Progressive conjunctival invasion of cornea in a child with Warburg-Cinotti Syndrome: a case report.

BACKGROUND: Warburg-Cinotti syndrome is a rare syndrome caused by de novo or inherited variants in discoding domain receptor tyrosine kinase 2 (DDR2). Only six cases have been reported worldwide and our knowledge of this disease remained sparse especially from an ophthalmological perspective, since previous literature mostly focused on systemic malformations or genetics. CASE PRESENTATION: A seven-year-old boy developed a gelatinous vascularized conjunctiva-like mass secondary to trauma. The mass enlarged and gradually invaded the cornea. With each surgical intervention, the mass recurred and grew even larger rapidly. The patient ended up with the mass covering the entire cornea along with symblepharon formation. Whole exome sequencing revealed a hemizygous variant in the DDR2 gene, which is consistent with Warburg-Cinotti syndrome. CONCLUSIONS: Considering Warburg-Cinotti syndrome, we should be vigilant of patients exhibiting progressive conjunctival invasion of the cornea, even those without systemic manifestations or a positive family history.

The crosstalk between DNA-damage responses and innate immunity.

DNA damage is typically caused during cell growth by DNA replication stress or exposure to endogenous or external toxins. The accumulation of damaged DNA causes genomic instability, which is the root cause of many serious disorders. Multiple cellular organisms utilize sophisticated signaling pathways against DNA damage, collectively known as DNA damage response (DDR) networks. Innate immune responses are activated following cellular abnormalities, including DNA damage. Interestingly, recent studies have indicated that there is an intimate relationship between the DDR network and innate immune responses. Diverse kinds of cytosolic DNA sensors, such as cGAS and STING, recognize damaged DNA and induce signals related to innate immune responses, which link defective DDR to innate immunity. Moreover, DDR components operate in immune signaling pathways to induce IFNs and/or a cascade of inflammatory cytokines via direct interactions with innate immune modulators. Consistently, defective DDR factors exacerbate the innate immune imbalance, resulting in severe diseases, including autoimmune disorders and tumorigenesis. Here, the latest progress in understanding crosstalk between the DDR network and innate immune responses is reviewed. Notably, the dual function of innate immune modulators in the DDR network may provide novel insights into understanding and developing targeted immunotherapies for DNA damage-related diseases, even carcinomas.

A small bowel adenocarcinoma harboring a DDR2 mutation in a celiac patient.

We present the case of a 62-year-old man with a history of celiac disease and IgA deficiency, following a strict gluten-free diet that was admitted to our hospital for recurrent abdominal pain, fatigue and melena. Esophagogastroduodenoscopy and colonoscopy with biopsies were normal. A video-capsule endoscopy was performed and revealed a sub-stenosing, vegetating, and bleeding lesion in the first jejunal loop. He underwent laparotomic surgery with resection of the involved segment with loco-regional lymphadenectomy. The pathological report described a poorly differentiated adenocarcinoma of the jejunum, stage IIIA (pT3pN1). Analysis of next-generation sequencing (NGS) of DNA on the surgical sample revealed a likely pathogenetic variant in exon 15 of the DDR2 gene (c.2003G > A) and a TP53 non-frame-shift deletion (c.585_602del). Considering the risk of recurrence, he was candidate to 6 months of adjuvant chemotherapy with platinum salt and fluoropyrimidine. Thirty-eight months after the diagnosis, the patient is still disease free and in good clinical condition. This is the first described case of SBA with DDR2 mutation. Considering the limited therapeutic options beyond surgery for SBA, molecular analyses could become promising for the search for potential targetable alterations for treatments with new available drugs.

Advances in the mechanism of small nucleolar RNA and its role in DNA damage response.

Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.

