• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

AbstractHedgehog (Hh) proteins elicit dose-dependent transcriptional responses by binding Patched receptors to activate transmembrane Smoothened (Smo) proteins. Activated Smo inhibits Ci/Gli transcription factor phosphorylation by Protein Kinase A (PKA) and consequent proteolytic processing to repressor forms; it also promotes nuclear transport and activity of full-length Ci/Gli proteins to induce Hh target genes. Smo-activated Fused (Fu) kinase drives Ci activation in Drosophila, while Suppressor of Fused (Su(fu)) counters full-length Ci/Gli activity and stabilizes full-length Ci/Gli by direct binding to at least three surfaces. Here, we used CRISPR-generated designercialleles to investigate alterations to Fu phosphorylation sites and to regions around Ci-Su(fu) interfaces under physiological conditions in Drosophila imaginal wing discs. Surprisingly, we identified alterations that activate Ci without significant loss of stabilization by Su(fu) and contributions of multiple Fu target sites to Ci activation in the absence of Su(fu), suggesting that the affected sites mediate Ci activation by regulating Ci-Ci, rather than Ci-Su(fu) interactions. We propose that those interactions maintain full-length Ci in a closed conformation that also facilitates, and is stabilized by, cooperative Ci-Su(fu) binding. Access to binding partners necessary for Ci activation is promoted through phosphorylation of at least four Fu sites on Ci, likely by directly disrupting Ci-Ci contacts and one Ci-Su(fu) interface without substantial Ci-Su(fu) dissociation, contrary to previous proposals. We also found that the Ci binding partner, Costal 2 (Cos2), which silences Ci in the absence of Hh, can facilitate Ci activation by Fu kinase.

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

Quarkonia production in heavy-ion collisions is an important experimental probe that sheds light on the heavy quark interaction with the nuclear medium. The bound quarkonium states undergo dissociation and recombination in PbPb collisions, where they can also experience the initial and final state effects such as shadowing and co-mover breakup. With the large datasets of pp and pPb collisions, and excellent vertexing capabilities allowing separation of the prompt and b-decay components, LHCb performs precise measurements of J/ψ, ψ(2S ) and, for the first time at the LHC, χc production and modification in small collision systems. This contribution will discuss these results, along with the first measurement of the nuclear modification factor of the exotic χc1(3872).

• Book : 316()
• Pub. Date : 2025
• Page : pp.04010-04010
• Keyword :

이 연구에서는 김정은 시대 북한의 핵 관련 법에 나타난 핵전략과 핵태세를 분석하였다. 북한은 미국의 대북 적대시 정책에 대한 대응으로 핵을 개발하였다고 주장하였으나, 김정은 시대 북한은 핵 관련 법을 제정하고 핵을 무기화하였으며 핵능력을 고도화하였으며 당 제8차 대회 이후에는 전술핵능력까지 구비하였다. 연구를 통해 북한이 핵을 군사적으로 사용할 능력을 구비하고 고도화하면서 핵전략과 핵태세가 공세적으로 변화하였음을 확인할 수 있었다. 북한의 핵능력이 고도화되면서 핵전략은 선언적 수준의 최소억지전략에서 대남 제한억지전략과 대미 최소억지전략으로 발전하였고, 핵태세 또한 현재는 가장 공세적인 비대칭확장태세 유형을 보여주고 있다. 북한의 핵·미사일 능력 고도화는 계속될 것이다. 북한의 핵능력증가에 따른 대응 방안 마련이 제한되는 우리로서는 궁극적으로 북한의 핵 위협이 증가하지 않도록 하는 것이 중요하다.

• Book : 7(1)
• Pub. Date : 2025
• Page : pp.1057-1091
• Keyword :

Axion-like particles (ALPs) are hypothetical pseudoscalar bosons, natural in extensions of the Standard Model. Their interactions with ordinary matter and radiation are suppressed, making it challenging to detect them in laboratory experiments. However, these particles, produced within stellar interiors, can provide an additional mechanism for energy loss, potentially influencing stellar evolution. Prominent methods for searching for such effects involve measuring the properties of red giants and helium-burning stars in globular clusters (GCs). Here we use published catalogs of stars selected as members of seven GCs on the basis of parallaxes and proper motions measured by Gaia (Data Release 3). Making use of previously derived theoretical relations and the new data, we find the upper limit on the ALP-electron coupling, g ae < 5.2 × 10–14 (95% CL), and an indication (3.3σ) to nonzero ALP-photon coupling, g aγ = $$(6.5_{{ - 1.3}}^{{ + 1.1}})$$ × 10–11 GeV–1. Given the precision of contemporary observational data, it is imperative to refine ALP constraints through more sophisticated analyses, which will be explored in detail elsewhere.

