@article{%a1.%Y_183,

title = {Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants},

author = {Young WJ and van der Most PJ and Bartz TM and Bos MM and Biino G and Duong T and Foco L and Lominchar JT and Muller-Nurasyid M and Nardone GG and Pecori A and Ramirez J and Repetto L and Schramm K and Shen X and van Duijvenboden S and van Heemst D and Weiss S and Yao J and Benjamins JW and Alonso A and Spedicati B and Biggs ML and Brody JA and Dörr M and Fuchsberger C and Gögele M and Guo X and Ikram MA and Jukema JW and Kaab S and Kanters JK; Lifelines Cohort Study; Lin HJ and Linneberg A and Nauck M and Nolte IM and Pianigiani G and Santin A and Soliman EZ and Tesolin P and Vaccargiu S and Waldenberger M and van der Harst P and Verweij N and Arking DE and Concas MP and De Grandi A and Girotto G and Grarup N and Kavousi M and Mook-Kanamori DO and Navarro P and Orini M and Padmanabhan S and Pattaro C and Peters A and Pirastu M and Pramstaller PP and Heckbert SR and Sinner M and Snieder H and Volker U and Wilson JF and Gauderman WJ and Lambiase PD and Sotoodehnia N and Tinker A and Warren HR and Noordam R and Munroe PB.},

url = {https://www.ahajournals.org/doi/10.1161/JAHA.123.034760?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed},

doi = {10.1161/JAHA.123.034760},

year  = {2024},

date = {2024-10-21},

journal = {Journal of the American Heart Association},

volume = {13},

issue = {17},

pages = {e034760},

abstract = {Background: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and results: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). Conclusions: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_182,

title = {Traffic light at DSB-transit regulation between gene transcription and DNA repair},

author = {Modafferi S and Esposito F and Tavella S and Gioia U and Francia S},

url = {https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.15024},

doi = {10.1002/1873-3468.15024},

year  = {2024},

date = {2024-10-21},

urldate = {2024-10-21},

journal = {FEBS letters},

abstract = {Transcription of actively expressed genes is dampened for kilobases around DNA lesions via chromatin modifications. This is believed to favour repair and prevent genome instability. Nonetheless, mounting evidence suggests that transcription may be induced by DNA breakage, resulting in the local de novo synthesis of non-coding RNAs (ncRNAs). Such transcripts have been proposed to play important functions in both DNA damage signalling and repair. Here, we review the recently identified mechanistic details of transcriptional silencing at damaged chromatin, highlighting how post-translational histone modifications can also be modulated by the local synthesis of DNA damage-induced ncRNAs. Finally, we envision that these entangled transcriptional events at DNA breakages can be targeted to modulate DNA repair, with potential implications for locus-specific therapeutic strategies},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{%a1.%Y_181,

title = {Bithiazole inhibitors of PI4KB show broad-spectrum antiviral activity against different viral families},

author = {Martina MG and Carlen V and Van der Reysen S and Bianchi E and Cabella N and Crespan E and Radi M and Cagno V},

url = {https://www.sciencedirect.com/science/article/pii/S0166354224002122?via%3Dihub},

doi = {10.1016/j.antiviral.2024.106003},

year  = {2024},

date = {2024-10-21},

journal = {Antiviral research},

abstract = {Broad-spectrum antivirals can be extremely important for pandemic preparedness. Targeting host factors dispensable for the host but indispensable for the virus can result in high barrier to resistance and a large range of viruses targeted. PI4KB is a lipid kinase involved in the replication of several RNA viruses, but common inhibitors of this target are mainly active against members of the Picornaviridae family. Herein we describe the optimization of bithiazole PI4KB inhibitors as broad-spectrum antivirals (BSAs) active against different members of the Picornaviridae, Coronaviridae, Flaviviridae and Poxviridae families. Since some of these viruses are transmitted via respiratory route, the efficacy of one of the most promising compounds was evaluated in an airway model. The molecule showed complete viral inhibition and absence of toxicity. These results pave the road for the development of new BSAs.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{%a1.%Y_180,

title = {A proteasome-dependent inhibition of SIRT-1 by the resveratrol analogue 4,4'-dihydroxy- trans- stilbene},

author = {Livraghi V and Mazza L and Chiappori F and Cardano M and Cazzalini O and Puglisi R and Capoferri R and Pozzi A and Stivala LA and Zannini L and Savio M},

url = {https://www.sciencedirect.com/science/article/pii/S2225411024000208?via%3Dihub},

doi = {10.1016/j.jtcme.2024.03.001},

year  = {2024},

date = {2024-10-21},

journal = {Journal of traditional and complementary medicine},

volume = {14},

number = {543},

issue = {5},

abstract = {Background and aim: Resveratrol (RSV), is a stilbene-based compound exerting wide biological properties. Its analogue 4,4'-dihydroxy-trans-stilbene (DHS) has shown improved bioavailability and antiproliferative activity in vitro and in vivo. One of the hypotheses on how resveratrol works is based on SIRT1 activation. Since their strict structural similarities, we have explored a potential interaction between DHS and SIRT1, in comparison with the parental molecule. Experimental procedure: Timing of incubation and concentrations of DHS have been determined using MTT assay in normal human lung fibroblasts. Untreated, DHS- or RSV-treated cells were harvested and analysed by Western Blotting or RT-PCR, in order to evaluate SIRT1 levels/activity and expression, and by Cellular Thermal shift assay (CETSA) to check potential DHS or RSV-SIRT1 interaction. Transfection experiments have been performed with two SIRT1 mutants, based on the potential binding pockets identified by Molecular Docking analysis. Results and conclusion: We unexpectedly found that DHS, but not RSV, exerted a time-dependent inhibitory effect on both SIRT1 protein levels and activity, the latter measured as p53 acetylation. At the mRNA level no significant changes were observed, whereas a proteasome-dependent mechanism was highlighted for the reduction of SIRT1 levels by DHS in experiments performed with the proteasome inhibitor MG132. Bioinformatics analysis suggested a higher affinity of RSV in binding all SIRT1 complexes compared to DHS, except comparable results for complex SIRT1-p53. Nevertheless, both CETSA and SIRT1 mutants transfected in cells did not confirm this interaction. In conclusion, DHS reduces SIRT1 protein level, thereby inhibiting its activity through a proteasome-mediated mechanism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_179,

title = {Applying molecular hybridization to design a new class of pyrazolo[3,4-d]pyrimidines as Src inhibitors active in hepatocellular carcinoma},

author = {{Di Maria S} and Passannanti R and Poggialini F and Vagaggini C and Serafinelli A and Bianchi E and Governa P and Botta L and Maga G and Crespan E and Manetti F and Dreassi E and Musumeci F and Carbone A and Schenone S},

url = {https://www.sciencedirect.com/science/article/pii/S0223523424008109?via%3Dihub},

doi = {10.1016/j.ejmech.2024.116929},

year  = {2024},

date = {2024-10-21},

journal = {European journal of medicinal chemistry},

volume = {280},

pages = {116929},

abstract = {Hepatocellular carcinoma (HCC) is the most common type of liver solid tumor and the second leading cause of cancer-related deaths worldwide. Although new treatment options have been recently approved, the development of tumor resistance and the poor prognosis for advanced HCC make the current standard of care unsatisfying. In this scenario, the non-receptor tyrosine kinase (TK) c-Src emerged as a promising target for developing new anti-HCC agents. Our group reported a large library of pyrazolo[3,4-d]pyrimidines active as potent c-Src inhibitors. Starting from these data, we applied a molecular hybridization approach to combine the in-house pyrazolo[3,4-d]pyrimidine SI192 with the approved TK inhibitor (TKI) dasatinib, with the aim of identifying a new generation of Src inhibitors. Enzymatic results prompted us to design second-generation compounds with a better binding profile based on a hit optimization protocol comprised of molecular modeling and on-paper rational design. This investigation led to the identification of a few nanomolar Src inhibitors active toward two HCC cell lines (HepG2 and HUH-7) selected according to their high and low c-Src expression, respectively. In particular, 7e showed an IC50 value of 0.7 nM toward Src and a relevant antiproliferative efficacy on HepG2 cells after 72h (IC50 = 2.47 μM). Furthermore, 7e exhibited a cytotoxic profile better than dasatinib. The ADME profile suggested that 7e deserves further investigation as a promising TKI in cancer therapies. Finally, 7e's ability to inhibit HepG2 cell proliferation, elicit an irreversible cytotoxic effect, arrest cellular migration, and induce apoptotic-mediated cell death was assessed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y__172,

