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1.
Cell Rep Med ; 5(5): 101547, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38703764

ABSTRACT

Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.


Subject(s)
Biomarkers, Tumor , Carcinoma, Renal Cell , Kidney Neoplasms , Proteogenomics , Humans , Proteogenomics/methods , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/metabolism , Transcriptome/genetics , Male , Female , Middle Aged , Gene Expression Regulation, Neoplastic
2.
Cancer Res Commun ; 3(6): 1093-1103, 2023 06.
Article in English | MEDLINE | ID: mdl-37377606

ABSTRACT

The development of novel therapies for brain metastases is an unmet need. Brain metastases may have unique molecular features that could be explored as therapeutic targets. A better understanding of the drug sensitivity of live cells coupled to molecular analyses will lead to a rational prioritization of therapeutic candidates. We evaluated the molecular profiles of 12 breast cancer brain metastases (BCBM) and matched primary breast tumors to identify potential therapeutic targets. We established six novel patient-derived xenograft (PDX) from BCBM from patients undergoing clinically indicated surgical resection of BCBM and used the PDXs as a drug screening platform to interrogate potential molecular targets. Many of the alterations were conserved in brain metastases compared with the matched primary. We observed differential expressions in the immune-related and metabolism pathways. The PDXs from BCBM captured the potentially targetable molecular alterations in the source brain metastases tumor. The alterations in the PI3K pathway were the most predictive for drug efficacy in the PDXs. The PDXs were also treated with a panel of over 350 drugs and demonstrated high sensitivity to histone deacetylase and proteasome inhibitors. Our study revealed significant differences between the paired BCBM and primary breast tumors with the pathways involved in metabolisms and immune functions. While molecular targeted drug therapy based on genomic profiling of tumors is currently evaluated in clinical trials for patients with brain metastases, a functional precision medicine strategy may complement such an approach by expanding potential therapeutic options, even for BCBM without known targetable molecular alterations. Significance: Examining genomic alterations and differentially expressed pathways in brain metastases may inform future therapeutic strategies. This study supports genomically-guided therapy for BCBM and further investigation into incorporating real-time functional evaluation will increase confidence in efficacy estimations during drug development and predictive biomarker assessment for BCBM.


Subject(s)
Brain Neoplasms , Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Precision Medicine , Phosphatidylinositol 3-Kinases/therapeutic use , Brain Neoplasms/drug therapy
3.
Cancer Cell ; 41(1): 139-163.e17, 2023 01 09.
Article in English | MEDLINE | ID: mdl-36563681

ABSTRACT

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Proteogenomics , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Treatment Outcome , Prognosis , Biomarkers, Tumor/genetics
4.
Korean J Med Educ ; 33(4): 393-404, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34875155

ABSTRACT

The required adjustments precipitated by the coronavirus disease 2019 crisis have been challenging, but also represent a critical opportunity for the evolution and potential disruptive and constructive change of medical education. Given that the format of medical education is not fixed, but malleable and in fact must be adaptable to societal needs through ongoing reflexivity, we find ourselves in a potentially transformative learning phase for the field. An Association for Medical Education in Europe ASPIRE Academy group of 18 medical educators from seven countries was formed to consider this opportunity, and identified critical questions for collective reflection on current medical education practices and assumptions, with the attendant challenge to envision the future of medical education. This was achieved through online discussion as well as asynchronous collective reflections by group members. Four major themes and related conclusions arose from this conversation: Why we teach: the humanitarian mission of medicine should be reinforced; what we teach: disaster management, social accountability and embracing an environment of complexity and uncertainty should be the core; how we teach: open pathways to lean medical education and learning by developing learners embedded in a community context; and whom we teach: those willing to take professional responsibility. These collective reflections provide neither fully matured digests of the challenges of our field, nor comprehensive solutions; rather they are offered as a starting point for medical schools to consider as we seek to harness the learning opportunities stimulated by the pandemic.