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

Background: The pathogenesis of deterministic radiation damage is not clearly understood, but it has been reported that fibroinflammatory pathways are up-regulated. We hypothesized that the number of adipose-derived stem/stromal cells (ASCs) decline after radiotherapies, preventing normalization of fibrosis and angiogenesis, resulting in chronic radiation damages that progress over time. Methods: Dorsal skin of 8-week-old male BALB/cfC3H mice was irradiated with 10 Gy weekly for 4 weeks. At 1, 3, 6, 9, and 12 months after radiotherapy (n = 5, 5, 5, 5, and 4), tissue hemoglobin oxygen saturation, and time until epithelialization were evaluated. Skin biopsies were measured for thickness and CD34+/isolectin− stem/stromal cell count. Nonirradiated (NRT) controls were evaluated at each time point as well (n = 5 each). Results: Compared with NRT controls, time until epithelialization was significantly longer at 1 month (28 ± 3, P < 0.01); not statistically different at 3 months (16 ± 2, P = 0.32); and lengthened over time at 6 months (20 ± 2, P = 0.21), 9 months (28 ± 2, P < 0.01), and 12 months (26 ± 3, P < 0.01), as did tissue oxygen saturation. The number of CD34+/isolectin– ASCs decreased over time, at 1 month (5.3 ± 1.3, P = 0.01), 3 months (6.0 ± 1.4, P = 0.03), 6 months (4.0 ± 0.8, P < 0.01), 9 months (1.7 ± 0.5, P < 0.01), and 12 months (0.3 ± 0.5, P < 0.01). The subcutaneous fatty layer was significantly thinner at 3 months (116 ± 33, P < 0.01), 6 months (147 ± 22, P = 0.02), 9 months (52 ± 12, P = 0.04), and 12 months (89 ± 19, P = 0.04), but not at 1 month (141 ± 18, P = 0.43). Conclusions: After 6 months postirradiation, the number of ASCs continued to decline over time, accompanied by irreversible progression of fibrosis, atrophy, and ischemia, which resulted in impaired wound healing.

• Book : 13(1)
• Pub. Date : 2025
• Page : pp.e6419-e6419
• Keyword :

• Book : ()
• Pub. Date : 2025
• Page :
• Keyword :

Introduction Pancreatic cancer is one of the most aggressive cancers. It occurs in men  more often than women. The primary therapy for these cancers is surgery; chemotherapy, radiation therapy, hormone therapy, or immunotherapy are also used.  More and better treatments are being sought for this disease. The use of PARP inhibitors in the treatment of pancreatic cancer has shown good results, so in this article we have done a review of the results of various studies on this topic. In this review, the results of studies on the use of various PARP inhibitors in pancreatic cancer of different hormonal status are presented. Purpose This article aims to give you an overview of the trials that have looked at the effects of different PARP inhibitors in the treatment of pancreatic cancer. PARP inhibitors are a relatively new cancer therapy with good results, so it is important to pay attention.    State of Knowledge In this article, I used the PubMed database and considered papers from the last 10 years, but most of the information in this review comes from papers published after 2020. I have also taken into account the recommendations of the FDA and the European Medicines Agency on the use of PARP inhibitors. Conclusions PARP inhibitors have shown significant effects on pancreatic cancer outcomes. The differences in outcomes depending on the type of cancer, the PARP inhibitor used, and the previous therapies used in a given patient tell us how important it is to individualize therapy in oncology. The findings of the studies presented in this review also point to the need for further research that could focus on identifying patients who may best benefit from treatment with PARP inhibitors, as well as studying synergistic effects in combination with other forms of therapy, such as immunotherapy or chemotherapy. The changes in treatment outcomes that these drugs can bring underscore the importance of exploring new therapeutic strategies in oncology.

