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A spatiotemporally dynamic therapy (SDT) is proposed as a powerful therapeutic modality that provides spatially dynamic responses of drug-carriers for adapting to the wound microenvironment. Herein, dynamic chitosan-poly (ethylene glycol) (CP) Schiff-base linkages are employed to perform SDT by directly converting a liquid drug Kangfuxin (KFX) into a gel formation. The obtained KFX-CP drug-gel with shape-adaptive property is used to treat a representative oral mucositis (OM) model in a spatiotemporally dynamic manner. The KFX-CP drug-gel creates an instructive microenvironment to regulate signaling biomolecules and endogenous cells behavior, thereby promoting OM healing by the rule of dynamically adjusting shape to fit the irregular OM regions first, and then provides space for tissue regeneration, over KFX potion control and the general hydrogel group of CP hydrogel and KFX-F127. Most interestingly, the regenerated tissue has ordered structure like healthy tissue. Therefore, the SDT provides a new approach for the design of next generation of wound dressing and tissue engineering materials., Graphical abstract Image 1, Highlights • Spatiotemporally dynamic therapy (SDT) is demonstrated via a shape self-adaptive drug-gel. • The KFX-CP drug-gel achieves a drug encapsulation efficiency of 100%. • SDT significantly promotes tissue regeneration with ordered structure. • Spatiotemporally dynamic response plays the key role in tissue re-modelling.

BACKGROUND Closure of the nasal skin defects that resulted from excision of the skin neoplasms represents a challenging problem in reconstructive surgery. Here, the use of the reading man procedure as a new alternative in reconstruction of the skin defects of the nose is presented. MATERIALS AND METHODS In this procedure, 2 local flaps designed in an unequal Z-plasty manner are used. Defect coverage is achieved by transposing the first flap to the defect area, whereas the second flap is used for closure of the first flap's donor site. In last 10 years, this technique has been used for closure of the nasal skin defects that resulted from removal of skin cancers in 28 patients (15 men and 13 women) aged from 45 to 98 years. The defects were ranging between 1.5 and 3.1 cm in diameter. RESULTS In all patients, a tension-free 1-stage closure was obtained. There was no patient with dog ear formation and/or distortion of the mobile anatomical structures, such as nasal tip, alar lobules, and nostrils. All patients healed without complications. A mean follow-up of 52 months (8 months to 6.5 years) revealed satisfactory cosmetic results in all patients. No tumor recurrence was observed. CONCLUSIONS Using the advantage of extra tissue relaxation provided by an unequal Z-plasty, the reading man procedure seems to be a useful alternative for the closure of nasal defects with alike local skin. As a critical achievement, this procedure does not require excision of additional healthy tissue. Borrowing tissue from multiple directions, it avoids dog ear formation and distortion of the mobile anatomic structures.

Background In radiotherapy, respiratory-induced tumor motion is typically measured using a single four-dimensional computed tomography acquisition (4DCT). Irregular breathing leads to inaccurate motion estimates, potentially resulting in undertreatment of the tumor and unnecessary dose to healthy tissue. The aim of the research was to determine if a daily pre-treatment 4DMRI-strategy led to a significantly improved motion estimate compared to single planning 4DMRI (with or without outlier rejection). Methods 4DMRI data sets from 10 healthy volunteers were acquired. The first acquisition simulated a planning MRI, the respiratory motion estimate (constructed from the respiratory signal, i.e. the 1D navigator) was compared to the respiratory signal in the subsequent scans (simulating 5–29 treatment fractions). The same procedure was performed using the first acquisition of each day as an estimate for the subsequent acquisitions that day (2 per day, 4–20 per volunteer), simulating a daily MRI strategy. This was done for three outlier strategies: no outlier rejection (NoOR); excluding 5% of the respiratory signal whilst minimizing the range (Min95) and excluding the datapoints outside the mean end-inhalation and end-exhalation positions (MeanIE). Results The planning MRI median motion estimates were 27 mm for NoOR, 18 mm for Min95, and 13 mm for MeanIE. The daily MRI median motion estimates were 29 mm for NoOR, 19 mm for Min95 and 15 mm for MeanIE. The percentage of time outside the motion estimate were for the planning MRI: 2%, 10% and 32% for NoOR, Min95 and MeanIE respectively. These values were reduced with the daily MRI strategy: 0%, 6% and 17%. Applying Min95 accounted for a 30% decrease in motion estimate compared to NoOR. Conclusion A daily MRI improved the estimation of respiratory motion as compared to a single 4D (planning) MRI significantly. Combining the Min95 technique with a daily 4DMRI resulted in a decrease of inclusion time of 6% with a 30% decrease of motion. Outlier rejection alone on a planning MRI often led to underestimation of the movement and could potentially lead to an underdosage. Trial registration: protocol W15_373#16.007

