Genome Maintenance in Mammalian Stem Cells.

Various stem cells in the body are tasked with maintaining tissue homeostasis throughout the life of an organism and thus must be resilient to intrinsic and extrinsic challenges such as infection and injury. Crucial to these challenges is genome maintenance because a high mutational load and persistent DNA lesions impact the production of essential gene products at proper levels and compromise optimal stem cell renewal and differentiation. Genome maintenance requires a robust and well-regulated DNA damage response suited to maintaining specific niches and tissues. In this review, we explore the similarities and differences between diverse stem cell types derived from (or preceding) all germ layers, including extraembryonic tissues. These cells utilize different strategies, including implementation of robust repair mechanisms, modulation of cell cycle checkpoints best suited to eliminating compromised cells, minimization of cell divisions, and differentiation in response to excessive damage.

Metabolic remodeling maintains a reducing environment for rapid activation of the yeast DNA replication checkpoint.

Nucleotide metabolism fuels normal DNA replication and is also primarily targeted by the DNA replication checkpoint when replication stalls. To reveal a comprehensive interconnection between genome maintenance and metabolism, we analyzed the metabolomic changes upon replication stress in the budding yeast S. cerevisiae. We found that upon treatment of cells with hydroxyurea, glucose is rapidly diverted to the oxidative pentose phosphate pathway (PPP). This effect is mediated by the AMP-dependent kinase, SNF1, which phosphorylates the transcription factor Mig1, thereby relieving repression of the gene encoding the rate-limiting enzyme of the PPP. Surprisingly, NADPH produced by the PPP is required for efficient recruitment of replication protein A (RPA) to single-stranded DNA, providing the signal for the activation of the Mec1/ATR-Rad53/CHK1 checkpoint signaling kinase cascade. Thus, SNF1, best known as a central energy controller, determines a fast mode of replication checkpoint activation through a redox mechanism. These findings establish that SNF1 provides a hub with direct links to cellular metabolism, redox, and surveillance of DNA replication in eukaryotes.

SLFN11 Blocks Stressed Replication Forks Independently of ATR.

SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.

Endothelial Cell Flow-Mediated Quiescence Is Temporally Regulated and Utilizes the Cell Cycle Inhibitor p27.

BACKGROUND: Endothelial cells regulate their cell cycle as blood vessels remodel and transition to quiescence downstream of blood flow-induced mechanotransduction. Laminar blood flow leads to quiescence, but how flow-mediated quiescence is established and maintained is poorly understood. METHODS: Primary human endothelial cells were exposed to laminar flow regimens and gene expression manipulations, and quiescence depth was analyzed via time-to-cell cycle reentry after flow cessation. Mouse and zebrafish endothelial expression patterns were examined via scRNA-seq (single-cell RNA sequencing) analysis, and mutant or morphant fish lacking p27 were analyzed for endothelial cell cycle regulation and in vivo cellular behaviors. RESULTS: Arterial flow-exposed endothelial cells had a distinct transcriptome, and they first entered a deep quiescence, then transitioned to shallow quiescence under homeostatic maintenance conditions. In contrast, venous flow-exposed endothelial cells entered deep quiescence early that did not change with homeostasis. The cell cycle inhibitor p27 (CDKN1B) was required to establish endothelial flow-mediated quiescence, and expression levels positively correlated with quiescence depth. p27 loss in vivo led to endothelial cell cycle upregulation and ectopic sprouting, consistent with loss of quiescence. HES1 and ID3, transcriptional repressors of p27 upregulated by arterial flow, were required for quiescence depth changes and the reduced p27 levels associated with shallow quiescence. CONCLUSIONS: Endothelial cell flow-mediated quiescence has unique properties and temporal regulation of quiescence depth that depends on the flow stimulus. These findings are consistent with a model whereby flow-mediated endothelial cell quiescence depth is temporally regulated downstream of p27 transcriptional regulation by HES1 and ID3. The findings are important in understanding endothelial cell quiescence misregulation that leads to vascular dysfunction and disease.

How Cells Respond to DNA Breaks in Mitosis.

DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to chromosomal instability if they are not repaired correctly. DSBs are especially dangerous in mitosis when cells go through the complex process of equal chromosome segregation into daughter cells. When cells encounter DSBs in interphase, they are able to arrest the cell cycle until the breaks are repaired before entering mitosis. However, when DSBs occur during mitosis, cells no longer arrest but prioritize completion of cell division over repair of DNA damage. This review focuses on recent progress in our understanding of the mechanisms that allow mitotic cells to postpone DSB repair without accumulating massive chromosomal instability. Additionally, we review possible physiological consequences of failed DSB responses in mitosis.

E6-Encoded by Cancer-Causing Human Papillomavirus Interacts with Aurora Kinase A To Promote HPV-Mediated Carcinogenesis.

The expression of human papillomavirus (HPV) oncoproteins perturbed multiple cellular events of the host cells, leading to the formation of cancer phenotypes. Our current and previous studies indicated that Aurora kinase A (AurA), a mitotic regulator that is often aberrantly expressed in human cancers, is preferentially bound to E6-encoded by cancer-causing HPV. AurA is believed to be important for the proliferation and survival of HPV-positive cells. Nonetheless, the interaction between AurA and E6, and the mechanism of how this association is involved in carcinogenesis, have not been elucidated clearly. Hence, we performed a series of biochemical assays to characterize the AurA-E6 association and complex formation. We found the C-terminus of E6, upstream of the PDZ binding motif of E6, is important to forming the AurA-E6 complex in the nucleus. We also showed that the expression level of E6 corresponded positively with AurA expression. Meanwhile, the functional consequences of the AurA-E6 association to AurA kinase function and host cellular events were also delineated. Intriguingly, we revealed that AurA-E6 association regulated the expression of cyclin E and phosphor-Histone H3, which are involved in G1/S and mitotic phases of the cell cycle, respectively. Depletion of AurA also reduced the invasive ability of HPV-positive cells. AurA inhibition may not be sufficient to reduce the oncogenic potential exerted by E6. Altogether, our study unleashed the mechanism of how HPVE6 deploy AurA to promote cancer phenotypes, particularly through dysregulation of cell cycle checkpoints and suggests that the AurA-E6 complex possesses a therapeutic value. IMPORTANCE We unveiled the mechanism of how HPV employs Aurora kinase A (AurA) of host cells to exert its oncogenic capability synergistically. We systematically characterized the mode of interaction between E6-encoded by cancer-causing HPV and AurA. Then, we delineated the consequences of AurA-E6 complex formation on AurA kinase function and changes to cellular events at molecular levels. Using a cell-based approach, we unleashed that disruption of AurA-E6 association can halt cancer phenotype exhibited by HPV-positive cancer cells. Our findings are vital for the designing of state-of-the-art therapies for HPV-associated cancers.

Differences in RAD51 transcriptional response and cell cycle dynamics reveal varying sensitivity to DNA damage among Arabidopsis thaliana root cell types.

Throughout their lifecycle, plants are subjected to DNA damage from various sources, both environmental and endogenous. Investigating the mechanisms of the DNA damage response (DDR) is essential to unravel how plants adapt to the changing environment, which can induce varying amounts of DNA damage. Using a combination of whole-mount single-molecule RNA fluorescence in situ hybridization (WM-smFISH) and plant cell cycle reporter lines, we investigated the transcriptional activation of a key homologous recombination (HR) gene, RAD51, in response to increasing amounts of DNA damage in Arabidopsis thaliana roots. The results uncover consistent variations in RAD51 transcriptional response and cell cycle arrest among distinct cell types and developmental zones. Furthermore, we demonstrate that DNA damage induced by genotoxic stress results in RAD51 transcription throughout the whole cell cycle, dissociating its traditional link with S/G2 phases. This work advances the current comprehension of DNA damage response in plants by demonstrating quantitative differences in DDR activation. In addition, it reveals new associations with the cell cycle and cell types, providing crucial insights for further studies of the broader response mechanisms in plants.

Small cell lung cancer: Novel treatments beyond immunotherapy.

