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Средновековната црква, лоцирана е во подножјето на археолошкиот “Цареви Кули” Струмица, на околу 200 м североисточно од фортификацијата. Црквата претставува дел од урбаното јадро на средновековна Струмица, изградена покрај една од комуникациите кои воделе до тврдината “Цареви Кули”. Во трудот ќе бидат презентирани, резултати од археолошките истражувања, изведени во 2015 и 2016 година и конзерваторско реставраторски работи кои започнаа во 2021 година.

11516 Background: In a phase III trial, GD had similar response and survival rates to doxorubicin when administered as first-line therapy to advanced STS pts. G and D have each demonstrated synergy with PD-1 blockade in pre-clinical or clinical studies. We hypothesized that GD plus R would be safe, tolerable, and have synergistic activity in STS. Methods: This is an ongoing open-label, single-center, phase I/II trial of R (INCMGA00012) combined with GD in pts with treatment-naïve unresectable or metastatic high-grade STS. Herein, we report the phase I results, which included a safety run-in followed by a 3+3 dose de-escalation design. G (900 mg/m2) was administered on days 1 and 8 and D (75 mg/m2) on day 8, in 21-day cycles. R (210 mg IV flat dose on the run-in portion and 375 mg on the dose de-escalation portion) was administered on day 1 of each cycle starting in cycle 2 and continued as monotherapy after completion of 6 cycles of GD. The primary endpoint of the phase I was to determine the recommended phase 2 dose (RP2D) of R plus GD. Secondary endpoints included describing the safety, assessing best overall response rate (ORR) by RECIST 1.1, disease control rate (DCR), and progression-free survival (PFS). Results: Thirteen pts were treated, 7on the run-in and 6 on the de-escalation portion. One pt progressed prior to starting R and was replaced. Median pt age was 53 (range 28 – 74) and 7 were female. Histologies included leiomyosarcoma (n = 6), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (2), pleomorphic liposarcoma (1), angiosarcoma (1), and myxofibrosarcoma (1). The Table lists treatment-related adverse events (TRAEs) that occurred in ≥ 20% pts in descending order of frequency. Additional Grade (Gr) 3 TRAEs occurring in 1 pt each, included: infusion reaction, leukopenia, anorectal infection, neutropenia, and pyelonephritis. Gr 3 pyelonephritis was the only dose-limiting toxicity. There were no Gr ≥ 4 TRAEs. One pt (Gr 3 elevated AST/ALT) required corticosteroids and cessation of study therapy. The RP2D was determined to be 375 mg of R plus GD. Twelve pts were evaluable for response. ORR was 17% (1 of 6; 95% CI 1 - 64%) and 50% (3 of 6; 95% CI 19% - 81%) in the run-in and de-escalation cohorts, respectively. DCR was 100% (6 of 6; 95% CI 52 - 100%) and 83% (5 of 6; 95% CI: 36 - 99%). PFS rates at 24 weeks were 60% (95% CI: 29 - 100%) and 44% (95% CI: 17 - 100%). Conclusions: R plus GD was generally safe and well tolerated with no unexpected safety signals to date. The phase II portion evaluating efficacy of R plus GD at the RP2D is ongoing. Clinical trial information: NCT04577014. [Table: see text]

TPS11588 Background: New treatment options are needed for sarcomas. Pazopanib is the only targeted agent approved for multiple soft tissue sarcoma (STS) subtypes with a response rate of 6% and a PFS of 4.6 months. Immunotherapy has a limited role in STS, as the SARC028 study of pembrolizumab demonstrated an overall response rate of 18%, with the highest response rate seen in the undifferentiated pleomorphic sarcoma (UPS) cohort at 23%. Lenvatinib is an oral, multi-tyrosine kinase inhibitor approved for the treatment of multiple cancer types including progressive, radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma with inhibitory activity against the receptor tyrosine kinases VEGFR 1-3, FGFR 1-3, KIT, PDGFR alpha/beta, and RET. Early outcomes with the combination of lenvatinib and pembrolizumab suggest that this regimen could be broadly superior to PD-1 targeting alone for several tumor types as high rates of objective response have been noted. The rationale for this study is based on preclinical work demonstrating the immunosuppressive effects of VEGF in the tumor immune microenvironment including inhibition of dendritic cell maturation, recruitment of immunosuppressive Tregs, MDSCs and TAMs and up-regulation of PD-1 on CD8+ cells. Methods: This is a pilot study evaluating the efficacy of lenvatinib and pembrolizumab in the treatment of select metastatic and/or unresectable sarcomas. Patients will be enrolled in one of five cohorts: Cohort A: leiomyosarcoma; Cohort B: UPS; Cohort C: vascular sarcomas (including angiosarcoma and epithelioid hemangioendothelioma); Cohort D: synovial sarcoma and malignant peripheral nerve sheath tumor; and Cohort E: bone sarcomas (limited to osteosarcoma and chondrosarcoma). Eligible patients should have had at least one prior therapy for unresectable and/or metastatic disease, but no more than three prior lines of therapy. Prior treatment with angiogenesis inhibitors or immunotherapy is excluded. Archival tissue is required for eligibility. Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily which will be continued daily thereafter. Subsequently, they will start pembrolizumab 200 mg intravenously every 21 days. The primary endpoint for each cohort is best overall response rate documented by RECIST v1.1 Criteria at 27 weeks. A sample size of 10 patients is planned for each of the five histological cohorts. If 2 or more confirmed responses are observed among the 10 patients in an arm, the drug combination will be considered positive and worthy of further investigation for that arm. Secondary endpoints are PFS, OS, duration of response and safety/tolerability of the combination. On-treatment biopsy and blood samples will be required for correlative assessments. Accrual in all cohorts is ongoing. Clinical trial information: NCT04784247.

