The Roles of ROS in Cancer Heterogeneity and Therapy

Cancer comprises a group of heterogeneous diseases encompassing high rates of morbidity and mortality. Heterogeneity, which is a hallmark of cancer, is one of the main factors related to resistance to chemotherapeutic agents leading to poor prognosis. Heterogeneity is profoundly affected by increasing levels of ROS. Under low concentrations, ROS may function as signaling molecules favoring tumorigenesis and heterogeneity, while under high ROS concentrations, these species may work as cancer modulators due to their deleterious, genotoxic or even proapoptotic effect on cancer cells. This double-edged sword effect represented by ROS relies on their ability to cause genetic and epigenetic modifications in DNA structure. Antitumor therapeutic approaches may use molecules that prevent the ROS formation precluding carcinogenesis or use chemical agents that promote a sudden increase of ROS causing considerable oxidative stress inside tumor mass. Therefore, herein, we review what ROS are and how they are produced in normal and in cancer cells while providing an argumentative discussion about their role in cancer pathophysiology. We also describe the various sources of ROS in cancer and their role in tumor heterogeneity. Further, we also discuss some therapeutic strategies from the current landscape of cancer heterogeneity, ROS modulation, or ROS production

Fumonisin B1-induced oxidative stress in human liver (HepG2) cells – an alternate mechanism of carcinogenesis.

Masters Degree. University of KwaZulu-Natal, Durban.Abstract available in pdf

Osteopontin: Relation between Adipose Tissue and Bone Homeostasis

Osteopontin (OPN) is a multifunctional protein mainly associated with bone metabolism and remodeling. Besides its physiological functions, OPN is implicated in the pathogenesis of a variety of disease states, such as obesity and osteoporosis. Importantly, during the last decades obesity and osteoporosis have become among the main threats to health worldwide. Because OPN is a protein principally expressed in cells with multifaceted effects on bone morphogenesis and remodeling and because it seems to be one of the most overexpressed genes in the adipose tissue of the obese contributing to osteoporosis, this mini review will highlight recent insights about relation between adipose tissue and bone homeostasis

“Finding stability”. Experienced and measured function in patients undergoing surgery for patellar instability

