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.

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.

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.

Electrochemical determination of an anti-hyperlipidimic drug pitavastatin at electrochemical sensor based on electrochemically pre-treated polymer film modified GCE / 药物分析学报

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.

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.

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.

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.

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.

Primary immunodeficiency diseases in adulthood.

Occasionally, patients present with clinical episodes of infectious disease that seem to fall beyond the scope of normal immunocompetence. Examples include infections that are unusually persistent, recurrent or resistant to treatment, or those involving unexpected dissemination of disease or atypical pathogens. Recent cellular and molecular advances in immunology help to inform the investigation and management of these cases and provide opportunities for family surveillance and disease prevention. More than 100 separate primary (inherited) immunodeficiency disease (PID) states have now been defined, each with a range of syndromic manifestations. Many of these are rare diseases of childhood, but some, either in atypical or attenuated forms, emerge for the first time in adulthood. We outline a diagnostic approach to five groups of PID presenting in adulthood and describe the recently launched web-based PID Register of Australia and New Zealand--a new mechanism for improving knowledge and service delivery to Australasian patients and their clinical carers.

HIV and tuberculosis co-infection in south-western Sydney: experience from a case series.

A case series of six patients with HIV and Mycobacterium tuberculosis co-infection is presented. All patients were overseas-born and in all but one there was profound immunodeficiency. We recommend HIV screening of all cases of M. tuberculosis and a high degree of suspicion of tuberculosis in immigrants with HIV infection from endemic areas. Management problems included delayed diagnosis, rapid progression, paradoxical reactions and requirement for surgical intervention in three patients. Therapeutic complications included possible drug malabsorption, adverse events and drug interactions. M. tuberculosis was fully drug sensitive in all cases.

Computer-aided manufacturing of implants for the repair of large cranial defects: an improvement of the stereolithography technique.

The objective of this study is to demonstrate the utility of geometric modeling in cranioplasty; in other words, to use geometric modeling to generate a prototype that will be used as the base structure of a composite prosthesis for covering cranial defects. This geometric model is easy to manipulate and can be modified. To achieve this goal, the top surface of a cranial bone flap is digitized using a portable coordinate measurement machine. Intentionally, a sub-surface of the bone flap, representing the skull defect, was not digitized. A geometric model of the bone flap is generated that includes the undigitized region. With the technique described in this paper the authors generated the geometric model of the undigitized region (the skull defect). The geometric model of the bone flap is further manipulated and a series of conical cavities are introduced. Prototypes of the geometric models are manufactured using stereolithography. The clinical implications of this technique are discussed.

Effect of an ointment containing boric acid, zinc oxide, starch and petrolatum on psoriasis.

A randomized double-blind controlled trial was undertaken to study the efficacy of a cow udder ointment versus petroalatum alone. A total of 30 patients participated in the study. Sixteen patients completed the trial with 8 of 9 patients improving in the active group and 6 of 7 patients improving in the placebo group. This difference was not statistically significant. The use of a cow udder ointment for psoriasis cannot be supported, particularly with the potential for side effects.

Earth-Based Observations of the Galileo Probe Entry Site

Earth-based observations of Jupiter indicate that the Galileo probe probably entered Jupiter's atmosphere just inside a region that has less cloud cover and drier conditions than more than 99 percent of the rest of the planet. The visual appearance of the clouds at the site was generally dark at longer wavelengths. The tropospheric and stratospheric temperature fields have a strong longitudinal wave structure that is expected to manifest itself in the vertical temperature profile.

Papillophlebitis and arteriolar occlusion in a pregnant woman.

Among the pathologic findings affecting the eye during pregnancy, microvascular abnormalities affecting both choroidal and retinal circulation have been reported in cases of complicated pregnancy. We report a case of papillophlebitis and arteriolar occlusion in a pregnant woman without any complications throughout her pregnancy. The patient was placed on glucocorticoids and her vision, visual fields and funduscopic appearance improved almost to normal. Despite the improvement with treatment, the contributing role of glucocorticoids in this case could not be fully determined. Papillophlebitis and arteriolar occlusion should be included among gestational-related vasculopathies.

Systemic diseases and the skin.

Skin lesions often give important diagnostic clues to underlying systemic disorders. A brief overview is given of the types of cutaneous presentations that may be related to an underlying organic disease.

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.

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.