Subject(s)
COVID-19 , Education, Medical , Humans , Pandemics , SARS-CoV-2 , Schools, Medical
5.
BMJ Open ; 10(12): e038341, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33262187

ABSTRACT

OBJECTIVE: To assess the impact of heart disease (HD) combined with depression on all-cause mortality in older people living in the community. DESIGN: A population-based cohort study. PARTICIPANTS: We examined the data of 1429 participants aged ≥60 years recruited in rural areas in Anhui province, China. Using a standard method of interview, we documented all types of HD diagnosed by doctors and used the validated Geriatric Mental Status-Automated Geriatric Examination for Computer Assisted Taxonomy algorithm to diagnose any depression for each participant at baseline in 2003. The participants were followed up for 8 years to identify vital status. MEASUREMENTS: We sought to examine all-cause mortality rates among participants with HD only, depression only and then their combination compared with those without these diseases using multivariate adjusted Cox regression models. RESULTS: 385 deaths occurred in the cohort follow-up. Participants with baseline HD (n=91) had a significantly higher mortality (64.9 per 1000 person-years) than those without HD (42.9). In comparison to those without HD and depression, multivariate adjusted HRs for mortality in the groups of participants who had HD only, depression only and both HD and depression were 1.46 (95% CI 0.98 to 2.17), 1.79 (95% CI 1.28 to 2.48) and 2.59 (95% CI 1.12 to 5.98), respectively. CONCLUSION: Older people with both HD and depression in China had significantly increased all-cause mortality compared with those with HD or depression only, and without either condition. Psychological interventions should be taken into consideration for older people and those with HD living in the community to improve surviving outcome.


Subject(s)
Heart Diseases , Rural Population , Aged , Aged, 80 and over , China/epidemiology , Cohort Studies , Depression/epidemiology , Humans
6.
J Epidemiol Community Health ; 74(6): 519-526, 2020 06.
Article in English | MEDLINE | ID: mdl-32341052

ABSTRACT

BACKGROUND: Little is known about the impact of socioeconomic status (SES) on incidence of stroke in China. This study aimed to examine the association of SES, which was measured by different indicators, with incidence of stroke and gender differences in the association. METHODS AND RESULTS: Two prospective cohort studies were conducted including 2852 participants aged ≥60 years in Anhui province and 3016 participants in four other provinces in China. During a median follow-up of 7.1 years, 211 incident stroke cases occurred in the Anhui cohort. The risk of stroke increased with living in rural areas (adjusted HR 2.49, 95% CI 1.19 to 5.22; women 3.64, 95% CI 1.17 to 11.32, men 2.23, 95% CI 0.81 to 6.19), but not significantly with educational level, occupational class, satisfactory income and financial problems (except for women with low education). The four-province cohort had 113 incident stroke cases over the 3.1 years' follow-up. The five SES indicators were not significantly associated with incident stroke (except for increased risk in men with high occupation), but additional measurement for actual income showed that incident stroke increased in women with low personal income and in men with high family income. Pooled data from the two cohorts demonstrated the impacts of rural living (1.66, 95% CI 1.08 to 2.57) and having high occupational class (1.56, 95% CI 1.01 to 2.38), and gender differences for women with low education (2.26, 95% CI 1.19 to 4.27). CONCLUSIONS: Rural living and being female with low SES are associated with increased stroke risk in China. Strategies to improve public health in the rural communities and gender-specific targets for health inequality should be an integral component of stroke interventions.


Subject(s)
Rural Population/statistics & numerical data , Social Class , Stroke/epidemiology , Urban Population/statistics & numerical data , Aged , Aged, 80 and over , China/epidemiology , Cohort Studies , Female , Humans , Incidence , Income , Male , Middle Aged , Prospective Studies , Sex Factors , Socioeconomic Factors
7.
J Immunother Cancer ; 6(1): 84, 2018 08 31.
Article in English | MEDLINE | ID: mdl-30170629