Background: Gliomas are primary cerebral tumors. Radiation therapy plays a key role in their treatment but with a risk of toxicity associated with the dose to and volume of normal tissue that is irradiated. With its precision properties allowing for the increased sparing of healthy tissue, proton therapy could be an interesting option for this pathology. Methods: Two reviewers performed a systematic review of original papers published between 2010 and July 2021 following PRISMA guidelines. We analyzed disease outcomes, toxicity outcomes, or dosimetry data in four separate groups: children/adults and individuals with low-/high-grade gliomas. Results: Among 15 studies, 11 concerned clinical and toxicity outcomes, and 4 reported dosimetry data. Proton therapy showed similar disease outcomes with greater tolerance than conventional radiation therapy, partly due to the better dosimetry plans. Conclusions: This review suggests that proton therapy is a promising technique for glioma treatment. However, studies with a high level of evidence are still needed to validate this finding.

Introduction In UK universities, caries removal teaching utilises plastic teeth. This format does not enable students to learn how to distinguish between tooth layers and caries via tactile feedback. The aim of this study was to the assess the applicability of a novel, 3D-printed carious tooth within caries removal teaching. Materials and methods Single-material 3D-printed teeth containing simulated tactile caries were developed and 14 final-year undergraduates were briefed to remove caries and minimise damage to healthy tissue within the tooth. Students completed evaluation questionnaires for their opinion of 3D-printed teeth in comparison to plastic teeth and perceived confidence to subsequently treat patients. Cavity preparation perimeters were measured, using photographs with a standard protocol. Heat map analysis illustrated variation in location and extent of cavity preparations produced by the cohort. Results Student feedback indicated the 3D-printed caries exercise was positively received, 71.4% agreed 3D-printed teeth would have better prepared students for patient treatment. 78.6% rated their pre-clinical stress/anxiety as ‘Very High’ or ‘High’ and 57.1% agreed that if pre-clinical teaching incorporated 3D-printed teeth, their stress/anxiety when treating their first caries patient would have been reduced. The average perimeter of cavity preparation indicated relative variation, with a maximum perimeter of 19.6mm and a minimum of 10.7mm, and a range of 8.9mm. Discussion Introducing 3D-printed teeth into preclinical teaching would allow students to gain confidence in clinically relevant experience in tactile aspects of caries treatment earlier in their training than currently possible. Conclusion This study demonstrates student acceptance of an alternative caries removal teaching method, with potential to increase aptitude in caries removal in a clinically relevant manner.

In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable, systemic radionuclide therapies could meet these criteria, even for treatment of micrometastases and single circulating tumour cells. The clinical use of α and β(−) particle-emitting molecular radionuclide therapies is rising, however clinical translation of Auger electron-emitting radionuclides is hampered by uncertainty around their exact subcellular localisation, which in turn affects the accuracy of dosimetry. This review aims to discuss and compare the advantages and disadvantages of various subcellular localisation methods available to localise radiopharmaceuticals and radionuclides for in vitro investigations.

Surgical intervention remains the cornerstone of the treatment of patients with spinal tumors. The presented literature review includes also the authors’ personal experience in the treatment of tumors. Pain relief, local control of a neoplasm growth and preservation of body functions are the main goals of this pathology treatment.Treatment of spinal tumors is based on the biology, location and extent of the neoplasm. If surgical treatment is indicated, en-bloc resection is the preferred method. This operation is based on the complete removal of the tumor in a single block entirely covered by a shell of healthy tissue. This surgical procedure can be challenging due to the proximity of the neural structures. Moreover, achieving clean resection margin around the tumor often requires the sacrifice of adjacent anatomic structures. A more comprehensive approach requires a combination of surgery, systemic therapy and radiotherapy to improve outcomes in patients with advanced spinal tumors.The fulfillment of oncological principles is fundamental to achieving best treatment outcomes for spinal tumors.

BACKGROUND: Post-therapeutic tissue is bradytrophic and thus has low perfusion values in PCT. In contrast, malignant tissue is expected to show higher perfusion values as cancer growth partially depends on angiogenesis. OBJECTIVES: This prospective study investigates perfusion computed tomography (PCT) for the post-therapeutic detection of cancer in the head and neck region. METHODS: 85 patients underwent PCT for 1) initial work-up of head and neck cancer (HNC; n=22) or 2) for follow-up (n=63). Regions of interest (ROIs) were placed in confirmed tumour, a corresponding location of benign tissue, and reference tissue. Perfusion was calculated using a single input maximum slope algorithm. Statistical analysis was performed with the Mann-Whitney U-test. RESULTS: PCT allowed significant differentiation of malignant tissue from post-therapeutic tissue after treatment for HNC (p=0.018). Significance was even greater after normalization of perfusion values (p=0.007). PCT allowed highly significant differentiation of HNC from reference tissue (p