11510 Background: Response to checkpoint inhibition (CPI) in sarcoma is overall low and varies between and within subtypes. Understanding tumor intrinsic determinants of this response may improve efficacy and patient selection. The de-repression of transposable elements (TEs), which are epigenetically silenced repetitive DNA elements of viral origin, is linked to anti-tumor immunity through an antiviral inflammatory response. We hypothesize that baseline expression of TEs and epigenetic regulators correlates with overall response rate (ORR) in sarcoma CPI clinical trials. Methods: This is a retrospective analysis of bulk RNA-sequencing data from pre-treatment biopsies of patients on CPI trials in sarcoma (pembrolizumab plus talimogene laherparepvec, nivolumab plus bempegaldesleukin, and pembrolizumab plus epacadostat). Sixty-seven samples from unique patients representing 12 subtypes were analyzed. The MCP counter deconvolution method and unsupervised clustering were used to group samples by immune phenotypes resulting in immune ‘hot’ and ‘cold’ clusters. ORR was defined by RECIST. To determine if baseline expression of TEs and epigenetic regulators significantly predicted immune types, we implemented a lasso penalized logistic regression. Results: Immune ‘hot’ tumors were characterized by increased immune infiltrates including CD8+ T-cells, B-cells, and NK cells vs ‘cold’ tumors. Patients with ‘hot’ vs ‘cold’ tumors had an ORR of 30.5% (11/36) vs. 3.2% (1/31) (p = 0.003; chi-squared). The best predictors of ‘hot vs ‘cold’ was the increased expression of multiple TE families including MER45A, MER57F, and LTR21B (respective lasso coefficients, 0.27, 0.07, and 0.07). Expression of IKZF1, a chromatin-interacting transcription factor, was also predictive (lasso coefficient, 0.35) and increased expression correlated with improved ORR (p = 0.003; unpaired t-test). TE and IKFZ1 expression was significantly correlated with CD8+ T-cell signaling and antiviral response pathways such as cGAS-STING (MER57F, r2= 0.43, padj = 1.75E-4; IKZF1, r2= 0.63, padj = 6.28E-9) and type II interferon (MER57F, r2= 0.67, padj = 2.51E-10; IKZF1, r2= 0.60, padj = 7.19E-8). Increased expression of cGAS-STING (p = 3.9E-4; unpaired t-test) and type II interferon pathways (p = 1.89E-10; unpaired t-test) was significant in ‘hot’ tumors. Conclusions: Immune ‘hot’ baseline immune profiles of sarcoma are associated with improved ORR to CPI and with increased expression of TEs and IKZF1. These differences in gene expression correlate with increased inflammatory signaling, which suggests a response to TE-encoded viral-like sequences that are typically epigenetically silenced. Induction of TE de-repression and IKZF1 expression through epigenetic targeting warrants pre-clinical investigation as a strategy to promote CPI response in sarcomas.

