Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

Research on the Shale Reservoir Sensitivity by Using the Mineral Analysis Method.

Shale reservoirs have diverse mineral types, and analyzing the sensitivity of the mineral composition to shale pores is of great scientific and engineering significance. In this paper, first, X-ray diffraction (XRD) experiments on shale mineral compositions are carried out, and the characteristics of pore structure changes after shale mineral compositions interacted with external fluids (slick water and backflow fluid) are elucidated. Then, the effects of quartz, kaolinite, and pyrite on the pore structure and permeability of shale on the susceptibility to slick water are studied. The results show that (a) quartz and clay minerals are the dominant constituents of each core, with some cores containing minor amounts of plagioclase feldspar and rhodochrosite. (b) The composition of the shale changed significantly following the action of external fluids. The average quartz content of pure shale decreased from 31.62% to 29.1%. The average content of quartz in siliceous shale decreased from 36.53% to 33.5%. The average content of quartz in carbonaceous shale decreased from 9.15% to 8.05%. (c) Factors affecting the sensitivity of shale pore structure and permeability to slick water are mainly quartz, kaolinite, and pyrite. The contents of quartz, kaolinite, and pyrite decreased by an average of 5.1%, 4.6%, and 0.9%, respectively, after slick water action.

Facile synthesis of amorphous/crystalline Ni-Fe thiophenedicarboxylate coordination polymer nanobelts for efficient water oxidation.

The oxygen evolution reaction (OER) is a complex four-electron transfer process that poses a significant challenge to the efficient production of hydrogen through water splitting. However, developing non-noble metal electrocatalyst with excellent OER performance is still a big challenge. Herein, we propose a new strategy for the in-situ growth of two-dimensional amorphous/crystalline thiophene-based Ni-Fe metal-organic frameworks (MOFs) using Ni-Fe foam (NFF) as metal source and current collector, and thiophene-2,5-dicarboxylic acid (TDC) as corrosion agent and ligand. TDC was ionized at high temperature to produce H+ ions that etch NFF to release Ni2+ and Fe2+ ions, which were coordinated with TDC to in situ synthesize two-dimensional Ni-Fe thiophenedicarboxylate coordination polymer (NiFe-TDC) nanobelts on NFF. The unique structure and synergistic effect of Ni and Fe ions of NiFe-TDC0.05 result in the excellent OER performance with an overpotential of 224 and 256 mV at current densities of 10 and 100 mA cm-2, respectively, and it can run stably for 100 h at a current density of 100 mA cm-2, indicating the outstanding stability. Furthermore, NiFe-TDC0.05 remains the excellent OER performance with an extremely low potential of 196 and 271 mV at current densities of 10 and 100 mA cm-2 in seawater with 1 mol L-1 (M) KOH, respectively. The assembled NiFe-TDC0.05 || Pt/C water electrolysis cell achieves a current density of 100 mA cm-2 at a low voltage of 1.78 V. The work provides a new method to prepare two dimensional MOFs for efficient water oxidation.

Synthesis of self-supported NiCoFe(OH)x via fenton-like effect corrosion for highly efficient water oxidation.

Efficientandinexpensiveoxygenevolutionreaction(OER)catalysts are essential for the electrochemical splitting of water into hydrogen fuel. Herein, we have successfully synthesized NiCoFe(OH)x nanosheets on Ni-Fe foam (NFF) by exploiting the Fenton-like effect of Co2+ and S2O82- to corrode the NFF foam. The as-prepared NiCoFe(OH)x/NFF exhibits the porous structure with the interconnected nanosheets that are firmly bonded to the conductive substrate of NFF, thereby enhancing ions and charge transfer kinetics. The unique structure and composition of NiCoFe(OH)x/NFF result in the low overpotentials of 200 and 262 mV at current densities of 10 and 100 mA cm-2, respectively, as well as a low Tafel slope of 53.25 mV dec-1. In addition, NiCoFe(OH)x/NFF displays low overpotentials of 267 and 294 mV at a high current density of 100 mA cm-2 in simulated and real seawater, respectively. Furthermore, the assembled NiCoFe(OH)x//Pt/C water electrolysis cell has achieved a current density of 10 mA cm-2 at a low voltage of 1.49 V, and displayed the good stability with slight attenuation for 110 h. The high OER performance of NiCoFe(OH)x is attributed to the co-catalytic effect of the three metal ions and the interconnected porous nanosheet structure.

TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.

PURPOSE: TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 - all pleiotropic modulators of the DNA Damage Response (DDR). Here, we investigated the role of TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC). METHODS: TIPRL1 mRNA (cBioportal) and protein expression (immunohistochemistry) in HNSCC samples were linked with clinical patient data. TIPRL1-depleted HNSCC cells were generated by CRISPR/Cas9 editing, and effects on colony growth, micronuclei formation (microscopy), cell cycle (flow cytometry), DDR signaling (immunoblots) and proteome (mass spectrometry) following RT were assessed. Mass spectrometry was used for TIPRL1 phosphorylation and interactomics analysis in irradiated cells. RESULTS: TIPRL1 expression was increased in tumor versus non-tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265. A non-phospho Ser265Ala mutant could not rescue the increased radiosensitivity phenotype of TIPRL1-depleted cells. While binding to PP2A-like phosphatases was confirmed, DNA-dependent protein kinase (DNA-PKcs), RAD51 recombinase and nucleosomal histones were identified as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation. CONCLUSIONS: Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of the DDR, highlighting its potential as a new HNSCC predictive marker and therapeutic target.

Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding.

Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination.

Bulky oxadithiolate-bridged [FeFe]­hydrogenase mimics [Fe2(µ-R2odt)(CO)4(κ2-diphosphine)] (R = Ph and H) with chelating diphosphines.

In order to develop an attractive generation of bulky oxadithiolate-bridged [FeFe]­hydrogenase mimics with chelating diphosphines, two new series of asymmetrically diphosphine-substituted diiron model complexes [Fe2(µ-R2odt)(CO)4(κ2-diphosphine)] (3-5) with bulky Ph2odt bridge and their reference counterparts (6-8) with common odt bridge were obtained from the Me3NO-assisted substitutions of diiron hexacarbonyl precursors [Fe2(µ-R2odt)(CO)6] (R2odt = (SCHR)2O, R = Ph (1) and H (2)) with different diphosphines such as (Ph2P)2NBn (labelled PNBnP, Bn = benzyl), (Ph2PCH2)2NBn (PCNBnCP), and (Ph2PCH2)2CH2 (DPPP)), respectively. All the as-prepared complexes have been characterized by elemental analysis, IR plus NMR spectroscopies, and particularly by X-ray crystallography for 3-8. It is interesting to note that complexes 3 and 6 chelating by small bite-angle PNBnP diphosphine have the favorable dibasal isomer whereas analogues 4, 5 and 7, 8 chelating by flexible backbone PCNBnCP or DPPP ligands possess the main apical-basal isomer in solution or in the solid state. Further, the electrochemical properties of two pairs of representative complexes 3, 6 and 5, 8 are explored and compared by cyclic voltammetry (CV) in the absence and presence of trifluoroacetic acid (CF3CO2H) as proton source, indicating that the complete protonations of 3, 6 and 5, 8 with higher concentration of CF3CO2H lead to two new catalytic waves for the electrocatalytic proton reduction to hydrogen (H2).

Biochar-based molybdenum slow-release fertilizer enhances nitrogen assimilation in Chinese flowering cabbage (Brassica parachinensis).

Low molybdenum (Mo) bioavailability in acidic soil obstructs vegetable nitrogen assimilation and thus increases the health risk of vegetable ingestion due to nitrate accumulation. Constantly providing available Mo in acidic soil is a challenge for decreasing nitrate accumulation in vegetables. In this study, three Mo application methods, including biochar-based Mo slow-release fertilizer (Mo-biochar), seed dressing, and basal application, were investigated to enhance Mo bioavailability in acidic soil and nitrogen assimilation in Chinese flowering cabbage (Brassica parachinensis). The results showed that Mo-biochar constantly and sufficiently supplied Mo nutrients throughout the growing period of Brassica parachinensis, as evidenced by the soil available Mo, plant Mo uptake, and Mo values. The improved Mo supply was attributed to the alleviation of acidic soil (pH from 5.10 to 6.99) and the slow release of Mo adsorbed on biochar. Mo-biochar increased the nitrate reductase (NR) activity by 238.6% and glutamate dehydrogenase activity by 27.5%, indicating an enhancement of the rate-limiting steps of nitrogen assimilation, especially for nitrate reduction and amino acid synthesis. The increase in Mo-containing NR could be directly ascribed to the high level of Mo in Brassica parachinensis. Compared with the control, the nitrate content of Brassica parachinensis decreased by 42.9% due to the nitrate reduction induced by increased NR. Additionally, Mo-biochar was beneficial to vegetable growth and quality. In contrast, the transformation from NO3- to NH4+ was blocked with Mo seed dressing and basal application because of low Mo bioavailability in the soil, resulting in a high nitrate content in Brassica parachinensis. Conclusively, Mo-biochar can slowly release Mo and improve the neutral environment for Mo bioavailability, which is an effective strategy to mitigate the high nitrate accumulation of vegetables planted in acidic soil.

