Lipid nanoemulsions and liposomes improve photodynamic treatment efficacy and tolerance in CAL-33 tumor bearing nude mice.

BACKGROUND: Photodynamic therapy (PDT) as promising alternative to conventional cancer treatments works by irradiation of a photosensitizer (PS) with light, which creates reactive oxygen species and singlet oxygen (1O2), that damage the tumor. However, a routine use is hindered by the PS's poor water solubility and extended cutaneous photosensitivity of patients after treatment. In our study we sought to overcome these limitations by encapsulation of the PS m-tetrahydroxyphenylchlorin (mTHPC) into a biocompatible nanoemulsion (Lipidots). RESULTS: In CAL-33 tumor bearing nude mice we compared the Lipidots to the existing liposomal mTHPC nanoformulation Foslip and the approved mTHPC formulation Foscan. We established biodistribution profiles via fluorescence measurements in vivo and high performance liquid chromatography (HPLC) analysis. All formulations accumulated in the tumors and we could determine the optimum treatment time point for each substance (8 h for mTHPC, 24 h for Foslip and 72 h for the Lipidots). We used two different light doses (10  and 20 J/cm2) and evaluated immediate PDT effects 48 h after treatment and long term effects 14 days later. We also analyzed tumors by histological analysis and performing reverse transcription real-time PCR with RNA extracts. Concerning tumor destruction Foslip was superior to Lipidots and Foscan while with regard to tolerance and side effects Lipidots were giving the best results. CONCLUSIONS: We could demonstrate in our study that nanoformulations are superior to the free PS mTHPC. The development of a potent nanoformulation is of major importance because the free PS is related to several issues such as poor bioavailability, solubility and increased photosensibility of patients. We could show in this study that Foslip is very potent in destroying the tumors itself. However, because the Lipidots' biocompatibility is outstanding and superior to the liposomes we plan to carry out further investigations and protocol optimization. Both nanoformulations show great potential to revolutionize PDT in the future.

Effective Biofilm Eradication on Orthopedic Implants with Methylene Blue Based Antimicrobial Photodynamic Therapy In Vitro.

Periprosthetic joint infections (PJI) are difficult to treat due to biofilm formation on implant surfaces, often requiring removal or exchange of prostheses along with long-lasting antibiotic treatment. This in vitro study investigated the effect of methylene blue photodynamic therapy (MB-PDT) on PJI-causing biofilms on different implant materials. MB-PDT (664 nm LED, 15 J/cm2) was tested on different Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Cutibacterium acnes strains in both planktonic form and grown in early and mature biofilms on prosthetic materials (polyethylene, titanium alloys, cobalt-chrome-based alloys, and bone cement). The minimum bactericidal concentration with 100% killing (MBC100%) was determined. Chemical and topographical alterations were investigated on the prosthesis surfaces after MB-PDT. Results showed a MBC100% of 0.5-5 µg/mL for planktonic bacteria and 50-100 µg/mL for bacteria in biofilms-independent of the tested strain, the orthopedic material, or the maturity of the biofilm. Material testing showed no relevant surface modification. MB-PDT effectively eradicated common PJI pathogens on arthroplasty materials without damage to the materials, suggesting that MB-PDT could be used as a novel treatment method, replacing current, more invasive approaches and potentially shortening the antibiotic treatment in PJI. This would improve quality of life and reduce morbidity, mortality, and high health-care costs.

