Studies of Some Synthesized Lanthanide Complexes Using Benzoic Acid Derivative and o-Phenanthroline.

Lanthanide complexes of p-nitrobenzoic acid(p-NBA) and o-phenanthroline(o-phen) namely [Ln2(Phen)2(p-NBA)3(NO3)2].2H2O where, Ln = Sm(III),Tb(III),Dy(III) and [Eu2(Phen)2(p-NBA)3].4H2O were synthesized and further characterized by Elemental analysis, UV spectroscopy, IR spectroscopy, (1)HNMR spectroscopy. Luminescence measurements were performed on all compounds in ethanolic solution. These complexes have showed narrow emission indicating that the organic ligands are better energy absorber and capable of transferring energy to the Ln (III) ion. Furthermore, we reported electronic spectral studies on [Eu2 (Phen)2 (p-NBA)3].4H2O in order to calculate following parameters, viz: Oscillator strength (f), Judd-Ofelt parameters Ωλ (λ = 2,4,6) and Radiative parameters. [Eu2 (o-Phen)2 (p-NBA)3].4H2O showed the strongest emission at 613 nm corresponds to (5)D0→(7)F2 hypersensitive transition, this emission is very sensitive to the environment. However, the larger value of Ω2 supports the presence of the hypersensitive transition (5)D0→(7)F2 which strictly depends on the nature of ligand. All electronic spectral parameters were calculated systemically.

Morphology and dynamics of the upper cloud layer of Venus.

Venus is completely covered by a thick cloud layer, of which the upper part is composed of sulphuric acid and some unknown aerosols. The cloud tops are in fast retrograde rotation (super-rotation), but the factors responsible for this super-rotation are unknown. Here we report observations of Venus with the Venus Monitoring Camera on board the Venus Express spacecraft. We investigate both global and small-scale properties of the clouds, their temporal and latitudinal variations, and derive wind velocities. The southern polar region is highly variable and can change dramatically on timescales as short as one day, perhaps arising from the injection of SO2 into the mesosphere. The convective cells in the vicinity of the subsolar point are much smaller than previously inferred, which we interpret as indicating that they are confined to the upper cloud layer, contrary to previous conclusions, but consistent with more recent study.

Deriving new mixing ratios for Venus atmospheric gases using data from the Pioneer Venus Large Probe Neutral Mass Spectrometer.

We present the first published method to convert data obtained by the Pioneer Venus Large Probe Neutral Mass Spectrometer (LNMS) into units of mixing ratio (ppm) and volume percent (v%) against CO2 and N2, the dominant Venus atmospheric gases, including conversion to density (kg m-3). These unit conversions are key to unlocking the untapped potential of the data, which represents a significant challenge given the scant calibration data in the literature. Herein, we show that our data treatments and conversions yield mixing ratios and volume percent values for H2O, N2, and SO2 that are within error to those reported for the gas chromatograph (LGC) on the Pioneer Venus Large Probe (PVLP). For the noble gases, we developed strategies to correct for instrument biases by treating the data as a relative scale and using PVLP and Venera-based measurements as calibration points. Together, these methods, conversions, calibrations, and comparisons afford novel unit conversions for the LNMS data and yield unified measures for Venus' atmosphere from the LNMS and LGC on the PVLP.•Conversion into mixing ratio (ppm), volume percent (v%), and density (kg m-3).•Mixing ratios are expressed against CO2 and N2.•LNMS and LGC measurements on the PVLP are consistent.

Effect of chlorine dioxide and sodium hypochlorite on the dissolution of human pulp tissue - An in vitro study.

BACKGROUND: Organic tissue dissolution is an important property of an irrigant which aids in the success of root canal treatment. Recent studies have advocated the use of Chlorine dioxide as an endodontic irrigant. The aim of this study is to compare the dissolution efficacy of chlorine dioxide and sodium hypochlorite on human pulp tissue. METHODS: In this study, 2% Sodium hypochlorite, 5% Chlorine dioxide and isotonic saline solution (control) were used. Thirty human pulp tissue specimens were exposed to three test solutions (n = 10) for 30 min following which the loss of weight was compared from the original weight by using a digital analytical balance. RESULTS: Sodium hypochlorite was more efficient in dissolving human pulp tissue when compared to Chlorine dioxide. Isotonic saline solution failed to dissolve any of the specimens. CONCLUSION: 5% Chlorine dioxide is capable of dissolving human pulp tissue but sodium hypochlorite was more effective.