title = {Phospholipase Cdelta-4 (PLCdelta4) Acts as a Nuclear Player to Influence Cyclin B Expression in the Embryonal Rhabdomyosarcoma Cell Lines RD and A204},

author = {Salucci S and Bavelloni A and Versari I and Burattini S and Bavelloni F and Gobbi P and Fanzani A and Codenotti S and Blalock W and Scotlandi K and Faenza I},

url = {https://www.mdpi.com/2218-273X/14/9/1180},

doi = {10.3390/biom14091180},

year  = {2024},

date = {2024-10-21},

journal = {Biomolecules},

volume = {14},

issue = {9},

pages = {1180},

abstract = {Rhabdomyosarcoma (RMS), the most common form of sarcoma typical of pediatric age, arises from the malignant transformation of the mesenchymal precursors that fail to differentiate into skeletal muscle cells. Here, we investigated whether the protein phospholipase C delta4 (PLCdelta4), a member of the PLC family involved in proliferation and senescence mechanisms of mesenchymal stromal stem cells, may play a role in RMS. Our molecular and morpho-functional data reveal that PLCδ4 is highly expressed in the fusion-negative, p53-positive, SMARCB1 heterozygous mutated embryonal RMS (ERMS) cell line A204, while it is poorly expressed in the ERMS cell lines RD (fusion-negative, MYC amplification, N-RAS (Q61H), homozygous mutated p53) and Hs729 (homozygous mutated p53) and the alveolar rhabdosarcoma (ARMS) cell line SJCRH30 (RH30; fusion positive, heterozygous mutated RARA, polyheterozygous mutated p53). To characterize the role of PLCdelta4, the RD cell line was stably transfected with wild-type PLCδ4 (RD/PLCδ4). Overexpressed PLCδ4 mainly localized to the nucleus in RD cells and contributed to the phosphorylation of PRAS40 (T246), Chk2(T68), WNK1(T60), and Akt 1/273 (S473), as revealed by proteome profiler array analysis. Overexpression of PLCdelta4 in RD cells enhanced cyclin B1 expression and resulted in G2/M-phase cell cycle arrest. In contrast, siRNA-mediated knockdown of PLCdelta4 in A204 cells resulted in reduced cyclin B1 expression. Our study identifies a novel role for nuclear PLCdelta4 as a regulator of cyclin B1 via Akt-dependent phosphorylation. The modulation of PLCdelta4 expression and its downstream targets could represent a crucial signaling pathway to block embryonal RMS cell proliferation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y__171,

title = {MicroRNA dysregulation in ataxia telangiectasia},

author = {Cirillo E and Tarallo A and Toriello E and Carissimo A and Giardino G and De Rosa A and Damiano C and Soresina A and Badolato R and Dellepiane RM and Baselli LA and Carrabba M and Fabio G and Bertolini P and Montin D and Conti F and Romano R and Pozzi E and Ferrero G and Roncarati R and Ferracin M and Brusco A and Parenti G and Pignata C},

url = {https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1444130/full},

doi = {10.3389/fimmu.2024.1444130},

year  = {2024},

date = {2024-10-21},

journal = {Frontiers in immunology},

volume = {15},

pages = {1444130},

abstract = {Introduction: Ataxia telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, a predisposition to malignancies, and high clinical variability. Profiling of microRNAs (miRNAs) may offer insights into the underlying mechanisms of complex rare human diseases, as miRNAs play a role in various biological functions including proliferation, differentiation, and DNA repair. In this study, we investigate the differential expression of miRNAs in samples from AT patients to identify miRNA patterns and analyze how these patterns are related to the disease. Methods: We enrolled 20 AT patients (mean age 17.7 ± 9.6 years old) and collected clinical and genetic data. We performed short non-coding RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and fibroblasts to compare the miRNA expression profile between AT patients and controls. Results: We observed 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblast samples. Among these, three DE-miRNAs, miR-342-3p, miR-30a-5p, and miR-195-5p, were further validated in additional AT samples, confirming their dysregulation. Discussion: We identified an AT-related miRNA signature in blood cells and fibroblast samples collected from a group of AT patients. We also predicted several dysregulated pathways, primarily related to cancer, immune system control, or inflammatory processes. The findings suggest that miRNAs may provide insights into the pathophysiology and tumorigenesis of AT and have the potential to serve as useful biomarkers in cancer research.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_162,

title = {CAPE derivatives: Multifaceted agents for chronic wound healing},

author = {Balaha M and Cataldi A and Ammazzalorso A and Cacciatore I and De Filippis B and Di Stefano A and Maccallini C and Rapino M and {Korona-Glowniak I} and Przekora A and {di Giacomo V}},

url = {https://onlinelibrary.wiley.com/doi/10.1002/ardp.202400165},

doi = {10.1002/ardp.202400165},

year  = {2024},

date = {2024-10-02},

urldate = {2024-08-06},

journal = {Archiv der Pharmazie},

abstract = {Chronic wounds significantly impact the patients' quality of life, creating an urgent interdisciplinary clinical challenge. The development of novel agents capable of accelerating the healing process is essential. Caffeic acid phenethyl ester (CAPE) has demonstrated positive effects on skin regeneration. However, its susceptibility to degradation limits its pharmaceutical application. Chemical modification of the structure improves the pharmacokinetics of this bioactive phenol. Hence, two novel series of CAPE hybrids were designed, synthesized, and investigated as potential skin regenerative agents. To enhance the stability and therapeutic efficacy, a caffeic acid frame was combined with quinolines or isoquinolines by an ester (1a-f) or an amide linkage (2a-f). The effects on cell viability of human gingival fibroblasts (HGFs) and HaCaT cells were evaluated at different concentrations; they are not cytotoxic, and some proved to stimulate cell proliferation. The most promising compounds underwent a wound-healing assay in HGFs and HaCaT at the lowest concentrations. Antimicrobial antioxidant properties were also explored. The chemical and thermal stabilities of the best compounds were assessed. In silico predictions were employed to anticipate skin penetration capabilities. Our findings highlight the therapeutic potential of caffeic acid phenethyl ester (CAPE) derivatives 1a and 1d as skin regenerative agents, being able to stimulate cell proliferation, control bacterial growth, regulate ROS levels, and being thermally and chemically stable. An interesting structure-activity relationship was discussed to suggest a promising multitargeted approach for enhanced wound healing.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_176,

title = {Sch9S6K controls DNA repair and DNA damage response efficiency in aging cells },

author = {Lucca C AND Ferrari E AND Shubassi G AND Ajazi A AND Choudhary R AND Bruhn C AND Matafora V AND Bachi A AND Foiani M},

url = {https://www.sciencedirect.com/science/article/pii/S2211124724006090?via%3Dihub},

doi = {10.1016/j.celrep.2024.114281},

year  = {2024},

date = {2024-09-05},

journal = {Cell Reports},

volume = {43},

issue = {6},

pages = {114281},

abstract = {Survival from UV-induced DNA lesions relies on nucleotide excision repair (NER) and the Mec1ATR DNA damage response (DDR). We study DDR and NER in aging cells and find that old cells struggle to repair DNA and activate Mec1ATR. We employ pharmacological and genetic approaches to rescue DDR and NER during aging. Conditions activating Snf1AMPK rescue DDR functionality, but not NER, while inhibition of the TORC1-Sch9S6K axis restores NER and enhances DDR by tuning PP2A activity, specifically in aging cells. Age-related repair deficiency depends on Snf1AMPK-mediated phosphorylation of Sch9S6K on Ser160 and Ser163. PP2A activity in old cells is detrimental for DDR and influences NER by modulating Snf1AMPK and Sch9S6K. Hence, the DDR and repair pathways in aging cells are influenced by the metabolic tuning of opposing AMPK and TORC1 networks and by PP2A activity. Specific Sch9S6K phospho-isoforms control DDR and NER efficiency, specifically during aging. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y,

