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1.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
2.
Ann Palliat Med ; 9(6): 4339-4345, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33183013

RESUMO

The majority of patients with lung cancer are in the late stage (stages IIIB or IV) when diagnosed. However, clinical features, treatment and prognosis of some patients in stage IIIB are somewhat different from those in stage IV. Several clinical trials of neoadjuvant immunotherapy are changing the treatment strategy for patients with stage IB-IIIA non-small cell lung cancer (NSCLC). It remains unclear whether patients with stage IIIB NSCLC could benefit from neoadjuvant immunotherapy because they are often excluded from clinical trials. The IMpower150 trial showed promising results in the clinics of atezolizumab plus bevacizumab plus chemotherapy in patients with epidermal growth factor receptor (EGFR) mutation positive NSCLC. However, reports of this treatment strategy on EGFR exon 20 mutations are still lacking. Osimertinib is effective for T790M mutation but results of targeted therapy in other EGFR exon 20 mutations are not favorable and there is currently no effective long-term therapy. Patients harboring EGFR exon 20 G779F mutation have not been reported to achieve a complete response (CR). Here, we report the case of a 55-year-old man who was diagnosed as stage IIIB (cT1bN3M0) pulmonary adenocarcinoma by supraclavicular lymph node biopsy. He was administered chemotherapy plus durvalumab before surgery. The disease was considered as a partial response (PR), and the postoperative pathology revealed that a pathologic CR had been achieved. At the time of writing, no signs of recurrence had been observed in the preceding 15 months. Our case provides a new treatment option for such patients.

3.
J Thorac Dis ; 12(8): 4262-4273, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32944338

RESUMO

Background: Circulating tumor cells (CTCs) carry a wealth of information on primary and metastatic tumors critical for enhancing the understanding of the occurrence, progression and metastasis of non-small cell lung cancer (NSCLC). However, the low sensitivity of traditional tumor detection methods limits the application of CTCs in the treatment and disease surveillance of NSCLC. Therefore, CTCs isolation and detection with high sensitivity is highly desired especially for NSCLC patients, which is significant because of high occurrence and mortality. While it is very challenging because of the lower expression of CTC positive biomarkers such as epithelial cell adhesion molecules and cytokeratins (EpCAM and CKs), herein we report a method based on peptide-functionalized magnetic nanoparticles with high CTC capture efficiency, which demonstrates superiority in NSCLC clinical applications. Methods: For analysis and comparison of the peptide-functionalized magnetic nanoparticles (TumorFisher, Nanopep Corp.) and the antibody-modified magnetic beads (CellSearch, Janssen Diagnostics, LLC), two NSCLC cell lines, A549 and NCI-H1975 were chosen to measure the binding affinity and capture efficiency. In order to compare the effect of the clinical application of these two detection systems, 7 early stage patients with NSCLC were enrolled in this study. To further explore the clinical utility of CTC counting in different stages, 81 NSCLC patients in stage I-IV were enrolled for CTC enumeration and statistical analysis. Results: The binding affinities of the recognition peptide to A549 and NCI-H1975 are 76.7%±11.0% and 70.1%±4.8%, respectively, which is similar with the positive control group (anti-EpCAM antibodies). CTCs were captured in 5/7 (71.4%) of early stage NSCLC patients with NSCLC in TumorFisher system, which is higher than CellSearch, and the false negative of TumorFisher is much lower than CellSearch. In a larger clinical cohort, the CTC numbers of NSCLC patients varied in different stages and the overall detection rate of TumorFisher was 59/81 (72.8%), with the similar proportion in stage I (21/29, 72.4%), II (17/22, 77.3%) and III (16/21, 76.2%). Conclusions: Highly efficient CTC isolation technique based on peptide-magnetic nanoparticles was firstly applied in NSCLC patients. Compared with the antibody-based the technique, the higher CTC detection rates (71.4%) in NSCLC patient blood samples were demonstrated for the patients in different stages, I-IV, especially in early stages. This indicates the feasibility of the clinical utility of this new technique in early stage screening, prognosis and therapy evaluation of NSCLC.