11503 Background: Prexasertib (PRX) is an inhibitor of CHK1, prevents DNA repair leading to mitotic catastrophe, and can enhance the activity of DNA-damaging chemotherapy. Translocation driven sarcomas exhibit high levels of replication stress and have demonstrated susceptibility to CHK1 inhibition in preclinical models. Desmoplastic small round cell tumor (DSRCT) and rhabdomyosarcoma (RMS) are aggressive sarcomas of children, adolescents and young adults for which novel therapies are urgently required. Methods: We conducted a phase I/II trial of PRX with irinotecan (irino) in patients ≥ 12 months of age with relapsed or refractory DSRCT or RMS. Eligible patients could have any number of prior therapies, including irino. Dose level 1 was PRX 80 mg/m2 on day 1 + irino 20 mg/m2 for 10 days. Dose levels 2 and 2A were PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 10 (level 2) or 5 (level 2A) days. All cycles were 21 days. The primary objectives were to determine the RP2D of PRX with irino, and to determine the best overall response rate (ORR) in 6 months at the RP2D (RECIST v1.1) in DSRCT, with 3 or more responses out of 16 considered promising. Results: 21 patients were enrolled (DSRCT: 19; 2 RMS:2). The RP2D was dose level 2A. Treatment was well tolerated with the most common adverse events being neutropenia (48%), nausea (48%), and fatigue (52%). Cytopenias were managed with the aid of growth factor support in all patients once the RP2D was established. The DSRCT expansion enrolled 13 of 16 planned patients due to discontinuation of PRX supply prior to study completion. Four patients remain on therapy at the time of this submission. Responses in DSRCT patients at all dose levels are shown in Table. Sixteen of 21 enrolled patients, and 5 of 6 patients achieving PR had previously received irino. The median (range) number of cycles was 7 (2-26). Both RMS patients treated at the RP2D experienced SD as best response. The estimated ORR at the RP2D was 23%, and lower boundary of the one-sided 90% confidence interval was 9%, exceeding the unpromising rate of 5%. The two-sided 90% confidence interval was 7 to 49%. In addition, 3 patients had a PR at doses lower than the RP2D, bringing the ORR for all dose levels (n = 19) to 32% (90%CI: 15 to 53%). Conclusions: The RP2D of PRX in combination with irino is PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 5 days in 21 day cycles with myelosuppression successfully managed with growth factor support. The study met its primary objective to consider PRX + irino promising in DSRCT and should be further investigated. Clinical trial information: NCT04095221. [Table: see text]

Die Lebens- und Arbeitswelten in den Langzeitinstitutionen sind im Wandel. Der Wunsch nach Autonomie und persönlicher Entfaltung nimmt stetig zu. Die Bedürfnisse der aktuellen und künftiger Generationen fordern Langzeitinstitutionen auf, neue Wege zu finden. Die Heime Kriens AG setzt auf die Ausgestaltung von beweglichen Strukturen und auf eine Alltagsgestaltung, welche lebendig bleibt, Individualität, Mitwirkung und Kreativität zu lässt. Mit dieser Arbeit verfolgt der Autor das Ziel, die agilen Arbeiten im Team genauer zu untersuchen. Er hat sich die Frage gestellt, wie innerhalb einer bestehenden hierarchischen Struktur agile Arbeitsmethoden gestaltet werden können. Zunächst setzt sich der Autor mit den theoretischen Hintergründen zum Wandel der Menschenbilder, Organisationsverständnis, agile Werte, Prinzipien und Methoden auseinander. Mittels Interviews konnte eine Ersterhebung vom Ist-Zustand eruiert werden um anschliessend daraus gezielte Interventionen sowie wichtige Erkenntnisse für den Veränderungsprozess abzuleiten. Ebenfalls wurden im Team zusammen verschiedene Themen anhand der Interviews Auswertung und konkrete Lernsituationen erarbeitet. Diese Arbeit regt zum Nachdenken an, zeigt die Herausforderungen bei der Gestaltung von neuen Arbeitsformen im Heimalltag auf und wie sich die gemeinsame Gestaltung von agilen Arbeiten auf die Motivation der Mitarbeitenden auswirkt., + Code Diss LU: hslusa mas msg + Fussnote: Masterarbeit MAS Management im Sozial- und Gesundheitsbereich, Hochschule Luzern – Soziale Arbeit, 2020 + NL-Code: NLLUHSA202012

PURPOSE To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS). PATIENTS AND METHODS Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score. RESULTS Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; P = .035). Non- BRCA homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; P = .004) compared with BRCA-altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- BRCA homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- BRCA homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; P < .001). High HRD score was not associated with a different PFS or OS. CONCLUSION Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- BRCA gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes.

На територијата на Општина Штип се наоѓаат повеќе христијански верски храмови во кои се изведува богослужба а чија изградба датира од средниот век па се до денешно време. Секако нивното постоење е од големо религискои и културно-историско значење. Но христијанските верски храмови не се имуни на негативни влијанија и последици од елементарните непогоди кои можат да доведат до нивно оштетување или во најлош случај и нивно целосно уништување. Поради тоа неопходна е процена на загрозеноста од елементарни напогоди кај овие верски храмови. Тоа ќе помогне за превземање на потребните мерки и активности за нивна заштита и спасување во случај на појава на некаков вид на елементарна непогода. Клучни зборови: Процена, загрозеност, христијански верски храм, Оштина Штип, елементарни непогоди.

Низ подрачјето на Општина Карбинци постојат повеќе христијански верски храмови. Сите тие покрај религиско имаат и културно-историско значење. Но како останатото материјално добро во општината така и христијанските верски храмови се подложни на негативни влијанија и последици од елементарните непогоди. Овие видови на опасности можат да доведат до нивно оштетување или уништување. Затоа потребна е процена на загрозеноста од елементарни напогоди кај овие верски храмови со цел понатаму да се превземат потребните мерки и активности за нивна заштита и спасување во случај на појава на вакви опасноти.