title = {Mechanical stress during confined migration causes aberrant mitoses and c-MYC amplification },

author = {Bastianello G AND Kidiyoor GR AND Lowndes C AND Li Q AND Bonnal R AND Godwin J AND Iannelli F AND Drufuca L AND Bason R AND Orsenigo F AND Parazzoli D AND Pavani M AND Cancila V AND Piccolo S AND Scita G AND Ciliberto A AND Tripodo C AND Pagani M AND Foiani M},

url = {https://www.pnas.org/doi/abs/10.1073/pnas.2404551121?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed},

doi = {10.1073/pnas.2404551121},

year  = {2024},

date = {2024-09-05},

urldate = {2024-09-05},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {121},

issue = {29},

pages = {e2404551121},

abstract = {Confined cell migration hampers genome integrity and activates the ATR and ATM mechano-transduction pathways. We investigated whether the mechanical stress generated by metastatic interstitial migration contributes to the enhanced chromosomal instability observed in metastatic tumor cells. We employed live cell imaging, micro-fluidic approaches, and scRNA-seq to follow the fate of tumor cells experiencing confined migration. We found that, despite functional ATR, ATM, and spindle assembly checkpoint (SAC) pathways, tumor cells dividing across constriction frequently exhibited altered spindle pole organization, chromosome mis-segregations, micronuclei formation, chromosome fragility, high gene copy number variation, and transcriptional de-regulation and up-regulation of c-MYC oncogenic transcriptional signature via c-MYC locus amplifications. In vivo tumor settings showed that malignant cells populating metastatic foci or infiltrating the interstitial stroma gave rise to cells expressing high levels of c-MYC. Altogether, our data suggest that mechanical stress during metastatic migration contributes to override the checkpoint controls and boosts genotoxic and oncogenic events. Our findings may explain why cancer aneuploidy often does not correlate with mutations in SAC genes and why c-MYC amplification is strongly linked to metastatic tumors. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y__169,

title = {Synergistic action of human RNaseH2 and the RNA helicase-nuclease DDX3X in processing R-loops},

author = {Secchi M and Garbelli A and Riva V and Deidda G and Santonicola C and Formica TM and Sabbioneda S and Crespan E and Maga G},

url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkae731/7742382?login=true},

doi = {10.1093/nar/gkae731},

year  = {2024},

date = {2024-09-02},

journal = {Nucleic acids research},

abstract = {R-loops are three-stranded RNA-DNA hybrid structures that play important regulatory roles, but excessive or deregulated R-loops formation can trigger DNA damage and genome instability. Digestion of R-loops is mainly relying on the action of two specialized ribonucleases: RNaseH1 and RNaseH2. RNaseH2 is the main enzyme carrying out the removal of misincorporated rNMPs during DNA replication or repair, through the Ribonucleotide Excision Repair (RER) pathway. We have recently shown that the human RNA helicase DDX3X possessed RNaseH2-like activity, being able to substitute RNaseH2 in reconstituted RER reactions. Here, using synthetic R-loop mimicking substrates, we could show that human DDX3X alone was able to both displace and degrade the ssRNA strand hybridized to DNA. Moreover, DDX3X was found to physically interact with human RNaseH2. Such interaction suppressed the nuclease and helicase activities of DDX3X, but stimulated severalfold the catalytic activity of the trimeric RNaseH2, but not of RNaseH1. Finally, silencing of DDX3X in human cells caused accumulation of RNA-DNA hybrids and phosphorylated RPA foci. These results support a role of DDX3X as a scaffolding protein and auxiliary factor for RNaseH2 during R-loop degradation.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{%a1.%Y_,

title = {Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma},

author = {Grisendi G and Dall'Ora M and Casari G and Spattini G and Farshchian M and Melandri A and Masicale V and Lepore F and Banchelli F and Costantini RC and D'Esposito A and Chiavelli C and Spano C and Spallanzani A and Petrachi T and Veronesi E and Ferracin M and Roncarati R and Vinet J and Magistri P and Catellani B and Candini O and Marra C and Eccher A and Bonetti LR and Horwtiz EM and Di Benedetto F and Dominici M},

url = {https://www.sciencedirect.com/science/article/pii/S2666379124004063?via%3Dihub},

doi = {10.1016/j.xcrm.2024.101685},

year  = {2024},

date = {2024-09-02},

urldate = {2024-09-02},

journal = {Cell reports. Medicine.},

volume = {5},

issue = {8},

pages = {101685},

abstract = {Pancreatic ductal adenocarcinoma (PDAC) still has a poor response to therapies, partly due to their cancer-associated fibroblasts (CAFs). Here, we investigate the synergistic impact of a combinatory approach between a known chemotherapy agent, such as gemcitabine (GEM), and gene-modified human mesenchymal stromal/stem cells (MSCs) secreting the pro-apoptotic soluble (s)TRAIL (sTRAIL MSCs) on both PDAC cells and CAFs. The combo significantly impacts on PDAC survival in 2D and 3D models. In orthotopic xenograft models, GEM and sTRAIL MSCs induce tumor architecture shredding with a reduction of CK7- and CK8/18-positive cancer cells and the abrogation of spleen metastases. A cytotoxic effect on primary human CAFs is also observed along with an alteration of their transcriptome and a reduction of the related desmoplasia. Collectively, we demonstrate a promising therapeutic profile of combining GEM and sTRAIL MSCs to target both tumoral and stromal compartments in PDAC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_172,

title = {Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives},

author = {Carosi F and Broseghini E and Fabbri L and Corradi G and Gili R and Forte V and Roncarati R and Filippini DM and Ferracin M},

url = {https://www.mdpi.com/2072-6694/16/15/2752},

doi = {10.3390/cancers16152752},

year  = {2024},

date = {2024-09-02},

urldate = {2024-09-02},

journal = {Cancers},

volume = {16},

issue = {15},

pages = {2752},

abstract = {The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_171,

title = {The multifaceted roles of the Ctf4 replisome hub in the maintenance of genome integrity},

author = {Branzei D and Bene S and Gangwani L and Szakal B},

url = {https://www.sciencedirect.com/science/article/pii/S1568786424001186?via%3Dihub},

doi = {10.1016/j.dnarep.2024.103742},

year  = {2024},

date = {2024-08-19},

journal = {Dna Repair},

volume = {142},

pages = {103742},

abstract = {At the core of cellular life lies a carefully orchestrated interplay of DNA replication, recombination, chromatin assembly, sister-chromatid cohesion and transcription. These fundamental processes, while seemingly discrete, are inextricably linked during genome replication. A set of replisome factors integrate various DNA transactions and contribute to the transient formation of sister chromatid junctions involving either the cohesin complex or DNA four-way junctions. The latter structures serve DNA damage bypass and may have additional roles in replication fork stabilization or in marking regions of replication fork blockage. Here, we will discuss these concepts based on the ability of one replisome component, Ctf4, to act as a hub and functionally link these processes during DNA replication to ensure genome maintenance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_170,

title = {R-loops and impaired autophagy trigger cGAS-dependent inflammation via micronuclei formation in Senataxin-deficient cells},

author = {Zannini L and Cardano M and Liberi G and Buscemi G},

url = {https://link.springer.com/article/10.1007/s00018-024-05380-3},

doi = {10.1007/s00018-024-05380-3},

year  = {2024},

date = {2024-08-19},

journal = {Cellular and molecular life sciences},

volume = {81},

issue = {1},

pages = {339},

abstract = {Senataxin is an evolutionarily conserved DNA/RNA helicase, whose dysfunctions are linked to neurodegeneration and cancer. A main activity of this protein is the removal of R-loops, which are nucleic acid structures capable to promote DNA damage and replication stress. Here we found that Senataxin deficiency causes the release of damaged DNA into extranuclear bodies, called micronuclei, triggering the massive recruitment of cGAS, the apical sensor of the innate immunity pathway, and the downstream stimulation of interferon genes. Such cGAS-positive micronuclei are characterized by defective membrane envelope and are particularly abundant in cycling cells lacking Senataxin, but not after exposure to a DNA breaking agent or in absence of the tumor suppressor BRCA1 protein, a partner of Senataxin in R-loop removal. Micronuclei with a discontinuous membrane are normally cleared by autophagy, a process that we show is impaired in Senataxin-deficient cells. The formation of Senataxin-dependent inflamed micronuclei is promoted by the persistence of nuclear R-loops stimulated by the DSIF transcription elongation complex and the engagement of EXO1 nuclease activity on nuclear DNA. Coherently, high levels of EXO1 result in poor prognosis in a subset of tumors lacking Senataxin expression. Hence, R-loop homeostasis impairment, together with autophagy failure and unscheduled EXO1 activity, elicits innate immune response through micronuclei formation in cells lacking Senataxin.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_169,