Small cell lung cancer (SCLC) arises in peribronchial locations and infiltrates the bronchial submucosa, including about 15% of lung cancer cases. Despite decades of research, the prognosis for SCLC patients remains poor because this tumor is characterized by an exceptionally high proliferative rate, strong tendency for early widespread metastasis and acquired chemoresistance. Omics profiling revealed that SCLC harbor extensive chromosomal rearrangements and a very high mutation burden. This led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy, which however resulted in a prolonged benefit only for a small subset of patients. Thus, the present review discusses the rationale and limitations of immunotherapeutic approaches, presenting the current biological understanding of aberrant signaling pathways that might be exploited with new potential treatments. In particular, new agents targeting DNA damage repair, cell cycle checkpoint, and apoptosis pathways showed several promising results in different preclinical models. Epigenetic alterations, gene amplifications and mutations can act as biomarkers in this context. Future research and improved clinical outcome for SCLC patients will depend on the integration between these omics and pharmacological studies with clinical translational research, in order to identify specific predictive biomarkers that will be hopefully validated using clinical trials with biomarker-selected targeted treatments.

Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia.

BACKGROUND: Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of TP53-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with TP53 mutations, has not been definitively evaluated. METHODS: Anti-leukemic effects of adavosertib were investigated using a relapsed TP53 isogenic cell model system, primary patient, and patient-derived ALL samples (n = 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively. RESULTS: Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (n = 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of TP53 mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL. CONCLUSIONS: Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL.

A detailed map of coupled circadian clock and cell cycle with qualitative dynamics validation.

BACKGROUND: The temporal coordination of biological processes by the circadian clock is an important mechanism, and its disruption has negative health outcomes, including cancer. Experimental and theoretical evidence suggests that the oscillators driving the circadian clock and the cell cycle are coupled through phase locking. RESULTS: We present a detailed and documented map of known mechanisms related to the regulation of the circadian clock, and its coupling with an existing cell cycle map which includes main interactions of the mammalian cell cycle. The coherence of the merged map has been validated with a qualitative dynamics analysis. We verified that the coupled circadian clock and cell cycle maps reproduce the observed sequence of phase markers. Moreover, we predicted mutations that contribute to regulating checkpoints of the two oscillators. CONCLUSIONS: Our approach underlined the potential key role of the core clock protein NR1D1 in regulating cell cycle progression. We predicted that its activity influences negatively the progression of the cell cycle from phase G2 to M. This is consistent with the earlier experimental finding that pharmacological activation of NR1D1 inhibits tumour cell proliferation and shows that our approach can identify biologically relevant species in the context of large and complex networks.

Oxytocin receptor is a promising therapeutic target of malignant mesothelioma.

Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G-protein-coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.

MicroRNA-29b regulates the radiosensitivity of esophageal squamous cell carcinoma by regulating the BTG2-mediated cell cycle.

BACKGROUND: Many patients with esophageal squamous cell carcinoma (ESCC) are inoperable due to old age or advanced stage; thus, radio- and chemotherapy are considered the standard treatments for these patients. However, due to the radiation resistance of tumor cells that may arise during radiotherapy, results are still not satisfactory. The authors' previous studies found that microRNA can affect radiosensitivity, and further microRNA research was conducted to improve the radiosensitivity of ESCC. METHODS: Cells were treated with silent miR-29b (si-miR-29b). Thereafter,proliferation, colony formation, cell cycle, and apoptosis were determined. The luciferase reporting assay was used to confirm the direct interaction between miR-29b and BTG2. Serum samples and clinical follow-up data of 75 elderly or advanced ESCC patients who could not tolerate surgery were collected. RESULTS: The expression level of miR-29 in ESCC serum was closely correlated to radiosensitivity (χ2 =8.36, p < 0.05) and correlated with overall survival (OS; hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.24-0.90). Function assays demonstrated that the number of cell clones increased after radiometry radiation, and the cell cycle was blocked in the G0/G1 phase (from 37.2 to 56.9%) in the si-miR-29b transfection group. Expression of BTG2 was upregulated and expression of cyclin D1 was downregulated (p < 0.05). Transfection of si-BTG2 can reverse this result and restore the expression level of cyclin D1 (p < 0.05). The target gene BTG2 of miR-29b was predicted using a bioinformatics tool and confirmed by dual-luciferase reporter assay. CONCLUSION: Silencing of miR-29b in ESCC cells can increase expression of BTG2 and decrease the level of intracellular cyclin D1, resulting in cell cycle arrest and accumulation in the G0/G1 phase. Because G0/G1-phase cells are insensitive to radiotherapy, the sensitivity of radiotherapy is reduced.