Venus: further evidence of vortex circulation.

A space-time composite of polar stereographic ultraviolet images of Venus from Mariner 10 shows a remarkable circumpolar vortex. The vortex is characterized by a cloud which appears similar to dense terrestrial stratus having an albedo that is 50 percent higher. Spiral streaks converge into it from low latitudes, akin to the spiral bands of a hurricane. The bright visible polar cloud is not axisymmetric but has roughly an elliptical shape. The high brightness of the polar cloud suggests that it has a different origin from the rest of the Venus cloud cover.

Satellite observations of smoke from oil fires in kuwait.

Extensive dark smoke clouds associated with burning oil wells in Kuwait have been seen in data from weather satellites since early February 1991. The smoke is dispersed over a wide area. Variable and strong low level winds have held most of the smoke plume below 3 to 5 kilometers within a few hundred kilometers of the source. Thin veils of smoke have been detected in METEOSAT data as far away as 2000 kilometers east of Kuwait, over southwestern Pakistan at heights between 6 and 7 kilometers. The occasional presence of convective clouds over the fires indicates that some scavenging of the smoke is taking place.

High winds of neptune: a possible mechanism.

Neptune receives only 1/900th of the earth's solar energy, but has wind speeds of nearly 600 meters per second. How the near-supersonic winds can be maintained has been a puzzle. A plausible mechanism, based on principles of angular momentum and energy conservation in conjunction with deep convection, leads to a regime of uniform angular momentum at low latitudes. In this model, the rapid retrograde winds observed are a manifestation of deep convection, and the high efficiency of the planet's heat engine is intrinsic from the room allowed at low latitudes for reversible processes, the high temperatures at which heat is added to the atmosphere, and the low temperatures at which heat is extracted.

Interior structure of neptune: comparison with uranus.

Measurements of rotation rates and gravitational harmonics of Neptune made with the Voyager 2 spacecraft allow tighter constraints on models of the planet's interior. Shock measurements of material that may match the composition of Neptune, the so-calied planetary ;;ice,'' have been carried out to pressures exceeding 200 gigapascals (2 megabars). Comparison of shock data with inferred pressure-density profiles for both Uranus and Neptune shows substantial similarity through most of the mass of both planets. Analysis of the effect of Neptune's strong differential rotation on its gravitational harmonics indicates that differential rotation involves only the outermost few percent of Neptune's mass.

Cloud images from the pioneer venus orbiter.

Ultraviolet images of Venus over a 3-month period show marked evolution of the planetary scale features in the cloud patterns. The dark horizontal Y feature recurs quasi-periodically, at intervals of about 4 days, but it has also been absent for periods of several weeks. Bow-shaped features observed in Pioneer Venus images are farther upstream from the subsolar point than those in Mariner 10 images.

Orbiter cloud photopolarimeter investigation.

The first polarization measurements of the orbiter cloud photopolarimeter have detected a planet-wide layer of submicrometer aerosols of substantial visible optical thickness, of the order of 0.05 to 0.1, in the lower stratosphere well above the main visible sulfuric acid cloud layer. Early images show a number of features observed by Mariner 10 in 1974, including planetary scale markings that propagate around the planet in the retrograde sense at roughly 100 meters per second and bright- and dark-rimmed cells suggesting convective activity at low latitudes. The polar regions are covered by bright clouds down to latitudes aproximately 50 degrees, with both caps significantly brighter (relative to low latitudes) than the south polar cloud observed by Mariner 10. The cellular features, often organized into clusters with large horizontal scale, exist also at mid-latitudes, and include at least one case in which a cell cuts across the edge of the bright polar cloud of the northern hemisphere.

Neptune's Wind Speeds Obtained by Tracking Clouds in Voyager Images.