Whether a refugium, a transit area, or both, the Balkan Peninsula played a crucial role in the population dynamics of Europe during prehistory. However, the Balkans Peninsula is poorly represented in the European archaeological record. This article presents the newly discovered Middle Palaeolithic stone tool assemblage from the Uzun Mera site in the eastern Republic of Macedonia. Following fieldwork that included diverse methods in survey and excavation, as well as techno-economical and taphonomic assessment of the recovered stone tools, Uzun Mera is reported here as a typical Middle Palaeolithic assemblage that follows the pattern of a highly variable Balkan complex. The quality of the raw material reflects a highly selective approach, resulting in relatively low lithological variability where small blocks of raw material used for knapping are still present on site. These results contribute to better understanding the Palaeolithic of the Balkans and inform the population process in a region where little investigation has been previously conducted.

Biofilms are a common and persistent cause of numerous illnesses. Compared to planktonic microbes, biofilm residing cells often demonstrate significant resistance to antimicrobial agents. Thus, methods for dislodging cells from the biofilm may increase the antimicrobial susceptibility of such cells, and serve as a mechanical means of increasing antimicrobial efficacy. Using Aspergillus fumigatus as a model microbe, we magnetically rotate microrods in and around biofilm. We show that such rods can improve the efficacy of antimicrobial Amphotericin B treatments in vitro. This work represents a first step in using kinetic magnetic particle therapy for disrupting fungal biofilms.

Purpose: Dedifferentiated liposarcoma (DDLS), one of the most common and aggressive sarcomas, infrequently responds to chemotherapy. DDLS survival and growth depend on underexpression of C/EBPα, a tumor suppressor and transcriptional regulator controlling adipogenesis. We sought to screen and prioritize candidate drugs that increase C/EBPα expression and may therefore serve as differentiation-based therapies for DDLS. Experimental Design: We screened known bioactive compounds for the ability to restore C/EBPα expression and inhibit proliferation selectively in two DDLS cell lines but not in normal adipose-derived stem cells (ASC). Selected hits' activity was validated, and the mechanism of the most potent, SN-38, was investigated. The in vivo efficacy of irinotecan, the prodrug of SN-38, was evaluated in DDLS xenograft models. Results: Of 3,119 compounds, screen criteria were met by 19. Validation experiments confirmed the DDLS selectivity of deguelin, emetine, and SN-38 and showed that they induce apoptosis in DDLS cells. SN-38 had the lowest IC50 (approximately 10 nmol/L), and its pro-apoptotic effects were countered by knockdown of CEBPA but not of TP53. Irinotecan significantly inhibited tumor growth at well-tolerated doses, induced nuclear expression of C/EBPα, and inhibited HIF1α expression in DDLS patient-derived and cancer cell line xenograft models. In contrast, doxorubicin, the most common treatment for nonresectable DDLS, reduced tumor growth by 30% to 50% at a dose that caused weight loss. Conclusions: This high-content screen revealed potential treatments for DDLS. These include irinotecan, which induces apoptosis of DDLS cells in a C/EBPα-dependent, p53-independent manner, and should be clinically evaluated in patients with advanced DDLS.

Background Patient experience surveys are widely used to capture the patient-reported quality of care and are increasingly being used for formal reporting purposes. There is evidence that certain patient subgroups are less likely to respond to traditional CAHPS surveys. As patient-facing technologies become more common, it is important to examine whether tablet-based patient experience surveys have the potential to promote responses from more diverse populations. Objectives To develop, gain perspectives about, and pilot an English and Spanish low-literacy adaptation of the Consumer Assessment of Healthcare Providers & Systems Clinician & Group Survey (CG-CAHPS) administered on a tablet device at the point of care. Research design Cognitive testing and evaluation of a quality improvement pilot comparing a tablet-based adaptation and traditional paper-based versions of the CG-CAHPS survey. Subjects English-speaking and Spanish-speaking patients receiving primary care in an urban community clinic. Measures To compare the acceptability of low-literacy tablet-based and traditional paper-based patient experience surveys, we examined the concordance of responses between survey modes and preferences for modality, as well as perspectives on usability and reporting care experiences. We examined demographic differences in responses to tablet-based versus mailed surveys from a quality improvement pilot. Results The majority of cognitive interview participants preferred a low-literacy, tablet-based survey over a paper-based survey with traditional wording. In a quality improvement pilot comparing tablet-based administration at the point of care versus mailed surveys, respondents to the tablet-based survey were more likely to be younger and Latino. Conclusions If designed with patient input, tablet-based surveys have the potential to improve the collection of patient experience data among diverse populations.