Purpose The development of collimating technologies has become a recent focus in pencil beam scanning (PBS) proton therapy to improve the target conformity and healthy tissue sparing through field-specific or energy-layer–specific collimation. Given the growing popularity of collimators for low-energy treatments, the purpose of this work was to summarize the recent literature that has focused on the efficacy of collimators for PBS and highlight the development of clinical and preclinical collimators. Materials and Methods The collimators presented in this work were organized into 3 categories: per-field apertures, multileaf collimators (MLCs), and sliding-bar collimators. For each case, the system design and planning methodologies are summarized and intercompared from their existing literature. Energy-specific collimation is still a new paradigm in PBS and the 2 specific collimators tailored toward PBS are presented including the dynamic collimation system (DCS) and the Mevion Adaptive Aperture. Results Collimation during PBS can improve the target conformity and associated healthy tissue and critical structure avoidance. Between energy-specific collimators and static apertures, static apertures have the poorest dose conformity owing to collimating only the largest projection of a target in the beam's eye view but still provide an improvement over uncollimated treatments. While an external collimator increases secondary neutron production, the benefit of collimating the primary beam appears to outweigh the risk. The greatest benefit has been observed for low- energy treatment sites. Conclusion The consensus from current literature supports the use of external collimators in PBS under certain conditions, namely low-energy treatments or where the nominal spot size is large. While many recent studies paint a supportive picture, it is also important to understand the limitations of collimation in PBS that are specific to each collimator type. The emergence and paradigm of energy-specific collimation holds many promises for PBS proton therapy.

After extensive screening of aerospace compounds in an effort to source a novel anticancer agent, RRx-001, a first-in-class dinitroazetidine small molecule, was selected for advancement into preclinical and clinical development. RRx-001 is a minimally toxic small molecule with a distinct chemical structure and mechanism of action. The paradox of RRx-001 is that it mediates both antitumor cytotoxicity and normal tissue protection. The question of exactly how RRx-001 does this, and by means of what mechanism(s), depending on the route of delivery, intravenous or intratumoral, are explored. RRx-001 is currently in phase 2 and 3 clinical trials for the treatment of multiple solid tumor malignancies and as a supportive care drug.

BACKGROUND Near-infrared spectroscopy can detect changes in tissue oxygenation postoperatively that predict flap necrosis. The authors hypothesized that this technology can be applied along with topical nitroglycerin to measure an improvement in tissue oxygenation that correlates with tissue salvage. METHODS Dorsal, random pattern flaps measuring 10 × 3 cm were raised using Sprague-Dawley rats. Tissue oxygenation was measured after flap elevation in 10 locations using the ViOptix Intra.Ox. Animals were divided into three groups that received 30 mg of topical nitroglycerin daily, twice-daily, or not at all. Oxygenation measurements were repeated on postoperative day 1 and animals were euthanized on day 7 and evaluated for tissue necrosis. RESULTS Tissue necrosis was greatest in controls (51.3 mm) compared to daily (28.8 mm) and twice-daily nitroglycerin (18.8 mm; p = 0.035). Three flap perfusion zones were identified: healthy (proximal, 50 mm), necrotic (distal, 20 mm), and watershed. Immediate postoperative tissue oxygenation was highest in healthy tissue (57.2 percent) and decreased to 33.0 and 19.3 percent in the watershed and necrotic zones, respectively (p < 0.001). One day after treatment with nitroglycerin, oxygenation in the healthy zone did not increase significantly (mean difference, -1.5 percent). The watershed (17.8 percent; p < 0.001) and necrotic zones (16.3 percent; p

This study systematically reviewed the published literature on the objective characterization of myofascial pain syndrome and myofascial trigger points using imaging methods. PubMed, Embase, Ovid, and the Cochrane Library databases were used, whereas citation searching was conducted in Scopus. Citations were restricted to those published in English and in peer-reviewed journals between 2000 and 2021. Of 1762 abstracts screened, 69 articles underwent full-text review, and 33 were included. Imaging data assessing myofascial trigger points or myofascial pain syndrome were extracted, and important qualitative and quantitative information on general study methodologies, study populations, sample sizes, and myofascial trigger point/myofascial pain syndrome evaluation were tabulated. Methodological quality of eligible studies was assessed based on the Quality Assessment of Diagnostic Accuracy Studies criteria. Biomechanical properties and blood flow of active and latent myofascial trigger points assessed via imaging were found to be quantifiably distinct from those of healthy tissue. Although these studies show promise, more studies are needed. Future studies should focus on assessing diagnostic test accuracy and testing the reproducibility of results to establish the best performing methods. Increasing methodological consistency would further motivate implementing imaging methods in larger clinical studies. Considering the evidence on efficacy, cost, ease of use and time constraints, ultrasound-based methods are currently the imaging modalities of choice for myofascial pain syndrome/myofascial trigger point assessment.

