ABSTRACT
Understanding the Li-ions conduction network and transport dynamics in polymer electrolyte is crucial for developing reliable all-solid-state batteries. In this work, advanced nano- X-ray computed tomography combined with Raman spectroscopy and solid state nuclear magnetic resonance are used to multi-scale qualitatively and quantitatively reveal ion conduction network of poly(ethylene) oxide (PEO)-based electrolyte (from atomic, nano to macroscopic level). With the clear mapping of the microstructural heterogeneities of the polymer segments, aluminium-oxo molecular clusters (AlOC) are used to reconstruct a high-efficient conducting network with high available Li-ions (76.7%) and continuous amorphous domains via the strong supramolecular interactions. Such superionic PEO conductor (PEO-LiTFSI-AlOC) exhibites a molten-like Li-ion conduction behaviour among the whole temperature range and delivers an ionic conductivity of 1.87 × 10-4 S cm-1 at 35 °Ï¹. This further endows Li electrochemical plating/stripping stability under 50 µA cm-2 and 50 µAh cm-2 over 2000 h. The as-built Li|PEO-LiTFSI-AlOC|LiFePO4 full batteries show a high rate performance and a capacity retention more than 90% over 200 cycling at 250 µA cm-2, even enabling a high-loading LiFePO4 cathode of 16.8 mg cm-2 with a specific capacity of 150 mAh g-1 at 50 °Ï¹.
ABSTRACT
Determining the causes of schizophrenia has been a notoriously intractable problem, resistant to a multitude of investigative approaches over centuries. In recent decades, genomic studies have delivered hundreds of robust findings that implicate nearly 300 common genetic variants (via genome-wide association studies) and more than 20 rare variants (via whole-exome sequencing and copy number variant studies) as risk factors for schizophrenia. In parallel, functional genomic and neurobiological studies have provided exceptionally detailed information about the cellular composition of the brain and its interconnections in neurotypical individuals and, increasingly, in those with schizophrenia. Taken together, these results suggest unexpected complexity in the mechanisms that drive schizophrenia, pointing to the involvement of ensembles of genes (polygenicity) rather than single-gene causation. In this Review, we describe what we now know about the genetics of schizophrenia and consider the neurobiological implications of this information.
ABSTRACT
Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD-atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD-CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.
ABSTRACT
Dog ownership has been associated with several complex traits, and there is evidence of genetic influence. We performed a genome-wide association study of dog ownership through a meta-analysis of 31,566 Swedish twins in 5 discovery cohorts and an additional 65,986 European-ancestry individuals in 3 replication cohorts from Sweden, Norway, and the United Kingdom. Association tests with >7.4 million single-nucleotide polymorphisms were meta-analyzed using a fixed effect model after controlling for population structure and relatedness. We identified 2 suggestive loci using discovery cohorts, which did not reach genome-wide significance after meta-analysis with replication cohorts. Single-nucleotide polymorphism-based heritability of dog ownership using linkage disequilibrium score regression was estimated at 0.123 (CI 0.038-0.207) using the discovery cohorts and 0.018 (CI -0.002 to 0.039) when adding in replication cohorts. Negative genetic correlation with complex traits including type 2 diabetes, depression, neuroticism, and asthma was only found using discovery summary data. Furthermore, we did not identify any genes/gene-sets reaching even a suggestive level of significance. This genome-wide association study does not, by itself, provide clear evidence on common genetic variants that influence dog ownership among European-ancestry individuals.
Subject(s)
Genome-Wide Association Study , Polymorphism, Single Nucleotide , White People , Dogs , Animals , Humans , White People/genetics , Linkage Disequilibrium , Female , Male , OwnershipABSTRACT
Understanding the temporal and spatial brain locations etiological for psychiatric disorders is essential for targeted neurobiological research. Integration of genomic insights from genome-wide association studies with single-cell transcriptomics is a powerful approach although past efforts have necessarily relied on mouse atlases. Leveraging a comprehensive atlas of the adult human brain, we prioritized cell types via the enrichment of SNP-heritabilities for brain diseases, disorders, and traits, progressing from individual cell types to brain regions. Our findings highlight specific neuronal clusters significantly enriched for the SNP-heritabilities for schizophrenia, bipolar disorder, and major depressive disorder along with intelligence, education, and neuroticism. Extrapolation of cell-type results to brain regions reveals important patterns for schizophrenia with distinct subregions in the hippocampus and amygdala exhibiting the highest significance. Cerebral cortical regions display similar enrichments despite the known prefrontal dysfunction in those with schizophrenia highlighting the importance of subcortical connectivity. Using functional MRI connectivity from cases with schizophrenia and neurotypical controls, we identified brain networks that distinguished cases from controls that also confirmed involvement of the central and lateral amygdala, hippocampal body, and prefrontal cortex. Our findings underscore the value of single-cell transcriptomics in decoding the polygenicity of psychiatric disorders and offer a promising convergence of genomic, transcriptomic, and brain imaging modalities toward common biological targets.