Во истражувањето претставена е прелиминарната анализа на камената индустрија од палеолитскиот локалитет на отворено Узун Мера, во с. Мустафино, Штипско. Прво, со цел да се разбере интегритетот на збирката камени орудија, беа испитани пост-депозиционите промени на површината на материјалот во однос со суровината и стратиграфската позиција. Покрај останатите, како најдоминантни типови на површинска промена на материјалот се истакнуваат физичкото оштетување на рабовите и сјајната (глос) патина. Исто така, извршена беше техно-типолошка класификација на орудијата со цел да се разбере управувањето со литичките ресурси на локално ниво, како и за компарација на артефактите со други гранични региони. Орудијата упатуваат на типична среднопалеолитска разноликост на камената индустријата, но присутни се и нетипични форми со несигурна хронолошка припадност. Како дополнување на техно-типолошката анализа беа испитани пост-депозиционите површински промени на материјалот, кои соодветно поделени и квантификувани можат да бидат солидна поткерпа при дефинирањето на различни периоди на употреба на материјалот. Анализираниот материјал потекнува од рекогносцирањата и археолошките ископувања во 2017 и 2018 година.

На целата територија на источните области на Република Македонија, со археолошки истражувања и историски извори, потврдена е само Епископијата на градот Баргала. Покрај епископијата како главно црковно седиште, постоеле и христијански центри со помал ранг од епископијата, кои имаат голема заслуга за ширењето на христијанството и во останатите делови на источните области на Република Македонија. Клучни зборови: Епископски, источни региони, ранохристијански центри, базилики, цркви.

Пештерата Топлата, дел од комплексот Пешти на реката Бабуна кај Велес, за прв пат е идентификувана како потенцијален археолошки локалитет пред 21 година од страна на Љ. Шаламанов-Коробар и нејзиниот тим. Во Јуни 2019, со цел проширување на истражувањата на Палеолитот во Источна и Централна Македонија, беа извршени сондажни ископувања во централниот дел на првата сала на пештерата. Предвидувањата на Коробар дека се работи за пештера со богат седимент, со потенцијални културни остатоци од праисторијата, се покажаа како точни. Само седиментот од Холоцен е со длабочина од приближно 1м и содржи културни слоеви од Енеолитот до ХХ век. Токму остатоците од Енеолитот, содржани во секвенца од три фази, ќе бидат презентирани овде. Прелиминарните согледувања говорат за активности во пештерата во една преодна фаза од Неолитот кон Енеолитот, како и две други фази од раниот Енеолит. Проучената површина е само 4м2, дополнително скратена од седумте средновековни јами. Малото количество на материјал говори за можно вкрстување на влијанија, како од Север и Исток, така и од Пелагонија. Повеќеслојната неолитска населба кај месноста Барутница, с. Амзабегово, Светиниколско, стои во основата на неолитската наука и периодизацијата на Неолитот во Македонија и пошироко. Благодарение на долгата стратиграфија, овој локалитет сведочи за животот на неолитските заедници од појавата на земјоделието, керамиката и перманентни населби, па се до периодот на културно-економска декаденција на овие земјоделци-пионери и појавата на нови вредности, веројатно под влијание на надворешни културни и демографски бранови. Според досегашните измерени апсолутни вредности, локалитетот живее помеѓу 6100 и 5000 години п.н.е. (калибрирани вредности). Целокупното знаење за овој локалитет се должи на ископувањата во 1960 под раководство на Ј. Корошец и С. Саржоски, и особено на ископувањата во 1969-70, во рамките на Југословенско-Американска експедиција, под раководство на М. Гарашанин и М. Гимбутас. Во Септември и Октомври 2019, половина век по последните ископувања, извршивме ревизиони ископувања, со цел да воспоставиме еден современ пристап и перцепција во проучувањето на овој извонредно важен локалитет. Постојат огромен број на прашања во врска со најраните земјоделски и урбани центри во Македонија, кои со примена на современа технологија и научни методи, овој локалитет ќе ни ги одговори. Овде ги претставуваме првите, прелиминарни резултати од новата истражувачка кампања.