Uptake and fate of surface modified silica nanoparticles in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is currently the eighth leading cause of cancer death worldwide. The often severe side effects, functional impairments and unfavorable cosmetic outcome of conventional therapies for HNSCC have prompted the quest for novel treatment strategies, including the evaluation of nanotechnology to improve e.g. drug delivery and cancer imaging. Although silica nanoparticles hold great promise for biomedical applications, they have not yet been investigated in the context of HNSCC. In the present in-vitro study we thus analyzed the cytotoxicity, uptake and intracellular fate of 200-300 nm core-shell silica nanoparticles encapsulating fluorescent dye tris(bipyridine)ruthenium(II) dichloride with hydroxyl-, aminopropyl- or PEGylated surface modifications (Ru@SiO2-OH, Ru@SiO2-NH2, Ru@SiO2-PEG) in the human HNSCC cell line UMB-SCC 745. RESULTS: We found that at concentrations of 0.125 mg/ml, none of the nanoparticles used had a statistically significant effect on proliferation rates of UMB-SCC 745. Confocal and transmission electron microscopy showed an intracellular appearance of Ru@SiO2-OH and Ru@SiO2-NH2 within 30 min. They were internalized both as single nanoparticles (presumably via clathrin-coated pits) or in clusters and always localized to cytoplasmic membrane-bounded vesicles. Immunocytochemical co-localization studies indicated that only a fraction of these nanoparticles were transferred to early endosomes, while the majority accumulated in large organelles. Ru@SiO2-OH and Ru@SiO2-NH2 nanoparticles had never been observed to traffic to the lysosomal compartment and were rather propagated at cell division. Intracellular persistence of Ru@SiO2-OH and Ru@SiO2-NH2 was thus traceable over 5 cell passages, but did not result in apparent changes in cell morphology and vitality. In contrast to Ru@SiO2-OH and Ru@SiO2-NH2 uptake of Ru@SiO2-PEG was minimal even after 24 h. CONCLUSIONS: Our study is the first to provide evidence that silica-based nanoparticles may serve as useful tools for the development of novel treatment options in HNSCC. Their long intracellular persistence could be of advantage for e.g. chronic therapeutic modalities. However, their complex endocytotic pathways require further investigations.

Medicinal plants from the Himalayan region for potential novel antimicrobial and anti-inflammatory skin treatments.

BACKGROUND AND OBJECTIVES: Adequate treatment of wounds remains one of the major medical needs globally, most notably in the regions with poor or limited access to health care. In many local and traditional systems of medicine, plants are often widely used for treating infected wounds. AIM AND OBJECTIVES: The overarching aim of this project was selection of potential species for use in a future treatment by combining with plant resources with aspects of antimicrobial photodynamic therapy (aPDT). Specifically, we focussed on species used locally in the Himalayan region for the treatment of skin disorders and then assessed the existing pharmacological evidence for key species based on the published evidence available. METHODS: Database searches were performed to identify relevant publications describing local and traditional uses of plants in the Himalayan region of Bhutan, PR China, India, Nepal and Pakistan. Using the Global Biodiversity Information Facility (GBIF), species were researched in terms of their distribution including in different climatic regions, focussing on species mostly found in higher climatic zones (based on the Köppen-Geiger climate classification). For species used in three or more countries and restricted to the higher altitudes, data on safety, pharmacology, as it relates to dermatological conditions, and phytochemistry were retrieved. KEY FINDINGS: The study identified a total of 606 species that are used in the treatment of various skin conditions often associated with infections reported in 84 articles. Common weeds like Ageratum conyzoides and Bidens pilosa, widely used and cultivated species like Centealla asiatiaca and Prunus armenica were excluded. This ultimately led to the identification of a core group of five widely used species restricted to the Himalayan region (Cedrus deodara, Nardostachys jatamansi, Pinus wallichiana, Pinus roxburghii and Valeriana jatamansi). CONCLUSIONS: Here we apply a novel approach comprising an assessment of the published information on the use of medicinal plants (i.e. local and traditional knowledge) in the context of their potential to be used in a biomedical form of clinical treatment - aPDT. Then, once sustainable sourcing based on access and benefit-sharing arrangements is in place, these species are investigated for their potential in wound treatment. Ultimately, the goal is to develop a new baseline for primary health care in some of the regions of the world with poor or limited access to health care.

"Tobacco Is the Chief Medicinal Plant in My Work": Therapeutic Uses of Tobacco in Peruvian Amazonian Medicine Exemplified by the Work of a Maestro Tabaquero.