title = {Guidelines for minimal information on cellular senescence experimentation in vivo},

author = {Ogrodnik M and Carlos Acosta J and Adams PD and {d'Adda di Fagagna F} and Baker DJ and Bishop CL and Chandra T and Collado M and Gil J and Gorgoulis V and Gruber F and Hara E and Jansen-Dürr P and Jurk D and Khosla S and Kirkland JL and Krizhanovsky V and Minamino T and Niedernhofer LJ and Passos JF and Ring NAR and Redl H and Robbins PD and Rodier F and Scharffetter-Kochanek K and Sedivy JM and Sikora E and Witwer K and von Zglinicki T and Yun MH and Grillari J and Demaria M},

url = {https://www.sciencedirect.com/science/article/pii/S0092867424006408?via%3Dihub},

doi = {10.1016/j.cell.2024.05.059},

year  = {2024},

date = {2024-08-19},

journal = {Cell},

volume = {187},

issue = {16},

pages = {4150-4175},

abstract = {Cellular senescence is a cell fate triggered in response to stress and is characterized by stable cell-cycle arrest and a hypersecretory state. It has diverse biological roles, ranging from tissue repair to chronic disease. The development of new tools to study senescence in vivo has paved the way for uncovering its physiological and pathological roles and testing senescent cells as a therapeutic target. However, the lack of specific and broadly applicable markers makes it difficult to identify and characterize senescent cells in tissues and living organisms. To address this, we provide practical guidelines called “minimum information for cellular senescence experimentation in vivo” (MICSE). It presents an overview of senescence markers in rodent tissues, transgenic models, non-mammalian systems, human tissues, and tumors and their use in the identification and specification of senescent cells. These guidelines provide a uniform, state-of-the-art, and accessible toolset to improve our understanding of cellular senescence in vivo.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Role of senataxin in R-loop-mediated neurodegeneration },

author = {Kannan A and Gangadharan Leela S and Branzei D and Gangwani L},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11277865/},

doi = {10.1093/braincomms/fcae239},

year  = {2024},

date = {2024-08-06},

urldate = {2024-08-06},

journal = {Brain communications},

volume = {6},

issue = {4},

abstract = {Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic target to treat neurodegenerative diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_168,

title = {FXR agonists INT-787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet-induced ob/ob mouse model of NASH },

author = {Di Pasqua LG and Cagna M and Palladini G and Croce AC and Cadamuro M and Fabris L and Perlini S and Adorini L and Ferrigno A and Vairetti M},

url = {https://onlinelibrary.wiley.com/doi/10.1111/liv.15767},

doi = {10.1111/liv.15767},

year  = {2024},

date = {2024-08-06},

journal = {Liver international},

volume = {44},

issue = {1},

pages = {214-227},

abstract = {Background and aims: We have previously shown in a model of hepatic ischaemia/reperfusion injury that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) restores reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), an inverse modulator of metalloproteases (MMPs) and inhibitor of the sheddases ADAM10 and ADAM17 involved in inflammation and fibrogenesis. Here, the effects of FXR agonists OCA and INT-787 on hepatic levels of RECK, MMPs, ADAM10 and ADAM17 were compared in a diet-induced ob/ob mouse model of non-alcoholic steatohepatitis (NASH). Methods: Lep ob/ob NASH mice fed a high-fat diet (HFD) or control diet (CD) for 9 weeks (wks) were treated with OCA or INT-787 0.05% dosed via HFD admixture (30 mg/kg/day) or HFD for further 12 wks. Serum alanine transaminase (ALT) and inflammatory cytokines, liver RECK, MMP-2 and MMP-9 activity as well as ADAM10, ADAM17, collagen deposition (Sirius red), hepatic stellate cell activation (α-SMA) and pCK+ reactive biliary cells were quantified. Results: Only INT-787 significantly reduced serum ALT, IL-1β and TGF-β. A downregulation of RECK expression and protein levels observed in HFD groups (at 9 and 21 wks) was counteracted by both OCA and INT-787. HFD induced a significant increase in liver MMP-2 and MMP-9; OCA administration reduced both MMP-2 and MMP-9 while INT-787 markedly reduced MMP-2 expression. OCA and INT-787 reduced both ADAM10 and ADAM17 expression and number of pCK+ cells. INT-787 was superior to OCA in decreasing collagen deposition and α-SMA levels. Conclusion: INT-787 is superior to OCA in controlling specific cell types and clinically relevant anti-inflammatory and antifibrotic molecular mechanisms in NASH.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_167,

title = {Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary },

author = {Cavazzoni A and Salamon I and Fumarola C and Gallerani G and Laprovitera N and Gelsomino F and Riefolo M and Rihawi K and Porcellini E and Rossi T and Mazzeschi M and Naddeo M and Serravalle S and Broseghini E and Agostinis F and Deas O and Roncarati R and Durante G and Pace I and Lauriola M and Garajova I and Calin GA and Bonafe’ M and D'Errico A and Petronini PG and Cairo S and Ardizzoni A and Sales G and Ferracin M.},

url = {https://www.sciencedirect.com/science/article/abs/pii/S1525001624004660?via%3Dihub},

doi = {10.1016/j.ymthe.2024.07.011},

year  = {2024},

date = {2024-08-06},

journal = {Molecular therapy},

abstract = {Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96) and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and fluorescence in situ hybridization analysis identified FGFR2 gene amplification in both models, in the form of homogeneously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both in vitro and in vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_166,

title = {Biochemical properties of chromatin domains define genome compartmentalization},

author = {Lucini F and Petrini C and Salviato E and Pal K and Rosti V and Gorini F and Santarelli P and Quadri R and Lembo G and Graziano G and Di Patrizio Soldateschi E and Tagliaferri I and Pinatel E and Sebestyén E and Rotta L and Gentile F and Vaira V and Lanzuolo C and Ferrari F},

url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkae454/7684597?login=true},

doi = {10.1093/nar/gkae454},

year  = {2024},

date = {2024-08-06},

journal = {Nucleic acids research},

volume = {52},

number = {e54},

issue = {12},

abstract = {Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined in a specific 3D nuclear compartment are expected to share similar epigenetic features and biochemical properties, in terms of accessibility and solubility. Based on this rationale, we developed the 4f-SAMMY-seq to map euchromatin and heterochromatin based on their accessibility and solubility, starting from as little as 10 000 cells. Adopting a tailored bioinformatic data analysis approach we reconstruct also their 3D segregation in active and inactive chromatin compartments and sub-compartments, thus recapitulating the characteristic properties of distinct chromatin states. A key novelty of the new method is the capability to map both the linear segmentation of open and closed chromatin domains, as well as their compartmentalization in one single experiment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Ex vivo characterization of acute myeloid leukemia patients undergoing hypomethylating agents and venetoclax regimen reveals a venetoclax-specific effect on non-suppressive regulatory T cells and bona fide PD-1+TIM3+ exhausted CD8+ T cells},

author = {Corradi G and Forte D and Cristiano G and Polimeno A and Ciciarello M and Salvestrini V and Bandini L and Robustelli V and Ottaviani E and Cavo M and Ocadlikova D and Curti A.},