Во 2017 година, за потребите на планираниот проект – изградба на карго аеродром во Овче Поле, беше извршена археолошка теренска проспекција на локацијата зафатена со проектот. При тоа беа откриени Палеолитски артефакти (камени орудија) на огромна површина. При понатамошно детално рекогносцирање беа утврдени границите на локалитетот, чија површина надминува 1 км2. Со цел утврдување на стратиграфијата и начинот на настанување на локалитетот, во текот на 2017 и 2018 беа извршени сондажни археолошки ископувања. Со досегашните теренски и кабинетско-лабораториски истражувања, беше потврдена припадноста на локалитетот кон Средниот Палеолит. Евидентирани се сите фази на изработка на камени орудија (јадра, кортикални и некортикални одбитоци и готови орудија), и кај сите нив се присутни атрибути на технологијата на изработка на камени орудија карактеристична за Homo neanderthalensis. Работна хипотеза во однос на настанувањето на овој локалитет е дека станува збор за секундарен депозит, односно во текот на значаен геолошки процес, поголема маса нанос е донесена на оваа локација од блиските ридови. Таа маса вклучува во себе како суровини (вулкански карпи), така и артефакти. Но сеуште целосно не е отфрлена и можноста дека при овој геолошки процес овде се донесени само суровините, додека камените орудија биле изработени на самата локација. Дополнителни гео-морфолошки и физички истражувања ќе дадат одговор на овие прашања. Овде се презентирани сите детаљи од досегашните две сезони на истражување на Узун Мера.

Атриумите во 4 и 5 век на целата територија во источното и западното римско царство, имаат иста улога. Тие претставуваат место од каде тргнува целата поворка кон базиликата, без разлика дали прво тргнува првосвештенството или верниците, и во нив остануваат само непокрстените христијани од каде можат да ја слушаат литургијата. Во 6 век како резултат на се поголемиот број на христијани, улогата на атриумите е променета и тие сега не се место, строго определно само за непокрстените туку и за покрстените христијани од каде можат да ја следат литургијата. На територијата на Р.Македонија, во рамките на археолошките истражувања, атриуми, откриени се во епикоспките центри: Стоби, Хераклеја, Скупи, Лихнид и Баргала.

Almost for all of the Ottoman memorials located in the East region, fires represent a potential danger that would cause their damage or destruction. The exception is those that are ruined and are not subject to assessment of the threat of natural disasters, as well as the Emir Kucuk Sultan's bridge, where only a flood occurs as a potential danger. Other types of natural disasters can't cause damages to this material good. Although such assessments, ie the type of danger and the degree of threat of the monuments are based on the Assessmets of the endangerment of the municipalities in the East region, still require a different concept and approach for all this. This means involvement of institutions and experts from several areas that have direct or indirect links with the protection of the material good in order to carry out detailed analysis that will provide an appropriate assessment of the threat of natural disasters at the monuments of the Ottoman period.This will enable timely and efficient implementation of measures and activities as well as rational utilization of the forces and means for protection and rescue of these monuments.

Рударството како потенцијал извршило силно влијание врз формирањето и развојот на цивилизациското живеење, почнувајќи од најстарите епохи на праисторијата. Во тој контекст посредни и непосредни импулси од таа активност се чуствуваат и во нашите краишта, и покрај тоа што не секогаш постојат експлицитни траги. Имено, тоа може да се следи речиси низ сите периоди на праисторијата, а како аргумент за рударењето и развојот на металургијата најчесто се изнесува фактот за присуството на трагите од материјалната култура, односно квантитот на предмети од метал. Првите поконкретни траги за експлоатацијата на рудните богатства во нашата земја можат да се следат уште од периодот на раната антика, за што покрај конкретните остатоци од згуришта и печки за топење на металите, постојат и пишани податоци преку кои најчесто индиректно може да се согледаат и потврдат активностите поврзани со рударството и металургијата. Сепак, дали поради степенот на истраженост на рударските населби во нашата земја или пак поради фактичките состојби, оваа дејност својот врв или институционализација ја доживува во периодот на римската доминација, особено во периодот на доцната антика. За развојот на оваа дејност во овој период постојат бројни потврди, а како новина е постоењето на рударските утврдувања, како и присуството на помали воени единици коишто биле ангажирани за одржување на безбедноста на рудниците, односно процесот на експлоатација и транспорт на рудата до крајните одредишта.

Реализираните истражувања во периодот 2007-2011 год. ги дополнуваат и делумно ги заокружуваат досегашните сознанија за секторот Епископиум. Со дефинирањето на дел од ново откриените содржини сè поочигледна е и намената на објектите прилепени кај обѕидието на просторот од аголната или кулата 6, па сè до североисточниот влез. Според карактерот на објектите, целиот споменат простор го вбројуваме во стопанско-економски простор кој бил во функција на епископскиот центар. Од досегашните сознанија засновани врз извлечените заклучоци при истражувањето на целиот овој простор видливи се две хронолошки издвоени градежни фази. Клучни зборови: Баргала, епископија, економија, работилница за стакло, лов