Hemin-Induced Transient Senescence Via DNA Damage Response: A Neuroprotective Mechanism Against Ferroptosis in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) poses acute fatality and long-term neurological risks due to hemin and iron accumulation from hemoglobin breakdown. Our observation that hemin induces DNA double-strand breaks (DSBs), prompting a senescence-like phenotype in neurons, necessitating deeper exploration of cellular responses. Using experimental ICH models and human ICH patient tissue, we elucidate hemin-mediated DNA damage response (DDR) inducing transient senescence and delayed expression of heme oxygenase (HO-1). HO-1 co-localizes with senescence-associated ß-Galactosidase (SA-ß-Gal) in ICH patient tissues, emphasizing clinical relevance of inducible HO-1 expression in senescent cells. We reveal a reversible senescence state protective against acute cell death by hemin, while repeat exposure leads to long-lasting senescence. Inhibiting early senescence expression increases cell death, supporting the protective role of senescence against hemin toxicity. Hemin-induced senescence is attenuated by a pleiotropic carbon nanoparticle that is a catalytic mimic of superoxide dismutase, but this treatment increased lipid peroxidation, consistent with ferroptosis from hemin breakdown released iron. When coupled with iron chelator deferoxamine (DEF), the nanoparticle reduces hemin-induced senescence and upregulates factors protecting against ferroptosis. Our study suggests transient senescence induced by DDR as an early potential neuroprotective mechanism in ICH, but the risk or iron-related toxicity supports a multi-pronged therapeutic approach.

Oncoproteins E6 and E7 upregulate topoisomerase I to activate the cGAS-PD-L1 pathway in cervical cancer development.

Background: Cervical cancer (CC) stands as a significant health threat to women globally, with high-risk human papillomaviruses as major etiologic agents. The DNA damage repair (DDR) protein topoisomerase I (TOP1) has been linked to various cancers, yet its distinct roles and mechanisms in CC are not fully elucidated. Methods: We investigated TOP1 expression in cervical intraepithelial neoplasia (CIN) and CC tissues utilizing qRT-PCR and IHC, correlating findings with patient prognosis. Subsequent knockdown studies were performed in vitro and in vivo to evaluate the influence of TOP1 on tumor growth, DNA repair, and inflammatory responses. Results: TOP1 was highly expressed in CIN and CC, negatively correlating with patient prognosis. Inhibition of TOP1 impeded CC cell growth and disrupted DNA repair. TOP1 was shown to regulate tumor-promoting inflammation and programmed death-ligand 1 (PD-L1) production in a cGAS-dependent manner. HPV oncoproteins E6 and E7 upregulated TOP1 and activated the cGAS-PD-L1 pathway. Conclusions: TOP1 acts as a DNA repair mediator, promoting CC development and immune evasion. Targeting the TOP1-cGAS-PD-L1 axis could be a potential therapeutic strategy for CC.

Poly (ADP-ribose) polymerase inhibitor therapy and mechanisms of resistance in epithelial ovarian cancer.

Advanced epithelial ovarian cancer is the commonest cause of gynaecological cancer deaths. First-line treatment for advanced disease includes a combination of platinum-taxane chemotherapy (post-operatively or peri-operatively) and maximal debulking surgery whenever feasible. Initial response rate to chemotherapy is high (up to 80%) but most patients will develop recurrence (approximately 70-90%) and succumb to the disease. Recently, poly-ADP-ribose polymerase (PARP) inhibition (by drugs such as Olaparib, Niraparib or Rucaparib) directed synthetic lethality approach in BRCA germline mutant or platinum sensitive disease has generated real hope for patients. PARP inhibitor (PARPi) maintenance therapy can prolong survival but therapeutic response is not sustained due to intrinsic or acquired secondary resistance to PARPi therapy. Reversion of BRCA1/2 mutation can lead to clinical PARPi resistance in BRCA-germline mutated ovarian cancer. However, in the more common platinum sensitive sporadic HGSOC, the clinical mechanisms of development of PARPi resistance remains to be defined. Here we provide a comprehensive review of the current status of PARPi and the mechanisms of resistance to therapy.

Lamin A/C facilitates DNA damage response by modulating ATM signaling and homologous recombination pathways.