url = {https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1386517/full},

doi = {10.3389/fimmu.2024.1386517},

year  = {2024},

date = {2024-08-06},

journal = {Frontiers in immunology},

volume = {15},

issue = {1386517},

abstract = {Acute myeloid leukemia (AML) is an aggressive heterogeneous disease characterized by several alterations of the immune system prompting disease progression and treatment response. The therapies available for AML can affect lymphocyte function, limiting the efficacy of immunotherapy while hindering leukemia-specific immune reactions. Recently, the treatment based on Venetoclax (VEN), a specific B-cell lymphoma 2 (BCL-2) inhibitor, in combination with hypomethylating agents (HMAs) or low-dose cytarabine, has emerged as a promising clinical strategy in AML. To better understand the immunological effect of VEN treatment, we characterized the phenotype and immune checkpoint (IC) receptors' expression on CD4+ and CD8+ T cells from AML patients after the first and second cycle of HMA in combination with VEN. HMA and VEN treatment significantly increased the percentage of naïve CD8+ T cells and TIM-3+ CD4+ and CD8+ T cells and reduced cytokine-secreting non-suppressive T regulatory cells (Tregs). Of note, a comparison between AML patients treated with HMA only and HMA in combination with VEN revealed the specific contribution of VEN in modulating the immune cell repertoire. Indeed, the reduction of cytokine-secreting non-suppressive Tregs, the increased TIM-3 expression on CD8+ T cells, and the reduced co-expression of PD-1 and TIM-3 on both CD4+ and CD8+ T cells are all VEN-specific. Collectively, our study shed light on immune modulation induced by VEN treatment, providing the rationale for a novel therapeutic combination of VEN and IC inhibitors in AML patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_165,

title = {Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer},

author = {Boufaied N and Chetta P and Hallal T and Cacciatore S and Lalli D and Luthold C and Homsy K and Imada EL and Syamala S and Photopoulos C and {Di Matteo A} and de Polo A and Storaci AM and Huang Y and Giunchi F and Sheridan PA and Michelotti G and Nguyen QD and Zhao X and Liu Y and Davicioni E and Spratt DE and Sabbioneda S and Maga G and Mucci LA and Ghigna C and Marchionni L and Butler LM and Ellis L and Bordeleau F and Loda M and Vaira V and Labbe' DP and Zadra G},

url = {https://aacrjournals.org/cancerres/article/84/11/1834/745520/Obesogenic-High-Fat-Diet-and-MYC-Cooperate-to},

doi = {10.1158/0008-5472.CAN-23-0519},

year  = {2024},

date = {2024-08-06},

urldate = {2024-08-06},

journal = {Cancer research},

volume = {84},

issue = {11},

pages = {1834-1855},

abstract = {Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Significance: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_161,

title = {CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells},

author = {Storci G and De Felice F and Ricci F and Santi S and Messelodi D and Bertuccio SN and Laprovitera N and Dicataldo M and Rossini L and De Matteis S and Casadei B and Vaglio F and Ursi M and Barbato F and Roberto M and Guarino M and Asioli GM and Arpinati M and Cortelli P and Maffini E and Tomassini E and Tassoni M and Cavallo C and Iannotta F and Naddeo M and Tazzari PL and Dan E and Pellegrini C and Guadagnuolo S and Carella M and Sinigaglia B and Pirazzini C and Severi C and Garagnani P and Kwiatkowska KM and Ferracin M and Zinzani PL and Bonafe’ M and Bonifazi F.},

url = {https://www.jci.org/articles/view/173096},

doi = {10.1172/JCI173096},

year  = {2024},

date = {2024-08-06},

journal = {Journal of clinical investigation},

volume = {134},

issue = {14},

pages = {e173096},

abstract = {Background: Predicting Immune-effector Cell Associated Neurotoxicity Syndrome (ICANS) in patients infused with Chimeric Antigen Receptor T cells (CAR-T) is still a conundrum. This complication, thought to be consequent to CAR-T cell activation, arises a few days after infusion, when circulating CAR-T cells are scarce and specific CAR-T cell-derived biomarkers are lacking. Methods: Human CD19.CAR-T cells were generated to gain insight into CAR+ extracellular vesicle (CAR+EV) release upon target engagement. A prospective cohort of 100 B-cell lymphoma patients infused with approved CD19.CAR-T cell products (axi-cel, brexu-cel and tisa-cel) was assessed for plasma CAR+EVs as potential biomarkers of in vivo CD19.CAR-T cell activation and predictors of ICANS. Human induced pluripotent stem cells (iPSCs)-derived neural cells were used as a model for CAR+EV-induced neurotoxicity. Results: In vitro, exosome-like CAR+EVs were released by CD19.CAR-T cells upon target engagement. In vivo, CAR+EVs were detectable as early as 1 hour in the plasma of patients. A concentration > 132.8 CAR+EVs/μl at hour +1 or > 224.5 CAR+EVs/μl at day +1 predicted ICANS in advance of 4 days, with a sensitivity up to 96.55% and a specificity up to 80.36%, outperforming other potential ICANS predictors. Enolase 2 (ENO2+) nanoparticles were released by iPSCs-derived neural cells upon CAR+EVs exposure and were increased in the plasma of ICANS patients. Conclusions: These results convey that plasma CAR+EVs are an immediate signal of CD19.CAR-T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_151,

title = {Collagen VI Deficiency Impairs Tendon Fibroblasts Mechanoresponse in Ullrich Congenital Muscular Dystrophy},

author = {Cenni V and Sabatelli P and Di Martino A and Merlini L and Antoniel M and Squarzoni S and Neri S and Santi S and Metti S and Bonaldo P and Faldini C.},

url = {https://www.mdpi.com/2073-4409/13/5/378},

doi = {10.3390/cells13050378},

year  = {2024},

date = {2024-08-06},

journal = {Cells},

volume = {13},

issue = {5},

pages = {378},

abstract = {The pericellular matrix (PCM) is a specialized extracellular matrix that surrounds cells. Interactions with the PCM enable the cells to sense and respond to mechanical signals, triggering a proper adaptive response. Collagen VI is a component of muscle and tendon PCM. Mutations in collagen VI genes cause a distinctive group of inherited skeletal muscle diseases, and Ullrich congenital muscular dystrophy (UCMD) is the most severe form. In addition to muscle weakness, UCMD patients show structural and functional changes of the tendon PCM. In this study, we investigated whether PCM alterations due to collagen VI mutations affect the response of tendon fibroblasts to mechanical stimulation. By taking advantage of human tendon cultures obtained from unaffected donors and from UCMD patients, we analyzed the morphological and functional properties of cellular mechanosensors. We found that the length of the primary cilia of UCMD cells was longer than that of controls. Unlike controls, in UCMD cells, both cilia prevalence and length were not recovered after mechanical stimulation. Accordingly, under the same experimental conditions, the activation of the Hedgehog signaling pathway, which is related to cilia activity, was impaired in UCMD cells. Finally, UCMD tendon cells exposed to mechanical stimuli showed altered focal adhesions, as well as impaired activation of Akt, ERK1/2, p38MAPK, and mechanoresponsive genes downstream of YAP. By exploring the response to mechanical stimulation, for the first time, our findings uncover novel unreported mechanistic aspects of the physiopathology of UCMD-derived tendon fibroblasts and point at a role for collagen VI in the modulation of mechanotransduction in tendons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_160,

title = {Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition},

author = {Ribeiro CF and Rodrigues S and Bastos DC and Fanelli GN and Pakula H and Foiani M and Zadra G and Loda M},

url = {https://www.science.org/doi/10.1126/scisignal.adh1922?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed},

doi = {10.1126/scisignal.adh1922},

year  = {2024},

date = {2024-05-28},

journal = {Science signaling},

volume = {17},

issue = {831},

abstract = {Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_159,

title = {4-Trifluoromethyl bithiazoles as broad-spectrum antimicrobial agents for virus-related bacterial infections or co-infections},

author = {Barbieri F and Carlen V and Martina MG and Sannio F and Cancade S and Perini C and Restori M and Crespan E and Maga G and Docquier JD and Cagno V and Radi M.},

