Razina hemoglobina u odgovoru na preoperativnu kemoiradijaciju u bolesnica s lokalno uznapredovalim rakom vrata maternice

Hemoglobin level is a very important prognostic factor in patients with gynecological carcinomas. Anemia in patients with cervical carcinoma occurs frequently and is due to the aggressive biological potential of a tumor as well as because of the poor response of patients to radiation therapy. Chemoradiation is a standard treatment followed by surgery in patients with locally advanced cervical carcinomas. Good overall results after such treatment, good quality of life, and almost no recidivism have established this method as a treatment of choice for patients with locally advanced cervical carcinomas. Sixty-four female patients with cervical carcinoma underwent neoadjuvant chemoradiation, followed by radical hysterectomy at the Department of Gynecologic Oncology, University Medical Center in Zagreb. The stages of the disease ranged from FIGO stage Ib1 to FIGO stage IIIa. Histopathological findings were squamous cell carcinoma and glandular carcinoma of the cervix. The ECOG performance status was graduated from 0 to 1. Neoadjuvant chemoradiation regimen included cisplatin (40 mg/m² once a week for 4 weeks) with concomitant radiotherapy (40 Gy total pelvic + brach therapy). Furthermore, the time interval between chemoradiation and surgery was evaluated. Response to chemoradiation therapy was observed, and the hemoglobin level and general conditions (according to the ECOG performance status) were evaluated. All the 64 patients had chemoradiation therapy prior to radical surgery. The median dosage at point A was 77.28 Gy and the median duration time of chemoradiation was 34.37 days. The time interval from chemoradiation to radical surgery was approximately 34.4 days. Hemoglobin levels decreased from 120.7 to 108.7 g/l at the end of concomitant chemoradiation. The mean tumor diameter was significantly decreased after neoadjuvant chemoradiation, and we classified the results after chemoradiation therapy as complete remission, partial remission, and stabilization of the disease, according to the WHO response criteria with respect to the size of a residual tumor. After chemoradiation and surgery, the hemoglobin level and long-term survival were evaluated. The correlation between the hemoglobin level and long-term survival after neoadjuvant chemoradiation and radical surgery in patients with different stages of cervical cancer was studied. We found that hemoglobin level could be a prognostic factor, but mostly, along with other prognostic factors, such as ECOG performance status, stage of the disease, dosage at point A, and interval between chemoradiation and surgery. However, we observed that the cellular types of tumor were of no significance.Razina hemoglobina važan je prognostički pokazatelj u odgovoru na zračenje bolesnica s ginekološkim malignomima. Anemija udružena s rakom vrata maternice česta je i pokazatelj je ne samo biološki agresivnijeg tumora već može biti i uzrokom slabijeg odgovora na zračenje. Kemoiradijacija je uobičajeni način liječenja bolesnica s lokalno uznapredovalim rakom vrata maternice s ciljem poboljšanja odgovora na liječenje i preživljenja. Operativni zahvat nakon neoadjuvantne kemoiradijacije smanjuje lokalni recidiv. U Zavodu za ginekološku onkologiju u razdoblju od 1/01 do 12/04 liječene su 64 bolesnice s rakom vrata maternice. Stadij bolesti određivao se prema FIGO-klasifikaciji (od Ib1-IIIa), patohistološki se radilo o pločastom i žljezdanom tipu raka vrata maternice, a opće stanje određivalo se prema ECOG-u (0-1). U svih bolesnica provedeno je vanjsko zračenje zdjelice u dozi od 40 Gy, a potom i unutarnje zračenje, 1 aplikacija LDR s Cezijem 137 u dozi od 35-38 Gy u točku A. Tijekom vanjskog zračenja bolesnice su primale 1x tjedno Cisplatinu u dozi od 40 mg/m2 ukupno 4x kao radiosenzibilizator. Nakon provedenog zračenja bolesnice su operirane (histerektomija s adneksektomijom uz resekciju forniksa vagine, a u nekih bolesnica učinjena je i zdjelična limfadenektomija). Za vrijeme zračenja pratili smo vrijednosti hemoglobina 1x tjedno kao i opće stanje koje smo stupnjevali prema ECOG-u. Sve bolesnice su prije operacije ozračene. Srednja doza u točku A bila je 77,2 Gy, prosječno vrijeme zračenja bilo je 34,37 dana. Vrijeme između završetka zračenja i operacije iznosilo je 34,4 dana. Razina hemoglobina i veličina tumora znatno su se smanjivali tijekom kemoiradijacije. Procjenu odgovora na kemoiradijaciju učinili smo na patohistološkom nalazu uklonjenog vrata maternice prema WHO podjeli kao potpuni odgovor (CR), djelomičan odgovor (PR) te stabilnu bolest (SD). Početna vrijednost hemoglobina te redovito praćenje razine hemoglobina tijekom kemoiradijacije pokazali su kako je veći postotak CR i PR u bolesnica s višim vrijednostima hemoglobina (>120 mg/L nasuprot <100 mg/L). Bazalne i kontrolne vrijednosti hemoglobina u bolesnica s lokalno uznapredovalim rakom vrata maternice koje su liječene kemoiradijacijom i operacijom pokazale su se kao dobar prognostički pokazatelj odgovora na primijenjeno liječenje. Ovaj pokazatelj mora se uzeti u obzir s ostalim kao što su: stupanj uznapredovalosti bolesti, histološka diferencijacija i opće stanje bolesnice

Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach

A year after the initial outbreak, the COVID-19 pandemic caused by SARS-CoV-2 virus remains a serious threat to global health, while current treatment options are insufficient to bring major improvements. The aim of this study is to identify repurposable drug candidates with a potential to reverse transcriptomic alterations in the host cells infected by SARS-CoV-2. We have developed a rational computational pipeline to filter publicly available transcriptomic datasets of SARS-CoV-2-infected biosamples based on their responsiveness to the virus, to generate a list of relevant differentially expressed genes, and to identify drug candidates for repurposing using LINCS connectivity map. Pathway enrichment analysis was performed to place the results into biological context. We identified 37 structurally heterogeneous drug candidates and revealed several biological processes as druggable pathways. These pathways include metabolic and biosynthetic processes, cellular developmental processes, immune response and signaling pathways, with steroid metabolic process being targeted by half of the drug candidates. The pipeline developed in this study integrates biological knowledge with rational study design and can be adapted for future more comprehensive studies. Our findings support further investigations of some drugs currently in clinical trials, such as itraconazole and imatinib, and suggest 31 previously unexplored drugs as treatment options for COVID- 19

Modulators of Oxidative Stress: Chemical and Pharmacological Aspects

This is editorial for the book, e. g. special issue of the journal &quot;Antioxidants”.This Special Issue collects seven original research manuscripts and six reviews addressing different pharmacological aspects of the modulation of oxidative stress by natural and synthetic small molecular weight compounds in regard to various therapeutic approaches in cardiovascular and neurodegenerative diseases, cancer and diabetes. Understanding the relationship between oxidative stress and underlying anti- and pro-oxidant mechanisms is crucial to understand mechanisms of diseases and also for the discovery and development of innovative, targeted therapeutic strategies

Involvement of NRF2 in Breast Cancer and Possible Therapeutical Role of Polyphenols and Melatonin

Abstract Oxidative stress is defined as a disturbance in the prooxidant/antioxidant balance in favor of the former and a loss of control over redox signaling processes, leading to potential biomolecular damage. It is involved in the etiology of many diseases, varying from diabetes to neurodegenerative diseases and cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor and reported as one of the most important oxidative stress regulators. Due to its regulatory role in the expression of numerous cytoprotective genes involved in the antioxidant and anti-inflammatory responses, the modulation of NRF2 seems to be a promising approach in the prevention and treatment of cancer. Breast cancer is the prevalent type of tumor in women and is the leading cause of death among female cancers. Oxidative stress-related mechanisms are known to be involved in breast cancer, and therefore, NRF2 is considered to be beneficial in its prevention. However, its overactivation may lead to a negative clinical impact on breast cancer therapy by causing chemoresistance. Some known “oxidative stress modulators”, such as melatonin and polyphenols, are suggested to play an important role in the prevention and treatment of cancer, where the activation of NRF2 is reported as a possible underlying mechanism. In the present review, the potential involvement of oxidative stress and NRF2 in breast cancer will be reviewed, and the role of the NRF2 modulators—namely, polyphenols and melatonin—in the treatment of breast cancer will be discussed

Ovarian Cancer: PCD and Brain Metastases

Paraneoplastic cerebellar degeneration (PCD), the one of the most common paraneoplastic syndromes, refer to clinical disorders associated mostly with lung, ovarian and breast cancer, but not directly caused by the cancer or its metastases. Pathologic finding is an extensive loss of Purkinje cells in the cerebellum. Immunohistocemicaly, the auto-antibodies on the Purkinje cells had been detected. Clinically, PCD is characterized by sub-acutely evolving pancerebellar symptoms. Neurological dysfunction may appear before the detection of the underlying cancer. Therefore, the surgical exploration is necessary for the final diagnosis. The patient undergoes specific therapy. Soon, neurological status of the patient gets irreparable worse. Death come usually 2–3 years after the first symptoms of the PCD occurs. Case of a 63-years old woman with PCD as the first evidence of her cancer is reported. The patient developed brain metastases and died almost 3 years after the first symptoms of PCD occur

Green One-Pot Synthesis of Coumarin-Hydroxybenzohydrazide Hybrids and Their Antioxidant Potency

Compounds from the plant world that possess antioxidant abilities are of special importance for the food and pharmaceutical industry. Coumarins are a large, widely distributed group of natural compounds, usually found in plants, often with good antioxidant capacity. The coumarin-hydroxybenzohydrazide derivatives were synthesized using a green, one-pot protocol. This procedure includes the use of an environmentally benign mixture (vinegar and ethanol) as a catalyst and solvent, as well as very easy isolation of the desired products. The obtained compounds were structurally characterized by IR and NMR spectroscopy. The purity of all compounds was determined by HPLC and by elemental microanalysis. In addition, these compounds were evaluated for their in vitro antioxidant activity. Mechanisms of antioxidative activity were theoretically investigated by the density functional theory approach and the calculated values of various thermodynamic parameters, such as bond dissociation enthalpy, proton affinity, frontier molecular orbitals, and ionization potential. In silico calculations indicated that hydrogen atom transfer and sequential proton loss–electron transfer reaction mechanisms are probable, in non-polar and polar solvents respectively. Additionally, it was found that the single- electron transfer followed by proton transfer was not an operative mechanism in either solvent. The conducted tests indicate the excellent antioxidant activity, as well as the low potential toxicity, of the investigated compounds, which makes them good candidates for potential use in food chemistry