ABSTRACT
Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Using genomic data, this study elucidates biological mechanisms, key risk factors, and causal pathways underlying their comorbidity. We show that CVDs share a large proportion of their genetic risk factors with MDD. Multivariate genome-wide association analysis of the shared genetic liability between MDD and atherosclerotic CVD (ASCVD) revealed seven novel loci and distinct patterns of tissue and brain cell-type enrichments, suggesting a role for the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic, and psychosocial/lifestyle risk factors. Finally, we found support for causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and demonstrated that the causal effects were partly explained by metabolic and psychosocial/lifestyle factors. The distinct signature of MDD-ASCVD comorbidity aligns with the idea of an immunometabolic sub-type of MDD more strongly associated with CVD than overall MDD. In summary, we identify plausible biological mechanisms underlying MDD-CVD comorbidity, as well as key modifiable risk factors for prevention of CVD in individuals with MDD.
ABSTRACT
OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
Subject(s)
Bipolar Disorder , Depression, Postpartum , Depressive Disorder, Major , Female , Humans , Animals , Mice , Depressive Disorder, Major/genetics , Genome-Wide Association Study , Depression, Postpartum/genetics , Genetic Predisposition to Disease , Bipolar Disorder/genetics , Polymorphism, Single Nucleotide/geneticsABSTRACT
Objective: Emerging evidence supports a bidirectional phenotypic association between stress-related disorders and autoimmune disease. However, the biological underpinnings remain unclear. Here, the authors examined whether and how shared genetics contribute to the observed phenotypic associations. Methods: Based on data from 4,123,631 individuals identified from Swedish nationwide registers, familial coaggregation of stress-related disorders (any disorder or posttraumatic stress disorder [PTSD]) and autoimmune disease were initially estimated in seven cohorts with different degrees of kinship. Polygenic risk score (PRS) analyses were then performed with individual-level genotyping data from 376,871 participants in the UK Biobank study. Finally, genetic correlation analyses and enrichment analyses were performed with genome-wide association study (GWAS) summary statistics. Results: Familial coaggregation analyses revealed decreasing odds of concurrence of stress-related disorders and autoimmune disease with descending kinship or genetic relatedness between pairs of relatives; adjusted odds ratios were 1.51 (95% CI=1.092.07), 1.28 (95% CI=0.971.68), 1.16 (95% CI=1.141.18), and 1.01 (95% CI=0.981.03) for monozygotic twins, dizygotic twins, full siblings, and half cousins, respectively. Statistically significant positive associations were observed between PRSs of stress-related disorders and autoimmune disease, as well as between PRSs of autoimmune disease and stress-related disorders. GWAS summary statistics revealed a genetic correlation of 0.26 (95% CI=0.140.38) between these two phenotypes and identified 10 common genes and five shared functional modules, including one module related to G-proteincoupled receptor pathways. Similar analyses performed for PTSD and specific autoimmune diseases (e.g., autoimmune thyroid disease) largely recapitulated the results of the main analyses. Conclusions: This study demonstrated familial coaggregation, genetic correlation, and common biological pathways between stress-related disorders and autoimmune disease.
Subject(s)
Autoimmune Diseases , Humans , Autoimmune Diseases/genetics , Genome-Wide Association Study , Genetic Predisposition to Disease/geneticsABSTRACT
Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
Subject(s)
Disease , Genetic Variation , Animals , Humans , Biological Evolution , Genome, Human , Genome-Wide Association Study , Genomics , Molecular Sequence Annotation , Polymorphism, Single Nucleotide , Disease/geneticsABSTRACT
Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.5% of the human genome as significantly constrained, and likely functional. We compared these scores to large-scale genome annotation, genome-wide association studies (GWAS), copy number variation, clinical genetics findings, and cancer data sets. Evolutionarily constrained positions are enriched for variants explaining common disease heritability (more than any other functional annotation). Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
ABSTRACT
PURPOSE: Preclinical cancer models harboring CCNE1 amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors. PATIENTS AND METHODS: Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR). RESULTS: Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue. CONCLUSION: Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.
Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Female , Humans , Carcinoma, Ovarian Epithelial/drug therapy , Bayes Theorem , Antineoplastic Agents/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Oncogene Proteins/genetics , Cyclin E , Protein-Tyrosine Kinases/genetics , Cell Cycle Proteins/geneticsABSTRACT
Although bivariate associations between attention-deficit/hyperactivity disorder (ADHD) and eating disorders in adolescent girls and boys have been previously identified, the mechanistic link underlying the symptom-level associations remains unclear. We evaluated shared genetic and environmental influences on ADHD symptoms and disordered eating in 819 female and 756 male twins from the Swedish TCHAD cohort using bivariate models. Common additive genetic and unique environmental effects accounted for majority of ADHD and disordered eating associations in a differential manner. For girls, the strongest genetic correlation was observed for cognitive/inattention problems-bulimia (0.54), with genetic factors accounting for 67% of the phenotypic correlation. For boys, the strongest genetic correlations were observed for conduct problems-bulimia and hyperactivity-bulimia (~ 0.54), accounting for 83% and 95% of the phenotypic correlation, respectively. As per our findings, the risk of comorbidity and shared genetics highlights the need for preventative measures and specialized treatment for ADHD and disordered eating in both sexes.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Bulimia , Feeding and Eating Disorders , Humans , Male , Adolescent , Female , Attention Deficit Disorder with Hyperactivity/genetics , Bulimia/complications , Bulimia/genetics , Twins/genetics , Feeding and Eating Disorders/genetics , Feeding and Eating Disorders/complications , ComorbidityABSTRACT
Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.
Subject(s)
Deafness , Hearing Loss , Animals , Cochlea , Genome-Wide Association Study , Hearing Loss/genetics , Humans , Mice , Stria VascularisABSTRACT
Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients' initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age < 45 years, body mass index ≥ 25 kg/m2, presence of the TP53 mutation, and elevated LDH > upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.
Subject(s)
Gene Amplification , Neoplasms , Clinical Trials, Phase I as Topic , Cyclin E/genetics , Humans , Middle Aged , Mutation , Neoplasms/genetics , Oncogene Proteins/genetics , Retrospective StudiesABSTRACT
Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.
Subject(s)
Intellectual Disability , Schizophrenia , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Humans , Intellectual Disability/genetics , Intelligence/genetics , Schizophrenia/genetics , SwedenABSTRACT
BACKGROUND: Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI-PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI-PEG 20 and PLD in patients with metastatic solid tumors. METHODS: Patients with advanced ASS1-deficient solid tumors were enrolled in this phase 1 trial of ADI-PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI-PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. RESULTS: Of 15 enrolled patients, 9 had metastatic HER2-negative breast carcinoma. We observed no dose-limiting toxicities or treatment-related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression-free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti-ADI-PEG 20 antibodies by week 8 in one third of patients. CONCLUSION: Concurrent IM injection of ADI-PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1-deficient solid tumors. Further evaluation of this combination is under discussion.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Argininosuccinate Synthase/deficiency , Doxorubicin/analogs & derivatives , Hydrolases/administration & dosage , Neoplasms/drug therapy , Polyethylene Glycols/administration & dosage , Adult , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Humans , Hydrolases/adverse effects , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasms/enzymology , Polyethylene Glycols/adverse effects , Progression-Free Survival , Survival RateABSTRACT
OBJECTIVE: To observe the effect of tiaoren tongdu acupuncture method (for regulating the function of the Conception Vessel and promoting the circulation of the Governor Vessel) on fractional anisotropy (FA) and upper-extremity motor function after cerebral infarction by diffusion densor imaging (DTI) technology. METHODS: The patients with cerebral infarction were divided into an acupuncture group and a control group according to the random number table method, 27 cases in each group. In the control group, the basic treatment with conventional medication was used. In the acupuncture group, on the basic treatment as the control group, the tiaoren tongdu acupuncture method was provided. Main acupoints included Baihui (GV20), Shuigou(GV26), Chengjiang(CV24), Guanyuan(CV4), Qihai (CV6), Zhongwan (CV12), Shenting(GV24) and Mingmen(GV4). Supplementary points included Jianyu(LI15), Chize(LU5), Houxi (SI3), Weizhong (BL40), Zusanli (ST36) and Taichong (LR3) on the affected side. The needles were retained for 30 min. Acupuncture was given once a day, at the interval of 1 days every week, consecutively for 4 weeks. The upper extremity Fugl-Meyer assessment (UE-FMA) was used to evaluate the motor function of upper extremity before and after treatment. DTI was adopted to observe the FA values of infarct focus, posterior limb of internal capsule (PLIC) and cerebral peduncle on the affected side, as well as FA values at the corresponding parts on the healthy side in the patients of two groups. The relative differences (rFA) were calculated. RESULTS: Compared with their own pretreatment, the UE-FMA value was significantly higher after treatment in either of two groups separately (P<0.05 in the control group, P<0.01 in the acupuncture group). The difference of UE-FMA before and after treatment in the acupuncture group was larger than that in the control group (P<0.05). The FA and rFA values in infarct focus were higher than those before treatment in the two groups (P<0.05). The FA and rFA differences before and after treatment in the infarct focus and PLIC on the affected side were higher in the acupuncture group as compared with the control group (P<0.05). The UE-FMA difference was positively correlated with the rFA difference of each part in either group (P<0.05), and the correlation was the strongest in PLIC on the affected side in either group (P<0.01). CONCLUSION: Tiaoren tongdu acupuncture significantly improves the upper limb movement function after cerebral infarction. The rFA value of PLIC combined with UE-FMA can be used to evaluate the therapeutic effect of acupuncture on the upper extremity movement after cerebral infarction.
Subject(s)
Acupuncture Therapy , Stroke , Acupuncture Points , Anisotropy , Cerebral Infarction/diagnostic imaging , Cerebral Infarction/therapy , Humans , Stroke/diagnostic imaging , Stroke/therapy , Treatment Outcome , Upper ExtremityABSTRACT
RATIONAL: Epidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion. PATIENT CONCERNS: A 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis. DIAGNOSIS: Next-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y). INTERVENTIONS: The patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019. OUTCOMES: The patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3âweeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18âmonths since initiation of 1st-line treatment. LESSONS: This is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.
Subject(s)
Adenocarcinoma/therapy , Brain Neoplasms/therapy , Lung Neoplasms/therapy , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/secondary , Antineoplastic Combined Chemotherapy Protocols , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/secondary , Combined Modality Therapy , ErbB Receptors/genetics , Humans , Immunotherapy , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Treatment OutcomeABSTRACT
Although numerous adsorbent materials have been reported for the capture of radioactive iodine, there is still demand for new absorbents that are economically viable and can be prepared by reliable synthetic protocols. Herein, we report a coordination-driven self-assembly strategy towards adsorbents for the sequential confinement of iodine molecules. These adsorbents are versatile heterometallic frameworks constructed from aluminum molecular rings of varying size, flexible copper ions, and conjugated carboxylate ligands. Additionally, these materials can quickly remove iodine from cyclohexane solutions with a high removal rate (98.8 %) and considerable loading capacity (555.06â mg g-1 ). These heterometallic frameworks provided distinct pore sizes and binding sites for iodine molecules, and the sequential confinement of iodine molecules was supported by crystallographic data. This work not only sets up a bridge between molecular rings and infinite porous networks but also reveals molecular details for the underlying host-guest binding interactions at crystallographic resolution.
ABSTRACT
Hyperprogressive disease (HPD) is a novel pattern of progression caused by immune checkpoint inhibitors (ICIs). It is characterized by a dramatic tumor surge and is associated with poor clinical outcomes. Up to now, the definition of HPD is still controversial across various studies. Although it has been indicated that HPD has related to multiple clinicopathological features and genetic alterations, it is lack of biomarker to predict its occurrence, and the potential mechanism remains unknown. This review is to summarize current data on HPD specialized in the field of non-small cell lung cancer. And we expect to provide helpful clinical strategies for oncologists using ICIs.â©.