INTRODUCTION: Harmful usage of tobacco is a public health problem of global concern and, in many countries, the main risk factor for non-communicable diseases. Yet, in the Peruvian Amazon, the geographical region believed to be tobacco's historical birthplace, this plant is associated with a strikingly different usage and repute: Tobacco (especially Nicotiana rustica L.) in this area is described as a potent medicinal plant, used topically or via ingestion to treat a variety of health conditions. The goal of this transdisciplinary field study was to investigate clinical applications of the tobacco plant as per Amazonian medicine exemplified in the practice of a reputed Maestro Tabaquero, an Amazonian traditional healer whose medical specialization focuses on tobacco-based treatments. METHODS: Using a transdisciplinary clinical approach, we conducted in-depth interviews with the tabaquero applying the systematizing expert interview method, in order to map modes of preparation and administration, indications, contraindications, effects, risks, adverse effects, and systemic aspects of tobacco-based remedies. RESULTS: The informant's descriptions revealed refined knowledge on this plant's therapeutic properties and scope, safety profile, and application techniques. The main indications mentioned included "problems of the mind," of the respiratory system, parasitic illnesses (intestinal/skin), gout, and Amazonian epistemic conditions described as spiritual-energetic in nature. A liquid remedy taken orally was his most commonly used preparation, with acute/sub-acute effects involving a pronounced psychoactive component (altered state of consciousness) and physiological response (emesis, nausea). A skilled tabaquero that knows how to dose, administer, and intervene in case of adverse effects was considered imperative for safe treatment delivery. CONCLUSIONS: To our knowledge, this is the first study employing a transdisciplinary clinical approach to examine therapeutic applications of tobacco by an Amazonian tabaquero. Our findings significantly contribute to the growing research literature on Amazonian medicine and emergent psychedelic-assisted therapies and could, in the long-term, open new treatment avenues in several domains. Forthcoming studies should assess toxicity/safety and clinical outcomes of patients receiving Amazonian tobacco-based treatment.

Who Turns to Amazonian Medicine for Treatment of Substance Use Disorder? Patient Characteristics at the Takiwasi Addiction Treatment Center.

OBJECTIVE: Complementary medicines are an emergent field in the treatment of substance use disorders (SUDs) and include Amazonian medicines, such as ayahuasca. The aim of this multimodal cross-sectional study was to investigate characteristics of people who seek treatment for SUDs at an accredited healthcare facility that applies Amazonian medicines along with conventional psychotherapy. METHOD: We collected clinical and sociodemographic data of consecutive admissions at the Takiwasi Addiction Treatment Center (Tarapoto, Peru) using structured questionnaires, interviews, and letters submitted upon program application describing motivation for treatment. RESULTS: The sample of 50 male participants admitted between 2014 and 2016 was culturally heterogeneous, including patients from Peru (42%), other Latin American countries (34%), and North America/Europe (24%). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria indicated dependencies on cannabis (72%), alcohol (52%), cocaine/base paste (48%), and others; multiple substance use was common (84%). Self-reported depression and anxiety scores showed moderate elevation. Comparison of Addiction Severity Index composite scores to a large U.S. sample suggested somewhat more severe problems in the drug and psychiatric domains. Common motives for selecting the program included interest in Amazonian medicine, the Takiwasi concept of treatment, and unfavorable experiences with past treatments. Being motivated by family, a desire for self-transformation, and spiritual/existential motives were common themes for treatment initiation. CONCLUSIONS: Our results suggest that the Amazonian medicine-based therapy attracts a diverse patient group not limited to regional residents and may be particularly appealing to more impaired SUD patients with a history of unsuccessful treatment. The sample's cultural diversity suggests an existing interest in such therapies among international SUD treatment-seeking patients. These findings are relevant in light of the need for improved SUD therapies and contribute to the emergent research literature on ayahuasca-based treatments.

Short-Term Treatment Effects of a Substance Use Disorder Therapy Involving Traditional Amazonian Medicine.