Images of Neptune obtained by the narrow-angle camera of the Voyager 2 spacecraft reveal large-scale cloud features that persist for several months or longer. The features' periods of rotation about the planetary axis range from 15.8 to 18.4 hours. The atmosphere equatorward of -53 degrees rotates with periods longer than the 16.05-hour period deduced from Voyager's planetary radio astronomy experiment (presumably the planet's internal rotation period). The wind speeds computed with respect to this radio period range from 20 meters per second eastward to 325 meters per second westward. Thus, the cloud-top wind speeds are roughly the same for all the planets ranging from Venus to Neptune, even though the solar energy inputs to the atmospheres vary by a factor of 1000.

Voyager 2 at neptune: imaging science results.

Voyager 2 images of Neptune reveal a windy planet characterized by bright clouds of methane ice suspended in an exceptionally clear atmosphere above a lower deck of hydrogen sulfide or ammonia ices. Neptune's atmosphere is dominated by a large anticyclonic storm system that has been named the Great Dark Spot (GDS). About the same size as Earth in extent, the GDS bears both many similarities and some differences to the Great Red Spot of Jupiter. Neptune's zonal wind profile is remarkably similar to that of Uranus. Neptune has three major rings at radii of 42,000, 53,000, and 63,000 kilometers. The outer ring contains three higher density arc-like segments that were apparently responsible for most of the ground-based occultation events observed during the current decade. Like the rings of Uranus, the Neptune rings are composed of very dark material; unlike that of Uranus, the Neptune system is very dusty. Six new regular satellites were found, with dark surfaces and radii ranging from 200 to 25 kilometers. All lie inside the orbit of Triton and the inner four are located within the ring system. Triton is seen to be a differentiated body, with a radius of 1350 kilometers and a density of 2.1 grams per cubic centimeter; it exhibits clear evidence of early episodes of surface melting. A now rigid crust of what is probably water ice is overlain with a brilliant coating of nitrogen frost, slightly darkened and reddened with organic polymer material. Streaks of organic polymer suggest seasonal winds strong enough to move particles of micrometer size or larger, once they become airborne. At least two active plumes were seen, carrying dark material 8 kilometers above the surface before being transported downstream by high level winds. The plumes may be driven by solar heating and the subsequent violent vaporization of subsurface nitrogen.

Sweet's syndrome in association with common variable immunodeficiency.

Sweet's syndrome (SS), a rare reactive neutrophilic dermatosis, has been reported to occur in association with a variety of systemic disorders, categorized by von den Diesch into idiopathic, paraneoplastic, pregnancy and parainflammatory subgroups. The parainflammatory group has been well defined, and includes a wide spectrum of infectious triggers and disorders of immune dysregulation. To date, however, no cases of SS have been described in the context of common variable immunodeficiency (CVID). We report a case of paediatric-onset SS, previously reported as idiopathic, with a subsequent diagnosis of CVID.

Cardiac magnetic resonance imaging-indeterminate/negative cardiac sarcoidosis revealed by 18F-fluorodeoxyglucose-positron emission tomography: two case reports and a review of the literature.

BACKGROUND: Sarcoidosis is an inflammatory disorder of immune dysregulation characterized by non-caseating granulomas that can affect any organ. Cardiac sarcoidosis is an under-recognized entity that has a heterogeneous presentation and may occur independently or with any severity of systemic disease. Diagnosing cardiac sarcoidosis remains problematic with endomyocardial biopsies associated with a high risk of complications. Several diagnostic algorithms are currently available that rely on histopathology or clinical and radiological measures. The dominant mode of diagnostic imaging to date for cardiac sarcoidosis has been cardiac magnetic resonance imaging with gadolinium enhancement. CASE PRESENTATIONS: We report the cases of two adult patients: case 1, a 50-year-old white man who presented with severe congestive cardiac failure; and case 2, a 37-year-old white woman who presented with complete heart block. Both patients had a background of untreated pulmonary sarcoidosis. Cardiac magnetic resonance imaging did not show evidence of sarcoidosis in either patient and both proceeded to 18F-fluorodeoxyglucose-positron emission tomography scans that were highly suggestive of cardiac sarcoidosis. Both patients were systemically immunosuppressed with orally administered prednisone and methotrexate and had subsequent improvement by clinical and nuclear medicine imaging measures. CONCLUSIONS: Current consensus guidelines recommend all patients with sarcoidosis undergo screening for occult cardiac disease, with thorough history and examination, electrocardiogram, and transthoracic echocardiogram. If any abnormalities are detected, advanced cardiac imaging should follow. While cardiac magnetic resonance imaging identifies the majority of cardiac sarcoidosis, early disease may not be detected. These cases demonstrate 18F-fluorodeoxyglucose-positron emission tomography is warranted following an indeterminate or normal cardiac magnetic resonance imaging if clinical suspicion remains high. Unidentified and untreated cardiac sarcoidosis risks significant morbidity and mortality, but early detection can facilitate disease-modifying immunosuppression and cardiac-specific interventions.

