This work is focused on the rational structural design of two isostructural Cu(II) nano-coordination polymers (NCPs) with uracil-1-acetic acid (UAcOH) (CP1n) and 5-fluorouracil-1-acetic acid (CP2n). Suitable single crystals for X-ray diffraction studies of CP1 and CP2 were prepared under hydrothermal conditions, enabling their structural determination as 1D-CP ladder-like polymeric structures. The control of the synthetic parameters allows their processability into water colloids based on nanoplates (CP1n and CP2n). These NCPs are stable in water at physiological pHs for long periods. However, interestingly, CP1n is chemically altered in culture media. These transformations provoke the partial release of its building blocks and the formation of new species, such as [Cu(UAcO)₂(H₂O)₄]·2H₂O (Cu(II)-complex), and species corresponding to the partial reduction of the Cu(II) centers. The cytotoxic studies of CP1n versus human pancreatic adenocarcinoma and human uveal melanoma cells show that CP1n produces a decrease in the cell viability, while their UAcOH and Cu(II)-complex are not cytotoxic under similar conditions. The copper reduction species detected in the hydrolysis of CP1n are closely related to the formation of the reactive oxygen species (ROS) detected in the cytotoxic studies. These results prompted us to prepare CP2n that was designed to improve the cytotoxicity by the substitution of UAcO by 5-FUAcO, taking into account the anticancer activity of the 5-fluorouracil moiety. The new CP2n has a similar behavior to CP1n both in water and in biological media. However, its subtle structural differences are vital in improving its cytotoxic activity. Indeed, the release during the hydrolysis of species containing the 5-fluorouracil moiety provokes a remarkable increase in cellular toxicity and a significant increase in ROS species formation.

Keywords: 5-fluorouracil; biological media; coordination polymers; cytotoxicity; nano-coordination polymers; uracil.

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n = 96) or accelerated phase (n = 51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in ≥CP2 (n = 70), in AP (n = 40) or in BC (n = 37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34⁺ count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors ≤36 years and with higher CD34⁺ dose in the graft.

The capsids of RNA viruses such as MS2 are great models for studying protein self-assembly because they are made almost entirely of multiple copies of a single coat protein (CP). Although CP is the minimal repeating unit of the capsid, previous studies have shown that CP exists as a homodimer (CP2) even in an acid-disassembled system, indicating that CP2 is an obligate dimer. Here, we investigate the molecular basis of this obligate dimerization using coarse-grained structure-based models and molecular dynamics simulations. We find that, unlike monomeric proteins of similar size, CP populates a single partially folded ensemble whose "foldedness" is sensitive to denaturing conditions. In contrast, CP2 folds similarly to single-domain proteins populating only the folded and the unfolded ensembles, separated by a prominent folding free energy barrier. Several intramonomer contacts form early, but the CP2 folding barrier is crossed only when the intermonomer contacts are made. A dissection of the structure of CP2 through mutant folding simulations shows that the folding barrier arises both from the topology of CP and the interface contacts of CP2. Together, our results show that CP2 is an obligate dimer because of kinetic stability, that is, dimerization induces a folding barrier and that makes it difficult for proteins in the dimer minimum to partially unfold and access the monomeric state without completely unfolding. We discuss the advantages of this obligate dimerization in the context of dimer design and virus stability.

Coordination polymers (CPs), new functional hybrid materials, have received important attention due to their structural features and many different applications such as gas storage, catalysis, energy storage, small molecule adsorption, luminescence, and chemical sensors. In this study, two newly synthesized metal-organic frameworks (MOFs); [Mn₂(µ₄-dmg)-(µ₄-dmg)(µ-bipy)]_n (CP1) and [Mn₂(µ₄-dmg)(µ₄-dmg)(µ-dpeten)]_n (CP2); were used for sensing of gaseous carbon dioxide with a spectrofluorometric method with a dye, 8-hydroxypyrene-1, 3, 6-trisulfonic acid (HPTS) as matrix additive material for the first time. The ion-pair form of the HPTS was used in the polymethyl methacrylate matrix as a thin film form. When the HPTS based sensing slides along with the CPs, resulted in many advances such as high relative signal change and larger linear response range, improved sensor dynamics, and higher sensitivity with respect to the additive-free form. More specifically, in the presence of silver nanoparticles (AgNPs), the variation in relative signal intensities of CP1 and CP2 doped HPTS sensing agents were measured as 60 and 40% for the concentration range of 0-10% pCO₂, respectively. The aim of this study is to enhance the CO₂ response of HPTS with doped CPs due to their useful attributes and potential applications containing selective gas absorption.

