The Role of the Mitochondrial Genome in Ageing and Carcinogenesis

Mitochondrial DNA mutations and polymorphisms have been the focus of intensive investigations for well over a decade in an attempt to understand how they affect fundamental processes such as cancer and aging. Initial interest in mutations occurring in mitochondrial DNA of cancer cells diminished when most were found to be the same mutations which occurred during the evolution of human mitochondrial haplogroups. However, increasingly correlations are being found between various mitochondrial haplogroups and susceptibility to cancer or diseases in some cases and successful aging in others

The therapeutic aspects of the endocannabinoid system (ECS) for cancer and their development: from nature to laboratory

The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field

Mucosal melanoma — clinical presentation and treatment based on a case series

Melanoma is malignant disease originating from melanocytes (pigment cells that occur mainly in the skin and constitute a type of defence from ultraviolet radiation). Melanocytes also occur outside of the skin (among others — in the eyeball, the mucosal lining of the digestive tract from the oral cavity to the anus, the nasal cavity and the paranasal sinuses, and the urinary and reproductive tracts). Many known cases of melanoma in the aforementioned locations exist. The main factor responsible for the development of skin melanoma is ultraviolet radiation. In the case of mucosal melanoma, aetiological factors are still unknown. Mucosal melanoma most often develops in places that are hidden and not accessible through standard testing. Therefore, the disease develops without any signs for a long period of time before the proper diagnosis is established (usually at a disseminated stage, at a point where no successful localised treatment can be applied), which, in combination with a more aggressive course in comparison to more typical locations (the skin, the eyeball), a different sensitivity to systemic treatment (usually the lack of a mutation in the BRAF gene), and the lack of a separate standardised treatment procedure, is the cause of worse outcomes and poor prognosis. Mucosal melanomas occur very rarely (about 1.5 % of all melanomas); however, the knowledge that a melanoma may also develop in locations that are often omitted during routine examination (the anus, the oral cavity, the urogenital region), may increase the chances of early diagnosis and attaining better treatment results. In this paper, a brief description of the characteristics of mucosal melanoma is presented, along with a presentation of the most common locations, symptoms, diagnostic possibilities, and available treatment (including immunotherapy). Based on the available literature and personal experience, several cases of patients treated in the Institute of Oncology are described.Czerniak jest nowotworem złośliwym rozwijającym się z melanocytów, które są komórkami barwnikowymi występującymi głównie w skórze i stanowiącymi swoistą ochronę skóry przed promieniowaniem ultrafioletowym. Melanocyty występują również poza skórą (miedzy innymi – gałka oczna, błona śluzowa przewodu pokarmowego od jamy ustnej do odbytu, jamy nosowej i zatok obocznych nosa oraz w drogach moczowo-płciowych. Znane są liczne przypadki, w których czerniak rozwija się w wymienionych lokalizacjach.   Głównym czynnikiem odpowiadającym za rozwój czerniaka skóry jest promieniowanie ultrafioletowe. W przypadkach czerniaków błon śluzowych czynniki etiologiczne nie są nadal poznane. Czerniak błon śluzowych rozwija się najczęściej w miejscach ukrytych i niedostępnych standardowemu badaniu. Choroba rozwija się zatem skrycie przez dłuższy czas zanim zostanie postawione prawidłowe rozpoznanie (zwykle w chwili stadium uogólnienia i braku możliwości zastosowania skutecznego leczenia miejscowego), co w połączeniu z bardziej agresywnym przebiegiem w porównaniu z czerniakami w innej lokalizacji (skóra, gałka oczna) oraz inną wrażliwością na leczenie systemowe (zwykle brak mutacji w genie BRAF) i brakiem odrębnych standardów postępowania jest przyczyną gorszych wyników leczenia i złego rokowania.   Czerniaki błon śluzowych występują bardzo rzadko (około 1,5 % wszystkich czerniaków), jednakże świadomość, że czerniak może rozwinąć się również w lokalizacjach, które nierzadko są pomijane w czasie rutynowego badania lekarskiego (odbyt, jama ustna, okolica urogenitalna), może zwiększyć szanse wczesnego rozpoznania i uzyskania lepszych wyników leczenia.   W niniejszej pracy opisano krótką charakterystykę czerniaków błon śluzowych z przedstawieniem najczęstszych lokalizacji, objawów, możliwości diagnostycznych  oraz dostępnego  leczenia (w tym – immunoterapia).  W oparciu o dostępne piśmiennictwo i własne doświadczenie opisano kilka przypadków chorych leczonych w Centrum Onkologii-Instytucie, w którym pracują autorzy.