11549 Background: Select sarcomas are infiltrated with immunosuppressive myeloid cells. DCC-3014 is an inhibitor of the CSF1R kinase that decreases tumor infiltrating myeloid cells in preclinical models. We hypothesized that DCC-3014 combined with the anti-PDL1 inhibitor avelumab would be safe and tolerable, decrease immunosuppressive myeloid cells, and increase cytotoxic T cells. Methods: This investigator initiated, open label, single center, phase I study of DCC-3014 plus avelumab in patients (pts) with unresectable or metastatic sarcoma utilized a standard 3+3 dose escalation design. DCC-3014 was administered on days 1-3 (loading dose of 20, 30, or 50 mg) followed by oral daily maintenance (10, 14, or 20 mg) in 28-day cycles; 800 mg of IV avelumab was administered q2weeks. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints defined the adverse event (AE) profile and assessed clinical efficacy. Peripheral blood CD14+Lin-HLA-DRlo myeloid-derived suppressor cells (MDSCs) were measured by flow cytometry. Results: 13 pts were treated; median age was 61 (range 32 – 71), 8 were female, and median prior lines of therapy was 5 (range 2 – 10). Histologic subtypes included leiomyosarcoma (LMS, n = 7), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (LPS, 2), synovial sarcoma (1), and pleomorphic LPS (1). The Table lists treatment-related AEs (TRAEs) of any grade (G) occurring in ≥ 10% of pts and all G ≥ 3 TRAEs, sorted by frequency. All pts had at least 1 TRAE. Seven pts (54%) had a G ≥ 3 TRAE. Most TRAEs were either G ≤ 2 or expected on-target effects of CSF1R inhibition. 1 of 6 pts on the highest dose level had a dose limiting toxicity (G4 elevated AST with abdominal pain) that resolved with treatment cessation. The highest dose level was declared the RP2D. Best objective response by RECIST 1.1 was stable disease in 3 pts; 2 had LMS and were treated at the highest dose level. At baseline, the mean proportion of monocytes in peripheral blood samples with an MDSC phenotype was 12.2% (range 7.1 – 19.9). 5 of 7 pts with serial blood samples had decreased circulating MDSCs (mean decrease of 26.9% from baseline to last time point). Conclusions: DCC-3014 combined with avelumab was safe and tolerable. Study therapy decreased circulating MDSCs in select patients; T cell analyses will be reported. Study expansion at the RP2D is ongoing. Clinical trial information: NCT04242238. [Table: see text]

The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and cholesterol trafficking inhibition leads to synergistic inhibition of mTOR, endothelial cell proliferation, and angiogenesis.

e23560 Background: Patients (pts) with synovial sarcoma (SS) and an HLA-A*02 genotype whose tumors express NY-ESO-1 may be eligible for clinical trials of adoptive T cell therapy. We reasoned that a next generation tumor sequencing platform utilizing matched normal DNA (MSK-IMPACT) could accurately identify HLA genotype. Although HLA-A*02 is necessary for some adoptive T cell therapies, the prognosis of this genotype on clinical outcome has not been described in SS. Methods: Pts with metastatic SS who consented to screen for a clinical trial of engineered T cells had high-resolution HLA genotyping performed with a Clinical Laboratory Improvement Amendments (CLIA)-certified test. Where feasible, HLA genotype and loss-of-heterozygosity (LOH) of HLA alleles were determined from IMPACT samples. Overall survival (OS) was estimated in three overlapping cohorts and stratified by HLA-A*02 status: pts treated with anthracyclines or alkylators in the first line, pazopanib in the second line or beyond, and all pts from time of metastasis. Results: 66 pts with SS were screened, but not treated with T cells; 30% (n = 20) were HLA-A*02-positive on a CLIA-certified outside test. 23 pts had HLA genotyping both by IMPACT and an outside laboratory, 22 (96%) of whom had concordant results. 3 pts had LOH of at least 1 HLA allele, including one with LOH of HLA*02:01 in the primary tumor. Among pts treated chemotherapy (n = 36) or pazopanib (n = 37), OS did not significantly differ between HLA-A*02-positive or negative pts. Univariable analyses of OS from the time of metastasis in the whole cohort identified primary tumor size and time to metastasis as variables significantly associated with outcome (hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.123 – 1.345 [P < 0.001] and HR 0.99, 95% CI 0.976 – 0.999 [P = 0.032], respectively). HLA-A*02-positive status and age did not reach the significance threshold (HR 1.95, 95% CI 0.995 – 3.813 [P = 0.052] and HR 1.021, 95% CI 0.999 – 1.044 [P = 0.061], respectively). Multivariable analysis found older age and larger tumor size were independently associated with significantly shorter OS (HR 1.03, 95% CI 1.002 – 1.049 [P = 0.037] and HR 1.2, 95% CI 1.127 – 1.37 [P < 0.001], respectively). Conclusions: Targeted exome panels like IMPACT that utilize matched tumor-normal DNA may accurately identify HLA genotype. Detection of LOH at HLA loci may identify a subgroup of pts who would be refractory to treatment with HLA-A*02-restricted engineered T cells. HLA-A*02 status was not associated with a statistically significant survival difference in pts with metastatic SS.