Chronic illness management today commonly involves alternative medicines. Substance use disorder (SUD), as a chronic psychosomatic illness, might benefit from a similar approach. The accredited Takiwasi Center offers such an SUD treatment program involving Amazonian medicine combined with psychotherapy. The current study assessed this integrative program's short-term therapeutic effects. We measured baseline data from 53 dependence-diagnosed males admitted to treatment (T1) and repeated clinical outcome variables at treatment completion (T2). Paired samples t-tests were used to assess changes between T1 and T2 (n = 36). Nearly all participants (age M= 30.86, SD= 8.17) were dependent on multiple substances, most prominently cannabis, alcohol, and cocaine-related drugs. A significant decrease (T1 to T2) was found for addiction severity outcomes drug use (p < .001), alcohol use (p < .001), psychiatric status (p < .001), and social/familial relationships (p < .001). Emotional distress also diminished significantly (p < .001), as did substance craving (p < .001). Quality of life increased significantly from T1 to T2 (p < .001). Our results provide first indications for significantly improved SUD symptoms after the Amazonian medicine-based treatment. These findings are preliminary given the design, but strongly encourage further investigation of this therapy, which in the long term may open new therapeutic avenues for SUDs.

Conceptions and practices of an integrative treatment for substance use disorders involving Amazonian medicine: traditional healers' perspectives.

OBJECTIVE: The harmful use of psychoactive substances represents one of today's largest public health problems. Yet, in spite of its global relevance, current treatment for substance use disorders (SUDs) is still not entirely successful. The purpose of this study was to investigate alternative treatments and conceptions from traditional Amazonian medicine adapted to SUDs. METHODS: We conducted semi-structured interviews with 13 practicing experts at a well-established addiction treatment center in the Peruvian Amazon and performed qualitative content analysis on the collected data. Main categories were deductively defined and corresponding subcategories inductively developed. RESULTS: Our findings revealed characteristic features and consequences, causes and antecedents, and treatment methods of SUDs as the main categories. Overall, concepts of disease etiology bore resemblance with contemporary biopsychosocial models of SUDs. The Amazonian therapeutic means however differed markedly from current Western ones. The main methods involved dietary retreats, healing ceremonies, and purging rituals. The integral application of Amazonian methods, as well as their traditional implementation according to prescribed ritual protocols, were emphasized by the experts as crucial for efficacy and safety of treatment delivery. CONCLUSION: We suggest further scientific attention to these therapies, including clinical studies, for which our results provide conceptual underpinnings. Findings from this research expand the cross-cultural understanding of SUDs and, in the long run, may enhance its treatment options.

Novel flexible light diffuser and irradiation properties for photodynamic therapy.

Many current light diffusers for photodynamic therapy are inflexible, and the applied light dose is difficult to adjust during treatment, especially on complex body surfaces. A thin and flexible luminous textile is developed using plastic optical fibers as a light distributor. The textile diffuser is evaluated for flexibility, irradiance, brightness distribution, and temperature rise with a 652-nm laser set to 100 mW. The bending force of the textile diffuser resembles a defined optical film. On the textile surface, an average output power of 3.6+/-0.6 mWcm(2) is measured, corresponding to a transmission rate of 40+/-3.8% on an area of 11 cm(2). Aluminum backing enhances the irradiance to the face (treatment side). The measured brightness distribution seems to lie within a range similar to other photodynamic therapy (PDT) devices. A power setting of 100 mW increases the temperature of the textile diffuser surface of up to 27 degrees C, and 1 W raises the temperature above 40 degrees C. Results confirm that the flexible textile diffuser supplies suitable radiation for low fluence rate photodynamic therapy on an area of several cm(2).

Photodynamic therapy of feline cutaneous squamous cell carcinoma using a newly developed liposomal photosensitizer: preliminary results concerning drug safety and efficacy.