Lamin A/C, a core component of the nuclear lamina, forms a mesh-like structure beneath the inner nuclear membrane. While its structural role is well-studied, its involvement in DNA metabolism remains unclear. We conducted sequential protein fractionation to determine the subcellular localization of early DNA damage response (DDR) proteins. Our findings indicate that most DDR proteins, including ATM and the MRE11-RAD50-NBS1 (MRN) complex, are present in the nuclease - and high salt-resistant pellet fraction. Notably, ATM and MRN remain stably associated with these structures throughout the cell cycle, independent of ionizing radiation (IR)-induced DNA damage. Although Lamin A/C interacts with ATM and MRN, its depletion does not disrupt their association with nuclease-resistant structures. However, it impairs the IR-enhanced association of ATM with the nuclear matrix and ATM-mediated DDR signaling, as well as the interaction between ATM and MRN. This disruption impedes the recruitment of MRE11 to damaged DNA and the association of damaged DNA with the nuclear matrix. Additionally, Lamin A/C depletion results in reduced protein levels of CtIP and RAD51, which is mediated by transcriptional regulation. This, in turn, impairs the efficiency of homologous recombination (HR). Our findings indicate that Lamin A/C plays a pivotal role in DNA damage repair (DDR) by orchestrating ATM-mediated signaling, maintaining HR protein levels, and ensuring efficient DNA repair processes.

Anti-tumor effects of the eIF4A inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas.

Inhibition of translation initiation using eIF4A inhibitors like (-)-didesmethylrocaglamide [(-)-DDR] and (-)-rocaglamide [(-)-Roc] is a potential cancer treatment strategy as they simultaneously diminish multiple oncogenic drivers. We showed that human and dog osteosarcoma cells expressed higher levels of eIF4A1/2 compared with mesenchymal stem cells. Genetic depletion of eIF4A1 and/or 2 slowed osteosarcoma cell growth. To advance preclinical development of eIF4A inhibitors, we demonstrated the importance of (-)-chirality in DDR for growth-inhibitory activity. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like (-)-DDR, (±)-DDR, and (-)-Roc, (±)-DDR-acetate increased γH2A.X levels and induced G2/M arrest and apoptosis. Consistent with translation inhibition, these rocaglates decreased the levels of several mitogenic kinases, the STAT3 transcription factor, and the stress-activated protein kinase p38. However, phosphorylated p38 was greatly enhanced in treated cells, suggesting activation of stress response pathways. RNA sequencing identified RHOB as a top upregulated gene in both (-)-DDR- and (-)-Roc-treated osteosarcoma cells, but the Rho inhibitor Rhosin did not enhance the growth-inhibitory activity of (-)-DDR or (-)-Roc. Nonetheless, these rocaglates potently suppressed tumor growth in a canine osteosarcoma patient-derived xenograft model. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas.

PARP inhibitors alone or in combination for prostate cancer.

DNA repair genomic aberrations in the Homologous Recombination pathway are identifiable in up to 25% of patients with advanced prostate cancer, making them more likely to benefit from treatment with poly (ADP-ribose) polymerase inhibitors (PARPi) alone or in combination with other therapies, particularly when BRCA driver genomic aberrations are documented. Although several clinical trials have demonstrated the efficacy of this approach, the validation of reliable biomarkers predictive of response still needs further improvement to refine patient selection. In this setting, the characterization of resistance mechanisms and the validation of novel biomarkers are critical to maximize clinical benefit and to develop novel treatment combinations to improve outcomes. In this review, we summarize the development of PARPi in prostate cancer as single agent as well as the efficacy of their combination with other drugs, and the future directions for their implementation in the management of advanced prostate cancer.

New treatment strategies for patients with metastatic prostate cancer Prostate cancer is the most common cancer in men worldwide. Alterations in the genes responsible for repairing damaged DNA are found in up to 25% of advanced prostate cancer patients. This inability of cells to repair damaged DNA allows tumours to grow, but it is also exploited by new treatments. An example of such therapies are the inhibitors of the Poly-ADP ribose polymerase, known as PARP inhibitors. PARP inhibitors are being developed alone and in combination with other drugs for the treatment of prostate cancer. In this manuscript, we provide an overview of the studies conducted in prostate cancer, as well as the future directions of PARP inhibitors for the management of the disease.

Pathogenic variants in human DNA damage repair genes mostly arose after the latest human out-of-Africa migration.