Objective Behçet’s disease is a rare and incurable condition where the body’s immune system attacks healthy tissue. Behçet’s can cause blood clots and ulcerations to form in every organ and system in the body, including deep and painful genital ulceration. The psychological impact of the disease on intimacy and relationships is unexplored. This study aimed to explore how the disease impacts on female patients’ intimate partner relationships. Methods Participants were seven female, UK patients with Behçet’s disease who were in committed relationships. In depth, semi-structured interviews lasting approximately 80 minutes were conducted via video conferencing about participants’ sexual functioning and intimate relationships. Data was analysed using Interpretative Phenomenological Analysis. Results Patients’ sexual relationships and intimacy were impacted by issues due to lack of knowledge of symptoms (misdiagnosis of herpes), issues due to symptoms (genital manifestations, painful sex, exhaustion), difficulties communicating with medical professionals, medication, partner support, and support from fellow Behçet’s patients. Discussion Female Behçet’s patients are at risk of developing psychological problems with intimacy due to symptoms, lack of knowledge of symptoms, and negative impacts of medication. Intimacy needs to be discussed in medical consultations so these issues can be addressed before a lack of intimacy negatively impacts relationships.

A terapia fotodinâmica (TFD) é uma reação fotoquímica que atua diretamente em tecidos tumorais com intuito de destruí-los, quando aplicada de maneira ideal, sem afetar o tecido saudável. Caso um sensibilizador localize um tecido tumoral por este é anulado, devido à produção de espécies tóxicas como resultado da transferência de energia da molécula para o tecido tumoral, destruindo a anomalia de forma segura. Em sistemas naturais, a biossíntese do óxido de nitrogênio (NO) e suas várias reações biológicas e fisiológicas ocorrem através da interação com metaloproteínas de ferro, rutênio, cobre, cobalto, dentre outros metais de transição. Assim, as reações de NO através de sua coordenação com centros de metal de transição possuem grande potencial e são principais candidatos para cumprir essa função, podem ser citados porfirinas e seus derivados como a tetraazaporfirina.

The gum and the gingival festoon in particular are essential elements of the good periodontal health and the harmony of the smile. How does this engage orthodontics? Orthodontists are directly concerned by the vertical position of the collars which they must consider. More indirectly, they can have an influence on the gum festoon and in particular on the papillae. The analysis of the literature of the undesirable effects of orthodontics on the periodontium is provided but with limited conclusions which do not constitute scientific evidence. It remains very important to analyze them in order to draw a guide of clinical conduct. The vestibular version and the alveolar expansion present risks of gingival recession that must be taken into account. The presence of the papillae responds to precise anatomical conditions that have to be controlled to avoid disastrous black triangles when aligning the teeth. The shape of the teeth is directly involved in these phenomena. Stripping may be an appropriate therapeutic response to prevent or limit these iatrogenic effects. The approach is first of all diagnostic (identification of the shape of the teeth, analysis of the dento-dental disharmony (DDD), evaluation of the amount of stripping and its consequences on the DDD) and then prognostic in order to establish the treatment plan... The author will illustrate this approach by the teachings of the literature and by clinical illustrations of treated cases. The balance of a smile is based on the respect of shapes, anatomical proportions and the conditions necessary for healthy tissue. It is our role to respect them in the project of establishing harmony. The beauty of the smile reflects the patient's own personality: « Orthodontists are the technicians of the semaphore of the soul », Axel Kahn, Journées de l'Orthodontie, 2007.

Persistent irritants that are resistant to innate and cognate immunity induce granulomas. These macrophage-dominated lesions that partially isolate the healthy tissue from the irritant and the irritant induced inflammation. Particles, toxins, autoantigens and infectious agents can induce granulomas. The corresponding lesions can be protective for the host but they can also cause damage and such damage has been associated with the pathology of more than a hundred human diseases. Recently, multiple molecular mechanisms underlying how normal macrophages transform into granuloma-inducing macrophages have been discovered and new information has been gathered, indicating how these lesions are initiated, spread and regulated. In this review, differences between the innate and cognate granuloma pathways are discussed by summarizing how the dendritic cell - T cell axis changes granulomatous immunity. Granuloma lesions are highly dynamic and depend on continuous cell replacement. This feature provides new therapeutic approaches to treat granulomatous diseases.

Background: In Indonesia, nasopharyngeal cancer ranks 4th most in malignancies. As a method of treatment, the development of radiotherapy has made it possible to give high doses to tumors with little risk of healthy tissue, but still maintain accuracy by performing geometry verification procedures. The purpose of this study was to determine the geometry verification procedure of nasopharyngeal cancer with EPID on the Linac plane in RSUP Dr. Kariadi Semarang; the average geometric shift that occurs and why is only done before fractions 1 and 4 only.Methods: This type of research is qualitative with a case study approach. The data is taken from February 2019 to June 2019 by the method of observation, documentation and interviews. The data obtained were analyzed by interactive models, making transcripts of interviews then reduced and processed in the form of open coding, presented in the form of quotations and concluded.Results: The results showed that the geometry verification procedure was started by making a calendar treatment, adjusting the patient's setup at the origin point, switching to the iso center point. Take the image portal with EPID AP and Lateral projections. Match image portals with DRR images. Then the geometric shift data were obtained with a mean shift from the iso center in 5 patient samples: vertical axis 0.15 cm to superior; longitudinal -0.01 cm anteriorly and laterally 0.04 cm to the right. Tolerance limit of 0.3 cm. This verification is only done before fractions 1 and 4 because of the high service load.Conclusion: The geometry verification procedure has been going well with the results of the shift is still below the tolerance limit. Verification information before the 1st and 4th fractions was not enough to assess the accuracy of the irradiation carried out properly maintained.

