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Molecules (Basel, Switzerland) Dec 2022Axially chiral heterobiaryl frameworks are privileged structures in many natural products, pharmaceutically active molecules, and chiral ligands. Therefore, a variety of... (Review)
Review
Axially chiral heterobiaryl frameworks are privileged structures in many natural products, pharmaceutically active molecules, and chiral ligands. Therefore, a variety of approaches for constructing these skeletons have been developed. Among them, de novo synthesis, due to its highly convergent and superior atom economy, serves as a promising strategy to access these challenging scaffolds including C-N, C-C, and N-N chiral axes. So far, several elegant reviews on the synthesis of axially chiral heterobiaryl skeletons have been disclosed, however, atroposelective construction of the heterobiaryl subunits by de novo synthesis was rarely covered. Herein, we summarized the recent advances in the catalytic asymmetric synthesis of the axially chiral heterobiaryl scaffold via de novo synthetic strategies. The related mechanism, scope, and applications were also included.
Topics: Biological Products; Catalysis; Skeleton
PubMed: 36500610
DOI: 10.3390/molecules27238517 -
BMC Cancer May 2023We aimed to examine whether patients with de novo and relapsed/progressed stage IIIB-IV non-small cell lung cancer (NSCLC) without epidermal growth factor receptor...
Survival differences between patients with de novo and relapsed/progressed advanced non-small cell lung cancer without epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements.
BACKGROUND
We aimed to examine whether patients with de novo and relapsed/progressed stage IIIB-IV non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have different prognoses.
METHODS
This retrospective study analyzed the Health Insurance Review and Assessment claims data in South Korea from 2013 to 2020. Patients with stage IIIB-IV NSCLC without EGFR or ALK mutations who received first-line palliative therapy between 2015 and 2019 were identified. Overall survival (OS), time to first subsequent therapy (TFST), and time to second subsequent therapy (TSST) were estimated using the Kaplan-Meier method. Multivariate Cox regression analysis was used to reveal the impact of de novo versus relapsed/progressed disease on OS. Treatment patterns, including treatment sequence, top five most frequent regimens, and time to treatment discontinuation, were described in both groups.
RESULTS
Of 14,505 patients, 12,811 (88.3%) were de novo, and 1,694 (11.7%) were relapsed/progressed. The median OS in the de novo group was 11.0 versus 11.5 months in the relapsed/progressed group (P = 0.002). The ongoing treatment probability was higher in relapsed/progressed patients than in de novo patients from 6.4 months since the initiation of first-line treatment (P < 0.001). Median TSST was shorter in the de novo group than in the relapsed/progressed group (9.5 vs. 9.9 months, P < 0.001). In multivariate analysis, de novo disease was associated with shorter OS (hazard ratio 1.07; 95% confidence interval 1.01-1.14). The overall treatment patterns for de novo and relapsed/progressed patients were similar.
CONCLUSIONS
De novo patients had poorer OS and TSST after the initiation of palliative therapy than relapsed/progressed patients. These findings suggest that the stage of the disease at the time of initial diagnosis should be considered in observational studies and clinical trials as a prognostic factor.
Topics: Humans; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 37248452
DOI: 10.1186/s12885-023-10950-y -
Journal of Epilepsy Research Dec 2022status epilepticus (SE) had worse outcome in comparison to the patients with SE who had previous history of epilepsy. The aim of the present study was to identify...
BACKGROUND AND PURPOSE
status epilepticus (SE) had worse outcome in comparison to the patients with SE who had previous history of epilepsy. The aim of the present study was to identify clinical features of convulsive status epilepticus (CSE) and the predictors of in-hospital mortality.
METHODS
Seventy-seven elderly (≥60 years of age) hospitalized patients with CSE were evaluated for clinical profile, aetiologies and predictors of in-hospital mortality.
RESULTS
The average age of the participants in the study was 65.96±6.72 years. In CSE, the most common aetiologies were acute symptomatic in 68.8% of cases, followed by remote symptomatic in 24.7%. In-hospital mortality in the CSE in the elderly was 30 (38.9%) in our series. Stroke was the leading cause of death among them (acute stroke in 23 cases and old infarct in 1 case), followed by post-traumatic (n=4) and CNS infection (n=2). On multivariate analysis, it was found that variables significantly related to mortality in CSE were low Glasgow coma scale (GCS) (adjusted odds ratio [AOR], 53.5; 95% confidence interval [CI], 5.17-555.14; =0.001) and lack of response to first line treatment (AOR, 0.06; 95% CI, 0.01-0.50; =0.01).
