Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer.

PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.

Using paint to investigate fires: an ATR-IR study of the degradation of paint samples upon heating.

Fire investigation is a challenging area for the forensic investigator. The aim of this work was to use spectral changes to paint samples to estimate the temperatures to which a paint has been heated. Five paint samples (one clay paint, two car paints, one metallic paint, and one matt emulsion) have been fully characterized by a combination of attenuated total reflectance Fourier transform infrared (ATR-IR), Raman, X-ray fluorescence spectroscopy and powder X-ray diffraction. The thermal decomposition of these paints has been investigated by means of ATR-IR and thermal gravimetric analysis. Clear temperature markers are observed in the ATR-IR spectra namely: loss of ν(C = O) band, >300°C; appearance of water bands on cooling, >500°C; alterations to ν(Si-O) bands due to dehydration of silicate clays, >700°C; diminution of ν(CO3 ) and δ(CO3 ) modes of CaCO3 , >950°C. We suggest the possible use of portable ATR-IR for nondestructive, in situ analysis of paints.

Enhancement of aged and denatured fingerprints using the cyanoacrylate fuming technique following dusting with amino acid-containing powders.

We have carried out experiments to investigate the aging of latent fingerprints deposited on black PVC over a period of 4-15 weeks. A thumbprint was used in each case and before deposition of the print the donor rubbed their thumb around their nose to add sebaceous deposits. We have studied the effect of heat, light, and moisture and we find that moisture is the most significant factor in the degradation of the latent print. We have attempted to enhance these latent prints by dusting with valine powder or powders composed of valine mixed with gold or red fluorescent commercial fingerprint powders. To make a direct comparison between "treated" and "untreated" prints, the prints were cut in half with one-half being "treated" and one-half not. Our studies show the best results being obtained when powders of valine and red fluorescent powders are applied prior to cyanoacrylate fuming.

A theoretical and practical test of geographical profiling with serial vehicle theft in a U.K. context.

Geographical profiling is an investigative methodology sometimes employed by the police to predict the residence of an unknown offender from the locations of his/her crimes. The validity of geographical profiling, however, has not been fully explored for certain crime types. This study, therefore, presents a preliminary test of the potential for geographical profiling with a sample of 145 serial vehicle thieves from the U.K. The behavioural assumptions underlying geographical profiling (distance decay and domocentricity) are tested and a simple practical test of profiling using the spatial mean is presented. There is evidence for distance decay but not domocentricity among the spatial behaviour of car thieves from the U.K. A degree of success was achieved when applying the spatial mean on a case-by-case basis. The level of success varied, however, and neither series length in days nor number of crimes could account for the variation. The findings question previously held assumptions regarding geographical profiling and have potential theoretical and practical implications for the study and investigation of vehicle theft in the U.K.

The effects of deprivation on the time spent examining crime scenes and the recovery of DNA and fingerprints.

DNA and fingerprint identifications are now accepted as an integral part of the investigation of a wide range of criminal offences from burglary and auto crime to serious and major crime. Despite this, there is still much variation between U.K. police forces in the recovery of fingerprint and DNA material from crime scenes. Analysis of burglary and auto crime data for Northamptonshire, U.K., during a 3-year period has enabled an examination of the relationship between the deprivation of the neighborhood in which the crime was committed and the level of service provided by Crime Scene Examiners. The results indicate that the time spent examining a crime scene for forensic evidence is not affected by the deprivation of the neighborhood. Further, there is no statistical significance between deprivation and the recovery of fingerprints from the crime scene. The relationship between deprivation and DNA recovery is, however, statistically significant with DNA being recovered more frequently from less deprived neighborhoods.

Value of DNA evidence in detecting crime.

DNA material is now collected routinely from crime scenes for a wide range of offences and the timely processing of the DNA is seen as key to its success in investigating and detecting crime. An analysis of DNA material recovered from the volume crime offences of residential burglary, commercial burglary, and theft of motor vehicle in Northamptonshire, U.K., in 2004 has enabled the DNA to be categorized into seven sources. Further analysis using a logistical regression has revealed a number of predictors, other than timeliness, that greatly influence whether the DNA material recovered from a crime scene enables the crime to be detected. The results indicate that a number of these predictors are of statistical significance and may be just as relevant in determining whether DNA successfully detects the crime as the timeliness of the processing of the DNA material. The most significant predictor was found to be investigating officer accreditation with location, quantity, and type of DNA material at the crime scene also being relevant. Accreditation of the Crime Scene Examiner recovering the DNA material was found not to be significant. Consideration is given to where further emphasis is needed by the U.K. police service to maximize the opportunities to detect volume crime with DNA.