Complex Mechanisms of Antimony Genotoxicity in Budding Yeast Involves Replication and Topoisomerase I-Associated DNA Lesions, Telomere Dysfunction and Inhibition of DNA Repair.

Antimony is a toxic metalloid with poorly understood mechanisms of toxicity and uncertain carcinogenic properties. By using a combination of genetic, biochemical and DNA damage assays, we investigated the genotoxic potential of trivalent antimony in the model organism Saccharomyces cerevisiae. We found that low doses of Sb(III) generate various forms of DNA damage including replication and topoisomerase I-dependent DNA lesions as well as oxidative stress and replication-independent DNA breaks accompanied by activation of DNA damage checkpoints and formation of recombination repair centers. At higher concentrations of Sb(III), moderately increased oxidative DNA damage is also observed. Consistently, base excision, DNA damage tolerance and homologous recombination repair pathways contribute to Sb(III) tolerance. In addition, we provided evidence suggesting that Sb(III) causes telomere dysfunction. Finally, we showed that Sb(III) negatively effects repair of double-strand DNA breaks and distorts actin and microtubule cytoskeleton. In sum, our results indicate that Sb(III) exhibits a significant genotoxic activity in budding yeast.

Chromosomal instability upregulates interferon in acute myeloid leukemia.

Chromosome instability (CIN) generates genetic and karyotypic diversity that is common in hematological malignancies. Low to moderate levels of CIN are well tolerated and can promote cancer proliferation. However, high levels of CIN are lethal. Thus, CIN may serve both as a prognostic factor to predict clinical outcome and as a predictive biomarker. A retrospective study was performed to evaluate CIN in acute myeloid leukemia (AML). Chromosome mis-segregation frequency was correlated with clinical outcome in bone marrow core biopsy specimens from 17 AML cases. Additionally, we induced chromosome segregation errors in AML cell lines with AZ3146, an inhibitor of the Mps1 mitotic checkpoint kinase, to quantify the phenotypic effects of high CIN. We observed a broad distribution of chromosome mis-segregation frequency in AML bone marrow core specimens. High CIN correlated with complex karyotype in AML, as expected, although there was no clear survival effect. In addition to CIN, experimentally inducing chromosome segregation errors by Mps1 inhibition in AML cell lines causes DNA damage, micronuclei formation, and upregulation of interferon stimulated genes. High levels of CIN appear to be immunostimulatory, suggesting an opportunity to combine mitotic checkpoint inhibitors with immunotherapy in treatment of AML.

Overproduction of a Dominant Mutant of the Conserved Era GTPase Inhibits Cell Division in Escherichia coli.

Cell growth and division are coordinated, ensuring homeostasis under any given growth condition, with division occurring as cell mass doubles. The signals and controlling circuit(s) between growth and division are not well understood; however, it is known in Escherichia coli that the essential GTPase Era, which is growth rate regulated, coordinates the two functions and may be a checkpoint regulator of both. We have isolated a mutant of Era that separates its effect on growth and division. When overproduced, the mutant protein Era647 is dominant to wild-type Era and blocks division, causing cells to filament. Multicopy suppressors that prevent the filamentation phenotype of Era647 either increase the expression of FtsZ or decrease the expression of the Era647 protein. Excess Era647 induces complete delocalization of Z rings, providing an explanation for why Era647 induces filamentation, but this effect is probably not due to direct interaction between Era647 and FtsZ. The hypermorphic ftsZ* allele at the native locus can suppress the effects of Era647 overproduction, indicating that extra FtsZ is not required for the suppression, but another hypermorphic allele that accelerates cell division through periplasmic signaling, ftsL*, cannot. Together, these results suggest that Era647 blocks cell division by destabilizing the Z ring.IMPORTANCE All cells need to coordinate their growth and division, and small GTPases that are conserved throughout life play a key role in this regulation. One of these, Era, provides an essential function in the assembly of the 30S ribosomal subunit in Escherichia coli, but its role in regulating E. coli cell division is much less well understood. Here, we characterize a novel dominant negative mutant of Era (Era647) that uncouples these two activities when overproduced; it inhibits cell division by disrupting assembly of the Z ring, without significantly affecting ribosome production. The unique properties of this mutant should help to elucidate how Era regulates cell division and coordinates this process with ribosome biogenesis.

