ELEMENTS OF SPACE ORGANIZATION MANAGEMENT OF ENTERPRISES IN THE METAL MATERIALS INDUSTRY

The article has as a starting point the presentation and analysis of the advantages of spatial organization of enterprises, as a management method. Thus, we analyze: creating the optimal conditions for the rhythmic realization of the production process; ensuring greater flexibility in the use of means of production; the possibility of carrying out a maintenance and repair activity of the equipment without disturbing the technological production process; ensuring an efficient management of the production unit. We also analyze, critically and comparatively, the disadvantages of spatial organization, such as: the need for a high qualification of workers; the need for a very high volume of transport and handling; technical quality control is much more complex in the conditions of a diversified production; the production cycle of manufactured products is long.

Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents

There has been accumulating evidence for the clinical benefit of chemoradiation therapy (CRT), whereas mechanisms in CRT-recurrent clones derived from the primary tumor are still elusive. Herein, we identified an aberrant BUB1B/BUBR1 expression in CRT-recurrent clones in bladder cancer (BC) by comprehensive proteomic analysis. CRT-recurrent BC cells exhibited a cell-cycle-independent upregulation of BUB1B/BUBR1 expression rendering an enhanced DNA repair activity in response to DNA double-strand breaks (DSBs). With DNA repair analyses employing the CRISPR/cas9 system, we revealed that cells with aberrant BUB1B/BUBR1 expression dominantly exploit mutagenic nonhomologous end joining (NHEJ). We further found that phosphorylated ATM interacts with BUB1B/BUBR1 after ionizing radiation (IR) treatment, and the resistance to DSBs by increased BUB1B/BUBR1 depends on the functional ATM. In vivo, tumor growth of CRT-resistant T24R cells was abrogated by ATM inhibition using AZD0156. A dataset analysis identified FOXM1 as a putative BUB1B/BUBR1-targeting transcription factor causing its increased expression. These data collectively suggest a redundant role of BUB1B/BUBR1 underlying mutagenic NHEJ in an ATM-dependent manner, aside from the canonical activity of BUB1B/BUBR1 on the G2/M checkpoint, and offer novel clues to overcome CRT resistance.

Cartilage Repair Activity during Joint-Preserving Treatment May Be Accompanied by Osteophyte Formation

Knee joint distraction (KJD) treatment has shown cartilage repair and clinical improvement in patients with osteoarthritis, as has high tibial osteotomy (HTO). Following KJD, TGFβ-1 and IL-6 were increased in synovial fluid (SF), factors related to cartilage regeneration, but also to osteophyte formation. As such, osteophyte formation after both joint-preserving treatments was studied. Radiographic osteophyte size was measured before, one year, and two years after treatment. Changes were compared with natural progression in patients from the CHECK cohort before undergoing total knee arthroplasty. An additional KJD cohort underwent SF aspiration, and one-year Altman osteophyte score changes were compared to SF-marker changes during treatment. After two years, both KJD (n = 58) and HTO (n = 38) patients showed an increase in osteophyte size (+6.2 mm2 and +7.0 mm2 resp.; both p < 0.004), with no significant differences between treatments (p = 0.592). Untreated CHECK patients (n = 44) did not show significant two-year changes (+2.1 mm2; p = 0.207) and showed significant differences with KJD and HTO (both p < 0.044). In SF aspiration patients (n = 17), there were significant differences in TGFβ-1 changes (p = 0.044), but not IL-6 (p = 0.898), between patients with a decrease, no change, or increase in osteophyte Altman score. Since KJD and HTO showed joint space widening and clinical improvement accompanied by osteophyte formation, increased osteophytosis after joint-preserving treatments may be a bystander effect of cartilage repair activity related to intra-articular factors like TGFβ-1 and raises questions regarding osteophyte formation as solely characteristic of the joint degenerative process.

Instability in NAD+ metabolism leads to impaired cardiac mitochondrial function and communication

Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.

Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells

Background Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive. Results We examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naïve PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naïve PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz to define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity. Conclusions Our data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naïve PSCs.

Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target

Precision medicine aims to identify specific molecular alterations, such as driver mutations, allowing tailored and effective anticancer therapies. Poly(ADP)-ribose polymerase inhibitors (PARPi) are the prototypical example of targeted therapy, exploiting the inability of cancer cells to repair DNA damage. Following the concept of synthetic lethality, PARPi have gained great relevance, particularly in BRCA1 dysfunctional cancer cells. In fact, BRCA1 mutations culminate in DNA repair defects that can render cancer cells more vulnerable to therapy. However, the efficacy of these drugs has been greatly affected by the occurrence of resistance due to multi-connected DNA repair pathways that may compensate for each other. Hence, the search for additional effective agents targeting DNA damage repair (DDR) is of crucial importance. In this context, BRCA1 has assumed a central role in developing drugs aimed at inhibiting DNA repair activity. Collectively, this review provides an in-depth understanding of the biology and regulatory mechanisms of DDR pathways, highlighting the potential of DDR-associated molecules, particularly BRCA1 and its interconnected partners, in precision cancer medicine. It also affords an overview about what we have achieved and a reflection on how much remains to be done in this field, further addressing encouraging clues for the advance of DDR targeted therapy.