ABSTRACT

BACKGROUND: Low absolute lymphocyte count (ALC) has previously been established as a marker of poor prognosis in multiple cancer types. There is growing evidence that ALC may also be associated with response to immunotherapy. This study explores whether response to PD1 inhibitors in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is associated with pretreatment ALC. METHODS: Thirty-four R/M HNSCC patients who received either nivolumab or pembrolizumab between January 2014 and May 2018 at Johns Hopkins were identified retrospectively. Pretreatment blood counts in patients with and without clinical benefit from PD1 inhibitors were compared. Time-to-progression analyses were performed by dichotomizing the study cohort with the threshold of ALC 600 cells/µl, which is approximately 1.5 standard deviations away from treatment-naïve baseline mean. RESULTS: Patients with lower ALC appeared to have significantly less clinical benefit from anti-PD1 therapy. Those patients with pretreatment ALC < 600 cells/µl also had shorter PFS than patients with pretreatment ALC ≥ 600 cells/µl (median PFS 60 days vs. 141 days, p < 0.05). These results were consistent with multivariate proportional hazards analyses demonstrating significant association with progression. These observations were further supported by an expansion cohort analysis incorporating additional fourteen R/M HNSCC patients who received other checkpoint immunotherapy regimens at our institution. CONCLUSIONS: This study for the first time demonstrates that pretreatment ALC is significantly associated with response to PD1 inhibitors in R/M HNSCC patients.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Lymphocyte Count , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Squamous Cell Carcinoma of Head and Neck/blood , Squamous Cell Carcinoma of Head and Neck/drug therapy , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Biomarkers , Chemoradiotherapy , Combined Modality Therapy , Female , Humans , Kaplan-Meier Estimate , Lymphopenia/blood , Male , Middle Aged , Molecular Targeted Therapy , Retreatment , Squamous Cell Carcinoma of Head and Neck/mortality , Squamous Cell Carcinoma of Head and Neck/pathology , Treatment Outcome
8.
J Otolaryngol Head Neck Surg ; 47(1): 20, 2018 Mar 07.
Article in English | MEDLINE | ID: mdl-29514718

ABSTRACT

BACKGROUND: Recent studies have examined the effects of brief electrical stimulation (BES) on nerve regeneration, with some suggesting that BES accelerates facial nerve recovery. However, the facial nerve outcome measurement in these studies has not been precise or accurate. Furthermore, no previous studies have been able to demonstrate the effect of BES on synkinesis. The objective of this study is to examine the effect of brief electrical stimulation (BES) on facial nerve function and synkinesis in a rat model. METHODS: Four groups of six rats underwent a facial nerve injury procedure. Group 1 and 2 underwent a crush injury at the main trunk of the nerve, with group 2 additionally receiving BES for 1 h. Group 3 and 4 underwent a transection injury at the main trunk, with group 4 additionally receiving BES for 1 h. A laser curtain model was used to measure amplitude of whisking at 2, 4, and 6 weeks. Fluorogold and fluororuby neurotracers were additionally injected into each facial nerve to measure synkinesis. Buccal and marginal mandibular branches of the facial nerve were each injected with different neurotracers at 3 months following injury. Based on facial nucleus motoneuron labelling of untreated rats, comparison was made to post-treatment animals to deduce whether synkinesis had taken place. All animals underwent trans-cardiac perfusion with subsequent neural tissue sectioning. RESULTS: At week two, the amplitude observed for group 1 and 2 was 14.4 and 24.0 degrees, respectively (p = 0.0004). Group 4 also demonstrated improved whisking compared to group 3. Fluorescent neuroimaging labelling appear to confirm improved pathway specific regeneration with BES following facial nerve injury. CONCLUSIONS: This is the first study to use an implantable stimulator for serial BES following a crush injury in a validated animal model. Results suggest performing BES after facial nerve injury is associated with accelerated facial nerve function and improved facial nerve specific pathway regeneration in a rat model.


Subject(s)
Crush Injuries/rehabilitation , Electric Stimulation/methods , Facial Nerve Injuries/rehabilitation , Nerve Regeneration/physiology , Synkinesis/rehabilitation , Animals , Canada , Crush Injuries/surgery , Disease Models, Animal , Facial Nerve Injuries/surgery , Female , Neurosurgical Procedures/methods , Random Allocation , Rats , Rats, Wistar , Treatment Outcome
9.
Mol Cancer Res ; 15(10): 1341-1353, 2017 10.
Article in English | MEDLINE | ID: mdl-28684636

