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1.
Int J Mol Sci ; 25(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38732204

RESUMO

The extraocular muscles (EOMs) possess unique characteristics that set them apart from other skeletal muscles. These muscles, responsible for eye movements, exhibit remarkable resistance to various muscular dystrophies and aging, presenting a significant contrast to the vulnerability of skeletal muscles to these conditions. In this review, we delve into the cellular and molecular underpinnings of the distinct properties of EOMs. We explore their structural complexity, highlighting differences in fiber types, innervation patterns, and developmental origins. Notably, EOM fibers express a diverse array of myosin heavy-chain isoforms, retaining embryonic forms into adulthood. Moreover, their motor innervation is characterized by a high ratio of nerve fibers to muscle fibers and the presence of unique neuromuscular junctions. These features contribute to the specialized functions of EOMs, including rapid and precise eye movements. Understanding the mechanisms behind the resilience of EOMs to disease and aging may offer insights into potential therapeutic strategies for treating muscular dystrophies and myopathies affecting other skeletal muscles.


Assuntos
Envelhecimento , Músculos Oculomotores , Humanos , Músculos Oculomotores/fisiologia , Envelhecimento/fisiologia , Animais , Distrofias Musculares , Junção Neuromuscular/fisiologia , Junção Neuromuscular/metabolismo , Músculo Esquelético/fisiologia , Músculo Esquelético/metabolismo
2.
Life (Basel) ; 14(5)2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38792657

RESUMO

Myelodysplastic syndrome (MDS) is a clonal disease derived from hematopoietic stem cells, characterized by ineffective hematopoiesis (resulting in peripheral blood cytopenia) and an increased risk of transformation into acute myeloid leukemia. MDS is caused by a complex combination of genetic mutations resulting in a heterogeneous genotype. Genetic studies have identified a set of aberrations that play a central role in the pathogenesis of MDS. In this article, we present a clinical case of MDS transformation into acute myeloid leukemia in the context of two cell lines exhibiting morphological, immunophenotypic, and dysmyelopoiesis markers and the presence of two heterozygous mutations in the TET2 gene.

3.
Biomedicines ; 11(12)2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38137564

RESUMO

Malignant neoplasms, including pancreatic cancer and melanoma, are major global health challenges. This study investigates melanoma pancreatic syndrome, a rare hereditary tumor syndrome associated with CDKN2A gene mutations. CDKN2A mutations contribute to a lifetime risk of melanoma ranging from 28% to 67%. This study reports the clinical features of six individuals with CDKN2A mutations and identifies recurrent alterations such as c.307_308del, c.159G>C and c.71G>C. It highlights the need for CDKN2A mutation testing in suspected cases of familial atypical multiple mole melanoma. Clinically significant variants show associations with melanoma and pancreatic cancer. The challenges of treating individuals with CDKN2A mutations are discussed, and the lack of specific targeted therapies is highlighted. Preclinical studies suggest a potential benefit of CDK4/6 inhibitors, although clinical trials show mixed results. This study underscores the importance of continued research into improved diagnostic and therapeutic strategies to address the complexities of hereditary cancer syndromes.

4.
Curr Issues Mol Biol ; 45(8): 6383-6394, 2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37623222

RESUMO

Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstudied Kyrgyz population. The study cohort included 113 patients with diagnosed gastric cancer from Kyrgyzstan. The age of patients was 57.6 ± 8.9. Next-generation sequencing analysis of genomic DNA was performed using a custom Roche NimbleGen enrichment panel. The results showed that 6.2% (7/113) of the patients had pathogenic or likely pathogenic genetic variants. Additionally, 3.5% (4/113) of the patients carried heterozygous pathogenic/likely pathogenic variants in high penetrance genes, such as TP53, POLD1, RET, and BRCA2. Moreover, 2.7% (3/113) of the patients carried heterozygous mutations in genes linked to autosomal recessive conditions, specifically PALB2, FANCA, and FANCD2. We have not identified any genetic variants in hereditary GC-associated genes: CDH1, STK11, SMAD4, BMPRIA, APC, MLH1, and others. Our study included patients with sporadic features of GC. The use of recognized criteria (NCCN, Gastric Cancer, Version 2.2022) would increase the number of identified genetic variants in hereditary GC-associated genes. Further research is required to determine the clinical relevance of the genetic variants identified in the current study.

