Methods for preventing and treating cancer using N-thiolated β-lactam compounds and analogs thereof

The subject invention concerns N-thiolated β-lactam compounds of formula A, wherein R1 is a hydrocarbon group having 1–8 carbon atoms; R3 is an organothio group; and R4 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, and analogs and pharmaceutically acceptable salts, esters and amides thereof. The subject invention also concerns methods for inducing tumor cell death or inhibiting tumor cell proliferation, and methods for inducing DNA damage, inhibiting DNA replication, activating p38 MAP kinase, or activating caspase cascade activation, or releasing cytochrome C from mitochondria into the cytoplasm in a tumor cell. Methods for treating cancer using N-thiolated β-lactam compounds, as well as pharmaceutical compositions comprising the same are further disclosed

Оценка социальных потерь здоровья населения, обусловленных промышленным загрязнением атмосферного воздуха выбросами взвешенных частиц (ВЧ10)

International audienceAccording to available estimates, about 3% of lethal outcomes from cardiac-pulmonary pathology and 5% from lung cancer are related to the impact of patriculate matters (PM). In the course of the study there were assessed social losses of population’s health (additional death cases) caused by risk conditions of atmospheric air pollution with PM of various air-dynamic diameter (PM10), proper to emissions of various industrial enterprises. It was established that 90% of population of cities under study live under high exposures (≥50 µg/m3) health and risks for population (IRM=10-3÷10-4), caused by PM10 emissions. Results showed that metallurgical industry is responsible for 7,2 to 2193 additional mortality cases. The impact of machine building enterprises – from 0.06 to 21 cases; coke and chemical – from 1.5 to 36 cases; mining – from 1.1 to 14,6 cases. The findings revealed 0.6 % increase in lifetime mortality for each 10 µg/m3 in 24-hour average PM10 concentration. Based on research outcomes, a set of instruments was developed for implementation of air pollution risk management programs aimed at mitigation of health risks from (PM10) in highly exposed groups.Согласно существующим оценкам, на долю воздействия взвешенных частиц относят около 3% смертей от кардиопульмонарной патологии и 5% смертей от рака легких. В ходе проведения исследований были оценены социальные потери здоровья населения (в виде дополнительных случаев смертей), обусловленные рисковыми условиями загрязнением атмосферного воздуха взвешенными частицами разного аэродинамического диаметра (ВЧ10), которые присущи выбросам разных видов промышленных предприятий. Установлено, что 90% насе­ления исследуемых городов проживает в условиях высоких экспозиций (≥50 мкг/м3) и рисков для здоровья населения (IRМ=10-3÷10-4), обусловленных выбросами ВЧ10. Оценено, что вероятные социальные потери здо­ровья населения от выбросов ВЧ10 разными видами промышленных предприятий составляют для: метал­лургических – от 7,2 до 2193 дополнительных случаев смертей на протяжении жизни; машиностроительных – от 0,06 до 21; коксохимических – от 1,5 до 36; горнорудных – от 1,1 до 14,6. Это позволило установить, что при увеличении среднесуточной концентрации ВЧ10, прирост смертности составляет 0,6% на каждые 10 мкг/м3. Проведенные исследования позволили разработать инструменты для внедрения программ уп­равления риском, обусловленного воздействием высоких экспозиций взвешенных частиц (ВЧ10) на состояние здоровья населения, которое проживает в зонах высокого риска

Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells

Intercellular communication within the bone marrow niche significantly promotes leukemogenesis and provides protection of leukemic cells from therapy. Secreted factors, intercellular transfer of mitochondria and the receptor–ligand interactions have been shown as mediators of this protection. Here we report that tunneling nanotubes (TNTs)—long, thin membranous structures, which have been identified as a novel mode of intercellular cross-talk—are formed in the presence of stroma and mediate transfer of cellular vesicles from stroma to leukemic cells. Importantly, transmission of vesicles via TNTs from stromal cells increases resistance of leukemic cells to the tyrosine kinase inhibitor, imatinib. Using correlative light-electron microscopy and electron tomography we show that stromal TNTs contain vesicles, provide membrane continuity with the cell bodies and can be open-ended. Moreover, trans-SILAC studies to reveal the non-autonomous proteome showed that specific sets of proteins are transferred together with cellular vesicles from stromal to leukemic cells, with a potential role in survival and adaptation. Altogether, our findings provide evidence for the biological role of the TNT-mediated vesicle exchange between stromal and leukemic cells, implicating the direct vesicle and protein transfer in the stroma-provided protection of leukemic cells

Antitumor Activity and Reductive Stress by Platinum(II) N-Heterocyclic Carbenes based on Guanosine**

Funding Information: We thank Fernanda Murtinheira for the support on the autophagy measurements. This work was supported by FCT – Fundação para a Ciência e a Tecnologia, I.P., through MOSTMICRO‐ITQB R&D Unit (UIDB/04612/2020, UIDP/04612/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020). M.I.P.S.L. was supported by fellowships PD/BD/135483/2018 and COVID/BD/152502/2022 from FCT. A.P. acknowledges the contract CEECINST/00102/2018. The NMR spectra were acquired at CERMAX–ITQB, supported by Infrastructure Project No. 022161 (co‐financed by FEDER through COMPETE 2020, POCI, PORL and FCT through PIDDAC). C.S.B. Gomes acknowledges the XTAL – Macromolecular Crystallography group for granting access to the X‐ray diffractometer. X‐ray infrastructure financed by FCT‐MCTES through project RECI/BBBBEP/0124/2012. FH was supported by Centre grants from FCT to the BioISI Research Unit (Refs. UIDB/04046/2020 and UIDP/04046/2020) and the Microscopy facility at FCUL (as a node of the Portuguese Platform of BioImaging, reference PPBI‐POCI‐01‐0145‐FEDER‐022122), and by individual grants through FCT (Ref. PTDC/FIS‐MAC/2741/2021) and the ARSACS Foundation (Canada). Maria Turos‐Cabal was supported by fellowship from the Spanish Association Against Cancer (AECC, SV‐19‐AECC‐FPI) and the Consejería de Economía y Empleo del Principado de Asturias (FICYT, Severo‐Ochoa BP20‐073). Publisher Copyright: © 2023 Wiley-VCH GmbH.Platinum(II) complexes bearing N-heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C−H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co-ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non-cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV-4-11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non-cancer cell line HEK-293.preprintinpres