The long non-coding RNA SAMMSON is essential for uveal melanoma cell survival.

Long non-coding RNAs (lncRNAs) can exhibit cell-type and cancer-type specific expression profiles, making them highly attractive as therapeutic targets. Pan-cancer RNA sequencing data revealed broad expression of the SAMMSON lncRNA in uveal melanoma (UM), the most common primary intraocular malignancy in adults. Currently, there are no effective treatments for UM patients with metastatic disease, resulting in a median survival time of 6-12 months. We aimed to investigate the therapeutic potential of SAMMSON inhibition in UM. Antisense oligonucleotide (ASO)-mediated SAMMSON inhibition impaired the growth and viability of a genetically diverse panel of uveal melanoma cell lines. These effects were accompanied by an induction of apoptosis and were recapitulated in two uveal melanoma patient derived xenograft (PDX) models through subcutaneous ASO delivery. SAMMSON pulldown revealed several candidate interaction partners, including various proteins involved in mitochondrial translation. Consequently, inhibition of SAMMSON impaired global, mitochondrial and cytosolic protein translation levels and mitochondrial function in uveal melanoma cells. The present study demonstrates that SAMMSON expression is essential for uveal melanoma cell survival. ASO-mediated silencing of SAMMSON may provide an effective treatment strategy to treat primary and metastatic uveal melanoma patients.

Loss-of-Function Mutations in TRAF7 and KLF4 Cooperatively Activate RAS-Like GTPase Signaling and Promote Meningioma Development.

Meningiomas are the most common benign brain tumors. Mutations of the E3 ubiquitin ligase TRAF7 occur in 25% of meningiomas and commonly cooccur with mutations in KLF4, yet the functional link between TRAF7 and KLF4 mutations remains unclear. By generating an in vitro meningioma model derived from primary meningeal cells, we elucidated the cooperative interactions that promote meningioma development. By integrating TRAF7-driven ubiquitinome and proteome alterations in meningeal cells and the TRAF7 interactome, we identified TRAF7 as a proteostatic regulator of RAS-related small GTPases. Meningioma-associated TRAF7 mutations disrupted either its catalytic activity or its interaction with RAS GTPases. TRAF7 loss in meningeal cells altered actin dynamics and promoted anchorage-independent growth by inducing CDC42 and RAS signaling. TRAF deficiency-driven activation of the RAS/MAPK pathway promoted KLF4-dependent transcription that led to upregulation of the tumor-suppressive Semaphorin pathway, a negative regulator of small GTPases. KLF4 loss of function disrupted this negative feedback loop and enhanced mutant TRAF7-mediated cell transformation. Overall, this study provides new mechanistic insights into meningioma development, which could lead to novel treatment strategies. SIGNIFICANCE: The intricate molecular cross-talk between the ubiquitin ligase TRAF7 and the transcription factor KLF4 provides a first step toward the identification of new therapies for patients with meningioma.

Mononuclear nickel(II) dithiolate complexes with chelating diphosphines: Insight into protonation and electrochemical proton reduction.