5.
BMC Med Genomics ; 16(1): 186, 2023 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-37573316

RESUMO

BACKGROUND: Xeroderma pigmentosum group E (XP-E) is one of the least common forms of XP, a rare syndrome where patients are prone to develop skin cancer in exposed sunlight areas. XP-E patients are generally not diagnosed until they are adults due to the mild phenotype. CASE PRESENTATION: two XP-E siblings, female, 23 years, and male, 25 years, from a Brazilian consanguineous family carrying the novel missense pathogenic variant in DDB2 gene, NM_000107.3:c.1027G > C, associated with skin cancer early-onset and severe phenotype, as nodular melanoma in the cornea and in the ear. CONCLUSION: The assessment of genomic variant pathogenicity was a challenge since this family belongs to an underrepresented population in genomic databases. Given the scarcity of literature documenting XP-E cases and the challenges encountered in achieving an early diagnosis, this report emphasizes the imperative of sun protection measures in XP-E patients. Additionally, it highlights the detrimental impact of the COVID-19 pandemic on cancer diagnosis, leading to the manifestation of a severe phenotype in affected individuals.


Assuntos
COVID-19 , Melanoma , Neoplasias Cutâneas , Xeroderma Pigmentoso , Masculino , Feminino , Humanos , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/epidemiologia , Xeroderma Pigmentoso/patologia , Brasil , Pandemias , Irmãos , COVID-19/epidemiologia , Melanoma/genética , Neoplasias Cutâneas/genética , Reparo do DNA , Proteínas de Ligação a DNA/genética
6.
Commun Med (Lond) ; 3(1): 109, 2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37567969

RESUMO

BACKGROUND: Xeroderma pigmentosum (XP) is a group of rare hereditary disorders with highly increased risk of skin tumors due to defective DNA repair. Recently we reported 34-fold increased risk of internal tumors in XP patients in comparison with general population. The molecular data and clinical practice on the internal tumors treatment in XP patients is limited and scarcely represented in the medical literature. In this work, we describe young patients with constitutive biallelic deactivation of the XPC gene developing gynecological tumors with somatic DICER1 mutations. METHODS: Whole genome sequencing was used to analyze in detail somatic mutational landscape and driver events of these rare tumors. RESULTS: We describe five early-onset gynecological tumors in four xeroderma pigmentosum group C (XP-C) young patients (11 to 19 years old) including vaginal embryonal rhabdomyosarcomas in monozygotic twin sisters, juvenile granulosa-cell tumor of the ovary and poorly differentiated stage IA Sertoli-Leydig cell tumor in 19-years old patient, and FIGO stage IC1 tumor of ovary in 13-years old patient. XP-C ovarian tumors harbor 4.4 times more single base substitutions than sporadic tissue-matched cancers and demonstrate XP-C specific mutation signature with strong transcriptional bias indicating inability of the cells to repair bulky DNA lesions of unknown etiology. A special mode of treatment was applied to avoid usage of chemotherapy which is toxic for XP patients. CONCLUSIONS: XP-C status should be accounted for prevention and specific treatment of gynecological tumors in young DNA repair-deficient XP patients.


Xeroderma pigmentosum group C (XP-C) is a rare inherited disorder resulting in a highly increased risk of skin and internal cancers due to the inability to efficiently repair DNA. In this study, we described four young XP-C patients who developed early-onset tumors affecting the female reproductive organs. We describe how we cared for these patients in the clinic. We looked at the genetic material within the tumors to better understand the mechanisms through which these tumors developed. We observed high numbers of specific types of changes in DNA, which are not typical for sporadic (non-inherited) gynecological tumors, but are characteristic of internal XP-C tumors. Further studies are needed to better understand the nature of these changes. Our findings highlight the important role of DNA repair in human tissues and cancer risk, and might inform future strategies for tumor prevention in XP-C patients.

7.
Materials (Basel) ; 16(13)2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37444953

RESUMO

The physics of high-Tc superconducting cuprates is obscured by the effect of strong electronic correlations. One way to overcome this problem is to seek an exact solution at least within a small cluster and expand it to the whole crystal. Such an approach is at the heart of cluster perturbation theory (CPT). Here, we developed CPT for the dynamic spin and charge susceptibilities (spin-CPT and charge-CPT), with the correlation effects explicitly taken into account by the exact diagonalization. We applied spin-CPT and charge-CPT to the effective two-band Hubbard model for the cuprates obtained from the three-band Emery model and calculated one- and two-particle correlation functions, namely, a spectral function and spin and charge susceptibilities. The doping dependence of the spin susceptibility was studied within spin-CPT and CPT-RPA, that is, the CPT generalization of the random phase approximation (RPA). In the underdoped region, both our methods resulted in the signatures of the upper branch of the spin excitation dispersion with the lowest excitation energy at the (π,π) wave vector and no presence of low-energy incommensurate excitations. In the high doping region, both methods produced a low energy response at four incommensurate wave vectors in qualitative agreement with the results of the inelastic neutron scattering experiments on overdoped cuprates.