BACKGROUND: Squamous cell carcinomas are common skin tumors in cats. We investigated photodynamic therapy (PDT) using a new liposomal photosensitizer as a minimally invasive, effective treatment that can be easily performed while achieving good cosmetic results. AIM: The goal of this study was to assess and describe possible toxicities using a liposomal formulation of the photosensitizer meta-(Tetrahydroxyphenyl)Chlorin (m-THPC) and investigate if favorable pharmacokinetics translate into favorable tumor response and control. ANIMALS: Eighteen client-owned cats with 20 spontaneous cutaneous squamous cell carcinomas were included in the study. METHODS: PDT was performed using a new, liposomal formulation of the photosensitizer. Toxicity, tumor response, and tumor control were evaluated retrospectively. RESULTS: No general adverse effects were observed in cats treated with the new liposomal formulation. Mild local toxicity such as erythema and edema were seen in 15% of the patients. All cats responded to therapy, with a complete response rate of 100%. The overall 1-year control rate was 75%. The tumor recurrence rate was 20% with a median time to recurrence of 172.25 +/-87.1) days. CONCLUSIONS AND CLINICAL IMPORTANCE: A new liposomal photosensitizer was successfully used for squamous cell carcinoma in cats and was well tolerated. There were no systemic adverse effects observed with the liposomal formulation. The favorable pharmacokinetics of the liposomal drug resulted in a favorable tumor response.

Short-term effectiveness of inpatient cancer rehabilitation: A longitudinal controlled cohort study.

Background: Inpatient rehabilitation for cancer patients has been demonstrated to improve patients' health related quality of life (HRQoL) effectively. The purpose of this study was to compare changes in general health and HRQoL of cancer patients who were referred to inpatient rehabilitation (IR) with those in two control groups who underwent outpatient management either with advice for inpatient rehabilitation (A+) or without (A-). Methods: In this naturalistic, longitudinal, controlled cohort study, changes in general health and HRQoL were assessed at either discharge of acute hospital or start of rehabilitation (baseline) and at the follow-up 3 weeks later or end of rehabilitation. Outcome variables included general health and HRQoL assessed by the Short Form 36 (SF-36) and the Functional Assessment of Cancer Therapy (FACT), and fatigue (FACT-F), depression and anxiety by the Hospital Anxiety and Depression Scale (HADS). Changes on the scores were compared with bivariate and multivariate analyses using standardized mean differences (SMD). Results: IR patients (n=133) were on average older, reported lower HRQoL and health, and suffered more frequently from carcinoma than patients of the A+ (n=30) and the A- (n=82) groups. In the IR patients, pain, physical functioning, mental health, vitality, and fatigue improved significantly compared to the A+ controls. Compared to the A- group, the bivariate effects were lower but still statistically significant on many scales. Conclusions: IR showed moderate, statistically significant superior effects over outpatient management of cancer patients after acute treatment. Findings indicate that inpatient cancer rehabilitation can be recommended as an effective management after acute treatment. As today, referrals to inpatient rehabilitation for cancer patients are still not based on structured standardized procedures, the implementation of such screening is needed to address patients' needs and to render the potential for rehabilitation more reliable.

Optimizing photodynamic therapy: in vivo pharmacokinetics of liposomal meta-(tetrahydroxyphenyl)chlorin in feline squamous cell carcinoma.

