Application of infrared thermography in computer aided diagnosis

The invention of thermography, in the 1950s, posed a formidable problem to the research community: What is the relationship between disease and heat radiation captured with Infrared (IR) cameras? The research community responded with a continuous effort to find this crucial relationship. This effort was aided by advances in processing techniques, improved sensitivity and spatial resolution of thermal sensors. However, despite this progress fundamental issues with this imaging modality still remain. The main problem is that the link between disease and heat radiation is complex and in many cases even non-linear. Furthermore, the change in heat radiation as well as the change in radiation pattern, which indicate disease, is minute. On a technical level, this poses high requirements on image capturing and processing. On a more abstract level, these problems lead to inter-observer variability and on an even more abstract level they lead to a lack of trust in this imaging modality. In this review, we adopt the position that these problems can only be solved through a strict application of scientific principles and objective performance assessment. Computing machinery is inherently objective; this helps us to apply scientific principles in a transparent way and to assess the performance results. As a consequence, we aim to promote thermography based Computer-Aided Diagnosis (CAD) systems. Another benefit of CAD systems comes from the fact that the diagnostic accuracy is linked to the capability of the computing machinery and, in general, computers become ever more potent. We predict that a pervasive application of computers and networking technology in medicine will help us to overcome the shortcomings of any single imaging modality and this will pave the way for integrated health care systems which maximize the quality of patient care

Detection of Breast Thermograms using Ensemble Classifiers

Mortality rate of breast cancer can be reduced by detecting breast cancer in its early stage. Breast thermography plays an important role in early detection of breast cancer, as it can detect tumors when the physiological changes start in the breast prior to structural changes. Computer Aided Detection (CAD) systems improve the diagnostic accuracy by providing a detailed analysis of images, which are not visible to the naked eye. The performance of CAD systems depends on many factors. One of the important factors is the classifier used for classification of breast thermograms. In this paper, we made a comparison of classifier performances using two ensemble classifiers namely Ensemble Bagged Trees and AdaBoost. Spatial and spectral features are used for classification. Ensemble Bagged Trees classifier performed better than AdaBoost in terms of accuracy of classification, but training time required is higher than AdaBoost classifier. An accuracy of 87%, sensitivity of 83% and specificity of 90.6% is obtained using Ensemble Bagged Trees classifier

A new approach for breast abnormality detection based on thermography

Breast cancer is one of the most common women cancers in the world. In this paper, a new approach based on thermography for the early detection of breast abnormality is proposed. The study involved 80 breast thermograms collected from the PROENG public database which consists of 50 healthy breasts and 30 with some findings. Image processing techniques such as segmentation, texture analysis and mathematical morphology were used to train a support vector machine (SVM) classifier for automatic detection of breast abnormality. After conducting several tests, we obtained very interesting and motivating results. Indeed, our method  showed a high performance in terms of sensitivity of 93.3%, a specificity of 90% and an accuracy of 91.25%. The final results let us conclude that infrared thermography with the help of an adequate automatic classification algorithm can be a valuable and reliable complementary tool for radiologist in detecting breast cancer and thereby helping to reduce mortality rates

DISRUPTION THROUGH INNOVATION: 3D PRINTING, A REVOLUTION IN THE PHARMACEUTICAL FIELD

During the last decade, 3D printing (3DP) has made waves across several field, up to enter people’s homes. In the pharmaceutical setting, its implementation is progressively growing, offering extensive scopes for creativity and practical benefits. The present thesis shows the results of research conducted during my PhD program. Specifically, Part I reports the successful application of Fused Deposition Modelling (FDM) technique to produce intravaginal rings (IVRs) endowed with antifungal activity against Candida Albicans, a fungus, whose over-proliferation is responsible for vaginal infection. The IVRs were loaded with different imidazole drugs, commonly employed in the conventional treatment protocol. The resulting devices proved an effective in vitro eradication of the pathogen, potentially delivered within one single application, since a sustained release was observed. Part II is dedicated to 4DP, in the manufacturing of a multipurpose smart implant, relevant for the fight against breast cancer. The polyvalence of the implant lies on the possibility of converging the anticancer activity with the care of the cosmetic outcome. Therefore, a smart hydrogel capable of morpho-transformation, under swelling, was selected as core material. The formulation and the printing parameters were optimized, to achieve optimal printability performance and high swelling rate. Furthermore, doxorubicin (DOX) was incorporated, to provide localized anticancer treatment, thus preventing undesirable systemic side effects, and potential recurrences, as suggested by the in vitro studies conducted on MDA-MB 231 cell line. Finally, in Part III, poly(3-hydroxybutyrate) (PHB) has been proposed as alternative biopolymer for Direct Powder Extrusion (DPE) technique. The idea stems from the need to identify and test specific excipients for 3DP applications. Thereby, PHB was blended with different percentages of a model drug to prove its versatility and processability performance. The thermal analysis confirmed the stability of the excipient at high temperatures. While the drug release over 21 days, suggested its potential use for prolonged drug delivery dosage forms. Overall, this thesis proposes new insights on the pharmaceutical application of different 3DP techniques, until investigating 4DP. Alternative therapeutic approaches have been proposed, having regard to the physical and mental well-being of the patient. Along with contributing to overcoming one of the main challenges that interposes between the actual integration of 3DP, that is the material selection.During the last decade, 3D printing (3DP) has made waves across several field, up to enter people’s homes. In the pharmaceutical setting, its implementation is progressively growing, offering extensive scopes for creativity and practical benefits. The present thesis shows the results of research conducted during my PhD program. Specifically, Part I reports the successful application of Fused Deposition Modelling (FDM) technique to produce intravaginal rings (IVRs) endowed with antifungal activity against Candida Albicans, a fungus, whose over-proliferation is responsible for vaginal infection. The IVRs were loaded with different imidazole drugs, commonly employed in the conventional treatment protocol. The resulting devices proved an effective in vitro eradication of the pathogen, potentially delivered within one single application, since a sustained release was observed. Part II is dedicated to 4DP, in the manufacturing of a multipurpose smart implant, relevant for the fight against breast cancer. The polyvalence of the implant lies on the possibility of converging the anticancer activity with the care of the cosmetic outcome. Therefore, a smart hydrogel capable of morpho-transformation, under swelling, was selected as core material. The formulation and the printing parameters were optimized, to achieve optimal printability performance and high swelling rate. Furthermore, doxorubicin (DOX) was incorporated, to provide localized anticancer treatment, thus preventing undesirable systemic side effects, and potential recurrences, as suggested by the in vitro studies conducted on MDA-MB 231 cell line. Finally, in Part III, poly(3-hydroxybutyrate) (PHB) has been proposed as alternative biopolymer for Direct Powder Extrusion (DPE) technique. The idea stems from the need to identify and test specific excipients for 3DP applications. Thereby, PHB was blended with different percentages of a model drug to prove its versatility and processability performance. The thermal analysis confirmed the stability of the excipient at high temperatures. While the drug release over 21 days, suggested its potential use for prolonged drug delivery dosage forms. Overall, this thesis proposes new insights on the pharmaceutical application of different 3DP techniques, until investigating 4DP. Alternative therapeutic approaches have been proposed, having regard to the physical and mental well-being of the patient. Along with contributing to overcoming one of the main challenges that interposes between the actual integration of 3DP, that is the material selection