The relationship between the detection of acquisitive crime by forensic science and drug-dependent offenders.

Drug- and nondrug-related acquisitive crime offences such as burglary, theft, and motor vehicle theft, were compared to assess whether drug abusers were more likely to be apprehended via forensic science techniques. Data were all acquisitive offences committed over a 6-year period within a police force area in England. Drug-dependent offenders committed a wider range of offence types than nondependent offenders, and they were significantly more likely to be detected via their DNA or fingerprints (p < 0.01). A logistic regression (n > 14,000) revealed a number of predictors that influence the detection of the crime by forensic techniques. The results indicate that a number of these predictors are of statistical significance; the most significant of these being drug use by the offender with sex, ethnicity, and employment status also being relevant. Age of the offender and number of offences committed were found not to be significant. Of the four hypotheses considered to explain this, the most likely was thought to be the physical and mental impact of drug use on crime scene behavior. Consideration is given to the disciplines of forensic science and forensic psychology working closely together to distinguish factors that influence crime scene behavior.

Visualizing Indented Writing on Thermal Paper by the Controlled Application of Heat.

Indented writing on thermal paper made with either one, two, or three sheets of paper above the thermal paper has been visualized by the controlled application of heat to the thermal paper at temperatures below the paper's normal color change temperature. Indentations created by applying a variable pressure to a steel letter stamp showed that, with one sheet above the thermal paper, indentations were more visible at lower pressures than with either two or three sheets above. Handwriting from 20 volunteers produced indented writing graded with most of the text clear and easy to read for all samples with one sheet above, half the samples with two sheets above and eight samples with three sheets above. Comparison with ESDA showed that, with three sheets above, there was a statistically significant difference (p < 0.01), with heating producing more samples than ESDA with most of the text clear and easy to read.

The Effectiveness of Trace DNA Profiling-A Comparison Between a U.S. and a U.K. Law Enforcement Jurisdiction.

Recovery, profiling, and speculative searching of trace DNA (not attributable to a body fluid/cell type) over a twelve-month period in a U.S. Crime Laboratory and U.K. police force are compared. Results show greater numbers of U.S. firearm-related items submitted for analysis compared with the U.K., where greatest numbers were submitted from burglary or vehicle offenses. U.S. multiple recovery techniques (double swabbing) occurred mainly during laboratory examination, whereas the majority of U.K. multiple recovery techniques occurred at the scene. No statistical difference was observed for useful profiles from single or multiple recovery. Database loading of interpretable profiles was most successful for U.K. items related to burglary or vehicle offenses. Database associations (matches) represented 7.0% of all U.S. items and 13.1% of all U.K. items. The U.K. strategy for burglary and vehicle examination demonstrated that careful selection of both items and sampling techniques is crucial to obtaining the observed results.

The Effect of Varying the Composition of Fingerprint Sweat Deposits on the Corrosion of Brass and Fingerprint Visibility.

Corrosion of α-phase brass by sebaceous sweat fingerprint deposits produced identifiable impressions in a majority of samples (n = 40) 4 days after deposition. Combining sebaceous with eccrine sweat yielded a greater percentage of identifiable fingerprint deposits, although this increase was not statistically significant. Production of identifiable fingerprints from eccrine sweat deposits was dependent on the sampling time of year with deposits taken during summer months giving similar percentages of identifiable fingerprints to sebaceous deposits. A statistically significant positive correlation was found between elapsed days after deposition and identifiable eccrine (ρ = 0.787, p < 0.05), sebaceous (ρ = 0.724, p < 0.05), and eccrine/sebaceous mixture (ρ = 0.908, p < 0.01) fingerprints deposited during summer months. The summer increase in the percentage of identifiable eccrine sweat deposits was statistically significant compared to winter eccrine deposits (p < 0.0001). Observations were consistent with results obtained from artificial sebaceous and eccrine sweat.

A Modified Electrostatic Adsorption Apparatus for Latent Fingerprint Development on Unfired Cartridge Cases.