CONCLUSIONS
In-hospital mortality in CSE patients was linked to a low GCS and a lack of response to first-line therapy. The most efficient strategy to prevent in-hospital mortality in the elderly is to treat CSE promptly and aggressively in the setting of stroke.
PubMed: 36685739
DOI: 10.14581/jer.22009 -
Liver Transplantation : Official... Jan 2004De novo malignancies are one of the current problems in patients with organ transplantation. The incidence has been considered to be higher as a result of increases of... (Review)
Review
De novo malignancies are one of the current problems in patients with organ transplantation. The incidence has been considered to be higher as a result of increases of oncogenic viruses in immunosuppressed organ recipients. Published reports have shown increased incidence of de novo tumors such as malignant lymphomas and cutaneous neoplasms but decreased incidence of breast cancer. A variety of factors affect de novo breast cancer development in organ recipients, including immunosuppression, viruses, and underlying disease. The aims of this review are to evaluate the incidence and management of patients with de novo breast cancer by giving the University of Pittsburgh's data, and to evaluate the incidence of de novo breast cancer in published reports in light of an age-adjusted rate. According to age-adjusted rates presented by the National Cancer Institute's Surveillance, Epidemiology and End Results data, we found increased incidence rate of de novo breast cancer in the previously published series. The University of Pittsburgh's incidence rate of de novo breast cancer was determined in a fashion similar to that for the Surveillance, Epidemiology and End Results data. Eighty-three percent of all patients were diagnosed at early stages, and it appeared to take longer for de novo breast cancer to develop in patients treated with tacrolimus than in patients treated with cyclosporine. In conclusion, surgical treatment of breast cancer in liver recipients is the same as treatment of breast cancer in patients without transplantation. However, the effects of chemotherapy, radiotherapy, and/or tamoxifen remain unclear in transplanted patients and need to be evaluated in larger studies.
Topics: Breast Neoplasms; Female; Humans; Immunosuppressive Agents; Incidence; Killer Cells, Natural; Liver Transplantation; Postoperative Complications; SEER Program
PubMed: 14755771
DOI: 10.1002/lt.20025 -
Current Opinion in Chemical Biology Jun 2020Engineered proteins are revolutionizing immunotherapy, but advances are still needed to harness their full potential. Traditional protein engineering methods use... (Review)
Review
Engineered proteins are revolutionizing immunotherapy, but advances are still needed to harness their full potential. Traditional protein engineering methods use naturally existing proteins as a starting point, and therefore, are intrinsically limited to small alterations of a protein's natural structure and function. Conversely, computational de novo protein design is free of such limitation, and can produce a virtually infinite number of novel protein sequences, folds, and functions. Recently, we used de novo protein engineering to create Neoleukin-2/15 (Neo-2/15), a protein mimetic of the function of both interleukin-2 (IL-2) and interleukin-15 (IL-15). To our knowledge, Neo-2/15 is the first de novo protein with immunotherapeutic activity, and in murine cancer models, it has demonstrated enhanced therapeutic potency and reduced toxicity compared to IL-2. De novo protein design is already showcasing its tremendous potential for driving the next wave of protein-based therapeutics that are explicitly engineered to treat disease.
Topics: Amino Acid Sequence; Animals; Immunotherapy; Interleukin-15; Interleukin-2; Mice; Models, Molecular; Neoplasms; Neoplasms, Experimental; Protein Binding; Protein Conformation; Protein Engineering; Structure-Activity Relationship
PubMed: 32371023
DOI: 10.1016/j.cbpa.2020.02.002 -
Genes Sep 2021The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number... (Review)
Review
The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of variants in CDH. This review gives an overview of the known disease-causing variants in CDH patients.
Topics: Aneuploidy; Chromosome Aberrations; DNA Copy Number Variations; Hernias, Diaphragmatic, Congenital; Humans; Mutation
PubMed: 34573387
DOI: 10.3390/genes12091405 -
Dermatopathology (Basel, Switzerland) 2015The aim of this study was to determine if nevus-associated melanoma differs in characteristics and prognosis from de novo melanoma.
AIM
The aim of this study was to determine if nevus-associated melanoma differs in characteristics and prognosis from de novo melanoma.