[Stimulatory and inhibitory signaling pathways of the T cell-APC interaction and the effect of TLR agonists on APCs]. / Stimulierende und inhibierende Signalwege der APZ- und T-Zell-Interaktion sowie Einfluss von TLR-Agonisten auf APZ.

BACKGROUND: CD8+ cells are key players in the identification and elimination of cancer cells. Cancers can escape an effective T cell response by inducing an exhausted cell state, which limits the cytotoxic capacity of the effector cells. Among other mechanisms, new checkpoint inhibitors reactivate exhausted, dysfunctional T cells. CD8+ T cells can eliminate tumor cells after presentation of tumor-specific antigens via antigen-presenting cells (APCs). APC-mediated tumor recognition is mainly stimulated by Toll-like receptors (TLRs). OBJECTIVE: This study investigates the effect of TLR agonists on APCs as well as stimulatory and inhibitory signaling pathways of the T cell-APC interaction. MATERIALS AND METHODS: Gene expression of interleukin (IL)12 and programmed death ligand 1 (PD-L1) was analyzed by quantitative polymerase chain reaction (qPCR) after 0, 8, 24, and 48 h of CD14+ cell stimulation with CpG. Protein expression of inhibitor of nuclear factor kappa B (IκBα) after CpG stimulation was investigated by western blot. CD8+ T cells were stimulated for 72 h with or without programmed cell death protein 1 (PD-1) checkpoint blockade and analyzed for expression of PD­1, Tim­3, CTLA4, and Lag3 by flow cytometry. RESULTS: TLR stimulation (by unmethylated CpG DNA) of APCs upregulates immunostimulatory signals such as IL12 expression but also activates immunoinhibitory signaling pathways such as PD-L1 expression. This signaling is NF-κB dependent. After blockade of the PD-1/PD-L1 signaling pathway, overexpression of other immune checkpoint inhibitory receptors was observed-a potential explanation for lacking therapeutic responses after TLR stimulation with PD­1 checkpoint blockade. CONCLUSION: TLR stimulation causes APCs in the tumor microenvironment to upregulate PD-L1 in an NF-κB-mediated fashion, thereby contributing to CD8+ T cell exhaustion. The effect of PD­1 blockade after TLR stimulation might be impaired due to upregulation of other checkpoint inhibitors.

Mifepristone mediates anti-proliferative effect on ovarian mesenchymal stem/stromal cells from female BRCA1-/2- carriers.

INTRODUCTION: Women with hereditary mutation in breast cancer-associated genes (BRCA1-/2- ) have a higher lifetime risk of developing ovarian cancer. Here, we aimed to investigate the effect of mifepristone, a selective progesterone receptor modulator of ovarian mesenchymal stem/stromal cells (MSC) from BRCA1-/2- carriers. MATERIAL AND METHODS: Ovarian BRCA1-/2- MSC were positively selected using the markers CD90, CD73 and CD105 from nine healthy women. The effect of dose response and combination treatment with mifepristone and analogs of progesterone- or glucocorticoid-receptors were investigated on BRCA1-/2- MSC in vitro using a panel of markers for proliferation (ki67, BrdU, CDK2, p21CIP ), apoptosis (BAX, BCL2, CASPASE3), tumor suppression (TP53, PTEN) and cell survival (PI3KCA, MAPK3, mTOR). RESULTS: The dose response with mifepristone treatment suggested an optimal effect with 10 µm mifepristone, exhibiting >90% viability and significantly reducing growth signaling markers (TP53 and MAPK3). Furthermore, combined treatment with progesterone plus mifepristone (PG+MIFE) gave an enhanced anti-proliferative effect in comparison with hydrocortisone plus mifepristone (HC+MIFE) by significantly reducing markers of proliferation (BrdU+ and Ki67 expression) and tumor suppressors (PTEN, TP53), and increasing the percentage of pro-apoptotic cells. Consequently, accumulation of p21CIP together with reduced levels of CDK2 confirms growth inhibition by reversibly arresting cell-cycle progression at the G1-S phase, not by inducing apoptosis. CONCLUSIONS: Our study showed an anti-proliferative effect on ovarian BRCA1-/2- MSC on in vitro combined treatment with mifepristone and progesterone. These findings suggest that mifepristone or other selective progesterone receptor modulators could be developed as a preventive treatment and postpone early use of prophylactic salpingo-oophorectomy as well as reduce the risk of ovarian cancer.

