The Efficacy of Therapeutic DNA Vaccines Expressing the Human Papillomavirus E6 and E7 Oncoproteins for Treatment of Cervical Cancer: Systematic Review

Cervical cancer is recognized as a serious public health problem since it remains one of the most common cancers with a high mortality rate among women despite existing preventative, screening, and treatment approaches. Since Human Papillomavirus (HPV) was recognized as the causative agent, the preventative HPV vaccines have made great progress over the last few years. However, people already infected with the virus require an effective treatment that would ensure long-term survival and a cure. Currently, clinical trials investigating HPV therapeutic vaccines show a promising vaccine-induced T-cell mediated immune response, resulting in cervical lesion regression and viral eradication. Among existing vaccine types (live vector, protein-based, nucleic acid-based, etc.), deoxyribonucleic acid (DNA) therapeutic vaccines are the focus of the study, since they are safe, cost-efficient, thermostable, easily produced in high purity and distributed. The aim of this study is to assess and compare existing DNA therapeutic vaccines in phase I and II trials, expressing HPV E6 and E7 oncoproteins for the prospective treatment of cervical cancer based on clinical efficacy, immunogenicity, viral clearance, and side effects. Five different DNA therapeutic vaccines (GX-188E, VGX-3100, pNGVL4a-CRT/E7(detox), pNGVL4a-Sig/E7(detox)/HSP70, MEDI0457) were well-tolerated and clinically effective. Clinical implementation of DNA therapeutic vaccines into treatment regimen as a sole approach or in combination with conservative treatment holds great potential for effective cancer treatment.

Bullous Hemorrhagic Dermatosis Induced By Heparin: An Indonesian Case Report

Introduction: Bullous haemorrhagic dermatosis is a rare clinical disorder which is usually related to a treatment with unfractionated heparin (UFH) or low molecular weight heparin (LMWH), characterized by multiple intra-epidermal haemorrhages distant from the site of injection. Presentation of Case: A 62-year-old male patient with coronary heart disease who received heparin treatment experienced several tense, haemorrhagic bullae located on the right arm area, close to the injection site, and followed by the formation of several hematomas on his back trunk 2 days after he had received UFH. The lesions regressed after discontinuation of heparin and supportive topical treatments. Discussion: The lesions in this patient have similar characteristic with heparin-induced skin necrosis and demonstrate thrombocytopenia probably related to heparin. There are some proposed hypotheses of pathophysiology which include hypersensitivity reaction and idiosyncratic dose-related reaction. Given the clinically course, the discontinuation of heparin treatment was essential for lesion regression in addition other supportive measures. Conclusion: Heparin-induced skin lesions may indicate the presence of life-threatening heparin-induced thrombocytopenia. An early diagnosis is crucial to enable discontinuation of heparin if required.

The Mouse Papillomavirus Epigenetic Signature is Characterised by DNA Hypermethylation after Lesion Regression

Papillomaviruses (PVs) are double-stranded DNA tumour viruses that can infect cutaneous and mucosal epidermis. Human papillomavirus (HPV) types have been linked to the causality of cutaneous squamous cell carcinoma (cSCC); however, HPV DNA is not always detected in the resultant tumour. DNA methylation is an epigenetic change that can contribute to carcinogenesis. We hypothesise that the DNA methylation pattern in cells is altered following PV infection. We tested if DNA methylation was altered by PV infection in the mouse papillomavirus (MmuPV1) model. Immunosuppressed mice were infected with MmuPV1 on cutaneous tail skin. Immunosuppression was withdrawn for some mice, causing lesions to spontaneously regress. Reduced representation bisulphite sequencing was carried out on DNA from the actively infected lesions, visibly regressed lesions, and mock-infected control mice. DNA methylation libraries were generated and analysed for differentially methylated regions throughout the genome. The presence of MmuPV1 sequences was also assessed. We identified 834 predominantly differentially hypermethylated fragments in regressed lesions, and no methylation differences in actively infected lesions. The promoter regions of genes associated with tumorigenicity, including the tumour suppressor protein DAPK1 and mismatch repair proteins MSH6 and PAPD7, were hypermethylated. Viral DNA was detected in active lesions and in some lesions that had regressed. This is the first description of the genome-wide DNA methylation landscape for active and regressed MmuPV1 lesions. We propose that the DNA hypermethylation in the regressed lesions that we report here may increase the susceptibility of cells to ultraviolet-induced cSCC.

Uterine Adenomyosis: From Disease Pathogenesis to a New Medical Approach Using GnRH Antagonists

Uterine adenomyosis is a common chronic disorder frequently encountered in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Despite its high prevalence, its etiopathogenesis is not yet fully understood, so there are currently no specific drugs to treat the disease. A number of dysregulated mechanisms are believed to contribute to adenomyosis development and symptoms, including sex steroid signaling, endometrial proliferation and invasiveness, and aberrant immune response. Abnormal sex steroid signaling, particularly hyperestrogenism and subsequent progesterone resistance, are known to play a pivotal role in its pathogenesis, which is why various antiestrogenic agents have been used to manage adenomyosis-related symptoms. Among them, gonadotropin-releasing hormone (GnRH) antagonists are swiftly gaining ground, with recent studies reporting efficient lesion regression and symptom alleviation. The aim of the present review is to compile available information on the pathogenesis of adenomyosis, explore the etiology and mechanisms of hyperestrogenism, and discuss the potential of antiestrogenic therapies for treating the disease and improving patient quality of life.