8.
Cancer Discov ; 13(9): 1998-2011, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37377403

RESUMO

Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. SIGNIFICANCE: In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K-mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR , Classe I de Fosfatidilinositol 3-Quinases , Fosfatidilinositol 3-Quinases
9.
Int J Mol Sci ; 24(11)2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37298385

RESUMO

Helicobacter pylori is one of the most common cause of human infections. Infected patients develop chronic active gastritis in all cases, which can lead to peptic ulcer, atrophic gastritis, gastric cancer and gastric MALT-lymphoma. The prevalence of H. pylori infection in the population has regional characteristics and can reach 80%. Constantly increasing antibiotic resistance of H. pylori is a major cause of treatment failure and a major problem. According to the VI Maastricht Consensus, two main strategies for choosing eradication therapy are recommended: individualized based on evaluating sensitivity to antibacterial drugs (phenotypic or molecular genetic method) prior to their appointment, and empirical, which takes into account data on local H. pylori resistance to clarithromycin and monitoring effectiveness schemes in the region. Therefore, the determination of H. pylori resistance to antibiotics, especially clarithromycin, prior to choosing therapeutic strategy is extremely important for the implementation of these treatment regimens.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Helicobacter pylori/genética , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Resistência Microbiana a Medicamentos , Amoxicilina
10.
Int J Mol Sci ; 24(9)2023 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-37175647

RESUMO

More than 275 million people in the world are carriers of a heterozygous mutation of the CFTR gene, associated with cystic fibrosis, the most common autosomal recessive disease among Caucasians. Some recent studies assessed the association between carriers of CFTR variants and some pathologies, including cancer risk. The aim of this study is to analyze the landscape of germline pathogenic heterozygous CFTR variants in patients with diagnosed malignant neoplasms. For the first time in Russia, we evaluated the frequency of CFTR pathogenic variants by whole-genome sequencing in 1800 patients with cancer and compared this with frequencies of CFTR variants in the control group (1825 people) adjusted for age and 10,000 healthy individuals. In the issue, 47 out of 1800 patients (2.6%) were carriers of CFTR pathogenic genetic variants: 0.028 (42/1525) (2.8%) among breast cancer patients, 0.017 (3/181) (1.7%) among colorectal cancer patients and 0.021 (2/94) (2.1%) among ovarian cancer patients. Pathogenic CFTR variants were found in 52/1825 cases (2.85%) in the control group and 221 (2.21%) in 10,000 healthy individuals. Based on the results of the comparison, there was no significant difference in the frequency and distribution of pathogenic variants of the CFTR gene, which is probably due to the study limitations. Obviously, additional studies are needed to assess the clinical significance of the heterozygous carriage of CFTR pathogenic variants in the development of various pathologies in the future, particularly cancer.


Assuntos
Neoplasias da Mama , Regulador de Condutância Transmembrana em Fibrose Cística , Humanos , Feminino , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Predisposição Genética para Doença , Mutação , Células Germinativas
11.
Nat Commun ; 14(1): 2561, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37142601

RESUMO

Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups. We find that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH knockout cell line reveal the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3' nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.


Assuntos
Neoplasias Cutâneas , Xeroderma Pigmentoso , Humanos , Xeroderma Pigmentoso/patologia , Raios Ultravioleta/efeitos adversos , Reparo do DNA/genética , Mutação , Neoplasias Cutâneas/genética , Genômica
12.
Cancer Discov ; 13(5): 1116-1143, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-36862804

RESUMO

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes compared with primary untreated tumors. Standard-of-care resistance biomarkers were identified only in lung and colon cancers-9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verified the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared with nontreated patients, thereby confirming their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve 6-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of the META-PRISM cohort for investigating resistance mechanisms and performing predictive analyses in cancer. SIGNIFICANCE: This study highlights the paucity of standard-of-care markers that explain treatment resistance and the promise of investigational and hypothetical markers awaiting further validation. It also demonstrates the utility of molecular profiling in advanced-stage cancers, particularly breast cancer, to improve the survival prediction and assess eligibility to phase I clinical trials. This article is highlighted in the In This Issue feature, p. 1027.


