Combating the Epigenome: Elucidation of Mechanisms Underlying Chemoresistance and Enhancing Tumor Immunogenicity

Chemotherapy and radiation therapy remain the backbone of cancer treatments, and now cancer immunotherapy offers promising new approaches for the treatment of malignancies. One of the major obstacles for chemo-based therapies is acquired chemoresistance. We find Regulator of G-protein signaling protein (RGS10) is an important regulator of cell survival and chemoresistance in ovarian cancer. Our findings further indicate RGS10 transcript expression is suppressed by DNA hypermethylation and histone deacetylation during acquired chemoresistance in ovarian cancer. We identify two important epigenetic regulators, HDAC1 and DNMT1, which exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Inhibition of DNMT1 or HDAC1 significantly increases RGS10 expression and cisplatin-mediated cell death. We further focus on modulation of death receptors in advanced colorectal cancer (CRC) cells. We use a combination treatment of irradiation and proteasome inhibition to further induce activation of tumor-specific immune responses. We investigate the effect of the 26S proteasome inhibitor bortezomib alone or in combination with radiotherapy, on the expression of death receptors in normal colon and in colorectal cancer cell lines. Our results indicate a combination of 26S proteasome inhibition and sub-lethal radiation significantly increases the sensitivity of carcinoma cells to apoptosis. Combination treatment up-regulates cell surface expression of DR4, DR5 and Fas by increasing their transcriptional activation. Thus, the combination treatment enhanced sensitivity to killing through FAS and TRAIL receptors by CD8+ T cells. We further characterized the mechanisms by which radiation controls CRC expression of death receptors. We have shown that sub-lethal irradiation increases expression of our target molecules by enhancing histone acetylation at promoter regions through decreasing binding of HDAC2 and HDAC3, and by DNA hypomethylation, via decreasing binding of DNMT1. In sum, our studies provide insight into the alteration of molecular pathways involved in cancer cell death and survival

Utilizing Ground-Based LIDAR Measurements to Aid Autonomous Airdrop Systems

Uncertainty in atmospheric winds represents one of the primary sources of landing error in airdrop systems. In this work, a ground-based LIDAR system samples the wind field at discrete points above the target and transmits real-time data to approaching autonomous airdrop systems. In simulation and experimentation, the inclusion of a light detection and ranging (LIDAR) system showed a maximum of 40% improvement over unaided autonomous airdrop systems. Wind information nearest ground level has the largest impact on improving accuracy

Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack

Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity

Serum acidic mammalian kinase as a new laboratory test to define subclinical inflammation in Familial Mediterranean fever

Aim: To investigate the relationship between acidic mammalian chitinase (CHIA) level and autoinflammatory diseases, especially in Familial Mediterranean fever. Methods: We first analyzed CHIA expression, methylation in various autoinflammatory diseases, including, SLE (Systemic Lupus Erythematosus), RA (Rheumatoid Arthritis), SJS (Stevens-Johnson syndrome), SSc (Systemic Sclerosis) and T1D (Type 1 diabetes) patients, case-control and correlation between the MEFV and CHIA genes by using bioinformatics tools. We then measured serum CHIA level in ninety individuals; thirty FMF attacks, thirty FMF remissions and thirty healthy control groups. Statistical analysis was used to evaluate the interaction between clinical parameters and serum CHIA level. The potential of serum CHIA level was tested using AUC and ROC analysis. Results: According to our ADEx analysis, we observed high CHIA expression in SLE, RA and T1D patients than in the control group. Moreover, we detected that the methylation level decreased in each disease, especially in the cg17143643 and cg7497781 probes. We also observed a correlation between MEFV and CHIA in these autoinflammatory diseases. According to our ELISA results, we also showed an increased CHIA level in FMF attack and remission as compared to the control group in serum (p <0.001, p =0.007; resp). We further observed a relationship between CHIA level and patients with amyloidosis, attack per month, and neutrophil and WBC levels.  Conclusion: Our primary data suggest that CHIA is related to FMF pathogenesis and can be followed in the subclinical period of the disease

Dizajn interakcija i razvoj web-aplikacije za zaslone osjetljive na dodir

U teorijskom dijelu rada objašnjen je dizajn interakcija kao pojam, primjena i najbolja praksa pri oblikovanju interakcija između korisnika i proizvoda koji se koristi te kako on utječe na korisničko iskustvo. U radu su prezentirani principi te najbolja praksa oblikovanja dizajna za kvalitetno korisničko iskustvo i interakciju s računalnim uređajima, fokusirajući se na korisnička sučelja uređaja sa zaslonom na dodir. Nakon dizajna, istražuje se web tehnologija kao popularni način za razvoj aplikacija zajedno s modernim alatima i programskim rješenjima za razvoj internetskih stranica. Uspoređuju se web-aplikacije s izvornim mobilnim aplikacijama i prezentira se koncept progresivnih web aplikacija. U praktičnom dijelu rada prolazi se kroz proces razvoja interaktivne webaplikacije za uređaj sa zaslonom velikih dimenzija osjetljivim na dodir. Webaplikacija razvijena pomoću React programske biblioteke, primjer je info-kioska na kojem više korisnika može istovremeno otkrivati sadržaj stupajući u interakciju pomoću različitih gesti dodira. Navode se korištene tehnologije i alati, kako je implementiran dizajn korisničkog sučelja te razvoj i implementacija gesti dodirom kao načina za korisničku interakciju manipulacijom elemenata u korisničkom sučelju