Keywords: 3,6-Trisulfonic acid trisodium (HPTS); 8-Hydroxypyrene-1; Coordination polymer; Optical CO(2) sensor; Silver nanoparticles.

The current treatment of leishmaniasis is based on few drugs that present several drawbacks such as high toxicity, difficult administration route, and low efficacy. These disadvantages raise the necessity to develop novel antileishmanial compounds allied to a comprehensive understanding of their mechanisms of action. Here, we elucidate the probably mechanism of action of the antileishmanial binuclear cyclopalladated complex [Pd(dmba)(μ-N₃)]₂ (CP2) in Leishmania amazonensis. CP2 causes oxidative stress in the parasite resulting in disruption of mitochondrial Ca²⁺ homeostasis, cell cycle arrest at S-phase, increasing the ROS production and overexpression of stress-related and cell detoxification proteins, collapsing the Leishmania mitochondrial membrane potential and promotes apoptotic-like features in promastigotes leading to necrosis or directs programmed cell death (PCD)-committed cells toward necrotic-like destruction. Moreover, CP2 is able to reduce the parasite load in both liver and spleen in Leishmania infantum-infected hamsters when treated for 15 days with 1.5 mg/Kg/day CP2, expanding its potential application in addition to the already known effectiveness on cutaneous leishmaniasis for the treatment of visceral leishmaniasis, showing the broad spectrum of action of this cyclopalladated complex. The data herein presented bring new insights into the CP2 molecular mechanisms of action, assisting to promote its rational modification to improve both safety and efficacy.

The design of new and inexpensive metal-containing functional materials is of great interest. Herein is reported a unique thermochromic near-IR emitting coordination polymer, 3D-[Cu₈I₈(L1)₂]_n, CP2, which is formed when ArS(CH₂)₄SAr (L1, Ar = 4-C₆H₄OMe) reacts with 2 equiv of CuI in EtCN. In MeCN, CP1 ([Cu₄I₄(L1)(MeCN)₂]_n, consisting of an alternating [-Cu₄I₄-L1-Cu₄I₄-L1-]_n chain where the Cu₄I₄ cubane units bear two metal-bound MeCN molecules, is formed. Heat-driven elimination of these MeCN's in solid CP1 also leads to CP2 through a predisposed organization of the Cu₄I₄ units prone to fusion after MeCN eliminations (i.e., a rare case of template effect). The CP2 structure exhibits parallel 1D-(Cu₈I₈)_n chains, (z-axis; designated 1D-[CuI]_n) as secondary building units (SBU) held together by parallel thioether ligands (x,y-axes), forming a nonporous 3D network. The structure of this 1D-[CuI]_n SBU is unprecedented and consists of a series of fused and twisted open Cu₄I₄ cubanes forming a fused poly(truncated rhombic dodecahedron). Unexpectedly, the compact 3D CP2 exhibits a solid-to-solid phase transition at 100 °C and a hysteresis of ∼20 °C. CP1 emits intensively (298 K: λ_emi = 564 nm; Φ_e = 0.35), whereas CP2 presents a strongly red-shifted weaker emission (298 K: λ_emi ∼ 740 nm, Φ_e < 0.0001). Moreover, CP2, which is stable over long periods of time, exhibits thermochromism where the emission intensity of the near-IR band decreases significantly at the benefit of a ligand-centered phosphorescence at 415 nm. Altogether, these properties listed above make CP2 exceptional. The low-energy singlet and triplet excited states have been assigned to ligand/metal-to-ligand charge transfer based on DFT and TD-DFT computations.

Photoluminescence (PL) intensity in organic or metal-organic emitters usually suffers from thermal quenching (TQ), which severely hinders their industrial applications. The development of negative thermal quenching (NTQ) and/or zero thermal quenching (ZTQ) materials depends on a better understanding of the mechanisms underpinning TQ in luminescent solids. In this work, we investigated the temperature dependence of thermally activated delayed fluorescence (TADF) in copper(I)-organic coordination polymers (CP) ligated with an imidazole or triazole derivative over a broad temperature range. The efficient PL emission of CP1 is heavily quenched as the crystalline samples are cooled to 77 K; the PL intensity shows the NTQ effect in the region of 77-238 K followed by a ZTQ effect in the temperature range of 238-318 K. No NTQ or ZTQ effect is observed for reference coordination polymer CP2, where the 1,2,4-triazole group was used instead of the imidazole one. Our work highlights the important role of the ligand's electronic structure in optimizing photophysical properties of coordination polymer emitters and may stimulate new efforts to design luminescent materials exhibiting NTQ and ZTQ effect at higher temperature.