ABSTRACT

Epithelial-to-mesenchymal transition (EMT) is an important physiologic process that drives tissue formation during development, but also contributes to disease pathogenesis, including fibrosis and cancer metastasis. Elevated expression of the FOXC1 transcription factor has been detected in several metastatic cancers that have undergone EMT. Therefore, mechanistic insight into the role of FOXC1 in the initiation of the EMT process was sought. It was determined that although Foxc1 transcript expression was elevated following TGFß1-induced EMT of NMuMG cells, FOXC1 was not required for this induction. RNA sequencing revealed that the mRNA levels of FGF receptor 1-isoform IIIc (Fgfr1-IIIc), normally activated upon TGFß1 treatment, were reduced in Foxc1 knockdown cells, and overexpression of Foxc1 was sufficient to induce Fgfr1-IIIc expression, but not EMT. Chromatin immunoprecipitation experiments demonstrated that FOXC1 binds to an Fgfr1 upstream regulatory region and that FOXC1 activates an Fgfr1 promoter element. Furthermore, elevated expression of Foxc1 led to increased Fgfr1-IIIc transcript. Foxc1 knockdown impaired the FGF2-mediated three-dimensional migratory ability of NMuMG cells, which was rescued by expression of FGFR1. In addition, elevated expression of FOXC1 and FGFR1 was also observed in migratory mesenchymal MDA-MB-231 breast cancer cells. Together, these results define a role for FOXC1 in specifying an invasive mesenchymal cell type by promoting FGFR1 isoform switching following induction of TGFß1-mediated EMT. Mol Cancer Res; 15(10); 1341-53. ©2017 AACR.


Subject(s)
Breast Neoplasms/genetics , Forkhead Transcription Factors/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Sequence Analysis, RNA/methods , Transforming Growth Factor beta1/pharmacology , Animals , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Movement , Epithelial-Mesenchymal Transition/drug effects , Female , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Neoplasm Invasiveness , RNA Isoforms/genetics
10.
Oncotarget ; 8(69): 114268-114280, 2017 Dec 26.
Article in English | MEDLINE | ID: mdl-29371985

ABSTRACT

The relationships between absolute lymphocyte counts (ALC), drug- related toxicities, and clinical responses remain unclear in cancer patients treated with PD-1 (programmed cell death 1) inhibitors. We performed a retrospective review of 167 adult solid tumor patients treated with nivolumab or pembrolizumab at a single institution between January 2015 and November 2016. Patients with an ALC >2000 at baseline had an increased risk of irAE (OR 1.996, p<0.05) on multivariate analysis. In a multivariate proportional hazards model, a shorter time to progression was noted in patients who were lymphopenic at baseline (HR 1.45 (p<0.05)) and at three months (HR 2.01 (p<0.05)). Patients with baseline lymphopenia and persistent lymphopenia at month 3 had a shorter time to progression compared to those who had baseline lymphopenia but recovered with ALC > 1000 at 3 months (HR 2.76, p<0.05). Prior radiation therapy was the characteristic most strongly associated with lymphopenia at 3 months (OR 2.24, p<0.001). These data suggest that patients with higher baseline lymphocyte counts have a greater risk for irAE, whereas patients with lymphopenia at baseline and persistent lymphopenia while on therapy have a shorter time to progression on these agents. These associations require further validation in additional patient cohorts.

11.
Structure ; 24(2): 243-51, 2016 Feb 02.
Article in English | MEDLINE | ID: mdl-26749448

ABSTRACT

The ß-barrel assembly machine (BAM) mediates folding and insertion of integral ß-barrel outer membrane proteins (OMPs) in Gram-negative bacteria. Of the five BAM subunits, only BamA and BamD are essential for cell viability. Here we present the crystal structure of a fusion between BamA POTRA4-5 and BamD from Rhodothermus marinus. The POTRA5 domain binds BamD between its tetratricopeptide repeats 3 and 4. The interface structural elements are conserved in the Escherichia coli proteins, which allowed structure validation by mutagenesis and disulfide crosslinking in E. coli. Furthermore, the interface is consistent with previously reported mutations that impair BamA-BamD binding. The structure serves as a linchpin to generate a BAM model where POTRA domains and BamD form an elongated periplasmic ring adjacent to the membrane with a central cavity approximately 30 × 60 Å wide. We propose that nascent OMPs bind this periplasmic ring prior to insertion and folding by BAM.


Subject(s)
Bacterial Outer Membrane Proteins/chemistry , Bacterial Outer Membrane Proteins/metabolism , Rhodothermus/metabolism , Bacterial Outer Membrane Proteins/genetics , Binding Sites , Models, Molecular , Mutation , Protein Binding , Protein Folding , Protein Structure, Secondary , Protein Structure, Tertiary , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Rhodothermus/chemistry , Rhodothermus/genetics
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