Assuntos
Neoplasias da Mama , Segunda Neoplasia Primária , Masculino , Humanos , Transcriptoma , Recidiva Local de Neoplasia , Neoplasias da Mama/tratamento farmacológico , Genômica , Perfilação da Expressão Gênica
13.
Cancer Discov ; 13(4): 858-879, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36669143

RESUMO

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. SIGNIFICANCE: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Interleucina-6 , Fator A de Crescimento do Endotélio Vascular , Neoplasias Pulmonares/genética , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Imunoterapia , Instabilidade Genômica , Inflamação/tratamento farmacológico , Inflamação/genética , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/genética
14.
Cancers (Basel) ; 16(1)2023 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-38201513

RESUMO

Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.

15.
Biology (Basel) ; 11(10)2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36290365

RESUMO

BACKGROUND: Approximately 5-10% of all cancers are associated with hereditary cancer predisposition syndromes (HCPS). Early identification of HCPS is facilitated by widespread use of next-generation sequencing (NGS) and brings significant benefits to both the patient and their relatives. This study aims to evaluate the landscape of genetic variants in patients with personal and/or family history of cancer using NGS-based multigene panel testing. MATERIALS AND METHODS: The study cohort included 1117 probands from Russia: 1060 (94.9%) patients with clinical signs of HCPS and 57 (5.1%) healthy individuals with family history of cancer. NGS analysis of 76 HCPS genes was performed using a custom Roche NimbleGen enrichment panel. RESULTS: Pathogenic/likely pathogenic variants were identified in 378 of 1117 individuals (33.8%). The predominant number (59.8%) of genetic variants was identified in BRCA1/BRCA2 genes. CHEK2 was the second most commonly altered gene with a total of 28 (7.4%) variants, and 124 (32.8%) genetic variants were found in other 35 cancer-associated genes with variable penetrance. CONCLUSIONS: Multigene panel testing allows for a differential diagnosis and identification of high-risk group for oncological diseases. Our results demonstrate that inclusion of non-coding gene regions into HCPS gene panels is highly important for the identification of rare spliceogenic variants with high penetrance.

16.
Nucleic Acids Res ; 50(18): 10264-10277, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36130228

RESUMO

The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria are responsible for aerobic respiration, it is expected that mtDNA mutational spectrum is affected by oxidative damage. Assuming that oxidative damage increases with age, we analyse mtDNA mutagenesis of different species in regards to their generation length. Analysing, (i) dozens of thousands of somatic mtDNA mutations in samples of different ages (ii) 70053 polymorphic synonymous mtDNA substitutions reconstructed in 424 mammalian species with different generation lengths and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH > GH substitutions (H: heavy strand notation) is twice bigger in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH > GH substitutions are also sensitive to the time spent single-stranded (TSSS) during asynchronous mtDNA replication we demonstrated that AH > GH substitution rate is a function of both species-specific generation length and position-specific TSSS. We propose that AH > GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.


Assuntos
Envelhecimento , DNA Mitocondrial , Mamíferos , Envelhecimento/genética , Animais , DNA Mitocondrial/genética , Mamíferos/genética , Mitocôndrias/genética , Mutação , Nucleotídeos
17.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35896284

RESUMO

BACKGROUND: Clinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood. METHODS: 4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD gene Msh2, leading to a massive accumulation of mutations after serial passages of cells. Insertions/deletion events and mutation load were evaluated by whole exome sequencing. Mice bearing highly mutated MMRD tumor or parental tumors were treated with αPD-1 and tumor volume was monitored. Immune cell type abundance was dynamically assessed in the tumor microenvironment and the blood by flow cytometry. Neutrophils were depleted in mice using αLY6G antibody, and regulatory T (Treg) cell population was reduced with αCD25 or anti-cytotoxic T-lymphocytes-associated protein 4 (αCTLA-4) antibodies. Patients with MMRD tumors treated with immune checkpoint blockade-based therapy were retrospectively identified and neutrophil-to-lymphocyte ratio (NLR) was evaluated and examined for correlation with clinical benefit. RESULTS: By recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy. CONCLUSIONS: TIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation.


Assuntos
Neutrófilos , Animais , Humanos , Camundongos , Neoplasias Encefálicas , Neoplasias Colorretais , Instabilidade de Microssatélites , Síndromes Neoplásicas Hereditárias , Estudos Retrospectivos , Microambiente Tumoral
18.
Inorg Chem ; 61(26): 10234-10241, 2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35736661