THE EFFECT OF DIFFERENT CUTTING TIMES ON THE MACRO MINERAL CONTENT OF ALFALFA (MEDICAGO SATIVA L.) GENOTYPES

This study was conducted to determine the effect of different cutting times on the important macro mineral contents of twenty-four alfalfa (Medicago sativa L.) genotypes. For this reason, a field trial was established according to separated plots in randomized blocks design with three replications in the Research Area of Agriculture Faculty of Dicle University, Diyarbakır, Turkey in 2020. The alfalfa genotypes were subjected to three different forage cutting times. The 1st, 2nd and 3rd cuttings were made respectively in the pre-flowering, 10% flowering and full flowering periods of alfalfa genotypes. In terms of all examined macro minerals in the study, there found to be statistically highly significant (P<0.01) differences between cutting times, genotypes and genotypes × cutting times interaction. In the research, the macro mineral contents of the genotypes changed between the cutting times as follows; calcium (Ca) 1.41%-1.81%, phosphorus (P) 0.37%-0.50%, magnesium (Mg) 0.31%-0.42% and potassium (K) 1.94%-3.42%. The results of the research revealed that Ca and Mg contents in forages of alfalfa genotypes increased with advancing plant maturity stage, whereas K and P contents decreased. In conclusion, according to the average of the cutting times, Resis (22) cultivar came to fore in terms of Ca content, while many genotypes, sharing the same statistical group, were found superior in terms of P, Mg and K contents

Conservative Feminism and its Potential to Interact with, Influence, and Transform Traditional Feminist Identity

The recent emergence of conservative female public figures has posed a challenge to the traditional notion of feminist thought. Although they define their particular form of success in terms of conservative ideology, many of these women operate according to feminist paradigms, and would not even have the opportunity to assume such a public role if it were not for the past feminist breakthroughs that have cleared the way. Their association with feminist logic and adoption of the feminist moniker notwithstanding, these conservative women most often speak out in reaction and opposition to traditional liberal feminist views and activism. Regardless of how the movement is principally defined, there seems to be a developing school of conservative feminist thought; whether or not it constitutes a legitimate movement that may counter or merge with feminism will have implications for the feminist identity and the shaping of various public policies regarding women\u27s interests

Svjedok po čuvenju i dopustivost njegova iskaza u sistemu kaznenog postupka SAD

Svjedok po čuvenju i pitanje dopustivosti njegova iskaza u okviru suđenja predstavlja jedno od, kako se to često navodi u američkoj pravnoj literaturi, najkompliciranijih i najsloženijih pitanja američkog dokaznog prava. Iako je u načelu izvođenje ovog dokaza zabranjeno, zbog njegova negiranja ustavnih odredbi kojima se garantira pravo na konfrontaciju, (suočenje), a prema kojima će: „optuženik uživati prava...da se konfrontira svjedocima optužbe” američko dokazno pravo ipak dozvoljava u jednom broju limitiranih slučajeva određene iznimke te time i njegovu dopustivost u postupku. Procesno-pravni razlozi postojanja navedene zabrane uzimanja iskaza svjedoka po čuvenju proizilaze iz nemogućnosti da se osoba koja je davatelj izvorne izjave podvrgne unakrsnom ispitivanju, čime se onemogućava provjera autentičnosti njenih tvrdnji i kredibilitet svjedoka. Vrhovni je sud SAD-a, međutim, u nekoliko predmeta, utvrdio da u određenim okolnostima nemogućnost, da se osoba koja je davatelj izvorne izjave podvrgne unakrsnom ispitivanju, neće predstavljati i kršenje klauzule konfrontacije što će za posljedicu imati i pravnu valjanost takvog dokaza u postupku. Pored općih razmatranja o zabrani ispitivanja svjedoka po čuvenju u američkom pravu, fokus autora je upravo na analizi iznimki od tog pravila, kao i razloga koji su američki pravni sistem doveli do usvajanja navedenih rješenja. Iako, navedena zabrana, nije našla značajnije mjesto u sistemima kaznenog postupka civilne pravne tradicije, autori su stava da izučavanje mehanizama zabrane saslušanja svjedoka po čuvenju u američkom pravu može biti od značaja za budući razvoj kaznenog procesnog prava zemalja Jugoistočne Evrope naročito, Bosne i Hercegovine, Hrvatske i Srbije. Ovo posebno iz razloga vrlo primjetne sklonosti zakonodavaca u ovim državama da se opredjeljuju za procesna rješenja koje je generiralo običajno pravo nasuprot svom civilno-pravnom naslijeđu