11508 Background: ETV1 and KIT are lineage-specific master transcriptional and signaling survival factors in GIST. In preclinical models, dual lineage targeting of ETV1 by MEK inhibition with BINI and KIT by imatinib are synergistic in suppressing GIST tumorigenesis and progression. This single-arm phase II study is designed to test the efficacy of the BINI+imatinib as a first-line treatment in patients (pts) with advanced GIST. Methods: Adult pts with untreated advanced GIST received imatinib (400mg daily) plus BINI (30mg twice daily), 28-day cycles. The primary endpoint (EP) was RECIST1.1 objective response rate (ORR) (complete response [CR]+partial response [PR]). The study was designed to detect a 20% improvement in the ORR of imatinib alone (unacceptable rate of 45%; acceptable rate of 65%). A sample size of 44 patients was required, using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1. Confirmed PR in > 24 pts would be considered positive. Secondary EPs included RR by Choi and EORTC criteria, resectability conversion rate (RCR), progression free survival (PFS), overall survival (OS) and long-term AEs. Correlatives included characterization of tumor genomics by MSK-IMPACT, cfDNA by MSK-ACCESS, ETV1 protein levels and transcriptomes and signaling inhibition. Results: At data cutoff of Jan 31, 2020, 38/39 pts with advanced GIST of all genotypes, including 3 KIT/PDGFRA-wild type GIST pts, were evaluable for primary EP. Median age 60 (range 29-78), 29% female. 26/38 pts with confirmed PR; Best ORR was 68.4% (two-sided 95% CI, 51-83%; one-sided 90% CI, 57-100%). 8/9 pts became resectable after treatment; RCR was 88.9% (95% CI, 52-100%). 13 pts remain on trial (2-159 weeks [wks]). 9 pts discontinued trial due to disease progression (11-159 wks); one pt progressed within 3 months, indicating primary resistance. Grade 3/4 toxicity included CPK elevation (asymptomatic, 61%), neutrophil decrease (11%), maculopapular rash (8%), anemia (8%). No unexpected toxicities observed. Correlation of outcome with MSK-IMPACT, MSK-Access and paired tumor biopsies will be presented. Conclusions: This study met its primary endpoint. BINI plus imatinib is highly effective in treatment-naive advanced GIST, with expected and manageable long-term treatment-associated toxicities. The combination strategy warrants further evaluation in direct comparison with imatinib in the frontline treatment of GIST. Clinical trial information: NCT01991379 .

Апстракт: Насилството во семејството претставува сложен криминолошки, социолошки, виктимолошки и кривичноправен предизвик на современото општество. Високата зачестеност, сериозните последици, како на непосредните, така и на посредните жртви, тешкотиите при откривањето и процесуирањето на сторителите, прават да оваа појава бара неодложна општествена рекација. Самата проблематика на насилството во семејството упатува на комплексноста и опасноста, и потребата на интердисциплинарно проучување и дејствување на превентивен и репресивен план. Семејното насилство е сложена и повеќестепена условена појава која се развива на различни начини и има различни обележја. Со добро организирање на сите релевантни општествени фактори и нивни пристап во решавањето на овој сложен и тешко воочлив проблем би се намалила појавноста на насилството во семејството. Клучни зборови: семејство, семејни фактори, насилство, семејно насилство

Road communication over the centuries has great significance for the development of cities. Of particular importance for the safety of people and goods transported through the roads are the road stations, which played the role of checkpoints for road protection. In our text, we will try to give a contribution to the study of the ancient road communication in the Republic of Macedonia, for the Astibo-Visianum route, which has not yet been processed.

Атриумите во 4 и 5 век на целата територија во источното и западното римско царство, имаат иста улога. Тие претставуваат место од каде тргнува целата поворка кон базиликата, без разлика дали прво тргнува првосвештенството или верниците, и во нив остануваат само непокрстените христијани од каде можат да ја слушаат литургијата. Во 6 век како резултат на се поголемиот број на христијани, улогата на атриумите е променета и тие сега не се место, строго определно само за непокрстените туку и за покрстените христијани од каде можат да ја следат литургијата. На територијата на Р.Македонија, во рамките на археолошките истражувања, атриуми, откриени се во епикоспките центри: Стоби, Хераклеја, Скупи, Лихнид и Баргала.

Археолошките истражувања во Киселичка Пештера беа реализирани, во рамките на проектот Пајонски утврдувања и населби по долината на река Брегалница. Во пештерата досега не се вршени археолошки истражувања. Во трудот ќе бидат презентирани резултатите од сондажните археолошки истражувања во внатрешноста на пештерата, реализирани во 2017 година. Клучни зборови: пештера, сонда, слој, јама

Во трудот ќе бидат презентирани резултатите од конзерваторско археолошките истражувања во наосот и во нартекстот, како и конзерваторско реставраторските работи, на подот во наосот. Клучни зборови:конзервација, реставрација, наос, нартекст