url = {https://pubs.rsc.org/en/content/articlelanding/2024/md/d3md00686g},

doi = {10.1039/d3md00686g},

year  = {2024},

date = {2024-05-28},

journal = {RSC medicinal chemistry},

volume = {15},

issue = {5},

pages = {1589-1600},

abstract = {Respiratory tract infections involving a variety of microorganisms such as viruses, bacteria, and fungi are a prominent cause of morbidity and mortality globally, exacerbating various pre-existing respiratory and non-respiratory conditions. Moreover, the ability of bacteria and viruses to coexist might impact the development and severity of lung infections, promoting bacterial colonization and subsequent disease exacerbation. Secondary bacterial infections following viral infections represent a complex challenge to be overcome from a therapeutic point of view. We report herein our efforts in the development of new bithiazole derivatives showing broad-spectrum antimicrobial activity against both viruses and bacteria. A series of 4-trifluoromethyl bithiazole analogues was synthesized and screened against selected viruses (hRVA16, EVD68, and ZIKV) and a panel of Gram-positive and Gram-negative bacteria. Among them, two promising broad-spectrum antimicrobial compounds (8a and 8j) have been identified: both compounds showed low micromolar activity against all tested viruses, 8a showed synergistic activity against E. coli and A. baumannii in the presence of a subinhibitory concentration of colistin, while 8j showed a broader spectrum of activity against Gram-positive and Gram-negative bacteria. Activity against antibiotic-resistant clinical isolates is also reported. Given the ever-increasing need to adequately address viral and bacterial infections or co-infections, this study paves the way for the development of new agents with broad antimicrobial properties and synergistic activity with common antivirals and antibacterials.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_158,

title = {TERRA ONTseq: a long read-based sequencing pipeline to study the human telomeric transcriptome},

author = {Rodrigues J and Alfieri R and Bione S and Azzalin C.},

url = {https://rnajournal.cshlp.org/content/early/2024/05/22/rna.079906.123.long},

doi = {10.1261/rna.079906.123},

year  = {2024},

date = {2024-05-28},

urldate = {2024-05-28},

journal = {RNA},

volume = {30},

issue = {8},

pages = {955-966},

abstract = {The long noncoding RNA TERRA is transcribed from telomeres in virtually all eukaryotes with linear chromosomes. In humans, TERRA transcription is driven in part by promoters comprising CpG dinucleotide-rich repeats of 29 base pairs (29 bp repeats), believed to be present in half of the subtelomeres. Thus far, TERRA expression has been analyzed mainly using molecular biology-based approaches that only generate partial and somehow biased results. Here, we present a novel experimental pipeline to study human TERRA based on long read sequencing (TERRA ONTseq). By applying TERRA ONTseq to different cell lines, we show that the vast majority of human telomeres produce TERRA and that the cellular levels of TERRA transcripts varies according to their chromosomes of origin. Using TERRA ONTseq, we also identified regions containing TERRA transcription start sites (TSSs) in more than half of human subtelomeres. TERRA TSS regions are generally found immediately downstream of 29 bp repeat-related sequences, which appear to be more widespread than previously estimated. Finally, we isolated a novel TERRA promoter from the highly expressed subtelomere of the long arm of chromosome 7. With the development of TERRA ONTseq, we provide a refined picture of human TERRA biogenesis and expression and we equip the scientific community with an invaluable tool for future studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y,

title = {An Adapted Questionnaire Tailored for Assessing the Risk of Vitamin D Deficiency in Children That Is Proving Useful in Guiding Clinical Interventions},

author = {Calcaterra V and Cena H and De Giuseppe R and Biino G and Grazi R and Manuelli M and Zanelli S and Tagi V and Vincenti A and Zuccotti G and Fabiano V.},

url = {https://www.mdpi.com/2072-6643/16/7/971},

doi = {10.3390/nu16070971},

year  = {2024},

date = {2024-05-28},

urldate = {2024-05-28},

journal = {Nutrients},

volume = {16},

issue = {7},

pages = {971},

abstract = {Background: The identification of vitamin D (VitD) deficiency in pediatric populations is essential for preventive healthcare. We refined and tested the Evaluation of Deficiency Questionnaire (EVIDENCe-Q) for its utility in detecting VitD insufficiency among children. Patients and methods: We enrolled 201 pediatric patients (aged between 3 and 18 years). Clinical evaluation and serum vitamin D levels were assessed in all subjects. The EVIDENCe-Q was updated to incorporate factors influencing VitD biosynthesis, intake, assimilation, and metabolism, with scores spanning from 0 (optimal) to 36 (poor). Results: We established scores for severe deficiency (<10 mg/dL) at 20, deficiency (<20 mg/dL) at 22, and insufficiency (<30 mg/dL) at 28. A score of 20 or greater was determined as the optimal cut-off for distinguishing VitD deficient from sufficient statuses, as evidenced by ROC curve analysis AUC = 0.7066; SE = 0.0841; sensitivity 100%, 95% CI 0.561-1. The most accurate alignment was seen with VitD insufficiency, defined as 25-OH-D3 < 20 ng/mL. Conclusions: This study confirms that the EVIDENCe-Q is a valid instrument for assessing the risk of vitamin D deficiency and insufficiency in children. It offers a practical approach for determining the need for clinical intervention and dietary supplementation of VitD in the pediatric population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_156,

title = {Histochemical and ultrastructural localization of triterpene saponins in Medicago truncatula},

author = {Zannino L and Carelli M and Milanesi G and Croce AC and Biggiogera M and Confalonieri M},

url = {https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jemt.24591},

doi = {10.1002/jemt.24591},

year  = {2024},

date = {2024-05-28},

urldate = {2024-05-28},

journal = {Microscopy research and technique},

volume = {87},

issue = {9},

pages = {2143-2153},

abstract = {In the Medicago genus, saponins are complex mixtures of triterpene pentacyclic glycosides extensively studied for their different and economically relevant biological and pharmaceutical properties. This research is aimed at determining for the first time the tissue and cellular localization of triterpene saponins in vegetative organs of Medicago truncatula, a model plant species for legumes, by histochemistry and transmission electron microscopy. The results showed that saponins are present mainly in the palisade mesophyll layer of leaves, whereas in stems they are mostly located in the primary phloem and the subepidermal cells of cortical parenchyma. In root tissue, saponins occur in the secondary phloem region. Transmission electron microscopy revealed prominent saponin accumulation within the leaf and stem chloroplasts, while in the roots the saponins are found in the vesicular structures. Our results demonstrate the feasibility of using histochemistry and transmission electron microscopy to localize M. truncatula saponins at tissue and cellular levels and provide important information for further studies on biosynthesis and regulation of valuable bioactive saponins on agronomic relevant Medicago spp., such as alfalfa (Medicago sativa L.). RESEARCH HIGHLIGHTS: The Medicago genus represents a valuable rich source of saponins, one of the most interesting groups of secondary plant metabolites, which possess relevant biological and pharmacological properties. Plant tissue and cellular localization of saponins is of great importance to better understand their biological functions, biosynthetic pathway, and regulatory mechanisms. We elucidate the localization of saponins in Medicago truncatula with histochemical and transmission electron microscopy studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y,

title = {The NFATc1/P2X7 receptor relationship in human intervertebral disc cells},

author = {Notarangelo MP and Penolazzi L and Lambertini E and Falzoni S and De Bonis P and Capanni C and Di Virgilio F and Piva R.},

url = {https://www.frontiersin.org/articles/10.3389/fcell.2024.1368318/full},

doi = {10.3389/fcell.2024.1368318},

year  = {2024},

date = {2024-05-28},

urldate = {2024-05-28},

journal = {Frontiers in cell and developmental biology},

volume = {12},

pages = {1368318},

abstract = {A comprehensive understanding of the molecules that play key roles in the physiological and pathological homeostasis of the human intervertebral disc (IVD) remains challenging, as does the development of new therapeutic treatments. We recently found a positive correlation between IVD degeneration (IDD) and P2X7 receptor (P2X7R) expression increases both in the cytoplasm and in the nucleus. Using immunocytochemistry, reverse transcription PCR (RT-PCR), overexpression, and chromatin immunoprecipitation, we found that NFATc1 and hypoxia-inducible factor-1α (HIF-1α) are critical regulators of P2X7R. Both transcription factors are recruited at the promoter of the P2RX7 gene and involved in its positive and negative regulation, respectively. Furthermore, using the proximity ligation assay, we revealed that P2X7R and NFATc1 form a molecular complex and that P2X7R is closely associated with lamin A/C, a major component of the nuclear lamina. Collectively, our study identifies, for the first time, P2X7R and NFATc1 as markers of IVD degeneration and demonstrates that both NFATc1 and lamin A/C are interaction partners of P2X7R.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_153,