Introduction: The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to genome instability and increased susceptibility to diseases, especially cancer. Understanding the evolution origin and arising time of DDR PV is crucial for comprehending disease susceptibility in modern humans. Methods: We used big data approach to identify the PVs in DDR genes in modern humans. We mined multiple genomic databases derived from 251,214 modern humans of African and non-Africans. We compared the DDR PVs between African and non-African. We also mined the DDR PVs in the genomic data derived from 5,031 ancient humans. We used the DDR PVs from ancient humans as the intermediate to further the DDR PVs between African and non-African. Results and discussion: We identified 1,060 single-base DDR PVs across 77 DDR genes in modern humans of African and non-African. Direct comparison of the DDR PVs between African and non-African showed that 82.1% of the non-African PVs were not present in African. We further identified 397 single-base DDR PVs in 56 DDR genes in the 5,031 ancient humans dated between 45,045 and 100 years before present (BP) lived in Eurasian continent therefore the descendants of the latest out-of-Africa human migrants occurred 50,000-60,000 years ago. By referring to the ancient DDR PVs, we observed that 276 of the 397 (70.3%) ancient DDR PVs were exclusive in non-African, 106 (26.7%) were shared between non-African and African, and only 15 (3.8%) were exclusive in African. We further validated the distribution pattern by testing the PVs in BRCA and TP53, two of the important genes in genome stability maintenance, in African, non-African, and Ancient humans. Our study revealed that DDR PVs in modern humans mostly emerged after the latest out-of-Africa migration. The data provides a foundation to understand the evolutionary basis of disease susceptibility, in particular cancer, in modern humans.

A highly selective inhibitor of discoidin domain receptor-1 (DDR1-IN-1) protects corneal epithelial cells from YAP/ACSL4-mediated ferroptosis in dry eye.

BACKGROUND AND PURPOSE: This study investigated the involvement of discoidin domain receptor (DDR) in dry eye and assessed the potential of specific DDR inhibitors as a therapeutic strategy for dry eye by exploring the underlying mechanism. EXPERIMENTAL APPROACH: Dry eye was induced in Wistar rats by applying 0.2% benzalkonium chloride (BAC), after which rats were treated topically for 7 days with DDR1-IN-1, a selective inhibitor of DDR1. Clinical manifestations of dry eye were assessed on Day-7 post-treatment. Histological evaluation of corneal damage was performed using haematoxylin and eosin (H&E) staining. In vitro, immortalized human corneal epithelial cells (HCECs) exposed to hyperosmotic stress (HS) were treated with varying doses of DDR1-IN-1 for 24 h. The levels of lipid peroxidation in dry eye corneas or HS-stimulated HCECs were assessed. Protein levels of DDR1/DDR2 and related pathways were detected by western blotting. The cellular distribution of acyl-CoA synthetase long chain family member 4 (ACSL4) and Yes-associated protein (YAP) was evaluated using immunohistochemistry or immunofluorescent staining. KEY RESULTS: In dry eye corneas, only DDR1 expression was significantly up-regulated compared with normal controls. DDR1-IN-1 treatment significantly alleviated dry eye symptoms in vivo. The treatment remarkably reduced lipid hydroperoxide (LPO) levels and suppressed the expression of ferroptosis markers, particularly ACSL4. Overexpression or reactivation of YAP diminished the protective effects of DDR1-IN-1, indicating the involvement of the Hippo/YAP pathway in DDR1-targeted therapeutic effects. CONCLUSIONS AND IMPLICATIONS: This study confirms the significance of DDR1 in dry eye and highlights the potential of selective DDR1 inhibitor(s) for dry eye treatment.

Anti-tumor Effects of the eIF4A Inhibitor Didesmethylrocaglamide and Its Derivatives in Human and Canine Osteosarcomas.

Inhibition of translation initiation using eIF4A inhibitors like (-)-didesmethylrocaglamide [(-)-DDR] and (-)-rocaglamide [(-)-Roc] is a potential cancer treatment strategy as they simultaneously diminish multiple oncogenic drivers. We showed that human and dog osteosarcoma cells expressed high levels of eIF4A1/2, particularly eIF4A2. Genetic depletion of eIF4A1 and/or 2 slowed osteosarcoma cell growth. To advance preclinical development of eIF4A inhibitors, we demonstrated the importance of (-)-chirality in DDR for growth-inhibitory activity. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like DDR and Roc, DDR-acetate increased the γH2A.X levels and induced G2/M arrest and apoptosis. Consistent with translation inhibition, these rocaglates decreased the levels of several mitogenic kinases, the STAT3 transcription factor, and the stress-activated protein kinase p38. However, phosphorylated p38 was greatly enhanced in treated cells, suggesting activation of stress response pathways. RNA sequencing identified RHOB as a top upregulated gene in both DDR- and Roc-treated osteosarcoma cells, but the Rho inhibitor Rhosin did not enhance the growth-inhibitory activity of (-)-DDR or (-)-Roc. Nonetheless, these rocaglates potently suppressed tumor growth in a canine osteosarcoma patient-derived xenograft model. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas.