Visualization of latent fingerprints on metallic surfaces by the method of applying electrostatic charging and adsorption is considered as a promising chemical-free method, which has the merit of nondestruction, and is considered to be effective for some difficult situations such as aged fingerprint deposits or those exposed to environmental extremes. In fact, a portable electrostatic generator can be easily accessible in a local forensic technology laboratory, which is already widely used in the visualization of footwear impressions. In this study, a modified version of this electrostatic apparatus is proposed for latent fingerprint development and has shown great potential in visualizing fingerprints on metallic surfaces such as cartridge cases. Results indicate that this experimental arrangement can successfully develop aged latent fingerprints on metal surfaces, and we demonstrate its effectiveness compared with existing conventional fingerprint recovery methods.

Enhancement of Latent Fingerprints on Fabric Using the Cyanoacrylate Fuming Method Followed by Infrared Spectral Mapping.

A method has been developed for the visualization of latent fingerprints on fabrics, which is based upon cyanoacrylate (superglue) fuming followed by imaging using an infrared microscope. Results show that imaging on smooth, shiny fabrics such as polyester, silk, nylon, and acetate of different colors and patterns can give an improvement over existing enhancement methods. Results for cotton and polycotton were less successful and it is thought this may be due a combination of the presence of the carbonyl functional group in these fabrics as well as their absorbency to fingerprint sweat. The carbonyl peak (1700 cm(-1) ) provided the optimum spectroscopic feature to map and image a fingerprint. Comparisons between infrared mapping at a specific frequency range and principal component analysis showed that improved imaging was obtained with principal component analysis.

A Noninvasive and Speculative Method of Visualizing Latent Fingerprint Deposits on Thermal Paper.

Latent fingerprint deposits on thermal paper have been visualized noninvasively at visible wavelengths when illuminated with a UV-A light source (peak 365 nm). A higher intensity UV source (250 W/m(2) at 0.38 m) gave superior fingerprint visibility when compared with a 60 W/m(2) (at 0.4 m) source. Removing the visible (blue) component of the light source emission did not adversely affect the visibility of the fingerprint. Sample fingerprints from 100 donors, when examined 24 h after deposition, produced identifiable fingerprints from nearly 34% of fingerprint deposits. A mechanism for the observed visibility is proposed based on low emission of visible wavelengths from areas of thermal paper coincident with the fingerprint deposit, when illuminated with UV. This is likely due to a weak color change in the thermal paper dye arising from protonated amino acid components of the sweat. This effect was not observed on nonthermal paper.

Response Assessment of Thermal Papers from Four Continents to Fingerprint Development by Heat.

Latent fingerprint deposits on thermal paper sourced from the U.S., China, the U.K., and Australia have been visualized by heating. U.S. and Chinese sourced paper produced two distinct types of fingerprint development. In one type (type 1), the paper dye colors where the deposit is present (as previously reported) and in the other type (type 2) the 'inverse' of this gives paper coloring only in areas not coincident with the deposit. Both development types gave identifiable fingerprints, the majority fading within 24 h of heating. Fingerprint development from U.K. and Australian sourced paper was exclusively type 1 and resistant to fading. Temperatures for fingerprint visualization were higher for U.S. paper (64-71°C) and Chinese paper (75-95°C) than for U.K. and Australian sourced paper (43-50°C). Particularly for Chinese sourced paper, these temperatures were within a few degrees of the normal paper color temperature. A mechanism for type 2 fingerprint development is proposed.

Comparison of chemical and heating methods to enhance latent fingerprint deposits on thermal paper.

A comparison is made of proprietary methods to develop latent fingerprint deposits on the inked side of thermal paper using either chemical treatment (Thermanin) or the application of heat to the paper (Hot Print System). Results with a trial of five donors show that the application of heat produces statistically significantly more fingerprint ridge detail than the chemical treatment for both fingerprint deposits aged up to 4 weeks and for a nine sequence depletion series. Subjecting the thermal paper to heat treatment with the Hot Print System did not inhibit subsequent ninhydrin chemical development of fingerprint deposits on the noninked side of the paper. A further benefit of the application of heat is the rapid development of fingerprint deposits (less than a minute) compared with up to 12 h for the Thermanin chemical treatment.

A calibration test for latent fingerprint development on thermal paper.