title = {Replicative senescence and high glucose induce the accrual of self-derived cytosolic nucleic acids in human endothelial cells},

author = {Ramini D and Giuliani A and Kwiatkowska KM and Guescini M and Storci G and Mensa' E and Recchioni R and Xumerle L and Zago E and Sabbatinelli J and Santi S and Garagnani P and Bonafe' M and Olivieri F.},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11032409/},

doi = {10.1038/s41420-024-01954-z},

year  = {2024},

date = {2024-05-28},

urldate = {2024-05-28},

journal = {Cell death discovery},

volume = {10},

number = {184},

issue = {1},

abstract = {Recent literature shows that loss of replicative ability and acquisition of a proinflammatory secretory phenotype in senescent cells is coupled with the build-in of nucleic acids in the cytoplasm. Its implication in human age-related diseases is under scrutiny. In human endothelial cells (ECs), we assessed the accumulation of intracellular nucleic acids during in vitro replicative senescence and after exposure to high glucose concentrations, which mimic an in vivo condition of hyperglycemia. We showed that exposure to high glucose induces senescent-like features in ECs, including telomere shortening and proinflammatory cytokine release, coupled with the accrual in the cytoplasm of telomeres, double-stranded DNA and RNA (dsDNA, dsRNA), as well as RNA:DNA hybrid molecules. Senescent ECs showed an activation of the dsRNA sensors RIG-I and MDA5 and of the DNA sensor TLR9, which was not paralleled by the involvement of the canonical (cGAS) and non-canonical (IFI16) activation of the STING pathway. Under high glucose conditions, only a sustained activation of TLR9 was observed. Notably, senescent cells exhibit increased proinflammatory cytokine (IL-1β, IL-6, IL-8) production without a detectable secretion of type I interferon (IFN), a phenomenon that can be explained, at least in part, by the accumulation of methyl-adenosine containing RNAs. At variance, exposure to exogenous nucleic acids enhances both IL-6 and IFN-β1 expression in senescent cells. This study highlights the accrual of cytoplasmic nucleic acids as a marker of senescence-related endothelial dysfunction, that may play a role in dysmetabolic age-related diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_152,

title = {Epithelial-to-mesenchymal transition and NF-kB pathways are promoted by a mutant form of DDB2, unable to bind PCNA, in UV-damaged human cells},

author = {Perucca P and Bassi E and Vetro M and Tricarico A and Prosperi E and Stivala LA and Cazzalini O},

url = {https://bmccancer.biomedcentral.com/articles/10.1186/s12885-024-12368-6},

doi = {10.1186/s12885-024-12368-6},

year  = {2024},

date = {2024-05-28},

journal = {BMC CANCER},

volume = {24},

issue = {1},

pages = {616},

abstract = {Background: DNA-Damaged Binding protein 2 (DDB2) is a protein involved in the early step of Nucleotide Excision Repair. Recently, it has been reported that DDB2 is involved in epithelial-to-mesenchymal transition (EMT), key process in tumour invasiveness and metastasis formation. However, its role is not completely known. Methods: Boyden chamber and cell adhesion assays, and ICELLigence analysis were performed to detect HEK293 adhesion and invasion. Western blotting and gelatine zymography techniques were employed to assess the EMT protein levels and MMP enzymatic activity. Immunofluorescence analysis and pull-down assays facilitated the detection of NF-kB sub-cellular localization and interaction. Results: We have previously demonstrated that the loss of DDB2-PCNA binding favours genome instability, and increases cell proliferation and motility. Here, we have investigated the phenotypic and molecular EMT-like changes after UV DNA damage, in HEK293 clones stably expressing DDB2Wt protein or a mutant form unable to interact with PCNA (DDB2PCNA-), as well as in HeLa cells transiently expressing the same DDB2 constructs. Cells expressing DDB2PCNA- showed morphological modifications along with a reduced expression of E-cadherin, an increased activity of MMP-9 and an improved ability to migrate, in concomitance with a significant upregulation of EMT-associated Transcription Factors (TFs), whose expression has been reported to favour tumour invasion. We observed a higher expression of c-Myc oncogene, NF-kB, both regulating cell proliferation and metastatic process, as well as ZEB1, a TF significantly associated with tumorigenic potential and cell migratory ability. Interestingly, a novel interaction of DDB2 with NF-kB was detected and found to be increased in cells expressing the DDB2PCNA-, suggesting a direct modulation of NF-kB by DDB2. Conclusion: These results highlight the role of DDB2-PCNA interaction in counteracting EMT since DDB2PCNA- protein induces in HEK293 transformed cells a gain of function contributing to the acquisition of a more aggressive phenotype.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_154,

title = {Molecular engineering of a spheroid-penetrating phage nanovector for photodynamic treatment of colon cancer cells},

author = {Turrini E and Ulfo L and Costantini PE and Saporetti R and Di Giosia M and Nigro M and Petrosino A and Pappagallo L and Kaltenbrunner A and Cantelli A and Pellicioni V and Catanzaro E and Fimognari C and Calvaresi M and Danielli A.},

url = {https://link.springer.com/article/10.1007/s00018-024-05174-7},

doi = {10.1007/s00018-024-05174-7},

year  = {2024},

date = {2024-05-14},

journal = {Cellular and molecular life sciences},

volume = {81},

issue = {1},

pages = {144},

abstract = {Photodynamic therapy (PDT) represents an emerging strategy to treat various malignancies, including colorectal cancer (CC), the third most common cancer type. This work presents an engineered M13 phage retargeted towards CC cells through pentavalent display of a disulfide-constrained peptide nonamer. The M13CC nanovector was conjugated with the photosensitizer Rose Bengal (RB), and the photodynamic anticancer effects of the resulting M13CC-RB bioconjugate were investigated on CC cells. We show that upon irradiation M13CC-RB is able to impair CC cell viability, and that this effect depends on i) photosensitizer concentration and ii) targeting efficiency towards CC cell lines, proving the specificity of the vector compared to unmodified M13 phage. We also demonstrate that M13CC-RB enhances generation and intracellular accumulation of reactive oxygen species (ROS) triggering CC cell death. To further investigate the anticancer potential of M13CC-RB, we performed PDT experiments on 3D CC spheroids, proving, for the first time, the ability of engineered M13 phage conjugates to deeply penetrate multicellular spheroids. Moreover, significant photodynamic effects, including spheroid disruption and cytotoxicity, were readily triggered at picomolar concentrations of the phage vector. Taken together, our results promote engineered M13 phages as promising nanovector platform for targeted photosensitization, paving the way to novel adjuvant approaches to fight CC malignancies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_150,

title = {Judith Campisi (1948-2024)},

author = {Wiley CD and Hara E and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/s43587-024-00603-5},

doi = {10.1038/s43587-024-00603-5},

year  = {2024},

date = {2024-03-18},

urldate = {2024-03-18},

journal = {Nature Aging},

volume = {4},

number = {435-436},

issue = {4},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_149,

title = {Molecular characterization of ANKRD1 in rhabdomyosarcoma cell lines: expression, localization, and proteasomal degradation.},

author = {Milosevic E and Novkovic M and Cenni V and Bavelloni A and Kojic S and Jasnic J},

