Increased risk for thromboembolic events from combination of a gynecologic malignancy with severe acute respiratory syndrome coronavirus 2 infection: a case report.

PURPOSE: During the severe acute respiratory syndrome coronavirus 2 pandemic, several patient groups are at particular risk. Mortality is higher among cancer patients and may be increased further by thromboembolic events, which are more common in coronavirus 2019 patients according to recent publications. We discuss the association of gynecologic malignancies, Severe acute respiratory syndrome coronavirus 2, and thromboembolism by reporting a case study and summarizing available literature. CASE REPORT: A 71-year-old Caucasian patient with ovarian cancer receiving first-line chemotherapy was diagnosed with deep vein thrombosis and pulmonary embolism. Routine screening revealed infection with severe acute respiratory syndrome coronavirus 2 in absence of specific symptoms. After uneventful recovery, oncologic treatment could be continued a few weeks later. METHODS: We performed a systematic review of the literature on PubMed following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The search included articles ahead of print, published between 1 December 2019 and 1 June 2020. Cross-searches were conducted on all relevant articles. RESULTS: We identified five articles meeting the defined criteria, including two retrospective studies, a review, a position paper, as well as a letter to the editor. CONCLUSION: Cancer patients infected with severe acute respiratory syndrome coronavirus 2 have a relatively poor outcome, which may partially be due to a higher rate of thromboembolic events. Thromboprophylaxis is recommended, and scoring systems are helpful in early detection. In cancer patients with severe acute respiratory syndrome coronavirus 2, individual risk for thromboembolic events should be taken into account when considering interruption versus continuation of antitumoral therapy. However, further data and studies are required.

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing.

Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of peripheral sensory nervature, inadequate nutrients and blood tissue supply. The most significant hallmark of chronic wounds is heavily aberrant immune skin function. The immune response in humans relies on a large network of signalling molecules and their interactions. Research studies have reported on the dual role of host defence peptides (HDPs), which are also often called antimicrobial peptides (AMPs). Their duality reflects their potential for acting as antibacterial peptides, and as immunodulators that assist in modulating several biological signalling pathways related to processes such as wound healing, autoimmune disease, and others. HDPs may differentially control gene regulation and alter the behaviour of epithelial and immune cells, resulting in modulation of immune responses. In this review, we shed light on the understanding and most recent advances related to molecular mechanisms and immune modulatory features of host defence peptides in human skin wound healing. Understanding their functional role in skin immunity may further inspire topical treatments for chronic wounds.

Dietary supplementation with sulforaphane ameliorates skin aging through activation of the Keap1-Nrf2 pathway.

Visible impairments in skin appearance, as well as a subtle decline in its functionality at the molecular level, are hallmarks of skin aging. Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-pathway, which is important in controlling inflammation and oxidative stress that occur during aging, can be triggered by sulforaphane (SFN), an isothiocyanate found in plants from the Brassicaceae family. This study aimed to assess the effects of SFN intake on age-related skin alterations. Male C57BL6 young (2 months) and old (21 months) mice were treated for 3 months with SFN diet (442.5 mg per kg) or control diet. The antioxidant capacities of the skin were increased in old SFN-treated animals as measured by mRNA levels of Nrf2 (P<.001) and its target genes NQO1 (P<.001) and HO1 (P<.01). Protein expression for Nrf2 was also increased in old SFN fed animals (P<.01), but not the protein expression of NQO1 or HO1. Additionally, ROS and MMP9 protein levels were significantly decreased (P<.05) in old SFN fed animals. Histopathological analysis confirmed that there was no difference in epidermal thickness in old, when compared to young, SFN treated animals, while the dermal layer thickness was lower in old vs. young, treated animals (P<.05). Moreover, collagen deposition was improved with SFN treatment in young (P<.05) and structurally significantly improved in the old mice (P<.001). SFN dietary supplementation therefore ameliorates skin aging through activation of the Nrf2-pathway.

Improved diabetic wound healing by LFcinB is associated with relevant changes in the skin immune response and microbiota.

Bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory properties; however, the effects on diabetic wound healing remain poorly understood. The wound healing potential of LFcinB was investigated with in vitro, ex vivo, and in vivo models. Cell migration and proliferation were tested on keratinocytes and on porcine ears. A type 1 diabetic mouse model was also used to evaluate wound healing kinetics, bacterial diversity patterns, and the effect of LFcinB on oxidative stress, macrophage phenotype, angiogenesis, and collagen deposition. LFcinB increased keratinocyte migration in vitro (p < 0.05) and ex vivo (p < 0.001) and improved wound healing in diabetic mice (p < 0.05), though not in normoglycemic control mice. In diabetic mouse wounds, LFcinB treatment led to the eradication of Bacillus pumilus, a decrease in Staphylococcus aureus, and an increase in the Staphylococcus xylosus prevalence. LFcinB increased angiogenesis in diabetic mice (p < 0.01), but this was decreased in control mice (p < 0.05). LFcinB improved collagen deposition in both diabetic and control mice (p < 0.05). Both oxidative stress and the M1-to-M2 macrophage ratios were decreased in LFcinB-treated wounds of diabetic animals (p < 0.001 and p < 0.05, respectively) compared with saline, suggesting a downregulation of inflammation in diabetic wounds. In conclusion, LFcinB treatment demonstrated noticeable positive effects on diabetic wound healing.

Tailoring amphotericin B as an ionic liquid: an upfront strategy to potentiate the biological activity of antifungal drugs.

Aspergillus species are the primary cause of invasive aspergillosis, which afflicts hundreds of thousands of patients yearly, with high mortality rates. Amphotericin B is considered the gold standard in antifungal drug therapy, due to its broad-spectrum activity and rarely reported resistance. However, low solubility and permeability, as well as considerable toxicity, challenge its administration. Lipid formulations of amphotericin B have been used to promote its slow release and diminish toxicity, but these are expensive and adverse health effects of their prolonged use have been reported. In the past decades, great interest emerged on converting biologically active molecules into an ionic liquid form to overcome limitations such as low solubility or polymorphisms. In this study, we evaluated the biological activity of novel ionic liquid formulations where the cholinium, cetylpyridinium or trihexyltetradecylphosphonium cations were combined with an anionic form of amphotericin B. We observed that two formulations increased the antifungal activity of the drug, while maintaining its mode of action. Molecular dynamics simulations showed that higher biological activity was due to increased interaction of the ionic liquid with the fungal membrane ergosterol compared with amphotericin B alone. Increased cytotoxicity could also be observed, probably due to greater interaction of the cation with cholesterol, the main sterol in animal cells. Importantly, one formulation also displayed antibacterial activity (dual functionality), likely preserved from the cation. Collectively, the data set ground for the guided development of ionic liquid formulations that could improve the administration, efficacy and safety of antifungal drugs or even the exploitation of their dual functionality.

Mechanistic Actions of microRNAs in Diabetic Wound Healing.

Wound healing is a complex biological process that is impaired under diabetes conditions. Chronic non-healing wounds in diabetes are some of the most expensive healthcare expenditures worldwide. Early diagnosis and efficacious treatment strategies are needed. microRNAs (miRNAs), a class of 18-25 nucleotide long RNAs, are important regulatory molecules involved in gene expression regulation and in the repression of translation, controlling protein expression in health and disease. Recently, miRNAs have emerged as critical players in impaired wound healing and could be targets for potential therapies for non-healing wounds. Here, we review and discuss the mechanistic background of miRNA actions in chronic wounds that can shed the light on their utilization as specific wound healing biomarkers.

Bone health and adherence to vitamin D and calcium therapy in early breast cancer patients on endocrine therapy with aromatase inhibitors.

OBJECTIVES: Randomized trials involving aromatase inhibitors (AIs) in the adjuvant treatment of breast cancer patients have reported increased osteoporosis risk. Bone loss can be reduced with appropriate life style, vitamin D and calcium supplements, and with bisphosphonate therapy. The aim of this analysis was to investigate adherence to vitamin D and calcium in postmenopausal breast cancer patients receiving adjuvant non-steroidal AIs, and oncologists' adherence to the bone health guidelines. MATERIAL AND METHODS: This prospective study included 438 newly diagnosed patients and those who have already been receiving non-steroidal AIs for up to 3.5 years. Median endocrine therapy duration before recruitment in the study was 10.5 months (interquartile 4.8-26.6). RESULTS: Densitometry was performed on 142 patients (32.4%) before initiation of endocrine therapy, and on additional 38 (8.6%) patients at second study visit. Densitometry was not performed on 258 (59%) patients. Vitamin D and calcium were prescribed to 329/438 (75.1%) patients at some point during the study. Patients who took more than 80% of the prescribed dose were considered adherent. Self-reported adherence was 88.4%. Osteoporosis was diagnosed in 24 patients (5.5%) of the total study population, bearing in mind that 258/438 (59%) patients did not have densitometry. Bisphosphonates were prescribed to 54/438 (12.3%) patients, whilst only 19 (35.2%) of those had osteoporosis. CONCLUSION: In this analysis, lack of oncologists' adherence to the bone health guidelines was observed. In addition, a significant proportion of the patients did not adhere to the vitamin D and calcium.