• Book : 77()
• Pub. Date : 2025
• Page : pp.56992-56992
• Keyword :

• Book : 33()
• Pub. Date : 2025
• Page : pp.100709-100709
• Keyword :

Background: Intrahepatic cholangiocarcinoma (ICC), a malignancy originating from the epithelial cells of bile ducts, has shown a notable rise in its incidence over the years. It ranks as the second most frequent primary liver cancer after hepatocellular carcinoma. This study investigates how independent prognostic factors, specifically, age and tumor stage, interact to impact mortality in ICC patients. Furthermore, it examines the clinical features, survival rates, and prognostic indicators of ICC cases diagnosed between 2010 and 2017. Methods: Using data from 5083 patients obtained from the Surveillance, Epidemiology, and End Results (SEER) database, this study evaluated demographic and clinical factors alongside overall mortality (OM) and cancer-specific mortality (CSM). Variables achieving a p-value below 0.1 in univariate Cox regression analysis were incorporated into multivariate Cox regression models to identify independent prognostic factors. Hazard ratios (HRs) exceeding 1 were interpreted as markers of poor prognosis. Additionally, this study explored the interaction between age and tumor stage in shaping survival outcomes. Results: The multivariate Cox proportional hazards analysis indicated higher OM in males (HR = 1.19, 95% CI: 1.12–1.26, p < 0.01) and residents of metropolitan counties with populations exceeding 250,000 (HR = 1.15, 95% CI: 1.01–1.31, p < 0.05). Conversely, lower OM was observed in individuals aged 40–59 years (HR = 0.58, 95% CI: 0.38–0.89, p < 0.05), those aged 60–79 years (HR = 0.65, 95% CI: 0.43–0.98, p < 0.05), and patients who received radiation therapy (HR = 0.78, 95% CI: 0.72–0.85, p < 0.01), chemotherapy (HR = 0.54, 95% CI: 0.51–0.58, p < 0.01), or surgery (HR = 0.29, 95% CI: 0.26–0.31, p < 0.01). For CSM, males exhibited higher risks (HR = 1.17, 95% CI: 1.10–1.25, p < 0.01), as did individuals in metropolitan counties with populations over 250,000 (HR = 1.18, 95% CI: 1.03–1.35, p < 0.05). Reduced CSM was observed in patients aged 40–59 years (HR = 0.52, 95% CI: 0.34–0.79, p < 0.01), those aged 60–79 years (HR = 0.57, 95% CI: 0.38–0.86, p < 0.01), and those undergoing radiation therapy (HR = 0.76, 95% CI: 0.70–0.83, p < 0.01), chemotherapy (HR = 0.55, 95% CI: 0.51–0.59, p < 0.01), or surgery (HR = 0.27, 95% CI: 0.25–0.30, p < 0.01). When examining the interaction between age and tumor stage, higher OM was observed in patients aged 40–59 with tumors involving lymph nodes (HR = 1.26, 95% CI: 1.14–2.67, p < 0.05). Similarly, CSM was elevated in patients aged 40–59 with lymph node involvement alone (HR = 2.60, 95% CI: 1.26–5.36, p < 0.05) or with direct spread (HR = 2.81, 95% CI: 1.04–7.61, p < 0.05). Among those aged 60–79, higher CSM was noted in cases with lymph node involvement only (HR = 2.24, 95% CI: 1.11–4.50, p < 0.05) or lymph node involvement accompanied by direct extension (HR = 2.93, 95% CI: 1.10–7.82, p < 0.05). Conclusions: This retrospective analysis, utilizing data from the SEER database, provides new insights into mortality patterns in intrahepatic cholangiocarcinoma (ICC). This study identifies a significant interplay between two key prognostic factors, emphasizing their collective role in influencing mortality outcomes. Despite the predominance of advanced-stage diagnoses, our analysis underscores the substantial survival benefits associated with treatment interventions, with surgical procedures demonstrating the most pronounced impact. These findings highlight the importance of recognizing patients who may benefit from timely and intensive therapeutic strategies. Furthermore, the results underscore the need for future prospective randomized studies to deepen our understanding of these interactions in ICC, particularly as advancements in precision oncology continue to refine patient care.

• Book : 13(2)
• Pub. Date : 2025
• Page : pp.31-31
• Keyword :