PATIENTS AND METHODS
The study included 118 melanoma patients. Clinical findings were retrospectively evaluated. For histopathological parameters, HE sections were reexamined. The differentiation between de novo and nevus-associated melanoma was based on the histopathological evidence of a precursor nevus. In addition, all analyses were repeated in all cases in which nevus-associated melanoma was defined based on patient anamnesis.
RESULTS
Among all patients, 28 (23.7%) had nevus-associated melanoma. Nevus-associated melanoma was most commonly located on the extremities (50%), followed by the trunk (25%), whereas de novo melanoma was most commonly located in the head and neck region (32.2%), followed by the acral region (31.1%). Other clinical findings and histopathological parameters did not differ significantly between the two groups (p > 0.05). The findings remained consistent following the repeated analysis of all cases in which nevus-associated melanoma was defined based on patient anamnesis.
CONCLUSIONS
Nevus-associated melanoma was most commonly located on the extremities and the trunk, whereas de novo melanoma was most commonly located in the head and neck and the acral region. Furthermore, nevus-associated melanoma was similar to de novo melanoma in terms of prognosis and other disease characteristics.
PubMed: 27047934
DOI: 10.1159/000375490 -
World Journal of Gastroenterology Sep 2019Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to...
BACKGROUND
Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and malignancies in liver transplant patients.
AIM
To study the role of immunosuppression on the incidence of malignancies in liver transplant recipients.
METHODS
A systematic literature examination about malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.
RESULTS
Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences.
CONCLUSION
The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of malignancies and may also help in treating liver transplant patients suffering from cancer.
Topics: Adult; Allografts; Child; Graft Rejection; Humans; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver; Liver Transplantation; Neoplasms; Patient Selection; Postoperative Complications; Withholding Treatment
PubMed: 31558879
DOI: 10.3748/wjg.v25.i35.5356 -
Journal of Cheminformatics Sep 2021Many contemporary cheminformatics methods, including computer-aided de novo drug design, hold promise to significantly accelerate and reduce the cost of drug discovery....
Many contemporary cheminformatics methods, including computer-aided de novo drug design, hold promise to significantly accelerate and reduce the cost of drug discovery. Thanks to this attractive outlook, the field has thrived and in the past few years has seen an especially significant growth, mainly due to the emergence of novel methods based on deep neural networks. This growth is also apparent in the development of novel de novo drug design methods with many new generative algorithms now available. However, widespread adoption of new generative techniques in the fields like medicinal chemistry or chemical biology is still lagging behind the most recent developments. Upon taking a closer look, this fact is not surprising since in order to successfully integrate the most recent de novo drug design methods in existing processes and pipelines, a close collaboration between diverse groups of experimental and theoretical scientists needs to be established. Therefore, to accelerate the adoption of both modern and traditional de novo molecular generators, we developed Generator User Interface (GenUI), a software platform that makes it possible to integrate molecular generators within a feature-rich graphical user interface that is easy to use by experts of diverse backgrounds. GenUI is implemented as a web service and its interfaces offer access to cheminformatics tools for data preprocessing, model building, molecule generation, and interactive chemical space visualization. Moreover, the platform is easy to extend with customizable frontend React.js components and backend Python extensions. GenUI is open source and a recently developed de novo molecular generator, DrugEx, was integrated as a proof of principle. In this work, we present the architecture and implementation details of GenUI and discuss how it can facilitate collaboration in the disparate communities interested in de novo molecular generation and computer-aided drug discovery.
PubMed: 34563271
DOI: 10.1186/s13321-021-00550-y -
Data in Brief Oct 2023The genus comprises of perennial, tropical, herbaceous plants that are distributed globally and possess both medicinal and ornamental properties. These plants contain a...
The genus comprises of perennial, tropical, herbaceous plants that are distributed globally and possess both medicinal and ornamental properties. These plants contain a variety of secondary metabolites, including compounds with antioxidant and antimicrobial properties. This is the first transcriptomic analysis of seven species from Peninsular Malaysia, utilizing leaves, stems, and roots as sample material. Paired-end Illumina HiSeq technology was used for data generation which includes raw data, cleaned reads, de novo assembly, and functional annotation. The data is accessible via NCBI BioProject (PRJNA936673).
PubMed: 37701715
DOI: 10.1016/j.dib.2023.109507