Changes in metabolic profile, iron and ferritin levels during the treatment of metastatic renal cancer - A new potential biomarker?

Metastatic renal cell carcinoma (mRCC) develops in approximately 33% of all renal cancer patients. First line treatment of mRCC includes drugs such as sunitinib, temsirolimus and pazopanib, with overall survival now reaching up to 43,6months in patients with favorable-risk metastatic disease. Several side-effects in mRCC treatment, such as hypothyroidism, can be used as positive prognostic factors and indicate good response to therapy. Hypercholesterolemia and hypertriglyceridemia independent of hypothyroidism are reported as side-effects in temsirolimus treatment and recently in sunitinib treatment, but the exact mechanism and significance of the changes remains elusive. Most likely, metabolic changes are caused by inhibition of mechanistic target of rapamycin (mTOR), a positive target of tumor growth suppression, but also a regulator of iron homeostasis. There are no clinical studies reporting changes in iron and ferritin levels during mRCC biotherapy, but we hypothesize that inhibition of mTOR will also affect iron and ferritin levels. If both lipid and iron changes correlate, there is a high possibility that both changes are primarily caused by mTOR inhibition and the level of change should correlate with the inhibition of mTOR pathway and hence the efficacy of targeted treatment. We lastly hypothesize that mRCC biotherapy causes hypercholesterolemia with a possibly improved cholesterol profile due to increase HDL/LDL ratio, so statins might not have a role as supplementary treatment, whereas a sharp rise in triglyceride levels seems to be the primary target for additional therapy.

Ionic Liquids as Unforeseen Assets to Fight Life-Threatening Mycotic Diseases.

Ionic liquids discovery has celebrated 100 years. They consist solely of ions, one of which is typically organic and asymmetrical. Remarkable physical and chemical properties stirred their use as alternative solvents in many chemical processes. The recent demonstration of their occurrence in nature might boost their interest in biological sciences. In the search of mechanistic understandings of ionic liquids' ecotoxicological impacts in fungi, we have analyzed the proteome, transcriptome, and metabolome responses to this chemical stress. Data illuminated new hypotheses that altered our research path - exploit ionic liquids as tools for the discovery of pathways and metabolites that may impact fungal development and pathogenicity. As we get closer to solve the primary effects of each ionic liquid family and their specific gene targets, the vision of developing antifungal ionic liquids and/or materials, by taking advantage of elegant progresses in this field, might become a reality. Task-designed formulations may improve the performance of conventional antifungal drugs, build functional coatings for reducing allergens production, or aid in the recovery of antifungal plant polymers. The frontier research in this cross-disciplinary field may provide us unforeseen means to address the global concern of mycotic diseases. Pathogenic and opportunistic fungi are responsible for numerous infections, killing annually nearly 1.5 million immunocompromised individuals worldwide, a similar rate to malaria or tuberculosis. This perspective will review our major findings and current hypotheses, contextualizing how they might bring us closer to efficient strategies to prevent and fight mycotic diseases.

[CLINICAL GUIDELINES FOR DIAGNOSIS, TREATMENT AND MONITORING OF PATIENTS WITH INVASIVE BREAST CANCER--CROATIAN ONCOLOGY SOCIETY]. / KLINICKE UPUTE HRVATSKOGA ONKOLOSKOG DRUSTVA ZA DIJAGNOZU, LIJECENJE I PRACENJE BOLESNICA/KA OBOLJELIH OD INVAZIVNOG RAKA DOJKE.

Breast cancer is the most common cancer in women. It can be diagnosed in early stage through screening, early detection and educational programs, and when diagnosed early it can be efficiently treated. Treatment modalities include surgery, chemotherapy, radiotherapy, hormonal therapy and targeted biologic therapy, according to the stage of the disease and patient condition. Treatment decisions should be made after multidisciplinary team discussion. Due to the significance of this disease it is important to define and implement standardized approach for diagnostic, treatment and monitoring algorithm as well. The following text presents the clinical guidelines in order to standardize the procedures and criteria for diagnosis, management, treatment and monitoring of patients with breast cancer in the Republic of Croatia.

EGFR and cyclin D1 in nodular melanoma: correlation with pathohistological parameters and overall survival.