A calibration test is described for monitoring the operation of equipment used to develop latent fingerprints on thermal paper by the application of either controlled or uncontrolled heat. A working solution of a water/glycerol emulsion and butylene glycol is applied to thermal paper by means of either a vinyl stamp and pad, or a marker pen. Varying the amount of butylene glycol enables the thermal paper to change color at different temperatures between approximately 40 and 60°C, which is below the normal color change temperature of the paper. The described test may be used to verify the correct operation, at different temperatures, of a controlled heat source during and after fingerprint development (such as the Hot Print System) or to monitor the paper temperature with an uncontrolled heat source (such as a warm air blower), thereby avoiding unintentional coloring of the entire paper surface.

Effect of temperature on the visualization by digital color mapping of latent fingerprint deposits on metal.

Visualization of fingerprint deposits by digital color mapping of light reflected from the surface of heated brass, copper, aluminum, and tin has been investigated using Adobe® Photoshop®. Metals were heated to a range of temperatures (T) between 50°C and 500°C in 50°C intervals with enhancement being optimal when the metals are heated to 250°C, 350°C, 50°C, and 300°C, respectively, and the hue values adjusted to 247°, 245°, 5°, and 34°, respectively. Fingerprint visualization after color mapping was not degraded by subsequent washing of the metals and color mapping did not compromise the visibility of the fingerprint for all values of T. The optimum value of T for fingerprint visibility is significantly dependent of the standard reduction potential of the metal with Kendall's Tau (τ) = 0.953 (p < 0.001). For brass, this correlation is obtained when considering the standard reduction potential of zinc rather than copper.

Identification of forged Bank of England £20 banknotes using IR spectroscopy.

Bank of England notes of £20 denomination have been studied using infrared spectroscopy in order to generate a method to identify forged notes. An aim of this work was to develop a non-destructive method so that a small, compact Fourier transform infrared spectrometer (FT-IR) instrument could be used by bank workers, police departments or others such as shop assistants to identify forged notes in a non-lab setting. The ease of use of the instrument is the key to this method, as well as the relatively low cost. The presence of a peak at 1400 cm(-1) arising from νasym (CO3(2-)) from the blank paper section of a forged note proved to be a successful indicator of the note's illegality for the notes that we studied. Moreover, differences between the spectra of forged and genuine £20 notes were observed in the ν(OH) (ca. 3500 cm(-1)), ν(C-H) (ca. 2900 cm(-1)) and ν(C=O) (ca. 1750 cm(-1)) regions of the IR spectrum recorded for the polymer film covering the holographic strip. In cases where these simple tests fail, we have shown how an infrared microscope can be used to further differentiate genuine and forged banknotes by producing infrared maps of selected areas of the note contrasting inks with background paper.

The effect of light exposure on the degradation of latent fingerprints on brass surfaces: the use of silver electroless deposition as a visualization technique.

We have studied the degradation of sebaceous fingerprints on brass surfaces using silver electroless deposition (SED) as a visualization technique. We have stored fingerprints on brass squares either (i) in a locked dark cupboard or (ii) in glass-filtered natural daylight for periods of 3 h, 24 h, 1 week, 3 weeks, and 6 weeks. We find that fingerprints on brass surfaces degrade much more rapidly when kept in the light than they do under dark conditions with a much higher proportion of high-quality prints found after 3 or 6 weeks of aging when stored in the dark. This process is more marked than for similar fingerprints on black PVC surfaces. Identifiable prints can be achieved on brass surfaces using both SED and cyanoacrylate fuming (CFM). SED is quick and straightforward to perform. CFM is more time-consuming but is versatile and can be applied to a wider range of metal surfaces than SED, for example brass surfaces which have been coated by a lacquer.

Development of latent fingerprints on thermal paper by the controlled application of heat.

Apparatus to produce a spatially and temporally uniform heat source is described and this is used to visualize latent fingerprints deposited onto thermal paper by raising the temperature of the paper. Results show an improvement over previous research when fingerprint deposits are aged or the developed fingerprints faint; visualization being enhanced by the use of a blue LED light source of 465 nm peak wavelength. An investigation of the components in fingerprint sweat likely to affect the solubility and hence color change of the dye present in the thermal paper has shown that polar protic solvents able to donate a proton are favored and a polar amino acid found commonly in eccrine fingerprint sweat (lysine) has been shown able to produce the desired color change. Aged fingerprint deposits on thermal paper from a variety of sources up to 4 years old have been visualized with this technique.