4.
J Phys Chem B ; 124(36): 7969-7978, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32804503

RESUMO

Pre-imidization has been found to have a determining role on the final properties of polyimide (PI) films. In this work, a series of 4,4'-(hexafluoroisopropylidene)diphthalic anhydride (6FDA)/2,2'-bis(trifluoromethyl)benzidine (TFMB) PI models with specified pre-imidization degree (pre-ID) were constructed and analyzed on the basis of molecular dynamic (MD) simulation to reveal the real-time evolution of structure and properties that occurred during the pre-imidization process. The MD results indicated that the Tg of the models increased obviously with increasing pre-ID, which corresponded to the increase of rigid PI chain segments that restricted the mobility of molecular chains. In addition, the increase of fractional free volume and mean square end-to-end distance indicated looser chain packing and more extended chain conformation during the pre-imidization process. As a further verification, a series of corresponding PI films were experimentally prepared via a controlled partially pre-imidization process. Mechanical properties of the prepared PI films were tested to be significantly enhanced, and the coefficient of thermal expansion decreased from 61.5 to 47.6 ppm/°C with pre-ID increasing from 0% to 100%, which could be attributed to the orderly molecular chain arrangement formed during the chemical pre-imidization process, as disclosed by MD simulation. This work paves the way for the observation of the real-time structure and property evolutions of PI materials, especially during the pre-imidization process.

6.
J Thorac Dis ; 12(5): 2771-2780, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32642185

RESUMO

Epidermal growth factor receptor (EGFR) L718Q is a rare resistant mutation which independently leads to third-generation tyrosine kinase inhibitor (TKI) resistance. Although a few studies have examined its resistance mechanisms, no effective treatment strategy has yet been proposed for patients with this mutation. Here, we report an effective treatment strategy for the rare EGFR L718Q mutation for the first time. A 44-year-old Chinese male patient initially presented with the sensitizing EGFR L858R mutation, and the progression-free survival (PFS) time after initial icotinib treatment was 9 months. When the progression of the disease (PD) and the EGFR T790M mutation were identified, he did not respond to the osimertinib treatment. Through comprehensive next-generation sequencing (NGS) of the surgical specimen, the rare EGFR L718Q mutation was eventually identified as having a frequency of 68.84%, together with an EGFR amplification with a copy number of 11.54. The previous treatment response was retrospectively explained, and the patient faced the challenge of not being able to benefit from any targeted therapy. Following chemotherapy with a personalized regimen which effectively modified the proportion of sensitive and resistant cells, significant response to osimertinib re-challenge was observed, and another PFS of 4.7 months was achieved. Unfortunately, four EGFR mutations, EGFR L858, T790M, L718Q, and C797S, were simultaneously detected in his late stage, and led to further progression of disease.

7.
Chem Commun (Camb) ; 56(67): 9691-9694, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32697814

RESUMO

Here, we developed an expedient access route to highly functionalized pyrroles from readily available α-amino acid ester hydrochlorides and alkynals via a cascade condensation/intramolecular cyclization followed by a unique C-N ester migration process. A variety of 1,2,3-trisubstituted pyrroles, which were difficult to acquire with the common methodologies, were successfully prepared in good yields under mild conditions.

8.
Zhongguo Fei Ai Za Zhi ; 23(7): 615-620, 2020 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-32702796

RESUMO

Precision medicine is an approach to rational treatment selection in the overall management of lung cancer nowadays. The introduction of the patient-derived organoid (PDO) model has established the "black-box" decision-making system from the perspective of in-vitro functional models. This may assist as a complement to the treatment selection strategy based on gene-drug correlation. Further validation must be done in multi-dimensional characteristics recapitulation of the primary tumor in organoids and in large-scale randomized controlled clinical trials. This article will give an introduction to the organoid model and review the application scenarios of organoids in the context of the precise treatment of existing lung cancer.

9.
BMC Pulm Med ; 20(1): 80, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245453

RESUMO

BACKGROUND: Synchronous multiple primary lung cancers (sMPLC) are rare forms of lung cancer, and their diagnosis remains as a significant challenge. Distinguishing sMPLC from advanced disease is important as their prognoses and therapeutic management vary dramatically. CASE PRESENTATION: The patient was a 56-year-old Chinese male who exhibited six synchronous invasive adenocarcinomas at diagnosis [T2(6)N0M0], and who achieved durable clinical benefit under adjuvant chemotherapy for 41 months following wedge resection and lobectomy. Whole-exome sequencing revealed that two lesions (L4 and L6) in the left upper lobe of the patient's lung shared 28 nonsynonymous mutations; thus, suggesting that the lesions may have arisen from a common ancestor at the early stages of tumorigenesis, and spread into distinct histologic subtypes. Moreover, while L5 was in the same lobe as L4 and L6, it represented a distinct lineage as it did not share any mutations with other lesions. Notably, the BRAF V600E oncogenic mutation was exclusive to L5. In addition, the KRAS G12C mutation was identified in three lesions (L1-L3) located in the right lung, which may have resulted from convergent evolution. CONCLUSION: We report a patient with six synchronous invasive adenocarcinomas who demonstrated durable clinical benefits under adjuvant chemotherapy following surgical treatment. While cancer staging is one of the many challenges associated with sMPLC, the data generated through next-generation sequencing can provide information on lesion origins, and thus, advance the era of precision medicine.