Considering that nodular melanoma (NM) has the potential to show an early distant metastasis, there is an urgent need for the discovery and evaluation of new diagnostic and prognostic biomarkers. We aimed to investigate the protein expression of membrane and nuclear epidermal growth factor receptor (EGFR), cyclin D1, and the corresponding gene status in NM samples and correlate the results obtained with clinicopathological parameters and overall survival of patients. Immunohistochemical and fluorescence in-situ hybridization analyses were carried out on tissue microarrays constructed from 110 NM samples, 30 compound nevi, and 38 dysplastic nevi. NM samples showed 24% strong cyclin D1 and 37% strong Ki67 protein expression compared with 3 and 0% strong cyclin D1 and Ki67 expression in the control group. Membrane EGFR expression was detected in 50% of NM cases, whereas EGFR gene amplification was detected in only 4% of NM cases. Multiple NM samples presented simultaneous membrane and nuclear EGFR expression. We found a negative correlation between tumor thickness and membrane EGFR expression. It was also observed that membrane EGFR 3+ NM samples presented ulceration significantly more often than membrane EGFR-negative (0) NM samples. In univariate analysis, carried out on 44 patients with follow-up data, both nuclear and membrane EGFR overexpression showed a correlation with a shorter overall survival. Nuclear EGFR (++, +++) showed 3.06 and membrane EGFR (2+, 3+) showed 2.76 higher risk of mortality compared with patients with low and negative nuclear and membrane EGFR expression (P<0.05).

[Analysis of sentinel lymph node in early breast cancer patient - Clinical Hospital Center Rijeka]. / Analiza limfnog cvora cuvara u bolesnica s ranim invazivnim rakom dojke - Klinicki bolnicki centar Rijeka.

Sentinel lymph node (SLN) biopsy is an accurate method for the detection of axillary metastases in early breast cancer patients and is of value as a replacement for axillary dissection. However, variations in the methods and protocols used for the pathological evaluation of SLN exist in everyday practice. Therefore, standardization how to detect, dissect, process, stain, assess and report SNL is required in order to stratify patients into adequate prognostic groups. The aim of this study was to present our experience in SLN analysis in patients with early breast cancer and clinical stage T1-2 and N0. In the period between 2003 and 2011, 1071 consecutive patients or 1915 SLN were analyzed. The protocol included intraoperative analysis of histological frozen sections and cytological imprint, followed by analysis of paraffin sections according to the protocol that included sections of whole SLN with the interval of 250 prm. According to the accepted protocol 75% of SLN were negative. The obtained results were correlated with literature data.

Mometasone furoate and nasal vascularisation in allergic patients.

Angiogenesis, the growth and proliferation of new blood vessels, is important in a variety of pathophysiological processes. However the role of angiogenesis in allergic rhinitis has not been well studied. Hence, the aim of this study was to compare the vascularisation of the nasal mucous membrane of non-allergic, non-treated allergic and allergic patients treated with mometasone furoate. A small piece of the nasal mucous membrane was taken from the frontal pole of the lower nasal shell from 90 patients. The patients were divided in three groups, each containing 30 patients. First group of patients (GP1) had a negative inhalatory allergen test, patients in second group (GP2) had positive test but were not under treatment and the third group of patients (GP3) had positive results with the same test and were treated with mometasone furoate for 15 days before analysis. Immunhistochemical staining with anti-CD31 and VEGF-C was performed. Vascular phase was determined by using length density. Differences in expression of CD31 and VEGF-C were compared using one-way ANOVA and Tukey HSD post-hoc tests. Significantly lower values of CD31 and VEGF-C expression were observed in GP1 in compare with GP2 and GP3 (p < 0.001, p = 0.013, resjpectively). In GP3 the microvessel density was significantly lower than in GP2 (p < 0.001), but higher than in GP1. Our results demonstrated that 15-day treatment with mometasone furoate results in a significant reduction of the density of vascular parameters in allergic patients.

[Clinical guidelines for diagnosing, treatment and monitoring patients with testicular cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka testisa Hrvatskoga Onkoloskog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Testicular tumors are the most common solid tumors in men between 15 and 34 years of age. The worldwide incidence of these tumors has doubled in the past 40 years. Germ cell tumors comprise 95% of malignant tumors arising in the testes and they are classified either as seminoma or nonseminoma. Testicular cancers have a high cure rates even in disseminated stage of the disease. The chemotherapy mostly contributed to these results but surgery is an inevitable part of successful treatment. In a significant number of these patients treatment algorithms with minimum side effects are designed with the intention to maintain same cure rates as previously used, more aggressive therapy. The following text presents the clinical guidelines in order to standardize the procedures and criteria for diagnosis, management, treatment and follow-up of patients with testicular cancer in Republic of Croatia.