Bakgrunn: Vurdering av knefunksjon er helt sentralt for diagnostikk, behandling og oppfølging av pasienter med ulike kneledds lidelser. Derfor er det behov for gyldige og pålitelige måleverktøy, inkludert pasientrapporterte utfallsmål og funksjonelle tester, for å kunne evaluere behandling og videre veilede pasienter og klinikere i beslutningstagning rundt retur til idrett. I dag mangler det etablerte retningslinjer for hvordan man best vurderer knefunksjon hos pasienter med patellainstabilitet. Derfor er det viktig å utforske hvordan pasientene selv opplever å leve med et ustabilt kneskjell og hvilke funksjonsproblemer de faktisk har. Formål: Å skaffe ny kunnskap om funksjonelle tester som brukes i avgjørelser om pasientene er klar for å returnere til idrett, i tillegg til å oversette og videre undersøke måleegenskapene til Norsk versjon av spørreskjemaet Banff Patellofemoral Instabilitets Instrument 2.0 (BPII 2.0). Videre har vi ønsket å utforske hvordan pasientene selv opplevde å leve med patellainstabilitet både før og etter kirurgi. Metoder: BPII 2.0 ble oversatt til Norsk (BPII 2.0-NO) før måleegenskapene ble undersøkt. Pasienter operert med patella stabiliserende kirurgi fylte ut BPII 2.0-NO, relaterte spørreskjema og gjennomførte funksjonelle tester før inngrepet og/eller seks måneder post operativt. Førsteinntrykk og innholds validitet, intern konsistens, test-retest reliabilitet, målefeil og konstrukt validitet ble undersøkt i studie I. For å undersøke gjennomførbarhet og egnethet av et sett med funksjonelle tester, fylte 78 pasienter fra en overlappende kohort (studie I og II) ut spørreskjema (BPII 2.0, NPI og et prosjektspesifikt aktivitetsskår) før de gjennomførte funksjonelle tester (YBT-LQ, hinketester og isokinetisk styrketest). Pasientene ble klarert for å returner til idrett hvis de passerte følgende kriterier: ≤4 cm sideforskjell i anterior retning og LSI ≥95% i sum skår på YBT-LQ, gjennomsnittlig LSI ≥85% på alle hinketestene og LSI ≥90% i isokinetisk muskelstyrke. For å utforske pasientenes opplevelser med å leve med patellar instabilitet deltok 15 pasienter i en kvalitativ studie. Intervjuene foregikk seks til 12 måneder etter kirurgi og data ble analysert med systematisk tekst kondensering. Resultater: Studie I: BPII 2.0 gav et tilfredsstillende første-inntrykk, hadde god innholds validitet og ingen gulv- eller takeffekt ble funnet. Videre hadde skjemaet svært høy intern konsistens (α 0.95) og test-retest reliabilitet ICC2.1 0.87 (95% KI 0.77-0.93). Målefeilen var lav (SEM 7.1) med en SDCind på 19.7 poeng og SDCgruppe på 2.8. Åtte av ni hypoteser som utgjorde grunnlaget for å bedømme konstrukt validitet ble bekreftet. Studie II: Sekstito pasienter (82%) gjennomførte alle de funksjonelle testene, mens bare elleve (14%) pasienter ble klarert for retur til idrett. Pasienter med bilaterale problemer hadde høyere LSI-skår sammenlignet med de med unilaterale plager, i tillegg presterte de dårligere på det kontralaterale benet. Omfanget av kirurgi (kun MPFL-R versus kombinert kirurgi) predikerte ikke selvrapportert- eller målt funksjon seks måneder etter kirurgi. Videre var det kun normalisert distanse i anterior retning i det involverte (68.5 ± 5,5 vs. 64.2 ± 7.5; P = 0,04) og det kontralaterale beinet (71.5 ± 4.0 vs. 68,0 ± 7.0; P = 0.01) som var påvirket av omfanget av kirurgi. Studie III: Deltakerne ga grundige og detaljerte beskrivelser av sine erfaringer med å leve med patellainstabilitet. Et sentralt funn var den omfattende innvirkningen instabiliteten hadde på deltakernes liv. De beskrev både mental og fysisk påvirkning. Historiene deres viste en konstant frykt for at patella skulle luksere. For flertallet var denne frykten til stede i årevis før operasjon, og noe av denne frykten opphørte ikke etter operasjon. De fire hovedtemaene fra analysene var: frykt for patella dislokasjoner påvirker daglige aktiviteter, 2) tilpasning til unngåelsesatferd, 3) å være annerledes, misforstått og stigmatisert påvirker selvfølelsen og 4) føler seg sterkere, men stoler likevel ikke helt på kneet etter operasjonen. Konklusjoner: BPII 2.0-NO viste gode måleegenskaper. Kombinasjonen av funksjonstester i studie II var gjennomførbar seks måneder etter patella stabiliserende kirurgi, men veldig få klarte testene noe som tyder på at seks måneder er for tidlig for retur til idrett testing. Foreslåtte kriterier og bruk av LSI ser ut til å være uegnet for pasientgruppen. Patellainstabilitet hadde en omfattende innvirkning på deltakernes hverdagsliv, inkludert evnen til å delta i sosiale- og fysiske aktiviteter både før og etter operasjon. Implikasjoner: Det trengs videre undersøkelser av hvilke tester og kriterier klinikere skal bruke for å vurdere om pasientene har tilfredsstillende knefunksjon for å returnere til idrett. Retur til idrett testing seks måneder etter operasjonen er for tidlig for de fleste pasienter. I tillegg bør behandlingen av disse pasientene inneholde økt oppmerksomhet mot uønskede psykologiske effekter som unngåelsesadferd.Background: Assessment of knee function after patellar stabilizing surgery is a central part of rehabilitation. Therefore, there is a need for valid and reliable tools, including both patient reported outcome measures (PROMs) and functional tests to evaluate treatment and to guide clinicians in for example return to sport decisions. Since conventional return to sport (RTS) assessment currently is lacking for patients with PI, it is important to explore how the patients experience living with this disorder and what functional problems they encounter. Purpose: To gain new knowledge about functional tests used to assess readiness for RTS and activities after surgery for PI. To examine the