Four structurally diverse coordination polymers 1-4 (CP1-CP4) were designed and constructed from Cd(II) ions and various carboxyl ligands (H₂oba, 4,4'-oxydibenzoic acid; H₂bpa, (E)-4,4'-(ethene-1,2-diyl)dibenzoic acid; H₂pbda, 4,4'-((1,3-phenylenebis(methylene))bis(oxy))dibenzoic acid) and the alkene containing ligand (CH₃-bpeb, 4,4'-((1E,1'E)-(2,5-dimethyl-1,4-phenylene)bis(ethene-2,1-diyl))dipyridine). CP1-CP4 possess Cd₂ binuclear secondary building units (SBUs). The geometry of the dicarboxylate ligands and the reaction conditions determined the final structure with a variety of motifs. CP1 possesses an interdigitated 2D structure, while CP2 consists of a 1D channel-like motif with isolated CH₃-bpeb molecules embedded in the channels. The solid-state structure of CP3 consists of two unique layers interpenetrated to form a 2D + 2D → 2D polycatenated backbone, while a 1D channel-like motif filled by isolated CH₃-bpeb molecules was observed for CP4. In all four coordination polymers pairs of CH₃-bpeb molecules were bound or encapsulated by the Cd₂ secondary building units at an appropriate distance and orientation for solid-state [2 + 2] photodimerization of one pair of CC bonds. Desolvation of CP3 with heat resulted in a decrease in solid-state fluorescence and a slowing of the rate of solid-state photodimerization.

KRAS mutation is very common in pancreatic cancer. How pancreatic cancer cells overcome oncogene-induced senescence is not fully understood. Our previous studies showed that up-regulation of TFCP2 (transcription factor CP2) in pancreatic cancer promoted the growth and metastasis of pancreatic cancer cells. However, whether TFCP2 plays an important role in pancreatic cancer cell senescence is not clear. In this study, we found upregulation of TFCP2 expression in pancreatic cancer was associated with KRAS mutation. Overexpression of TFCP2 inhibited cell senescence. Knockdown of TFCP2 promoted cell senescence. Mechanistically, the interaction between TFCP2 and SREBP2 (sterol regulatory element binding transcription factor 2) synergistically activated the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis, and statins could reverse the inhibitory effect of TFCP2 on senescence. In conclusion, our study reveals a new mechanism underlying the TFCP2 regulation of pancreatic cancer cell senescence, providing a new target for the treatment of pancreatic cancer.

Keywords: SREBP2; TFCP2; cell senescence; cholesterol synthesis; pancreatic cancer.

Background: Motor attempt and motor imagery (MI) are two common motor tasks used in brain-computer interface (BCI). They are widely researched for motor rehabilitation in patients with hemiplegia. The differences between the motor attempt (MA) and MI tasks of patients with hemiplegia can be used to promote BCI application. This study aimed to explore the accuracy of BCI and event-related desynchronization (ERD) between the two tasks. Materials and Methods: We recruited 13 patients with stroke and 3 patients with traumatic brain injury, to perform MA and MI tasks in a self-control design. The BCI accuracies from the bilateral, ipsilesional, and contralesional hemispheres were analyzed and compared between different tasks. The cortical activation patterns were evaluated with ERD and laterality index (LI). Results: The study showed that the BCI accuracies of MA were significantly (p < 0.05) higher than MI in the bilateral, ipsilesional, and contralesional hemispheres in the alpha-beta (8-30 Hz) frequency bands. There was no significant difference in ERD and LI between the MA and MI tasks in the 8-30 Hz frequency bands. However, in the MA task, there was a negative correlation between the ERD values in the channel CP1 and ipsilesional hemispheric BCI accuracies (r = -0.552, p = 0.041, n = 14) and a negative correlation between the ERD values in channel CP2 and bilateral hemispheric BCI accuracies (r = -0.543, p = 0.045, n = 14). While in the MI task, there were negative correlations between the ERD values in channel C4 and bilateral hemispheric BCI accuracies (r = -0.582, p = 0.029, n = 14) as well as the contralesional hemispheric BCI accuracies (r = -0.657, p = 0.011, n = 14). As for motor dysfunction, there was a significant positive correlation between the ipsilesional BCI accuracies and FMA scores of the hand part in 8-13 Hz (r = 0.565, p = 0.035, n = 14) in the MA task and a significant positive correlation between the ipsilesional BCI accuracies and FMA scores of the hand part in 13-30 Hz (r = 0.558, p = 0.038, n = 14) in the MI task. Conclusion: The MA task may achieve better BCI accuracy but have similar cortical activations with the MI task. Cortical activation (ERD) may influence the BCI accuracy, which should be carefully considered in the BCI motor rehabilitation of patients with hemiplegia.