Radiotherapy (RT) is a cancer treatment that uses high doses of radiation to kill cancer cells and shrink tumors. Although great success has been achieved on radiotherapy, there is still an intractable challenge to enhance radiation damage to tumor tissue and reduce side effects to healthy tissue. Radiosensitizers are chemicals or pharmaceutical agents that can enhance the killing effect on tumor cells by accelerating DNA damage and producing free radicals indirectly. In most cases, radiosensitizers have less effect on normal tissues. In recent years, several strategies have been exploited to develop radiosensitizers that are highly effective and have low toxicity. In this review, we first summarized the applications of radiosensitizers including small molecules, macromolecules, and nanomaterials, especially those that have been used in clinical trials. Second, the development states of radiosensitizers and the possible mechanisms to improve radiosensitizers sensibility are reviewed. Third, the challenges and prospects for clinical translation of radiosensitizers in oncotherapy are presented.

The treatment of scars and impact by them their deformations, as well as the formation of pathological scars, remain one of the most difficult and insufficiently explored problems of plastic and reconstructive surgery. The most severe type of pathological scars is keloid a tumor-like growth of immature connective tissue due to uncontrolled proliferative fibroblast activity. The simple removal of keloids even within healthy tissue was often accompanied by their recurrence. Here presented clinical observation of the patient with benign fibroma of 1 finger of the right foot, who had after excision of formation, keloid scar has developed. Repeated operations with keloid excision and the use of free skin plastic have proved ineffective. Only long-term therapy with diprospan injections for 1.5 years allowed to achieve cure of the patient.

Due to the difficulties in early diagnosis of pancreatic adenocarcinoma (PAAD), many patients fail to receive optimal therapeutic regimens. The Secretory-Carrier-Membrane-Proteins (SCAMPs) are known to be dysregulated in a range of human diseases due to their characterized roles in mammalian cell exocytosis inferred from their functions as integral membrane proteins. However, the expression and prognostic value of SCAMPs in PAAD is poorly characterized. We compared cancer vs. healthy tissue and found that the expression of SCAMPs1-4 was upregulated in PAAD compared to normal tissue. In contrast, SCAMP5 expression was downregulated in PAAD. Moreover, the expression of SCAMPs1-4 was enhanced in PAAD cell lines according to Cancer Cell Line public database. Furthermore, the HPA, GEPIA databases and immunohistochemical analysis from 238 patients suggested that the loss of SCAMP1 led to improved overall survival (OS), whilst lower SCAMP5 levels led to a poorer OS. The univariate and multivariate analysis showed that SCAMP1 and SCAMP5 expression were independent prognostic factors of PAAD. In addition, the cBioPortal for Cancer Genomics, LinkedOmics datasets, and the GEPIA were used to identify the co-expression genes of SCAMP1,5 and the correlation between SCAMPs members. We conclude that SCAMPs 1 and 5 significantly represent promising diagnosis and prognostic biomarkers.

Inflammation of the gastrointestinal (GI) tract accompanies several diseases, including Crohn’s disease. Currently, video capsule endoscopy and deep bowel enteroscopy are the main means for direct visualisation of the bowel surface. However, the use of optical imaging limits visualisation to the luminal surface only, which makes early-stage diagnosis difficult. In this study, we propose a learning enabled microultrasound ( $\mu $ US) system that aims to classify inflamed and non-inflamed bowel tissues. $\mu $ US images of the caecum, small bowel and colon were obtained from mice treated with agents to induce inflammation. Those images were then used to train three deep learning networks and to provide a ground truth of inflammation status. The classification accuracy was evaluated using 10-fold evaluation and additional B-scan images. Our deep learning approach allowed robust differentiation between healthy tissue and tissue with early signs of inflammation that is not detectable by current endoscopic methods or by human inspection of the $\mu $ US images. The methods may be a foundation for future early GI disease diagnosis and enhanced management with computer-aided imaging.