Electrochemical determination of an anti-hyperlipidimic drug pitavastatin at electrochemical sensor based on electrochemically pre-treated polymer film modified GCE.

An electrochemically pretreated silver macroporous (Ag MP) multiwalled carbon nanotube modified glassy carbon electrode (PAN-Ag MP-MWCNT-GCE) was fabricated for the selective determination of an anti-hyperlipidimic drug, pitavastatin (PST). The fabricated electrochemical sensor was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The fabricated electrode was employed in quantifying and determining PST through differential pulse adsorptive stripping voltammetry (DPAdSV) and CV. The electrode fabrication proceeded with remarkable sensitivity to the determination of PST. The effect of various optimized parameters such as pH, scan rate (ν), accumulation time (tacc), accumulation potential (Uacc) and loading volumes of Ag MP-MWCNT suspension were investigated to evaluate the performance of synthesized electrochemical sensor and to propose a simple, accurate, rapid and economical procedure for the quantification of PST in pharmaceutical formulations and biological fluids. A linear response of PST concentration in the range 2.0×10-7-1.6×10-6 M with low detection (LOD) and quantification (LOQ) limits of 9.66±0.04 nM and 32.25±0.07 nM, respectively, were obtained under these optimized conditions.

Familial tapetoretinal degeneration and epilepsy.

Tapetoretinal degeneration is described in two siblings in association with generalized major motor seizures and intellectual impairment. Neither of these patients have the characteristic dysmorphic features or biochemical abnormalities seen in previously described cases, which are reviewed. Inheritance was probably autosomal recessive.

Ocular findings in patients with arteriovenous malformations of the head and neck.

The hospital charts of 71 patients with congenital arteriovenous malformation of the head or neck, excluding carotid-cavernous sinus fistulas, yiedled 25 patients, referred to the ophthalmology service for examination. Of these, 22 patients had ocular findings; additionally, 12 patients with visual complaints or ocular findings were not referred for ocular examination. Forty-seven percent of all patients had ocular signs and symptoms including subjective visual complaints, visual field loss, ophthalmic artery pressure changes, nystagmus and motility findings, orbital and ocular vascular abnormalities, and fundus changes including optic atrophy, hypoxic retinopathy, and papilledema. Every patient with known or suspected arteriovenous malformation of the head or neck should have a thorough ocular examination. The findings can generally be correlated with the anatomic location and size of the lesion.

Cilioretinal circulation and branch arterial occlusion associated with preretinal arterial loops.

Three patients had occlusion of preretinal loops and associated branch arterial occlusion. On fluorescein angiography all three eyes showed extensive cilioretinal circulation and that the occluded preretinal loops were part of the cilioretinal vascular anomaly. This supports the hypothesis that one form of preretinal arterial loop is associated with a malformation of the cilioretinal circulation.

Optic neuritis and systemic lymphoma.

A 26-year-old man with stage IV poorly differentiated lymphocytic lymphoma complained of visual loss of two weeks' duration. Examination revealed visual acuity of light perception in the right eye secondary to optic neuritis and other tests revealed the presence of lymphomatous leptomeningeal infiltration. Combined treatment with intrathecal methotrexate, prednisone, and whole brain radiation resulted in rapid long-lasting recovery of visual function of the right eye. The cerebrospinal fluid contained a large amount of thymus-derived lymphocytes and the subsequent clinical course observed with characteristic of T-cell or malignant lymphoblastic lymphoma.