Keywords: BCI accuracies; brain-computer interface; event-related desynchronization; motor attempt; motor imagery.

The critical power (CP) and maximal lactate steady state (MLSS) are operational surrogates of the maximal metabolic steady state (MMSS). However, their concordance and their agreement with MMSS remains variable likely due to methodological factors.

Purpose: To compare the concordance between CP and MLSS estimated by various models and criteria and their agreement with MMSS.

Methods: After a ramp-test, ten recreationally active males performed four-to-five severe-intensity constant-power output (PO) trials to estimate CP, and three-to-four constant-PO trials to determine MLSS and identify MMSS. CP was computed using the 3-parameter hyperbolic (CP3-hyp), 2-parameter hyperbolic (CP2-hyp), linear (CPlin), and inverse of time (CP1/Tlim) models. In addition, the model with lowest combined parameter error identified the "best-fit" CP (CPbest-fit). MLSS was determined as an increase in blood lactate concentration ≤ 1 mM during constant-PO cycling from the 5th (MLSS10-30), 10th (MLSS10-30), 15th (MLSS15-30), 20th (MLSS20-30), or 25th (MLSS25-30) to 30th minute. MMSS was identified as the greatest PO associated with the highest submaximal steady state V[Combining Dot Above]O2 (MV[Combining Dot Above]O2ss).

Results: Concordance between the various CP and MLSS estimates was greatest when MLSS was identified as MLSS15-30, MLSS20-30, and MLSS25-30. The PO at MV[Combining Dot Above]O2ss was 243 ± 43 W. Of the various CP models and MLSS criteria, CP2-hyp (244 ± 46 W) and CPlin (248 ± 46 W) and MLSS15-30 and MLSS20-30 (both 245 ± 46 W), respectively displayed, on average, the greatest agreement with MV[Combining Dot Above]O2ss. Nevertheless, all CP models and MLSS criteria demonstrated some degree of inaccuracies with respect to MV[Combining Dot Above]O2ss.

Conclusions: Differences between CP and MLSS can be reconciled with optimal methods of determination. When estimating MMSS, from CP the error margin of the model-estimate should be considered. For MLSS, MLSS15-30 and MLSS20-30 demonstrated the highest degree of accuracy.

Purpose: The study aimed to determine which of the five classical ballet positions is the most demanding regarding muscular activity, values of external rotation in the hip joints, angular values of foot progression as well as the inclination (tilt) of the pelvis in the sagittal plane.

Methods: In this cross-sectional study, 14 female pre-professional ballet dancers (aged 11-16) participated. Participants were tasked with the sequential adoption of five classical ballet positions (CP1-CP5). The electromyographic activity of the muscles of the trunk and the lower limb was recorded with surface electrodes. Kinematic data including hip and knee external rotation, foot progression angle and pelvic tilt were collected using a motion capture system.

Results: Symmetric positions CP1 and CP2 were not as demanding as asymmetric CP3-CP5. Higher values of hip and foot external rotation without greater muscular effort in CP2 than CP1 was noticed. Considering asymmetric positions, CP3 did not trigger a greater activity of hip or foot muscular groups than CP4 and CP5. CP4 was characterised by the greatest pelvic anterior tilt and the lowest activity of GM in the forward lower limb. In CP5, forward lower limb entailed a higher activity of muscles supporting the foot than in the remaining positions.

Conclusion: In terms of biomechanics, the most demanding classical ballet position in pre-professional dancers is CP4, followed by CP5, CP3, CP1 and CP2. This finding can be applied in educational methodology of dancers, figure skaters, synchronized swimmers, acrobatic gymnasts, rhythmic gymnasts or cheerleaders.