10.
Org Lett ; 22(4): 1426-1430, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32003567

RESUMO

An asymmetric and efficient approach for the total syntheses of (+)-stemarin and the proposed structures of stemara-13(14)-en-18-ol and stemara-13(14)-en-17-acetoxy-18-ol are described. The key features of the strategy include a Lewis acid-induced cationic polyene cyclization and an ODI-[5+2] cycloaddition/pinacol-type 1,2-acyl migration cascade.

11.
PeerJ ; 7: e8299, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31875161

RESUMO

Background: Integrins play a crucial role in the regulation process of cell proliferation, migration, differentiation, tumor invasion and metastasis. ITGA11, ITGB4 and ITGB8 are three encoding genes of integrins family. Accumulative evidences have proved that abnormal expression of ITGA11, ITGB4 and ITGB8 are a common phenomenon in different malignances. However, their expression patterns and prognostic roles for patients with non-small cell lung cancer (NSCLC) have not been completely illustrated. Methods: We investigated the expression patterns and prognostic values of ITGA11, ITGB4 and ITGB8 in patients with NSCLC through using a series of databases and various datasets, including ONCOMINE, GEPIA, HPA, TCGA and GEO datasets. Results: We found that the expression levels of ITGA11 and ITGB4 were significantly upregulated in both LUAD and LUSC, while ITGB8 was obviously upregulated in LUSC. Additionally, higher expression level of ITGB4 revealed a worse OS in LUAD. Conclusion: Our findings suggested that ITGA11 and ITGB4 might have the potential ability to act as diagnostic biomarkers for both LUAD and LUSC, while ITGB8 might serve as diagnostic biomarker for LUSC. Furthermore, ITGB4 could serve as a potential prognostic biomarker for LUAD.

12.
ChemistrySelect ; 4(31): 9185-9189, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-32149184

RESUMO

The formation and characterization of positively surface charged TiN surfaces were investigated for improving dental implant survival. Surface nitrogen atoms of a traditional TiN implant were converted to a positive charge by a quaternization reaction which greatly increased the antibacterial efficiency. Ti, TiN, and quaternized TiN samples were incubated with human patient subgingival bacteria for 4 hours at 37°C in an anaerobic environment with an approximate 40% reduction in counts on the quaternized surface over traditional Ti and TiN. The samples were challenged with Streptococcus Mutans and fluorescent imaging confirmed significant reduction in the quaternized TiN over the traditional Ti and TiN. Contact angle measurement and X-Ray Photoelectron Spectroscopy (XPS) were utilized to confirm the surface chemistry changes. The XPS results found the charged quaternized nitrogen peak at 399.75 eV that is unique to the quaternized sample.

13.
Dalton Trans ; 46(48): 17032-17040, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29184928

RESUMO

The construction of novel heterojunctions is precisely deemed to be an effective strategy to facilitate photo-generated carrier separation and boost charge utilization efficiency, leading to much enhanced photocatalytic activities. Herein, in situ of growing ultrafine SnS2 nanoparticles on a porous g-C3N4 sheet (SnS2/g-C3N4) 0D/2D heterojunction was achieved via a low-temperature solvothermal process. Combined with various characterization techniques, it is revealed that SnS2 dots with a diameter of 3 nm distribute evenly on the surface of the g-C3N4 substrate with strong C-S bonds. The photocatalytic activities are evaluated by the degradation of Rhodamine B (RhB) under visible light irradiation, showing a much enhanced photodegradation efficiency of 96.8% over 105 min irradiation and an enhanced reaction rate constant (k = 3.3% min-1, 8.25 and 8.05 times that of pure g-C3N4 and SnS2). The improved photocatalytic activities could be ascribed to the efficient electron-hole separation of porous g-C3N4, which is caused by the ultrafine SnS2 dots linked with the g-C3N4 substrate through C-S bonds. Therefore, the recombination efficiency is decreased. In addition, reactive active species trapping experiments prove that the superoxide radical (˙O2-) and holes (h+) are the main active species in this photocatalytic system. The photodegradation mechanism of the SnS2/g-C3N4 heterojunction is analyzed and demonstrated in detail.

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