Inspired by the metal active sites of [FeFe]- and [NiFe]­hydrogenases, a series of mononuclear Ni(II) ethanedithiolate complexes [{(Ph2PCH2)2×}Ni(SCH2CH2S)] (X = NCH2C5H4N-p (2a), NCH2C6H5 (2b), NCH2CHMe2 (2c), and CH2 (2d)) with chelating diphosphines were readily synthesized through the room-temperature treatments of mononuclear Ni(II) dichlorides [{(Ph2PCH2)2×}NiCl2] (1a-1d) with ethanedithiol (HSCH2CH2SH) in the presence of triethylamine (Et3N) as acid-binding agent. All the as-prepared complexes 1a-1d and 2a-2d are fully characterized through elemental analysis, nuclear magnetic resonance (NMR) spectrum, and by X-ray crystallography for 1b, 2a-2d. To further explore proton-trapping behaviors of this type of mononuclear Ni(II) complexes for catalytic hydrogen (H2) evolution, the protonation and electrochemical proton reduction of 2a-2c with aminodiphosphines (labeled PCNCP = (Ph2PCH2)2NR) and reference analogue 2d with nitrogen-free diphosphine (dppp = (Ph2PCH2)2CH2) are studied and compared under trifluoroacetic acid (TFA) as a proton source. Interestingly, the treatments of 2a-2d with excess TFA resulted in the unexpected formation of dinuclear Ni(II)-Ni(II) dication complexes [{(Ph2PCH2)2×}2Ni2(µ-SCH2CH2S)](CF3CO2)2 (3a-3d) and mononuclear Ni(II) N-protonated complexes [{(Ph2PCH2)2N(H)R}Ni(SCH2CH2S)](CF3CO2) (4a-4c), which has been well supported by high-resolution electrospray ionization mass spectroscopy (HRESI-MS), NMR (31P, 1H) as well as fourier transform infrared spectroscopy (FT-IR) techniques, and especially by X-ray crystallography for 3d. Additionally, the electrochemical properties of 2a-2d are investigated in the absence and presence of strong acid (TFA) by using cyclic voltammetry (CV), showing that the complete protonation of 2a-2d gave rise to dinuclear Ni2S2 species 3a-3d for electrocatalytic proton reduction to H2.

A risk-based approach for the safety analysis of eight trace elements in Chinese flowering cabbage (Brassica parachinensis L.) in China.

BACKGROUND: Most countries set regulatory values for the total trace element (TE) concentrations in soil, although there is growing interest in using a risk-based approach to evaluate the bioavailable TE using dilute salt extractants or other soil parameters, including pH and organic carbon. The present study compares the current regulatory system (based on total TEs and pH) and a risk-based approach using 0.01 mol L-1 CaCl2 to estimate the bioavailable fraction. RESULTS: In total, 150 paired samples of Chinese flowering cabbages (Brassica parachinensis) and their growth soils were collected, and the total and extractable concentrations of chromium (Cr), cadmium (Cd), lead (Pb), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As) and mercury (Hg), as well as soil pH and organic matter content, were measured. No more than 3.33% of the edible parts exceeded Chinese food safety standards, even when growing in soils exceeding the current regulatory thresholds by over 50%. The total soil Cd (1.5 mg kg-1 ), as well as the extractable concentrations of Cd (0.1 mg kg-1 ), Ni (0.03 mg kg-1 ) and Zn (0.1 mg kg-1 ), are the key factors affecting the TE concentrations in B. parachinensis. CONCLUSION: Our findings suggest that the current soil regulatory guidelines for safe production of B. parachinensis are overly strict and conservative. A risk-based approach based on the extractable TE concentrations would provide a better indication for plant uptake of soil TEs and avoid the waste of farmlands that can still produce safe vegetables. Future research should focus on providing crop-specific available TE concentration guidelines to promote effective utilization of farmlands. © 2021 Society of Chemical Industry.

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

Loss of 9p21 Regulatory Hub Promotes Kidney Cancer Progression by Upregulating HOXB13.

Loss of chromosome 9p21 is observed in one-thirds of clear-cell renal cell carcinoma (ccRCC) and is associated with poorer patient survival. Unexpectedly, 9p21 LOH does not lead to decreased expression of the 9p21 tumor suppressor genes, CDKN2A and CDKN2B, suggesting alternative mechanisms of 9p-mediated tumorigenesis. Concordantly, CRISPR-mediated 9p21 deletion promotes growth of immortalized human embryonic kidney epithelial cells independently of the CDKN2A/B pathway inactivation. The 9p21 locus has a highly accessible chromatin structure, suggesting that 9p21 loss might contribute to kidney cancer progression by dysregulating genes distal to the 9p21 locus. We identified several 9p21 regulatory hubs by assessing which of the 9p21-interacting genes are dysregulated in 9p21-deleted kidney cells and ccRCCs. By focusing on the analysis of the homeobox gene 13 (HOXB13) locus, we found that 9p21 loss relieves the HOXB13 locus, decreasing HOXB13 methylation and promoting its expression. Upregulation of HOXB13 facilitates cell growth and is associated with poorer survival of patients with ccRCC. IMPLICATIONS: The results of our study propose a novel tumor suppressive mechanism on the basis of coordinated expression of physically associated genes, providing a better understanding of the role of chromosomal deletions in cancer.