Background and purpose: Proton therapy has been proposed as a technique to improve the long-term quality of life of breast cancer patients. This is due to its ability to reduce the dose to healthy tissue compared to conventional X-ray therapy. The aim of this study was to investigate the risk of secondary carcinogenesis due to proton therapy compared to hybrid IMRT for breast treatments. Material and methods: In this study, the Pinnacle treatment planning system was used to simulate treatment plans for 15 female left-sided whole breast cancer patients with deep inspiration breath hold scans. Two treatment plans were generated for each patient: hybrid intensity modulated radiotherapy (h-IMRT) and intensity modulated proton therapy (IMPT). Using the dose-volume histograms (DVHs) from these plans, the mean lifetime attributed risk (LAR) for both lungs and the contralateral breast were evaluated using the BEIR VII and Schneider full risk models. Results: The results from both risk models show lower LAR estimates for the IMPT treatment plan compared to the h-IMRT treatment plan. This result was observed for all organs of interest and was consistent amongst the two separate risk models. For both treatment plans, the organs from most to least at risk were: ipsilateral lung, contralateral breast, and contralateral lung. In all cases, the risk estimated via the BEIR VII model was higher that the Schneider full risk model. Conclusion: The use of proton therapy for breast treatments leads to reduced risk estimates for secondary carcinogenesis. Therefore, proton therapy shows promise in improving the long term treatment outcome of breast patients. Refereed/Peer-reviewed

The concept of targeted radionuclide therapy (TRT) is the accurate and efficient delivery of radiation to disseminated cancer lesions while minimizing damage to healthy tissue and organs. Critical aspects for successful development of novel radiopharmaceuticals for TRT are: i) the identification and characterization of suitable targets expressed on cancer cells; ii) the selection of chemical or biological molecules which exhibit high affinity and selectivity for the cancer cell-associated target; iii) the selection of a radionuclide with decay properties that suit the properties of the targeting molecule and the clinical purpose. The Center for Radiopharmaceutical Sciences (CRS) at the Paul Scherrer Institute in Switzerland is privileged to be situated close to unique infrastructure for radionuclide production (high energy accelerators and a neutron source) and access to C/B-type laboratories including preclinical, nuclear imaging equipment and Swissmedic-certified laboratories for the preparation of drug samples for human use. These favorable circumstances allow production of non-standard radionuclides, exploring their biochemical and pharmacological features and effects for tumor therapy and diagnosis, while investigating and characterizing new targeting structures and optimizing these aspects for translational research on radiopharmaceuticals. In close collaboration with various clinical partners in Switzerland, the most promising candidates are translated to clinics for 'first-in-human' studies. This article gives an overview of the research activities at CRS in the field of TRT by the presentation of a few selected projects., Chimia, 74 (12), ISSN:0009-4293

The high prescribed dose of anticancer drugs and their resulting adverse effects on healthy tissue are significant drawbacks to conventional chemotherapy (CTP). Ideally, drugs should have the lowest possible degree of interaction with healthy cells, which would diminish any adverse effects. Therefore, an ideal scenario to bring about improvements in CTP is the use of technological strategies to ensure the efficient, specific, and selective transport and/or release of drugs to the target site. One practical and feasible solution to promote the efficiency of conventional CTP is the use of ultrasound (US). In this review, we highlight the potential role of US in combination with lipid-based carriers to achieve a targeted CTP strategy in engineered smart drug delivery systems.

Tissue formalin fixation and paraffin embedding (FFPE) is a standard method for long-term preservation and morphological and molecular analysis. The aim of this study was to analyze the effect of storage time on the integrity of DNA isolated from three different healthy FFPE tissues. DNA was isolated from FFPE heart, liver and brain tissues obtained from autopsy and archived from 1988 to 2017 using two different methods of DNA isolation: phenol-chloroform-isoamyl alcohol (PCI) and PureLink Genomic DNA Kit. The quantification and purity of DNA was measured spectrophotometrically at 260 nm and 280 nm. The quality of isolated DNA was evaluated by PCR amplification of GPD1 (150 bp), ACTB (262 bp) and RPL4 (407 bp) genes. The histomorphological characteristics of FFPE tissues were not significantly changed during 30 years of storage. Higher yield (272.9 ± 10.3 µg) and purity (A260/280 = 2.05) of DNA was obtained using the PCI method for DNA isolation from FFPE liver tissue. The PCI extraction method showed reproducible and consistent results in PCR amplification of all of three examined genes. The GPD1 gene can be amplified up to 30 years, the ACTB gene in the same samples up to 26 years and the RPL4 gene up to 6 years of storage in FFPE blocks. Although the best yield and purity of isolated DNA (using both isolation methods) was obtained from FFPE liver tissue, the DNA with the most preserved integrity was obtained from brain tissue archived up to 30 years. This is the first report using long-term archived healthy FFPE tissues (up to 30 years) that shows that the DNA isolated from these tissues is of preserved integrity and can be used in molecular autopsy.

Ollier disease is a rare congenital disease in which multiple enchondromas occur. The tumors can transform to malignant chondrosarcomas of various histologic grades. The patient we described has been treated in our orthopedic department six times, always being referred on account of new lesions. The tumors were excised with margins of healthy tissue. Each tumor was subjected to a histological examination to determine its type and grade. Chondroid tumors should be diagnosed carefully, because the treatment depends on their histologic features. If surgery is performed, removal of the tumor with a margin of healthy tissue is crucial for the patient’s well-being and good prognosis.