DNA Damage Stress: Cui Prodest?

DNA is an entity shielded by mechanisms that maintain genomic stability and are essential for living cells; however, DNA is constantly subject to assaults from the environment throughout the cellular life span, making the genome susceptible to mutation and irreparable damage. Cells are prepared to mend such events through cell death as an extrema ratio to solve those threats from a multicellular perspective. However, in cells under various stress conditions, checkpoint mechanisms are activated to allow cells to have enough time to repair the damaged DNA. In yeast, entry into the cell cycle when damage is not completely repaired represents an adaptive mechanism to cope with stressful conditions. In multicellular organisms, entry into cell cycle with damaged DNA is strictly forbidden. However, in cancer development, individual cells undergo checkpoint adaptation, in which most cells die, but some survive acquiring advantageous mutations and selfishly evolve a conflictual behavior. In this review, we focus on how, in cancer development, cells rely on checkpoint adaptation to escape DNA stress and ultimately to cell death.

[Studies on radiotherapy of head and neck cancer : Highlights of the 2019 ASCO Annual Meeting]. / Strahlentherapeutische Studien bei Kopf-Hals-Tumoren : Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: Radiotherapy is an important treatment option in patients with head and neck. At this year's annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, results of several studies on radiotherapy in patients with head and neck cancer were presented. MATERIALS AND METHODS: All abstracts and presentations from this year's ASCO Annual Meeting on radiotherapy in patients with head and neck cancer were screened and the most interesting results selected for further review. RESULTS: The ORATOR trial compared primary surgery in patients with oropharyngeal carcinoma (OPSCC) with primary radiochemotherapy (RCT), particularly in terms of swallowing, for which superiority of RCT was demonstrated. Furthermore, results were presented on the question of optimal cisplatin dosage in patients receiving adjuvant RCT. Higher cisplatin doses showed better outcome. In patients with nasopharyngeal carcinoma (NPC), neoadjuvant chemotherapy before RCT is a comparable alternative to RCT followed by adjuvant chemotherapy. In addition, results of studies were presented that examined the tolerability of combining immunotherapy with radiotherapy in the first-line setting. CONCLUSION: The data presented show promising approaches for the further development of radiotherapy, particularly in terms of combined RCT as well as the optimal sequencing and dosing of systemic therapies.

[Salivary gland malignancies-highlights of the 2019 ASCO Annual Meeting]. / Maligne Speicheldrüsentumoren ­ Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: Due to their comparatively low incidence, salivary gland carcinomas have only been the subject of isolated clinical studies in recent years. In addition, surgery with/without adjuvant radiotherapy is considered standard treatment. Systemic therapies have received little attention and are only used for advanced and distantly metastasized salivary gland malignancies. OBJECTIVE: The contributions with the highest relevance for this year's meeting of the American Society of Clinical Oncology (ASCO) were to be reviewed. MATERIALS AND METHODS: A total of 12 contributions pertaining to clinical studies on salivary gland malignancies were identified, eight of which were classified as relevant for future changes to the therapeutic landscape. RESULTS: Three studies dealt with different combinations of a checkpoint blockade, and each showed a low response rate. In addition, studies on targeted therapies depending on the results of a mutation analysis and expression of HER2 or the androgen receptor were presented. CONCLUSION: A favorable response of HER2-positive salivary gland carcinomas to an antibody-drug conjugate could be shown. Furthermore, no convincing data regarding response to programmed cell death protein 1 (PD1)/programmed death ligand 1 (PD-L1) inhibitors in advanced salivary gland cancer were presented. Further studies and ideas for new treatment approaches will be needed to improve the therapeutic options for patients with salivary gland carcinoma.