[Clinical guidelines for diagnosing, treatment and monitoring patients with bladder cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka mokracnog mjehura Hrvatskoga Onkolokog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Urothelial cancer is the most common bladder cancer. Hematuria is the most common presenting symptom in patients with bladder cancer. The most common diagnostics of bladder cancer is performed by transurethral resection of bladder after which pathohistological diagnosis is set. It is necessary to determine whether the cancer penetrated in muscle layer (muscle-invasive cancer) or not (muscle-noninvasive cancer). Decision on therapeutic modality depends on the clinical stage of disease and on prognostic and risk factors. For muscle non-invasive bladder cancer transurethral resection is preferred with or without intravesical instillation of Bacillus Calmette-Guérin (BCG). For invasive cancer the method of choice is radical cystectomy. Radiotherapy is used in radical and palliative purposes. Metastatic disease is most frequently treated by chemotherapy metotrexate/vinblastine/doxorubicine/cisplatin (MVAC) or gemcitabine/cisplatin (GC). The purpose of this article is to present clinical recommendations to set standards of procedures and criteria in diagnostics, treatment and follow up of patients with bladder cancer in the Republic of Croatia.

[Clinical guidelines for diagnosing, treatment and monitoring patients with prostate cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka prostate Hrvatskoga Onkoloskog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Prostate adenocarcinoma is the second most common solid neoplasm in male population in Croatia. It rarely causes symptoms unless it is advanced. The finding of PSA rise is the most common reason for diagnostic workout. Treatment plan is based on TNM classification, Gleason score and PSA. Clinically localized disease is successfully treated by radical prostatectomy or radiotherapy with or without hormonal therapy. Locally advanced disease is treated with radiotherapy and hormonal therapy. Metastatic disease can be controlled for many years by androgen deprivation. For castration resistant disease appropriate treatment is chemotherapy or secondary hormonal therapy. The following paper presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, management, treatment and monitoring of patients with prostate cancer in the Republic of Croatia.

[Clinical recommendations for treating and monitoring patients with renal cancer]. / Klinicke upute za dijagnozu, lijecenje i pracenje bolesnika oboljelih od raka bubrega.

Clear cell renal carcinoma is the most common kidney cancer. It is generally asymptomatic. A small percentage of patients present with hematuria, flank pain and abdominal mass. It is usually detected accidentally during radiologic examination. The diagnosis of kidney cancer is confirmed by pathohistological findings after completion of the diagnostic process. The decision about treatment is made based on clinical assessment of disease stage and other risk factors. Depending on that, treatment options include surgery, and considering high resistance of kidney cancer on chemotherapy and hormone therapy, use of targeted therapies (immunotherapy, tyrosine kinase inhibitors) and palliative radiotherapy. The following text presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, treatment and monitoring of patients with kidney cancer in the Republic of Croatia.

Identification of the C2∏-X2Σ+ band system of AlO in the ultraviolet galvanoluminescence obtained during aluminum anodization.

The first galvanoluminescence spectrum in the ultraviolet region obtained during anodization of high purity aluminum samples annealed at temperature above 525°C is presented. An intense broad peak with the maximum at about 31,900 cm(-1) is assigned to the transitions (some of them heretofore unobserved) between vibrational levels of the C(2)∏→X(2)Σ(+) spectral system of AlO, partly overlapped with the A(2)Σ(+)→X(2)∏ system of OH.

The "round block" surgical technique in the management of multicentric fibroadenomas.

The "round block" surgical technique in the treatment of a female patient with multiple, multicentric fibroadenomas in both breasts is presented. The advantages of this technique for patients with multicentric benign breast lesions are minimal postoperative scar and a favourable aesthetic result. Breast dimensions and the areolar diameter were measured in 203 subjects of Primorsko-Goranska county during examination in the Out-Patient Hospital for Breast Diseases, including the operated patient. Smaller breast dimensions and a larger areolar diameter provide an easier access to any part of the breast due to a smaller distance between the incision and a fibroadenoma and a larger circumference of circular periareolar incision, thus facilitating the surgery. The analysis of average, maximum and minimum values measured shows that the "round block" technique can be performed in all cases of multiple and multicentric fibroadenomas regardless of breast size, areolar diameter and the location of fibroadenoma in the breast.

Ionic liquids: a pathway to environmental acceptability.

Ionic liquids were initially proposed as replacements for conventional organic solvents; however, their chemistry has developed remarkably and offers unexpected opportunities in numerous fields, ranging from electrochemistry to biology. As a consequence of ionic liquids advancing towards potential and actual applications, a comprehensive determination of their environmental, health and safety impact is now required. This critical review aims to present an overview of the current understanding of the toxicity and environmental impact of the principal ionic liquid groups, and highlights some emerging concerns. Each cation type is considered separately, examining the significance of the biological data, and identifying the most critical questions, some yet unresolved. The need for more, and more detailed, studies is highlighted (176 references).