psychometric properties of the Norwegian version of the Banff Patellofemoral Instability Instrument 2.0 (BPII 2.0) and to deepen insights on how the patients themselves experience to live with PI before and after surgery. Methods: The BPII 2.0 was translated into Norwegian (BPII 2.0-NO) before the measurement properties were examined. Patients surgically treated for recurrent PI completed BPII 2.0-NO, related questionnaires and functional tests before and/or six months postoperatively. A sub-group of 50 patients completed the BPII 2.0-NO twice with a two-week interval. We evaluated content validity, internal consistency, test–retest reliability, measurement error and construct validity. To examine feasibility and appropriateness of the functional assessment, 78 patients from an overlapping cohort (Study I and II) completed PROMs (the BPII 2.0, the NPI and the project-specific activity questionnaire) before they underwent functional testing (Y-balance test-lower quarter (YBT-LQ), single-legged hop tests and isokinetic strength tests). RTS clearance criteria were defined as: ≤4 cm YBT-LQ test anterior reach difference between legs, leg symmetry index (LSI) ≥95% in the YBT-LQ composite score, mean sum score LSI ≥85% of all single-leg hop tests and LSI ≥90% in isokinetic quadriceps strength. To explore the experience of living with PI, 15 patients from the same cohort participated in a qualitative study, using semi-structured interviews six to 12 months after surgery. The data were analysed by systematic text condensation. Results: Study I: BPII 2.0-NO demonstrated good face and content validity. No floor or ceiling effects were found, and internal consistency was excellent (α 0.95). Test-retest reliability was high ICC2.1 0.87 (95% CI 0.77-0.93) and measurement error low (SEM 7.1) with an SDCind of 19.7 points and SDCgroup of 2.8. Eight of nine hypothesis about construct validity were confirmed. Study II: Sixty-four patients (82%) were able to complete all functional tests, while only eleven (14%) patients were deemed ready for RTS, passing all return-to-sport clearance criteria. Patients with bilateral problems had higher LSI scores compared to individuals with unilateral instability and demonstrated worse performance in the contralateral leg. The extent of surgery (MPFL-R only versus combined surgery) did not predict self-reported function or functional performance at the follow-up. Further, only normalized anterior reach distance in involved (68.5 ± 5.5 vs 64.2 ± 7.5; P=.04) and contralateral leg (71.5 ± 4.0 vs 68.0 ± 7.0; P=.01) were affected by the extent of surgery, with a minor correlation (-.234, P=.04 and -.208, P=.06). Study III: Participants offered rich and detailed descriptions of the impact and lived experience of PI. A key finding was that PI had a large impact on participants’ lives. It was described to affect their mental as well as physical well-being. Their stories display a constant fear of dislocating the patella and for the majority, this was present for years before treatment was commenced and some fear still remained after surgery. The four major themes that emerged from the data were; fear of patella dislocations governs everyday life activities, 2) adaptation to avoidance behaviour, 3) feeling different, misunderstood, and stigmatized affects self-esteem and 4) feeling stronger, but still not fully confident in the knee after surgery. Conclusion: The BPII 2.0-NO demonstrated good measurement properties. The current combination of functional tests seems feasible to conduct at six months after patellar stabilizing surgery. However, for patients with PI suggested clearance standards and the use of leg-symmetry-index seems inappropriate. PI had a far-reaching impact in participants` everyday life, affecting ability to participate in social life and physical activities both before and after surgery. Implications: Appropriate tests and the level of performance that suggests readiness for RTS after surgery for PI needs further exploration. RTS testing at six months postoperative seems premature, and patients should be informed that they probably cannot expect to return to sports at this timepoint. The overall treatment of patients with PI should incorporate increased attentions towards unwanted psychological issues such as adaptive behaviour and raised awareness of the knee both before and after surgery.Doktorgradsavhandlin

The role of oxidative stress during inflammatory processes

The production of various reactive oxidant species in excess of endogenous antioxidant defense mechanisms promotes the development of a state of oxidative stress, with significant biological consequences. In recent years, evidence has emerged that oxidative stress plays a crucial role in the development and perpetuation of inflammation, and thus contributes to the pathophysiology of a number of debilitating illnesses, such as cardiovascular diseases, diabetes, cancer, or neurodegenerative processes. Oxidants affect all stages of the inflammatory response, including the release by damaged tissues of molecules acting as endogenous danger signals, their sensing by innate immune receptors from the Toll-like (TLRs) and the NOD-like (NLRs) families, and the activation of signaling pathways initiating the adaptive cellular response to such signals. In this article, after summarizing the basic aspects of redox biology and inflammation, we review in detail the current knowledge on the fundamental connections between oxidative stress and inflammatory processes, with a special emphasis on the danger molecule high-mobility group box-1, the TLRs, the NLRP-3 receptor, and the inflammasome, as well as the transcription factor nuclear factor-κ