PURPOSE: The aim of the present study was to optimize and simplify photodynamic therapy using a new liposomal formulation of the photosensitizer meta-(tetrahydroxyphenyl)chlorin [m-THPC (Foscan); liposomal m-THPC (Fospeg)] and to reduce systemic reactions to the photosensitizer. EXPERIMENTAL DESIGN: To examine the pharmacokinetics of liposomal m-THPC, we determined tissue and plasma variables in feline patients with spontaneous squamous cell carcinoma. In vivo fluorescence intensity measurements of tumor and skin were done with a fiber spectrophotometer after i.v. injection of m-THPC or liposomal m-THPC in 10 cats. Blood samples, drawn at several time points after photosensitizer administration, were analyzed by high-performance liquid chromatography. RESULTS: None of the liposomal m-THPC-treated cats showed side effects during or after drug injection. Fluorescence intensities, fluorescence ratios (tumor fluorescence divided by skin fluorescence), and bioavailability in the tumor were 2 to 4 times higher with liposomal m-THPC compared with m-THPC. Liposomal m-THPC concentration in the tumor increased constantly to reach a maximum at 4 hours after injection. Plasma concentration and bioavailability were approximately 3 times higher with liposomal m-THPC compared with m-THPC measured at the time points of highest plasma concentration. The distribution half-life was shorter with liposomal m-THPC, resulting in maximal tumor accumulation up to 5.5 times earlier. Maximal tumor accumulation and maximal fluorescence ratio with liposomal m-THPC occurred at the same time point, indicating maximal selectivity. In both groups, all cats responded to therapy. CONCLUSIONS: Liposomal m-THPC was well tolerated by all cats and seems to have superior pharmacokinetic properties compared with m-THPC. The efficacy of the drug warrants further study.

Performance of a contact textile-based light diffuser for photodynamic therapy.

BACKGROUND: Medical textiles offer a unique contact opportunity that could provide value-added comfort, reliability, and safety for light or laser-based applications. We investigated a luminous textile diffuser for use in photodynamic therapy. METHODS: Textile diffusers are produced by an embroidery process. Plastic optical fibers are bent and sewn into textile to release light by macrobending. A reflective backing is incorporated to improve surface homogeneity, intensity, and safety. Clonogenic assay (MCF-7 cells) and trypan blue exclusion (NuTu19 cells) tests were performed in vitro using 0.1µg/ml m-THPC with three textile diffusers and a standard front lens diffuser. Heating effects were studied in solution and on human skin. PDT application in vivo was performed with the textile diffuser on equine sarcoids (three animals, 50mW/cm(2), 10-20J) and eight research animals. Lastly, computer simulations were performed to see how the textile diffuser might work on a curved object. RESULTS: At low fluency rate, there is a trend for the textile diffuser to have lower survival rates than the front lens diffuser for both cell lines. The textile diffuser was observed to retain more heat over a long period (>1min). All animals tolerated the treatments well and showed similar initial reactions. The simulations showed a likely focusing effect in a curved geometry. CONCLUSIONS: The initial feasibility and application using a textile-based optical diffuser has been demonstrated. Possibilities that provide additional practical advantages of the textile diffuser are discussed.

Early apoptotic responses in transgenic mouse mammary carcinoma for photodynamic therapy.

BACKGROUND: Male transgenic mice expressing the human RAS gene on an FVB strain background develop adenocarcinoma of the breast between 7 and 8 weeks of age. We have utilized this mammary tumour model to investigate apoptotic responses following photodynamic therapy (PDT) with a chlorin-based, water-soluble photosensitizer. METHODS: Detection of apoptosis was accomplished by use of the antibody M30 against a neo-epitope of caspase-cleaved cytokeratin 18 that becomes available at an early stage of the apoptotic cascade. Mice bearing multiple tumours were injected with the photosensitizer intraperitoneally, and following a drug-light interval of 96h, 40J/cm(2) of 652nm laser light was applied to one tumour per animal, while the other tumours were protected from light to serve as host controls. The M30 antibody was used for standard immunohistochemistry of tumour sections and flow cytometric detection of epitope expression coupled to cell cycle analysis in tumour cell populations retrieved from paraffin blocks. RESULTS: M30 staining was significantly increased within 2h following light treatment and persisted until 96h after treatment. Flow cytometric analysis for the S-phase fraction (SPF) of tumour cells post-PDT showed a substantial decrease in SPF at 2h post PDT, and recovery of SPF within 96h. CONCLUSIONS: Cytokeratin 18 cleavage seems to be both an early and ongoing event during the cellular response to PDT. Calculating the M30/SPF ratio at both 2h and 96h suggested distinct cellular dynamics at early and late time points, and we propose the M30/SPF ratio as a tumour dynamic index (TDI) to monitor events post PDT.