RESUMO

The strength and sign of superexchange interactions are often predicted on the basis of the bond angles between magnetic ions, but complications may arise in situations with a nontrivial arrangement of the magnetic orbitals. We report on a novel molecular tetramer compound [Cu(H2O)dmbpy]2[V2O2F8] (dmbpy = 4,4'-dimethyl-2,2'-bipyridyl) that is composed of triangular "CuV2" fragments and displays a spin gap behavior. By combining first-principles calculations and electronic models, we reveal that superexchange Cu-V interactions carry drastically different coupling strengths along two Cu-F-V pathways with comparable bond angles in the triangular "CuV2" fragment. Counterintuitively, their strong disparity is found to originate from the restricted symmetry of the half-filled Cu dx2-y2 orbital stabilized by the crystal field, leading to one dominating antiferromagnetic Cu-V coupling in each fragment. We revisit the magnetic properties of the reported spin-gapped chain compound [enH2]Cu(H2O)2[V2O2F8] (enH2 = ethylene diammonium) containing similar triangular "CuV2" fragments, and the magnetic behavior of the molecular tetramer and the chain compounds is rationalized as that of weakly coupled spin dimers and spin trimers, respectively. This work demonstrates that fundamentally different magnetic couplings can be observed between magnetic ions with similar bond angles in a single spin motif, thus providing a strategy to introduce various exchange interactions combined with low dimensionality in heterometallic Cu(II)-V(IV) compounds.

19.
Orphanet J Rare Dis ; 17(1): 104, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35246173

RESUMO

BACKGROUND: Xeroderma pigmentosum (XP) is a rare, autosomal, recessive DNA repair-deficiency disorder with a frequency of 1-3 per million livebirths in Europe and USA but with higher frequencies in isolated islands or in countries with a high level of consanguinity. XP is characterized by high incidence of skin cancers on sun-exposed sites. Recent improvement in life expectancy of XP patients suggests an increased risk of frequently aggressive and lethal internal tumors. Our purpose was to quantify relative risks of internal tumor development for XP patients by tumor type, XP-subtype, patients' ages and ethnicity through comparison with the US general population. METHODS: We analyzed four independent international well-characterized XP cohorts (from USA, UK, France and Brazil) with a total of 434 patients, where 11.3% developed internal tumors and compared them to the American general population. We also compiled, through PubMed/Medline, a dataset of 89 internal tumors in XP patients published between 1958 and 2020. RESULTS: In the combined 4-XP cohort, relative risk of internal tumors was 34 (95% confidence interval (CI) 25-47) times higher than in the general population (p-value = 1.0E-47) and tumor arose 50 years earlier. The XP-C group was at the highest risk for the 0-20 years old-patients (OR = 665; 95% CI 368-1200; p-value = 4.3E-30). The highest risks were observed for tumors of central nervous system (OR = 331; 95% CI 171-641; p-value = 2.4E-20), hematological malignancies (OR = 120; 95% CI 77-186; p-value = 3.7E-36), thyroid (OR = 74; 95% CI 31-179; p-value = 1.2E-8) and gynecological tumors (OR = 91; 95% CI 42-193; p-value = 3.5E-12). The type of mutation on the XPC gene is associated with different classes of internal tumors. The majority of French XP-C patients (80%) are originated from North Africa and carried the XPC delTG founder mutation specific from the South Mediterranean area. The OR is extremely high for young (0-20 years) patients with more than 1300-fold increase for the French XPs carrying the founder mutation. CONCLUSION: Because the age of XP population is increasing due to better sun-protection and knowledge of the disease, these results are of particular importance for the physicians to help in early prevention and detection of internal tumors in their XP patients. Few preventive blood analyses or simple medical imaging may help to better detect early cancer appearance in this population.


Assuntos
Neoplasias Cutâneas , Xeroderma Pigmentoso , Adolescente , Adulto , Criança , Pré-Escolar , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Humanos , Lactente , Recém-Nascido , Mutação , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Xeroderma Pigmentoso/epidemiologia , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/patologia , Adulto Jovem
20.
Nano Lett ; 22(5): 2070-2076, 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35225628

RESUMO

The mechanical properties of the layered crystals in the few layer limit are largely unexplored. We employ a picosecond ultrasonic technique to access the corresponding mechanical parameters. Temporal variation of the reflection coefficient of the Al film that covers hBN/WSe2/hBN (where hBN is hexagonal boron nitride) heterostructures on a sapphire substrate after the femtosecond laser pulse excitation is carefully measured using an interferometric technique with spatial resolution. The laser pulse generates a broadband sound wave packet propagating perpendicularly to the Al plane and partially reflecting from the heterostructural interfaces. The demonstrated technique allows one to resolve a WSe2 monolayer embedded in hBN. We apply a multilayered model of the optoacoustical response to evaluate the mechanical parameters, in particular, the rigidity of the interfaces. Mapping of the Fourier spectra of the response visualizes different composition regions and may serve as an acoustic tomography tool. Almost zero phonon dissipation below 150 GHz demonstrates the van der Waals heterostructures' potential for nanoacoustical applications.

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