This paper deals with an optimal control problem for a haptotaxis model which describes two types of cancer cell invading the surrounding healthy tissue. Cancer cells can be treated by therapeutic agents (radiotherapy or chemotherapy) considered as the control variable. Our primary goal is to characterize an optimal control which balances the therapeutic benefits with its side effects. Firstly, the global bounded weak solution of state system in spatial dimensions $$1\le N\le 5$$ are obtained by using the Banach fixed-point theorem and a new iteration criterion of $$L^p$$ estimates as well as the adapted Moser-type iteration technique of $$L^\infty $$ estimates. Subsequently, the existence of optimal pair is proved by applying the technique of minimizing sequence. Furthermore, we derive the first-order necessary optimality condition by means of the Lipschitz continuity of the control-to-state mapping and the methods of convex perturbation. Finally, we present numerically the spatio-temporal dynamics of species, optimal control and optimal regimen of therapeutic agents administrated to illustrate the concrete realization of the theoretical results obtained in this work, and to validate some clinical findings.

FLASH radiotherapy is a new irradiation method in which large doses of ionizing radiation are delivered to tumors almost instantly (a few milliseconds), paradoxically sparing healthy tissue while preserving anti-tumor activity. Although this technique is primarily studied in the context of electron and photon therapies, proton delivery at high dose rates can also reduce the adverse side effects on normal cells. So far, no definitive mechanism has been proposed to explain the differences in the responses to radiation between tumor and normal tissues. Given that living cells and tissues consist mainly of water, we set out to study the effects of high dose rates on the radiolysis of water by protons in the energy range of 150 keV – 500 MeV (i.e., for linear energy transfer (LET) values between ∼72.2 and 0.23 keV/μm, respectively) using Monte Carlo simulations. To validate our methodology, however, we, first, report here the results of our calculations of the yields (G values) of the radiolytically produced species, namely the hydrated electron ([Formula: see text]), •OH, H•, H2, and H2O2, for low dose rates. Overall, our simulations agree very well with the experiment. In the presence of oxygen, [Formula: see text] and H• atoms are rapidly converted into superoxide anion or hydroperoxyl radicals, with a well-defined maximum of [Formula: see text] at ∼1 μs. This maximum decreases substantially when going from low-LET 500 MeV to high-LET 150 keV irradiating protons. Differences in the geometry of the proton track structure with increasing LET readily explain this diminution in [Formula: see text] radicals.

Several antibody-drug conjugates (ADCs) have failed to achieve a sufficiently large therapeutic window in patients due to toxicity induced by unspecific payload release in the circulation or ADC uptake into healthy organs. Herein, we describe the successful engineering of ADCs consisting of novel linkers, which are efficiently and selectively cleaved by the tumor-associated protease legumain. ADCs generated via this approach demonstrate high potency and a preferential activation in tumors compared to healthy tissue, thus providing an additional level of safety. A remarkable tolerance of legumain for different linker peptides, including those with just a single asparagine residue, together with a modifier of the physicochemical metabolite profile, proves the broad applicability of this approach for a tailored design of ADCs.

Sequencing the first human genome in 2003 took 15 years and cost $2.7 billion. Advances in sequencing technologies have since decreased costs to the point where it is now feasible to resequence a whole human genome for $1000 in a single day. These advances have allowed the generation of huge volumes of high‐quality human sequence data used to construct increasingly large catalogs of both population‐level and disease‐causing variation. The existence of such databases, coupled with a high‐quality human reference genome, means we are able to interrogate and annotate all types of genetic variation and identify pathogenic variants for many diseases. Increasingly, sequencing‐based approaches are being used to elucidate the underlying genetic cause of autoimmune diseases, a group of roughly 80 polygenic diseases characterized by abnormal immune responses where healthy tissue is attacked. Although sequence data generation has become routine and affordable, significant challenges remain with no gold‐standard methodology to identify pathogenic variants currently available. This review examines the latest methodologies used to identify pathogenic variants in autoimmune diseases and considers available sequencing options and subsequent bioinformatic methodologies and strategies. The development of reliable and robust sequencing and analytic workflows to detect pathogenic variants is critical to realize the potential of precision medicine programs where patient variant information is used to inform clinical practice., Although sequence data generation has become routine and affordable, significant challenges remain with no gold‐standard methodology to identify pathogenic variants currently available. This review examines the latest methodologies used to identify pathogenic variants in autoimmune disease and considers available sequencing options and subsequent bioinformatic methodologies and strategies. The development of reliable and robust sequencing and analytic workflows to detect pathogenic variants is critical to realize the potential of precision medicine programs where patient variant information is used to inform clinical practice.

To deliver the desired absorbed dose to the tumor and save the neighboring healthy tissue the sources of errors in the assessment of the therapeutic dose should be minimized. In the current work, 6...