3-(2,4-Dichloro­phen­oxy)-1-(4-meth­oxy­phen­yl)-4-(3-nitro­phen­yl)azetidin-2-one

In the title compound, C22H16Cl2N2O5, the nearly planar four-membered β-lactam ring [maximum deviations of 0.011 (2) for the N atom] makes dihedral angles of 68.34 (13), 83.04 (13) and 3.37 (13)° with the dichloro-, nitro- and meth­oxy­phenyl rings, respectively. The crystal structure is stabilized by C—H⋯O hydrogen-bond inter­actions. In addition, a π–π stacking inter­action [centroid–centroid distance = 3.6622 (12) Å] is observed between the β-lactam and nitro­phenyl rings

Pothole Prevention and Innovative Repair

Pothole repairs continue to be a major maintenance problem for many highway agencies. There is a critical need for finding long-lasting, cost-effective materials and construction technologies for repairing potholes. This research effort investigates critical components associated with pothole formation and pothole repair and proposes solutions to reduce the occurrence of potholes and increase the durability of pothole repairs. The components include investigating and documenting pavement preservation activities, experimental work on traditional repair materials as well as innovative materials and technologies for pothole repairs, stress analysis of pothole repairs to identify whether certain geometric configurations are more beneficial than others, evaluating cost analyses to determine the effectiveness of various repair methods. A number of conclusions and recommendations were made. Potholes are mainly caused by the delayed response to timely fixing common pavement distresses. The state of Minnesota has a number of preservation strategies that are available and have been successfully used. Recommendations are made to improve these strategies using documents made available as part of new Every Day Counts, EDC-4, initiative. Currently, there are no required specifications for patching materials. Mechanical testing can be used to select patching materials based on the estimated durability of the pothole repair, such as short-, medium-, and long-term. A number of new materials and technologies are available for more durable solutions for winter pothole repairs, however, they require additional heat source and are more expensive

4-1BBL-containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells

Chronic and acute myeloid leukemia evade immune system surveillance and induce immunosuppression by expanding proleukemic Foxp31 regulatory T cells (Tregs). High levels of immunosuppressive Tregs predict inferior response to chemotherapy, leukemia relapse, and shorter survival. However, mechanisms that promote Tregs in myeloid leukemias remain largely unexplored. Here, we identify leukemic extracellular vesicles (EVs) as drivers of effector proleukemic Tregs. Using mouse model of leukemia-like disease, we found that Rab27adependent secretion of leukemic EVs promoted leukemia engraftment, which was associated with higher abundance of activated, immunosuppressive Tregs. Leukemic EVs attenuated mTOR-S6 and activated STAT5 signaling, as well as evoked significant transcriptomic changes in Tregs. We further identified specific effector signature of Tregs promoted by leukemic EVs. Leukemic EVs-driven Tregs were characterized by elevated expression of effector/tumor Treg markers CD39, CCR8, CD30, TNFR2, CCR4, TIGIT, and IL21R and included 2 distinct effector Treg (eTreg) subsets: CD301CCR8hiTNFR2hi eTreg1 and CD391TIGIThi eTreg2. Finally, we showed that costimulatory ligand 4-1BBL/CD137L, shuttled by leukemic EVs, promoted suppressive activity and effector phenotype of Tregs by regulating expression of receptors such as CD30 and TNFR2. Collectively, our work highlights the role of leukemic extracellular vesicles in stimulation of immunosuppressive Tregs and leukemia growth. We postulate that targeting of Rab27a-dependent secretion of leukemic EVs may be a viable therapeutic approach in myeloid neoplasms

Monte Carlo simulations of ion channeling in crystals containing dislocations and randomly displaced atoms

N/

Origin and production of silver in early medieval Poland

Modern archaeology makes use of analytical methods in order to answer questions about deposit and technological provenience of artefacts. This paper discusses selected and the most interesting, results obtained during the completion of a research project which focuses on silver from the 10th and 11th centuries in Poland. In total, 200 silver artefacts known from Polish hoards (found in Kalisz-Dobrzec, Nowa Obra, Wolsztyn District, Zalesie, Olsztyn District, Słuszków and Jastrzębniki, Kalisz District, Kalisz-Rajsków and Stojkowo, Kołobrzeg District and Naruszewo, Płońsk District) were studied. A micro-invasion LA-ICP-MS (Laser Inductively Coupled Plasma Mass Spectrometry) was used for determinining lead isotope ratios in silver. The data obtained were evaluated using statistical methods which allowed reliable isotopic ratios in inhomogeneous alloy to be obtained. In order to study the provenance of silver, the obtained lead isotope ratios in the artefacts were compared with those of silver deposits. The use of SEM-EDX allowed the tracing of morphological changes and the measurement of quantitative elemental composition of coins, raw silver and jewellery according to technological traits