Mechanisms of melanoma resistance to treatment with BRAF and MEK inhibitors

Several mechanisms of resistance to inhibition of BRAF activity in melanoma cells have been described so far. Genetic studies have shown that mutations in MEK1 kinase (MAP kinase kinase), which result in constitutive activation of ERK kinase, result in resistance to treatment. Another mechanism of the acquired BRAF inhibition resistance is the accumulation of activating mutations in the NRAS oncogene, which drives the activation of CRAF. This in turn leads to a permanent activation of the signal transduction to MEK and ERK. Another important mechanism of resistance is the formation of variants of the BRAF V600E gene splicing, including variants that lack exons 4 to 8 containing the RAS-binding domain. The presence of the p61 BRAF V600E variant leads to the constitutive ERK signal, which is resistant to RAF inhibition. In addition, treatment resistance is affected by hyperactivation of tyrosine kinase receptors such as platelet-derived factor receptor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and erythropoietin-producing hepatocellular receptors (EPH) – leading to the induction of the 3-phosphoinositol kinase pathway (PI3K) in patients treated with BRAF or MEK inhibitors. Another interesting path of BRAFi/MEKi resistance is over-expression of the epidermal growth factor receptor (EGFR) through ne­gative feedback in patients treated with BRAF inhibitors (BRAFi) – EGFR is not normally expressed in untreated melanomas

The role of octadecanoids and functional mimics in soybean defense responses

Oxylipins of the jasmonate pathway and synthetic functional analogs have been analyzed for their elicitor like activities in an assay based on the induced accumulation of glyceollins, the phytoalexins of soybean (Glycine max L.), in cell suspension cultures of this plant. Jasmonic acid (JA) and its methyl ester showed weak phytoalexininducing activity when compared to an early jasmonate biosynthetic precursor, 12-oxophytodienoic acid (OPDA), as well as to the bacterial phytotoxin coronatine and certain 6-substituted indanoylLisoleucine methyl esters, which all were highly active. Interestingly, different octadecanoids and indanoyl conjugates induced the accumulation of transcripts of various defenserelated genes to different degrees, indicating distinct induction competencies. Therefore, these signaling compounds and mimics were further analyzed for their effects on signal transduction elements, such as the transient enhancement of the cytosolic Ca2+ concentration and MAP kinase activation, which are known to be initiated by a soybean pathogenderived {[}beta]glucan elicitor. In contrast to the {[}beta]glucan elicitor, none of the other compounds tested triggered these early signaling elements. Moreover, endogenous levels of OPDA and JA in soybean cells were shown to be unaffected after treatment with {[}beta]glucans. Thus, OPDA and JA, which are functionally mimicked by coronatine and a variety of 6-substituted derivatives of indanoylLisoleucine methyl ester, represent highly efficient signaling compounds of a lipidbased pathway not deployed in the {[}beta]glucan elicitorinitiated signal transduction

Renin angiotensin system deregulation as renal cancer risk factor (Review)

For numerous years, the non-cardiovascular role of the renin-angiotensin system (RAS) was underestimated, but recent studies have advanced the understanding of its function in various processes, including carcinogenesis. Numerous evidence comes from preclinical and clinical studies on the use of antihypertensive agents targeting the RAS, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers. It has been demonstrated that the use of ACEIs can alter the incidence of renal cell carcinoma (RCC) and may have a positive effect by prolonging patient survival. It has an effect on the complex action of ACEI, resulting in decreased angiotensin II (Ang-II) production and altered levels of bradykinin or Ang 1-7. The present review discusses the existing knowledge on the effects of ACE and its inhibitors on RCC cell lines, xenograft models, and patient survival in clinical studies. A brief introduction to molecular pathways aids in understanding the non-cardiovascular effects of RAS inhibitors and enables the conduction of studies on combined cancer treatment with the application of ACEIs. Recent evidence regarding the treatment of hypertension associated with tyrosine kinase inhibitors, one of the most pronounced and common side effects in modern RCC treatment, are also outlined. Captopril, an ACEI, may be used to lower blood pressure in patients, particularly due to its additional renoprotective actions

Impact of minority concentration on fundamental (H)D ICRF heating performance in JET-ILW

ITER will start its operation with non-activated hydrogen and helium plasmas at a reduced magnetic field of B-0 = 2.65 T. In hydrogen plasmas, the two ion cyclotron resonance frequency (ICRF) heating schemes available for central plasma heating (fundamental H majority and 2nd harmonic He-3 minority ICRF heating) are likely to suffer from relatively low RF wave absorption, as suggested by numerical modelling and confirmed by previous JET experiments conducted in conditions similar to those expected in ITER's initial phase. With He-4 plasmas, the commonly adopted fundamental H minority heating scheme will be used and its performance is expected to be much better. However, one important question that remains to be answered is whether increased levels of hydrogen (due to e. g. H pellet injection) jeopardize the high performance usually observed with this heating scheme, in particular in a full-metal environment. Recent JET experiments performed with the ITER-likewall shed some light onto this question and the main results concerning ICRF heating performance in L-mode discharges are summarized here