Diiron and trinuclear NiFe2 dithiolate complexes chelating by PCNCP ligands: Synthetic models of [FeFe]- and [NiFe]-hydrogenases.

To further develop the biomimetic chemistry of [FeFe]- and [NiFe]-hydrogenases for catalytic proton reduction to hydrogen (H2), two serials of dinuclear diiron and trinuclear NiFe2 dithiolate complexes with chelating PCNCP ligands, namely, Fe2(µ-edt)(CO)4{κ2-(Ph2PCH2)2NR} (1a-1c) and Fe2(CO)6(µ3-S)2Ni{(Ph2PCH2)2NR} (2a-2c) where edt = SCH2CH2S and PCNCP = (Ph2PCH2)2NR [R = Bui (CH2CHMe2), But (CMe3), and Bun (CH2CH2CH2Me)], have been synthesized in moderate yields. All the new complexes 1a-1c and 2a-2c have been fully characterized by elemental analysis, FT-IR, NMR spectroscopy, and single-crystal X-ray diffraction analysis. More importantly, to explore the influence of transition metal cores (i.e., nickel and iron) on the electrochemical and electrocatalytic properties of hydrogenase-inspired molecular catalysts for H2 evolution, the cyclic voltammetries (CVs) of 1a-1c and 2a-2c are studied and compared in nBu4NPF6/DMF solution without and with acetic acid (HOAc) as a proton source. This finding suggests that (i) complexes 1a-1c and 2a-2c are all found to be active for electrocatalytic H2 evolution, but (ii) they display the distinct redox behaviors and electrocatalytic proton reduction abilities.

The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking.

RATIONALE: Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches. OBJECTIVE: Bleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders. METHODS AND RESULTS: Whole-body and vascular specific knockout of Lztr1 results in perinatal lethality due to cardiovascular dysfunction. Lztr1 deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in Lztr1-depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in Lztr1 haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in Lztr1 knockout mice Conclusions: Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of LZTR1-mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.

Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3.

Dysregulated splicing is a common event in cancer even in the absence of mutations in the core splicing machinery. The aberrant long non-coding transcriptome constitutes an uncharacterized level of regulation of post-transcriptional events in cancer. Here, we found that the stress-induced long non-coding RNA (lncRNA), LINC02657 or LASTR (lncRNA associated with SART3 regulation of splicing), is upregulated in hypoxic breast cancer and is essential for the growth of LASTR-positive triple-negative breast tumors. LASTR is upregulated in several types of epithelial cancers due to the activation of the stress-induced JNK/c-JUN pathway. Using a mass-spectrometry based approach, we identified the RNA-splicing factor SART3 as a LASTR-interacting partner. We found that LASTR promotes splicing efficiency by controlling SART3 association with the U4 and U6 small nuclear ribonucleoproteins (snRNP) during spliceosome recycling. Intron retention induced by LASTR depletion downregulates expression of essential genes, ultimately decreasing the fitness of cancer cells.

Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas.

Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)-negative and HPV-positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups. Here, we searched for optimal radiosensitization approaches for HPV-positive and HPV-negative HNSCCs by performing a targeted CRISPR-Cas9 screen. We found that inhibition of base excision repair resulted in a better radiotherapy response in HPV-positive HNSCC, which is correlated with upregulation of genes involved in base excision repair. In contrast, inhibition of nonhomologous end-joining and mismatch repair showed strong effects in both HNSCC groups. We validated the screen results by combining radiotherapy with targeted inhibition of DNA repair in several preclinical models including primary and recurrent patient-derived HNSCC xenografts. These findings underline the importance of stratifying HNSCC patients for combination treatments.