Use of inpatient rehabilitation for cancer patients in Switzerland: who undergoes cancer rehabilitation?

QUESTION UNDER STUDY: Rehabilitation for cancer patients aims to reduce physical disability and mental distress resulting from the disease and its treatment. However, little is known about the use of cancer inpatient rehabilitation in Switzerland in relation to sociodemographic and medical characteristics. The main purpose of this study was to evaluate whether there are differences in sociodemographic and medical characteristics between patients who underwent inpatient rehabilitation (users) and those who did not (nonusers). METHODS: A total of 238 cancer patients from the University Hospital Zurich were included. The sociodemographic and medical characteristics of inpatient rehabilitation users were assessed and compared with those of nonusers. We analysed the differences between inpatient rehabilitation users and nonusers. RESULTS: Of the patients included, 101 (42.4%) used inpatient rehabilitation. They were less likely to be employed (p = 0.029), stayed longer in hospital (p <0.001), and were more likely to have semiprivate or private supplementary health insurance (p = 0.030) than nonusers. There were differences in cancer site (p = 0.001). Patients with tumours of the digestive organs or of the thoracic organs were more likely to use rehabilitation, whereas breast cancer patients were less likely to use it. Stratified analyses showed that male patients with semiprivate or private supplementary health insurance (p = 0.037), lower education (p = 0.039), and lower likelihood of employment (p = 0.051) were more likely to use rehabilitation. Women with an advanced tumour stage used inpatient rehabilitation more often (p = 0.012). CONCLUSIONS: Findings show the influence of duration of hospitalisation, insurance type, cancer site, employment status, and gender on the use of inpatient cancer rehabilitation. The results indicate the need of structured standardised procedures for medical referral to be implemented based on screening.

Association between promyelocyte protein and small ubiquitin-like modifier protein and the progression of cervical neoplasia.

OBJECTIVE: To examine the association between the size and number of promyelocyte protein-containing nuclear bodies, their colocalization with the small ubiquitin-like modifier protein, and existing histopathologic staging of cervical neoplasia progressing toward squamous cell carcinoma. METHODS: Fluorescence-based immunodetection of the promyelocyte protein and the small ubiquitin-like modifier protein was performed on paraffin-embedded and histopathologically graded human uterine cervical tissues. Quantitative measurements of the size and number of the promyelocyte protein-containing nuclear bodies were made and statistically analyzed. RESULTS: We found that promyelocyte protein-containing nuclear bodies exhibit changes in both size and number throughout the continuum of cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma. An increase in number and size of the bodies occurs with progression from normal to CIN I/CIN II. In CIN III, two new subcategories of nuclear body are present with distinctly different promyelocyte protein patterns, with the type B CIN III losing the small ubiquitin-like modifier protein partnership. In squamous cell carcinoma, we see the loss of this colocalization in both well and poorly differentiated tumors, with a distinctly different promyelocyte protein pattern. Well-differentiated tumors have bigger nuclear bodies that are more numerous than those of the poorly differentiated tumors. CONCLUSION: These data support the use of promyelocyte and small ubiquitin-like modifier proteins as a cytodiagnostic marker that parallels cervical cancer progression.

Effects of chlorin-mediated photodynamic therapy combined with fluoropyrimidines in vitro and in a patient.

Although photodynamic therapy (PDT) is becoming an additional cancer therapy, only little is known about its interactions with other drugs and treatment modalities in vitro and in vivo. We investigated the combination of 5-fluoro-2'-deoxyuridine (5FdUr), a chemotherapeutic drug, with 5,10,15,20-tetra( m-hydroxyphenyl)chlorin (mTHPC), a potent photosensitizer. Two cell lines, MCF-7 and LNCaP, were either simultaneously or consecutively incubated with both drugs and irradiated with laser light to activate mTHPC, and cell survival was determined. The combination of the two treatments was additive or antagonistic in LNCaP cells but additive or synergistic in MCF-7 cells depending on the protocol and concentration of 5FdUr. In one patient with multiple basal cell carcinoma, the effect of the combination of 5-fluorouracil administration followed by PDT resulted in significantly stronger effects than expected, leading to severe oedema, redness and ulceration. The healing process was delayed by 2 months compared to PDT alone. It is therefore important to find optimal conditions under which PDT and chemotherapy combinations do not fall outside the therapeutic window.