Bioluminescent imaging in induced mouse models of endometriosis reveals differences in four model variations

Our understanding of the etiology and pathophysiology of endometriosis remains limited. Disease modelling in the field is problematic as many versions of induced mouse models of endometriosis exist. We integrated bioluminescent imaging of ‘lesions’ generated using luciferase-expressing donor mice. We compared longitudinal bioluminescence and histology of lesions, sensory behavior of mice with induced endometriosis and the impact of the GnRH antagonist Cetrorelix on lesion regression and sensory behavior. Four models of endometriosis were tested. We found that the nature of the donor uterine material was a key determinant of how chronic the lesions were as well as their cellular composition. The severity of pain-like behavior also varied across models. Whilst Cetrorelix significantly reduced lesion bioluminescence in all models, it had varying impacts on pain-like behavior. Collectively, our results demonstrate key differences in the progression of the ‘disease’ across different mouse models of endometriosis. We propose that validation and testing in multiple models, each of which may be representative of the different subtypes / heterogeneity observed in women should become a standard approach to discovery science in the field of endometriosis.

The mouse papillomavirus epigenetic signature is characterised by DNA hypermethylation after lesion regression

The β genus of human papillomaviruses (HPVs) infect cutaneous epidermis. They contribute to the development of cutaneous squamous cell carcinoma (cSCC) in individuals with epidermodysplasia verruciformis, and increase susceptibility to UV-induced cSCC. This has been demonstrated in UV-exposed mice previously infected with mouse papillomavirus (MmuPV1). However, the mechanism by which β-HPVs contribute to cSCC is unclear. We propose that viral infection leaves a DNA methylation signature following resolution of the active lesion that may contribute to increased susceptibility to UV-induced cSCC.

Tofacitinib alters STAT3 signaling and leads to endometriosis lesion regression

Endometriosis is a widespread gynecologic condition affecting up to 15% of women of reproductive age. The Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway is upregulated in endometriosis and is a therapeutic target. Here we sought to determine the effect of Tofacitinib, a JAK inhibitor in widespread clinical use, on JAK/STAT signaling in endometriosis and lesion growth. Endometriosis was surgically induced in C57BL/6 mice using homologous uterine horn transplantation. Lesions were allowed to form over 4 weeks followed by Tofacitinib (10 mg/kg) or vehicle administered by oral gavage over 4 weeks. Tofacitinib treatment in vivo led to endometriosis lesion regression and reduced adhesion burden compared to vehicle treatment. In vitro studies on Ishikawa cells showed that Tofacitinib reduced hypoxia-inducible factor 1α and vascular endothelial growth factor mRNA levels at 12 and 24 h. Western blot analysis showed that Tofacitinib effectively reduced STAT3 phosphorylation in Ishikawa cells and human primary stromal and epithelial cells from eutopic endometrium of patients with and without endometriosis. This study suggests that the inhibition of JAK/STAT signaling using Tofacitinib may be a viable method for the treatment of endometriosis.

Photodynamic Therapy as an adjunct in the Treatment of Medication-Related Osteonecrosis of the Jaw: A Case Report

Introduction: Medication-related osteonecrosis of the jaw (MRONJ) corresponds to an adverse effect of the use of drugs such as bisphosphonates and denosumab. This condition is often associated with pain, infection, purulent secretion, paraesthesia, tooth mobility and halitosis, decreasing the patient’s quality of life. The management of MRONJ tends to be conservative, through the guidance of oral hygiene, antibiotic therapy and mouthwashes. However, the use of antimicrobial photodynamic therapy (aPDT) has shown promise in the treatment of these injuries. The purpose of this article is to report a case of MRONJ treatment associated with aPDT. Case Report: A 75-year-old patient, with a history of breast cancer and use of intravenous Zoledronic Acid, presented with bilateral MRONJ lesions in tuberosity on the right and left sides. Treatment was conservatively instituted with the use of aPDT as an adjuvant. After 12 aPDT sessions, complete regression of the lesion was observed. However, after two weeks, the presence of a new lesion was noted, this time in the anterior region of the maxilla. The same protocol previously established was followed and after two aPDT sessions, the patient returned with complete lesion regression. Conclusion: The use of aPDT may represent an important adjuvant within a set of clinical protocols in the treatment of MRONJ.

Efficacy of Platelet Gel in Children with Stomatitis during Chemotherapy

Introduction. Stomatitis (oral mucositis) is a very serious adverse effect of anticancer therapy, and it may exacerbate treatment outcomes as well as prognoses. Stomatitis is associated with pain during chewing and swallowing, causing discomfort and interfering with eating. It can also lead to weight loss and a delay in child growth and development. None of the numerous therapies used for stomatitis management can be considered universal or sufficiently effective. Allogeneic platelet gel, a formulation that adheres closely to mucosal lesions and is rich in growth factors, may be an effective treatment for accelerating the erosion-healing process. Methods. A prospective, open-label study on the efficacy of platelet gel used for the treatment of stomatitis in children during chemotherapy. Platelet gel was applied to oral mucosal lesions four times a day. Results. 28 patients with Grade II and Grade III stomatitis were enrolled in the study. The first day after applying platelet gel, 93% of patients reported relief from pain. Within 4 to 5 days, one degree of mucosal lesion regression was reported in 89% of patients, indicating a 3 to 5 day reduction in therapy compared to our previous experience. In only two patients did we observe mild adverse events in the form of a burning sensation. Conclusion. Platelet gel contributed to both pain reduction and acceleration of the oral mucosa healing process. It is a safe and effective therapy for children with stomatitis induced by chemotherapy.