The indiscriminate application of various pesticides leads to toxicity to the humans, animals, fishes and threatens the environment and ecosystem. The present study was aimed to investigate pesticide degrading bacteria from the pesticide contaminated sample and to localize organophophate hydrolase activity from the bacteria. Sediment sample was selected as the source of microorganism for the degradation of chlorpyrifos. Enterobacter aerogenes CP2 and Streptococcus pyogenes CP11 isolated from the contaminated sample removed 77 ± 1.8%, 74.2 ± 3.1 chlorpyrifos. These strains have the potential to utilize pesticide as the source of carbon and energy. The pesticides inoculated with both CP 2 and CP 11 enhanced biodegradation of chlorpyrifos at optimized condition. E. aerogenes CP2 and S. pyogenes CP11 produced organophosphate hydrolase activity and localized enzyme biosynthesis. Organophosphate hydrolase activity was high in intracellular, followed by outer membrane and extracellular sample for both bacteria. The treated wastewater has no impact on the seed germination indicated normal cell division, cell elongation and indole-3 acetic acid synthesis. The strain CP2 has the rapid rate of organophosphate degradation among Enterobacter species.

Keywords: Biodegradation; Chlorpyrifos; Enterobacter; Organophosphate; Organophosphate hydrolase; Streptococcus.

An outstanding treatment challenge related to aesthetic monolithic materials is to mask discolored substrates in aesthetic areas. The purpose of the study is to evaluate the substrate masking ability of different resin composite materials and the influence of their association with luting agents and substrates. Five types of 2M2 HT (high translucency) resin composite materials were selected: Vita Enamic [E] and four types of nanoparticle-filled composites Lava Ultimate [L], Cerasmart [C], Shofu HC [S], and Hyramic [H]. Resin composite Vita VM LC with different shades was used for the substrates: 2M2, 3M2, and CP2. Variolink Esthetic Try-inpastes neutral, light+, and warm+ colors were chosen to simulate the luting agent color. Optical parameters (TP (translucency), CR (contrast ratio), and OP (opalesce)) and color differences ΔE (chromatic difference) were calculated. Statistical analyses were performed to evaluate the comparisons between the groups and establish correlations. TP average values for all materials were in the range of 21.49-24.53. OP average values were in the rage of 6.31-7.85. OP is moderate positive correlated to TP and CR is negative and strong correlated to TP. Related to materials, average color changes decrease as following: E > H > C > L > S. Referring to the tryin material, warm colors induce marked color changes of the restoration. The differences of the color changes determined by all studied substrates are significant. For the final aesthetic aspect of the restoration, it is essential to consider the underlying dental structure, luting agent, and restoration material as a whole unit. The masking ability of the investigated resin matrix ceramic materials materials shows differences, the best behavior demonstrated Shofu HC and Lava Ultimate. Marked color changes are related to high chroma substrates. For substrates with a darker color, the association with warm try-in pastes lead to marked color changes, but with neutral and light try-in pastes at most perceivable.

Keywords: luting material; masking ability; resin-composite; substrate.

The deployment of alkaline anion exchange membranes (AEMs) in flow battery applications has the advantage of a low cationic species crossover rate. However, the alkaline stability conjugated to the low conductivity of hydroxide ions of anion exchange membranes (AEMs) still represents a major drawback for the large deployment of such technology. In this study, three types of tetraarylpolyphosphonium (pTAP)-based copolymers (namely, CP1, CP2, and CP3) are synthesized and blended with chitosan and polyvinylidene fluoride (PVDF) for the fabrication of AEMs. Chitosan, a green biopolymer, was employed as a blend to enhance the water uptake of the base ionomer matrix. It is proposed that the abundancy of hydroxyl groups in chitosan improves considerably the ionic conductivity, water transport, and ion selectivity of the membrane, together with facilitating the dispersion of the chitosan in the pTAP copolymer matrix. The purpose of blending PVDF is instead to provide stable mechanical strength to the composite blend. The chemical, mechanical, and thermal stabilities of the three fabricated composite-blend membranes (i.e., CM1, CM2, and CM3) were characterized. All the membranes exhibited a high water retaining capacity of up to 36.26% (recorded for CM2) along with a hydroxyl ion conductivity of 17.39 mS cm^-1. Due to the strong interactions between pTAP copolymers, chitosan, and PVDF polymers (confirmed also by Fourier transform infrared spectroscopy), the studied anion exchange membranes are able to retain up to 97% of the original OH conductivity after 1 M KOH treatment at room temperature for 100 h. The three membranes, namely, CM1, CM2, and CM3, have vanadium ion permeabilities measured at 20 °C of 1.775 × 10^-8, 1.718 × 10^-8, and 1.648 × 10^-8 cm²/s, respectively, which are lower than that for the commercially available Nafion. The good stability and remarkable cell performance of the composite-blend membranes reported here make them definitely excellent candidates for the future generation of vanadium redox flow batteries.