Chromothripsis is a novel biomarker for prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms.

This study aimed to identify the role of chromothripsis as a novel biomarker in the prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms (pNENs). We conducted next-generation gene sequencing in a cohort of 30 patients with high-grade (G3) pNENs. As a reference, a similar analysis was also performed on 25 patients with low-grade (G1/G2) pancreatic neuroendocrine tumors (pNETs). Chromothripsis and its relationship with clinicopathological features and prognosis were investigated. The results showed that DNA damage response and repair gene alteration and TP53 mutation were found in 29 and 11 patients, respectively. A total of 14 out of 55 patients had chromothripsis involving different chromosomes. Chromothripsis had a close relationship with TP53 alteration and higher grade. In the entire cohort, chromothripsis was associated with a higher risk of distant metastasis; both chromothripsis and metastasis (ENETS Stage IV) suggested a significantly shorter overall survival (OS). Importantly, in the high-grade pNENs group, chromothripsis was the only independent prognostic indicator significantly associated with a shorter OS, other than TP53 alteration or pathological pancreatic neuroendocrine carcinomas (pNECs) diagnosis. Chromothripsis can guide worse prognosis in pNENs, and help differentiate pNECs from high-grade (G3) pNETs.

Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders.

Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss of genome integrity, is a common feature among both neurodegenerative (mayo-trophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) and psychiatric (schizophrenia, autism, bipolar depression) disorders. Genomic instability is associated with the accumulation of persistent DNA damage and the activation of DNA damage response (DDR) pathways, as well as pathologic neuronal cell loss or senescence. Typically, DDR signaling ensures that genomic and proteomic homeostasis are maintained in both dividing cells, including neural progenitors, and post-mitotic neurons. However, dysregulation of these protective responses, in part due to aging or environmental insults, contributes to the progressive development of neurodegenerative and/or psychiatric disorders. In this Special Issue, we introduce and highlight the overlap between neurodegenerative diseases and neuropsychiatric disorders, as well as the emerging clinical, genomic, and molecular evidence for the contributions of DNA damage and aberrant DNA repair. Our goal is to illuminate the importance of this subject to uncover possible treatment and prevention strategies for relevant devastating brain diseases.

Development and therapeutic potential of DNA-dependent protein kinase inhibitors.

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

Evolution and challenges of DDR: A policy review through the prism of Colombia's DDR experience.

Disarmament, demobilization, and reintegration (DDR) processes have undergone significant evolution in recent decades, reflecting the complex dynamics of the transition from conflict to peace. This paper presents a comparative analysis of three generations of DDR processes, illustrating the shift from a primarily security-focused approach to a comprehensive strategy that includes socioeconomic development, political participation, and community engagement. In Colombia, a country with a long history of armed conflict, the process of DDR has undergone significant changes. These changes were made to adapt to the intricate realities of war, peace agreements, and social integration. During its evolution, DDR in Colombia has encountered challenges in expanding beyond the traditional scope of disarmament and demobilization to include the crucial aspect of reintegration. This highlights the significance of addressing the varied needs of ex-combatants and ensuring their sustainable integration into civilian life. The findings emphasize the importance of flexible and context-sensitive DDR frameworks that acknowledge the distinct challenges and opportunities of each post-conflict scenario. This provides valuable insights for future peacebuilding efforts worldwide.

Tau beyond Tangles: DNA Damage Response and Cytoskeletal Protein Crosstalk on Neurodegeneration.

Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons' DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders.

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity-A Narrative Review.

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic ß cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid ß-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging.

The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma.

The DNA damage response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway as well as abnormalities in the DDR/MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.