Dermatofibrosarcoma protuberans (DFSP) is a rare, locally infiltrating, rarely metastasizing, soft tissue tumour. Due to its indistinct margins, local aggressive behaviour and high recurrence rate, the surgical approach is complex. Micrographic surgery and variants of this technique, e.g. Tubingen torte technique (TTT), should be considered as first-line treatment. To confirm that TTT is a safe and tissue-sparing technique, relative to theoretical wide local excision (WLE), for the same lesions, as recommended by the guidelines in the literature. Seventeen patients with histologically confirmed DFSP, treated with TTT between September 2014 and February 2019, were retrospectively analysed. For each patient, the final TTT excision area was calculated and compared with the theoretical equivalent area based on WLE. The difference in area was calculated and presented as percentage difference of preserved healthy skin based on the two approaches. In our patients, the mean preoperative lesion size was 4.55 ± 5.34 cm2. The mean final total excised area was 17.73 ± 11.75 cm2 for TTT and 53.65 ± 15.57 cm2 for WLE. The amount of preserved healthy tissue using the micrographic technique was significant; 69.15% (95% CI: 62.95–75.36) of healthy tissue was preserved using TTT. No recurrence or metastases were observed in any of the patients after a median follow-up period of 38.00 ± 21 months. In our experience, TTT remains a safe, effective and tissue-sparing treatment for DFSP patients, especially when it is essential to spare tissue and in challenging locations.

Introduction Teaching dental caries removal is limited by the material and methods available in the preclinical teaching space. Plastic teeth do not simulate the tactile feel of a lesion and natural teeth do not allow for standardised training and assessment. A novel method for simulating caries has been reported. Here, to investigate the construct validity of a caries simulation, whether haptic simulation could contribute to the understanding of caries removal, the performance of first-year dental students on the haptic simulation exercise is compared with that of experienced dentists. Method A virtual block comprising healthy dentine, pulp, enamel and a carious lesion with significant spread along the amelodentinal junction (ADJ) was developed for the Simodont dental trainer. The case was presented to 112 first-year students and 17 clinicians following a 15 min training period on a block which contained green caries and displayed live progress throughout the exercise. All participants were given the same verbal instructions: to remove all unsupported enamel and caries along the ADJ while retaining as much healthy tissue as possible. Results Clinicians performed better than the dental novices in precision and overall performance. Clinicians removed more material on average, except for healthy dentine, of which similar amounts were removed by both groups. Discussion We presented a novel haptic caries exercise and investigated the construct validity of the task. The simulation may bridge the gap between preclinical and clinical dental education in caries removal. Conclusion Clinically experienced dentists outperformed novices on a haptic caries simulation exercise. The exercise may be a useful tool for assessing conceptual understanding of caries removal.

Basal cell carcinoma (BCC) are the commonest cutaneous malignancy and incidence continues to increase. There is a need to expand the therapeutic toolbox to increase options for patients that are unsuitable for or unwilling to undergo the current therapies. Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief pulsed electrical field and combined with low dose chemotherapeutics to ablate malignancies. It is a simple technique causing minimal damage to the surrounding healthy tissue and has the potential to avoid the need for complex reconstruction. ECT is an established treatment for skin metastases but its role as a primary treatment modality is not demonstrated. A prospective randomised control trial evaluating ECT against the gold standard of treatment, Surgery, was performed for patients with primary BCC and patients followed for 5 years. All lesions treated with ECT (n = 69) responded although 8/69 (12%) needed a second treatment to ensure a complete response. All surgical lesions (n = 48) showed histological evidence of complete excision with 2/48 (4%) undergoing a second excision. At 5 years, in the surgical arm there was no evidence of recurrence in 39/40 (97.5%) lesions with 1/40 (2.5%) confirmed recurrence. In the ECT arm there was no evidence of recurrence in 42/48 lesions (87.5%). There was 5 confirmed recurrences. These groups show statistical equivalence in this non inferiority study design (p = 0.33). ECT is an effective and durable treatment option for primary BCC and should be considered as part of the armamentarium of options available.

Background and objective Diffuse reflectance spectroscopy (DRS) offers a fast, non-invasive, and low-cost alternative for cervical cancer diagnosis. We aim to develop a method for screening precancerous lesions based on DRS. Material and methods Characteristic parameters of cervical tissue were extracted from spectra, including optical characteristic parameters such as absorption and scattering coefficients, and some slope and area parameters of the spectrum. Data were randomly divided into training (60%) and test (40%) sets. Of the 210 included patients, 166 were healthy, 22 had erosion of the cervix, and 31 had cervical intraepithelial neoplasia (CIN). The support vector machine (SVM) algorithm was used to classify normal and abnormal cervical tissue based on 11 characteristic parameters. Results The SVM with linear kernel function, applied on the training data, could distinguish tissue with lesions from healthy tissue with an accuracy of 1.00. When the classifiers were applied to the test set, erosion of cervix and CIN could be discriminated from healthy tissue with an accuracy of 0.95 ( ± 0.03). Conclusions This research shows that the diagnostic algorithm can be valuable for non-invasive diagnosis of cervical cancer. This is a significant step toward the development of a tool for tissue assessment of cervical cancer.