url = {https://link.springer.com/article/10.1007/s00418-024-02272-2},

doi = {10.1007/s00418-024-02272-2},

year  = {2024},

date = {2024-03-18},

urldate = {2024-03-18},

journal = {Histochemistry and cell biology},

volume = {161},

issue = {5},

pages = {435},

abstract = {Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children and adolescents. Respecting the age of the patients and the tumor aggressiveness, investigation of the molecular mechanisms of RMS tumorigenesis is directed toward the identification of novel therapeutic targets. To contribute to a better understanding of the molecular pathology of RMS, we investigated ankyrin repeat domain 1 (ANKRD1), designated as a potential marker for differential diagnostics. In this study, we used three RMS cell lines (SJRH30, RD, and HS-729) to assess its expression profile, intracellular localization, and turnover. They express wild-type ANKRD1, as judged by the sequencing of the open reading frame. Each cell line expressed a different amount of ANKRD1 protein, although the transcript level was similar. According to western blot analysis, ANKRD1 protein was expressed at detectable levels in the SJRH30 and RD cells (SJRH30 > RD), but not in the HS-729, even after immunoprecipitation. Immunocytochemistry revealed nuclear and cytoplasmic localization of ANKRD1 in all examined cell lines. Moreover, the punctate pattern of ANKRD1 staining in the nuclei of RD and HS-729 cells overlapped with coilin, indicating its association with Cajal bodies. We have shown that RMS cells are not able to overexpress ANKRD1 protein, which can be attributed to its proteasomal degradation. The unsuccessful attempt to overexpress ANKRD1 in RMS cells indicates the possibility that its overexpression may have detrimental effects for RMS cells and opens a window for further research into its role in RMS pathogenesis and for potential therapeutic targeting.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_148,

title = {Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28-29 September 2023.},

author = {Ceccarini G and Akinci B and Araujo-Vilar D and Beghini M and Brown RJ and Tudela JC and Corradin V and Donadille B and Ruiz JJ and Jeru I and Lattanzi G and Maffei M and McIlroy GD and Nobécourt E and Perez de Tudela N and Rochford J and Sanders R and Schnurbein JV and Tews D and Vantyghem MC and Vatier C and Vigouroux C and Santini F.},

url = {https://www.sciencedirect.com/science/article/pii/S0003426624000362?via%3Dihub},

doi = {10.1016/j.ando.2024.03.002},

year  = {2024},

date = {2024-03-18},

urldate = {2024-03-18},

journal = {Annales d'endocrinologie},

volume = {S0003-4266},

issue = {24},

abstract = {Lipodystrophic syndromes are rare diseases affecting primarily the development or maintenance of the adipose tissue but are also distressing indirectly multiple organs and tissues, causing in most of the cases reduced life expectancy and quality of life. Lipodystrophy syndromes are multifaceted disorders caused by genetic mutations or autoimmune and iatrogenic mechanisms, many subtypes are now recognized and classified but the disease remains remarkably underdiagnosed. The European Consortium of Lipodystrophies (ECLip) was founded in 2014 as a non-profit network of European centers of excellence working in the field of lipodystrophies aiming at promoting international collaborations to increase basic scientific understanding and clinical management of these syndromes. The network has developed a European Patient Registry as a collaborative research platform for consortium members. ECLip and ECLip registry activities involve patient advocacy groups to increase public awareness and to advice on research activities relevant from the patients perspective. The annual ECLip congress gives an update on the research results of the various network groups members.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_147,

title = {ZEB1 shapes AML immunological niches, suppressing CD8 T cell activity while fostering Th17 cell expansion},

author = {Bassani B and Simonetti G and Cancila V and Fiorino A and Ciciarello M and Piva A and Khorasani AM and Chiodoni C and Lecis D and Gulino A and Fonzi E and Botti L and Portararo P and Costanza M and Brambilla M and Colombo G and Schwaller J and Tzankov A and Ponzoni M and Ciceri F and Bolli N and Curti A and Tripodo C and Colombo MP and Sangaletti S},

url = {https://www.sciencedirect.com/science/article/pii/S2211124724001220?via%3Dihub},

doi = {10.1016/j.celrep.2024.113794},

year  = {2024},

date = {2024-03-11},

journal = {Cell reports},

volume = {43},

issue = {2},

pages = {113794},

abstract = {Acute myeloid leukemia (AML) progression is influenced by immune suppression induced by leukemia cells. ZEB1, a critical transcription factor in epithelial-to-mesenchymal transition, demonstrates immune regulatory functions in AML. Silencing ZEB1 in leukemic cells reduces engraftment and extramedullary disease in immune-competent mice, activating CD8 T lymphocytes and limiting Th17 cell expansion. ZEB1 in AML cells directly promotes Th17 cell development that, in turn, creates a self-sustaining loop and a pro-invasive phenotype, favoring transforming growth factor beta (TGF-beta), interleukin-23 (IL-23), and SOCS2 gene transcription. In bone marrow biopsies from AML patients, immunohistochemistry shows a direct correlation between ZEB1 and Th17. Also, the analysis of ZEB1 expression in larger datasets identifies two distinct AML groups, ZEB1high and ZEB1low, each with specific immunological and molecular traits. ZEB1high patients exhibit increased IL-17, SOCS2, and TGF-beta pathways and a negative association with overall survival. This unveils ZEB1's dual role in AML, entwining pro-tumoral and immune regulatory capacities in AML blasts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_145,

title = {SnapShot: Tolerating replication stress},

author = {Szakal B and Giannattasio M and Branzei D},

url = {https://www.sciencedirect.com/science/article/abs/pii/S1097276523009760?via%3Dihub},

doi = {10.1016/j.molcel.2023.11.031},

year  = {2024},

date = {2024-02-13},

urldate = {2024-02-13},

journal = {Molecular cell},

volume = {84},

issue = {1},

pages = {182},

abstract = {Completion of DNA replication relies on the ability of replication forks to traverse various types of DNA damage, actively transcribed regions, and structured DNA. The mechanisms enabling these processes are here referred to as DNA damage tolerance pathways. Here, we depict the stalled DNA replication fork structures with main DNA transactions and key factors contributing to the bypass of such blocks, replication restart, and completion. To view this SnapShot, open or download the PDF.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Y_144,

title = {A bioartificial and vasculomorphic bone matrix-based organoid mimicking microanatomy of flat and short bones},

author = {Toni R and Barbaro F and Di Conza G and Zini N and Remaggi G and Elviri L and Spaletta G and Quarantini E and Quarantini M and Mosca S and Caravelli S and Mosca M and Ravanetti F and Sprio S and Tampieri A},

url = {https://onlinelibrary.wiley.com/doi/10.1002/jbm.b.35329},

doi = {10.1002/jbm.b.35329},

year  = {2024},

date = {2024-02-12},

journal = {Journal of biomedical materials research. Part B, Applied biomaterials},

volume = {112},

issue = {1},

pages = {e35329},

abstract = {We engineered an in vitro model of bioartificial 3D bone organoid consistent with an anatomical and vascular microenvironment common to mammalian flat and short bones. To achieve this, we chose the decellularized-decalcified matrix of the adult male rat scapula, implemented with the reconstruction of its intrinsic vessels, obtained through an original intravascular perfusion with polylevolactic (PLLA), followed by coating of the PLLA-fabricated vascularization with rat tail collagen. As a result, the 3D bone and vascular geometry of the native bone cortical and cancellous compartments was reproduced, and the rat tail collagen-PLLA biomaterial could in vitro act as a surrogate of the perivascular extracellular matrix (ECM) around the wall of the biomaterial-reconstituted cancellous vessels. As a proof-of-concept of cell compatibility and site-dependent osteoinductive properties of this bioartificial 3D construct, we show that it in vitro leads to a time-dependent microtopographic positioning of rat mesenchymal stromal cells (MSCs), initiating an osteogenic fate in relation to the bone compartment. In addition, coating of PLLA-reconstructed vessels with rat tail collagen favored perivascular attachment and survival of MSC-like cells (mouse embryonic fibroblasts), confirming its potentiality as a perivascular stroma for triggering competence of seeded MSCs. Finally, in vivo radiographic topography of bone lesions in the human jaw and foot tarsus of subjects with primary osteoporosis revealed selective bone cortical versus cancellous involvement, suggesting usefulness of a human 3D bone organoid engineered with the same principles of our rat organoid, to in vitro investigate compartment-dependent activities of human MSC in flat and short bones under experimental osteoporotic challenge. We conclude that our 3D bioartificial construct offers a reliable replica of flat and short bones microanatomy, and promises to help in building a compartment-dependent mechanistic perspective of bone remodeling, including the microtopographic dysregulation of osteoporosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}