Veterinary photodynamic therapy: a review.

Whereas in human medicine photodynamic therapy represents a well-known and recognized treatment option for diverse indications, it is still little known and unfortunately not yet established treatment option for pets. Various photosensitizers and light sources have been used and clinical results have been published. The main indication is a frequently occurring skin tumor in cats: in situ carcinoma/squamous cell carcinoma, mainly found in not or only slightly pigmented areas of the head. For early stages of this tumor, promising results have been published, partly using new, selective drugs to decrease light sensitivity after systemic administration and to increase response rates. Other possible indications are urinary tract neoplasia of dogs and equine sarcoids, the latter representing very common tumors in horses where no effective treatment is known so far. This review article summarizes the role of photodynamic therapy in veterinary medicine.

Conceptions and practices of an integrative treatment for substance use disorders involving Amazonian medicine: traditional healers' perspectives

Objective: The harmful use of psychoactive substances represents one of today's largest public health problems. Yet, in spite of its global relevance, current treatment for substance use disorders (SUDs) is still not entirely successful. The purpose of this study was to investigate alternative treatments and conceptions from traditional Amazonian medicine adapted to SUDs. Methods: We conducted semi-structured interviews with 13 practicing experts at a well-established addiction treatment center in the Peruvian Amazon and performed qualitative content analysis on the collected data. Main categories were deductively defined and corresponding subcategories inductively developed. Results: Our findings revealed characteristic features and consequences, causes and antecedents, and treatment methods of SUDs as the main categories. Overall, concepts of disease etiology bore resemblance with contemporary biopsychosocial models of SUDs. The Amazonian therapeutic means however differed markedly from current Western ones. The main methods involved dietary retreats, healing ceremonies, and purging rituals. The integral application of Amazonian methods, as well as their traditional implementation according to prescribed ritual protocols, were emphasized by the experts as crucial for efficacy and safety of treatment delivery. Conclusion: We suggest further scientific attention to these therapies, including clinical studies, for which our results provide conceptual underpinnings. Findings from this research expand the cross-cultural understanding of SUDs and, in the long run, may enhance its treatment options.

Photodynamic mechanisms induced by a combination of hypericin and a chlorin based-photosensitizer in head and neck squamous cell carcinoma cells.

The aim of this study was to elucidate photodynamic therapy (PDT) effects mediated by hypericin and a liposomal meso-tetrahydroxyphenyl chlorin (mTHPC) derivative, with focus on their 1:1 mixture, on head and neck squamous cell carcinoma cell lines. Absorption, excitation and photobleaching were monitored using fluorescence spectrometry, showing the same spectral patterns for the mixture as measured for single photosensitizers. In the mixture mTHPC showed a prolonged photo-stability. Singlet oxygen yield for light-activated mTHPC was Φ(Δ) = 0.66, for hypericin Φ(Δ) = 0.25 and for the mixture Φ(Δ) = ~0.4. A linear increase of singlet oxygen yield for mTHPC and the mixture was found, whereas hypericin achieved saturation after 35 min. Reactive oxygen species fluorescence was only visible after hypericin and mixture-induced PDT. Cell viability was also more affected with these two treatment options under the selected conditions. Examination of death pathways showed that hypericin-mediated cell death was apoptotic, with mTHPC necrotic and the 1:1 mixture showed features of both. Changes in gene expression after PDT indicated strong up-regulation of selected heat-shock proteins. The application of photosensitizer mixtures with the features of reduced dark toxicity and combined apoptotic and necrotic cell death may be beneficial in clinical PDT. This will be the focus of our future investigations.