Metafizyka w ekologii? Ekosystem jako Złożony System Adaptacyjny

Metaphysics in ecology? Ecosystem as a Complex Adaptive System. The meta- physical exploration regarding the origin and evolution of life is also present in ecology, however, does not refer to individual organisms, but entire ecological systems, such as ecosystems and the biosphere. Ecosystem (the biosphere) can be considered as a Com- plex Adaptive System, consisted of numerous, diverse, and autonomous entities, con- nected by a dense network of interactions. The essential feature of complex systems is the ability to learn and to self-organization, which is a result of adaptation to changes in the environment. Understanding the ecosystem structure and functioning as well as pathways of its evolution is one of the greatest challenges of modern ecology. Ecological studies are often dominated by the reductionist approach, whereby all aspects of life can be explained by physical, chemical, or molecular processes. However, studies on complex systems has shown that the rules describing these systems can not be derived from the basic principles; their behavior defies the basic laws of physics, and in fact is very difficult to predict. Moreover, some aspects of ecology related to the dynamics of living systems violate all the postulates of Newton. Interactions between particular components of a complex ecological systems are asymmetrical, casual, indeterminate, and non-linear. The evolution of the ecosystem can be explained by process ecology that reflects the natural tendency to self-organization of the complex system. The unpredictability of the behavior of complex systems and the inability to provide all the complex ecological processes within the framework of Newtonian dynamics has created a new space in the world that has so far appeared as closed, atomistic and determined. The space in which the reunion between science and faith is becoming increasingly possible.Metafizyczne poszukiwania dotyczące pochodzenia i ewolucji życia są również obecne w ekologii, jednakże odnoszą się nie do pojedynczych organizmów, ale całych systemów ekologicznych, takich jak ekosystem czy biosfera. Ekosystem (biosfe- ra) może być rozważany jako Złożony System Adaptacyjny, na który składają się liczne, różnorodne i autonomiczne jednostki, połączone gęstą siecią interakcji. Istotną cechą złożonych systemów jest zdolność do uczenia się oraz do samoorganizacji, która jest rezultatem adaptowania się do zmian w środowisku. Zrozumienie struktury i funkcjo- nowania ekosystemu oraz ścieżek jego ewolucji stanowi obecnie jedno z największych wyzwań współczesnej ekologii. W badaniach ekologicznych często dominuje podejście redukcjonistyczne, według którego wszystkie aspekty życia można wyjaśnić na poziomie procesów fizycznych i chemicznych bądź molekularnych. Jednakże badania prowadzone nad złożonymi systemami pokazały, że zasady opisujące te układy nie mogą zostać wy- prowadzone z reguł podstawowych, a ich zachowanie wymyka się podstawowym prawom fizyki i jest w rzeczywistości bardzo trudne do przewidzenia. Co więcej, pewne aspekty ekologii związane z dynamiką żywych układów są wręcz pogwałceniem wszystkich postulatów Newtona. Interakcje pomiędzy poszczególnymi komponentami złożonego systemu ekologicznego są asymetryczne, przypadkowe, niezdeterminowane i nieliniowe. Ewolucja ekosystemu może być wytłumaczona poprzez ekologię procesu, odzwiercie- dlającą naturalną tendencję złożonego układu do samoorganizacji. Nieprzewidywalność zachowania złożonych układów oraz niemożność ujęcia wszystkich kompleksowych procesów ekologicznych w ramy dynamiki newtonowskiej stworzyła nową przestrzeń w świecie, który do tej pory jawił się jako zamknięty, atomistyczny i zdeterminowany. Przestrzeń, w której spotkanie pomiędzy nauką a wiarą staje się coraz bardziej możliwe

Epithelioid sarcoma

Epithelioid sarcoma (ES) is a very rare sarcoma characterised by loss of INI-1. Enzinger first described ES in 1970, but the histopathologic differential diagnosis of ES remains challenging. There are two ES subtypes, the classical type with spindle epithelioid to central pseudogranulomatous cells, and the proximal type, which is predominantly composed of epithelioid and rhabdoid cells. ES symptoms and signs are not specific and depend on tumor localization. The only treatment for ES is radical excision with a microscope-radical margin. In general, the best treatment for ES in extremes is radical resecin with a wide margin or amputation with or without lymph node dissection. Surgery may be followed by adjuvant chemotherapy and/or radiation therapy. Referral of patients with ES to a sarcoma centre that offers hypofractionation RT trials and multidisciplinary clinical trials should be considered upfront. Neoadjuvant chemotherapy with ifosfamide and doxorubicin with / or without radiation therapy must be used after multidisciplinary team discussion. On 23 January 2020, the US Food and Drug Administration (FDA) first approved tazemetostat – an inhibitor of zeste homolog 2 Enhancer -  therapy for metastatic ES or locally advanced ES not eligible for radical resection

Influence of waxes remelting used in investment casting on their thermal properties and linear shrinkage

This paper presents the results of thermal properties and linear shrinkage of jewelry waxes utilized in investment casting. Three types of jewelry waxes were cyclically processed (by heating, holding in a molten state and cooling)in the temperature range between 25 and 90 °C for about 7 hours. The samples were tested after 5th, 10th and 15thcycle. The remelting was designed to simulate the process of waxes reusability for production of patterns. Changes in thermal properties of waxes were determined using differential scanning calorimetry (DSC) and linear shrinkage values were specified. The conducted examinations allowed to establish the way of multiple utilization of waxes in producing precise models