Homologous recombination DNA repair defects in PALB2-associated breast cancers

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display biallelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, largescale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2- associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.. The authors thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. Research reported in this paper was supported in part by the Breast Cancer Research Foundation and the Sarah Jenkins Fund, a Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute (grant No. P30CA008748; MSK), a grant of the Ministry of Health of the Czech Republic (NV15-29959A), Charles University projects PROGRES Q28/LF1 and SVV2019/260367, an HIR Grant UM.C/HlR/ MOHE/06 from the Ministry of Higher Education, Malaysia, and the National Health and Medical Research Council, Australia (NHMRC, Project Grant APP1029974). kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. W.D.F. was funded in part by Susan G Komen. A.L. was supported by the China Scholarship Council. T.N.-D. is an Early Career Fellow of the National Breast Cancer Foundation and M.S. is a NHMRC Senior Research Fellow of the National Health and Medical Research Council. M.T. was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Addenbrooke’s Hospital and European Union Seventh Framework Program (2007–2013)/European Research Council (310018). S.P. was supported by the Swiss National Science Foundation (Ambizione grant number: PZ00P3_168165). J.S.R-F. is partly funded by the Breast Cancer Research Foundation and Britta Weigelt by Cycle for Survival

Homologous recombination DNA repair defects in PALB2-associated breast cancers.

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.ER

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

Erratum: Publisher Correction: Homologous recombination DNA repair defects in PALB2-associated breast cancers.

[This corrects the article DOI: 10.1038/s41523-019-0115-9.]

Preparation and Stabilization of High Molecular Weight Poly (acrylonitrile-<i>co</i>-2-methylenesuccinamic acid) for Carbon Fiber Precursor

Bifunctional comonomer 2-methylenesuccinamic acid (MLA) was designed and synthesized to prepare acrylonitrile copolymer P (AN-co-MLA) using mixed solvent polymerization as a carbon fiber precursor. The effect of monomer feed ratios on the structure and stabilization were characterized by elemental analysis (EA), Fourier transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC), X-ray diffraction (XRD), proton nuclear magnetic (1H NMR), and differential scanning calorimetry (DSC) for the P (AN-co-MLA) copolymers. The results indicated that both the conversion and molecular weight of polymerization reduce gradually when the MLA content is increased in the feed and that bifunctional comonomer MLA possesses a larger reactivity ratio than acrylonitrile (AN). P (AN-co-MLA) shows improved stabilization compared to the PAN homopolymer and poly (acrylonitrile-acrylic acid-methacrylic acid) [P (AN-AA-MA)], showing features such as lower initiation temperature, smaller cyclic activation energy, wider exothermic peak, and a larger stabilization degree, which are due to the ionic cyclization reaction initiated by MLA, confirming that the as-prepared P (AN-co-MLA) is the potential precursor for high-performance carbon fiber

Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin

Background:Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mito-chondrial calcium uniporter regulatory factor 1 (MCUR1) is commonly overexpressed in HCC to increase cellular ATP levels. Due to the highly aggressive characteristics of HCC, it is essential to identify new diagnostic biomarkers and therapeutic targets that may facilitate the diagnosis of HCC and the development of effective anti-HCC treatments.Methods:A series of in vitro and in vivo experiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC.Results:The expression of circ_0000098 was higher in HCC tissues compared to paired adjacent tissues. According to the receiver-operating characteristic curves, circ_0000098 functioned as a potential diagnostic tumor marker in HCC. Our experiments indicated that circ_0000098 served as a key oncogenic circRNA to increase HCC cell prolifera-tion and invasion in vitro and HCC progression in vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3′-UTR of MCUR1, circ_0000098 positively regulated MCUR1 expression in HCC cells and finally promoted HCC progression. On the other hand, inhibiting circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing P-glycoprotein (P-gp, MDR1) expression and intracellular ATP levels. Either downregulation of MCUR1 or overexpression of miR-383 improved DOX sensitivity in HCC cells. Subsequently, a short hairpin RNA targeting circ_0000098 (referred to as sh-1) and doxorubicin (DOX) were encapsulated into platelets (PLTs), referred to as DOX/sh-1@PLT. Activated DOX/sh-1@PLT through HCC cells resulted in the creation of platelet-derived particles that were capable of delivering the DOX/sh-1 combination into HCC cells and promoting intracellu-lar DOX accumulation. Furthermore, our in vivo experiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance

Toll-like receptor 2-Melatonin feedback loop regulates the activation of spinal NLRP3 inflammasome in morphine-tolerant rats

Background and Purpose: Morphine is amongst the most effective analgesics available for the management of severe pain. However, prolonged morphine treatment leads to analgesic tolerance which limits its clinical usage. Previous studies have demonstrated that melatonin ameliorates morphine tolerance by reducing neuroinflammation. However, little is known about the relationship between Toll like receptor 2 (TLR2) and neuroinflammation in morphine tolerance. The aim of this study was to explore the role of TLR2 in morphine tolerance and its connections with melatonin and Nod-like receptor protein 3 (NLRP3) inflammasome. Methods: Sprague-Dawley rats were treated with morphine for 7 days and tail-flick latency test was performed to identify the induction of analgesic tolerance. The roles of TLR2 in microglia activation and morphine tolerance were assessed pharmacologically, and the possible interactions between melatonin, TLR2 and NLRP3 inflammasome were investigated. Key Results: Morphine tolerance was accompanied by increased TLR2 expression and NLRP3 inflammasome activation in spinal cord. whereas melatonin level was down-regulated. Chronic melatonin administration resulted in a reduced TLR2 expression and NLRP3 inflammasome activation. Moreover, the analgesic effect of morphine was partially restored. Inhibition of TLR2 suppressed the microglia and NLRP3 inflammasome activation, as well as restored the spinal melatonin level while attenuated the development of morphine tolerance. Furthermore, the inhibition of microglia activation ameliorated morphine tolerance via inhibiting TLR2-NLRP3 inflammasome signaling in spinal cord. Conclusion: In this study, we directly demonstrate a TLR2-melatonin negative feedback loop regulating microglia and NLRP3 inflammasome activation during the development of morphine tolerance

Tensile failure mechanisms investigation of mesophase pitch-based carbon fibers based on continuous defective graphene nanoribbon model

Mesophase pitch (MPP)-based carbon fibers exhibit outstanding mechanical properties, notably an exceptionally high Young’s modulus. Despite extensive investigations into the microstructure of MPP-based carbon fibers, the influence of these factors on deformation mechanisms under tension remains unclear. This study employs the continuous defective graphene nanoribbons (dGNR) atomistic structure model for molecular dynamics simulations to explore the tensile failure mechanisms of MPP-based carbon fibers. In the simulation model, the structure of the defective region was generated through high-temperature annealing, and a transition region was introduced to prevent distortion and damage to the active graphene edges. The simulation reveals the evolutionary process of the microstructure of MPP-based carbon fibers under tension and achieves Young’s modulus predictions with greater accuracy than theoretical models. Additionally, the study shows that different strengths of interactions between adjacent graphene nanoribbons can lead to two distinct failure modes. Models with larger crystallite dimensions along the fiber axis and lower average defective concentrations exhibit geometric deformation coordination between adjacent nanoribbons, potentially elucidating the increasing strength trend in MPP-based carbon fibers with rising graphitization levels. Our simulations provide insights into the tensile failure mechanisms of MPP-based carbon fibers, offering valuable guidance for regulating their microstructure to enhance mechanical performance