Calcium electroporation and electrochemotherapy for cancer treatment:Importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy

Abstract Calcium electroporation is a novel anti-cancer treatment investigated in clinical trials. We explored cell sensitivity to calcium electroporation and electroporation with bleomycin, using viability assays at different time and temperature points, as well as heat calorimetry, lipidomics, and flow cytometry. Three cell lines: HT29 (colon cancer), MDA-MB231 (breast cancer), and HDF-n (normal fibroblasts) were investigated for; (a) cell survival dependent on time of addition of drug relative to electroporation (1.2 kV/cm, 8 pulses, 99 µs, 1 Hz), at different temperatures (37 °C, 27 °C, 17 °C); (b) heat capacity profiles obtained by differential scanning calorimetry without added calcium; (c) lipid composition by mass spectrometry; (d) phosphatidylserine in the plasma membrane outer leaflet using flow cytometry. Temperature as well as time of drug administration affected treatment efficacy in HT29 and HDF-n cells, but not MDA-MB231 cells. Interestingly the HT29 cell line displayed a higher phase transition temperature (approximately 20 °C) versus 14 °C (HDF-n) and 15 °C (MDA-MB231). Furthermore the HT29 cell membranes had a higher ratio of ethers to esters, and a higher expression of phosphatidylserine in the outer leaflet. In conclusion, lipid composition and heat capacity of the membrane might influence permeabilisation of cells and thereby the effect of calcium electroporation and electrochemotherapy

The medicinal chemistry of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro)

Although peptides and proteins are considered as lead compounds for the discovery and development of new therapeutic agents, poor metabolic and physical properties have limited their optimisation as drug candidates (Adessi & Soto, 2002). Research by medicinal chemists however, generated the discovery of structural similarities between some peptides and diketopiperazines and the common occurrence of such compounds in natural products. This discovery initiated the synthesis of diketopiperazines from amino acids in an attempt to bypass the previously mentioned limitations of using peptides as drug candidates (Dinsmore & Beshore, 2002). Diketopiperazines (DKPs) are the simplest form of cyclic dipeptides, and a class of unexplored bioactive peptides that have great potential for the future. The compounds are relatively simple to synthesise and are prevalent in nature (Prasad, 1995). The DKP backbone is rigid and therefore poses conformational constraint on the compounds. This rigidity allows for simple conformational analysis of the compounds and also gives insight into the conformational requirements for interaction with the targets involved in their biological activity. The reduced conformational freedom also increases the receptor specificity and thus the compounds are proposed to have less unfavourable effects (Anteunis, 1978). The aim of the study was to synthesise compounds that would exhibit metabolic stability, receptor specificity and enhanced lipophilicity which would increase the bioavailability of the compounds. This was to be achieved by the introduction of fluorine and chlorine elements into the DKPs. The structure of the DKPs would be altered which in turn would improve the physicochemical properties and the biological activity of the compounds (Naumann, 1999). Cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) were synthesised using the method of Milne et al. (1992) and by boiling the linear counterparts under reflux in sec-butanol-toluene. The structures of the synthesised DKPs were elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy and molecular modeling. Qualitative analysis and evaluation of the physicochemical properties of the DKPs were performed using high-performance liquid chromatography, scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry and x-ray powder diffraction. The study aimed to determine the biological activity of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) with respect to their anticancer, antimicrobial, haematological and antidiabetic effects. The anticancer results obtained indicated that the percentage inhibition produced by both DKPs were lower than those proposed by Graz et al. (2000) for proline-containing DKPs where, a greater than 50% inhibition was observed for cyclo(Phe-Pro). Antimicrobial studies revealed that both DKPs demonstrated marginal effects on Gram-positive and Gram-negative organisms but showed significant effects against C. albicans. The haematological studies revealed that cyclo(D-Phe-2Cl-Pro) at a screening concentration of 12.5 mM, significantly decreased the levels of D-dimer (P < 0.0001). The antidiabetics studies showed limited activity of the DKPs in inhibiting the activity of α-glucosidase and α-amylase enzymes