Keywords: all-vanadium redox flow battery; anion exchange membrane; chemical stability; ion permeability; phosphonium copolymer.

MicroRNAs (miRNAs) have been implicated in nerve injury and demyelination; however, their functions in peripheral nerves remain unclear. To determine the potential functions of miRNAs, an miRNA array was carried out. Here, miRNA array analysis of neuregulin-treated Schwann cells revealed 18 upregulated (> 2-fold) and 13 downregulated (> 2-fold) miRNAs. After sciatic nerve injury, miR708-5p was highly expressed in neuregulin-treated Schwann cells, whereas it was downregulated during postnatal development. A predicted functional interaction was found between miR708-5p and transcription factor CP2-like protein 1 (TFCP2L1) using a bioinformatics tool. This finding suggested that miR708-5p may regulate TFCP2L1. During sciatic nerve development, TFCP2L1 was upregulated on postnatal days 1 and 4, while it was downregulated after nerve axotomy and crush injury. Notably, TFCP2L1 was upregulated in cAMP-treated Schwann cells. We also found that activity of the myelin protein zero promoter was downregulated in TFCP2L1 siRNA-treated Schwann cells, whereas it was upregulated in TFCP2L1-overexpressing cells. Immunofluorescence analysis showed that TFCP2L1 was localized in Schwann cells. In addition, miR708-5p overexpression promoted migration of Schwann cells, while miR-708-5p inhibitor inhibited migration. miR708-5p inhibitor also blocked the migration of TFCP2L1 siRNA-treated Schwann cells. These findings indicate the functions of miR708-5p in TFCP2L1 regulation in the peripheral nervous system occur via regulation of Schwann cell migration.

Keywords: Sciatic nerve; TFCP2L1; microRNA; microRNA 708-5p.

Background: Integrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic cancer and promoted its progression. However, the mechanism of ITGA2 overexpression and other mechanisms for promoting the progression of pancreatic cancer are still unclear.

Methods: The GEPIA database was used to confirm the expression of ITGA2 in pancreatic cancer. To verify the influence of ITGA2 and TGF-β on the morphological changes of pancreatic cancer and tumor cell progression, we conduct CCK8 test, plate cloning, flow cytometry experiments and animal experiments. Then we conduct Western blot, RT-qPCR to explore the relationship between ITGA2 and TGF-β, and then find the key molecules which can regulate them by immunoprecipitation, Western blot, RT-qPCR, CHIP, nuclear and cytoplasmic separation test.

Results: The results of the present study show that the abnormal activation of KRAS induced the overexpression of ITGA2 in pancreatic cancer. Moreover, ITGA2 expression significantly suppressed the activation of the TGF-β pathway. ITGA2 silencing enhanced the anti-pancreatic cancer proliferation and tumor growth effects of TGF-β. Mechanistically, ITGA2 expression suppressed the activation of the TGF-β pathway by inhibiting the SMAD2 expression transcriptionally. In addition, it interacted with and inhibited the nuclear translocation of TFCP2, which induced the SMAD2 expression as a transcription factor. Furthermore, TFCP2 also induced ITGA2 expression as a transcription factor, and the TFCP2 feedback regulated the ITGA2-TFCP2-SMAD2 pathway.

Conclusions: Taken together, these results indicated that ITGA2 expression could inhibit the activation of the TGF-β signaling pathway in pancreatic cancer via the TFCP2-SMAD2 axis. Therefore, ITGA2, by effectively enhancing the anti-cancer effects of TGF- β, might be a potential clinical therapeutic target for pancreatic cancer.

Keywords: Integrin α2; Pancreatic cancer; SMAD2; TGF-β; Transcription factor CP2.