Quality of life and functional outcomes in tongue cancer patients: a long-term, prospective, comparative study.

BACKGROUND: The tongue has an indispensable role in communication, swallowing and breathing. Tongue cancer treatment involves direct resection of the tumor and surrounding tissue, which can limit many essential functions of the tongue. There are few patient-reported quality of life studies involving tongue cancer exclusively. There is also a lack of data on the outcomes of quality of life regarding different reconstructive methods, adjuvant non-surgical therapies and other predicting factors. Our objective is to assess the quality of life, functional status, and predicting factors in patients with tongue cancer up to one year after surgical resection. MATERIAL AND METHODS: Thirty-six patients with tongue cancer were prospectively identified between October of 2017 and January 2021. Patients were examined before and one, three, six and twelve months after surgical resection with the validated University of Washington Quality of Life questionnaire (UW-QOL). Data collection included patient age, sex, TNM staging, size of resection, neck dissection, tracheostomy, reconstructive method and adjuvant therapies. Outcome scores were compared using the Friedman test. Multiple linear regression analysis was used to identify the predictors of quality of life and functional status. RESULTS: The use of UWQOL scores as dependent variables revealed the following predicting factors: age, tobacco use, radiotherapy, chemotherapy, reconstruction method and neck dissection. CONCLUSIONS: The most relevant findings in our study are that flap reconstruction becomes increasingly necessary when a glossectomy resection is over 45 mm, in order to maintain tongue function. We established that the reconstructive flap type does not influence quality of life in the long term. Also, we have found that cervical sentinel node biopsy provides better quality of life over neck dissection in the first 3 months after surgery.

Population-specific Mutation Patterns in Breast Tumors from African American, European American, and Kenyan Patients.

Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer. SIGNIFICANCE: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients.

Diabetes-associated breast cancer is molecularly distinct and shows a DNA damage repair deficiency.

Diabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.

Protein expression of the gp78 E3 ligase predicts poor breast cancer outcome based on race.

Women of African ancestry suffer higher rates of breast cancer mortality compared with all other groups in the United States. Though the precise reasons for these disparities remain unclear, many recent studies have implicated a role for differences in tumor biology. Using an epitope-validated antibody against the endoplasmic reticulum-associated E3 ligase, gp78, we show that elevated levels of gp78 in patient breast cancer cells predict poor survival. Moreover, high levels of gp78 are associated with poor outcomes in both ER+ and ER- tumors, and breast cancers expressing elevated amounts of gp78 protein are enriched in gene expression pathways that influence cell cycle, metabolism, receptor-mediated signaling, and cell stress response pathways. In multivariate analysis adjusted for subtype and grade, gp78 protein is an independent predictor of poor outcomes in women of African ancestry. Furthermore, gene expression signatures, derived from patients stratified by gp78 protein expression, are strong predictors of recurrence and pathological complete response in retrospective clinical trial data and share many common features with gene sets previously identified to be overrepresented in breast cancers based on race. These findings implicate a prominent role for gp78 in tumor progression and offer insights into our understanding of racial differences in breast cancer outcomes.

Fabrication of pH-degradable supramacromolecular microgels with tunable size and shape via droplet-based microfluidics.

This study presents a versatile method to synthesize stimuli-responsive microgels with supramolecular cross-links exhibiting tunable size and shape via droplet-based microfluidics. The natural polyphenol tannic acid (TA) is used to cross-link poly(N-vinylcaprolactam) (PVCL) chains in aqueous droplets by the formation of hydrogen bonds and hydrophobic interactions between the phenolic groups of TA and the carbonyl group and the hydrophobic segments of lactam ring of PVCL chains. The obtained microgels exhibit diameters in the range of 130-150µm in swollen state in aqueous solution. Synthesized microgels exhibit pH-responsive behavior: at low pH microgels deswell and shrink due to the protonation of phenolic groups and enhanced hydrophobic interactions; at high pH microgels swell and disintegrate due to the deprotonation of phenolic groups and destruction of hydrogen bonds with PVCL chains. Additionally, we present supramacromolecular microgels in cylindrical shape with different aspect ratios using a new design of microfluidic chip by varying flow rates at high concentration of the prepolymerized precursor combined with rapid pH-triggered on-chip gelation. Furthermore, developed synthesis methodology allows on-chip encapsulation of colloidal objects into large supramacromolecular microgels during the cross-linking step. The complete and fast release of objects by pH-triggered degradation indicates that the pH-responsive supramacromolecular microgels can be used for controlled loading/release of various payloads, like probiotics. Moreover, cell studies of L929 fibroblast clearly show the biocompatibility of the microgels.

Adjuvant durvalumab for esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: a placebo-controlled, randomized, double-blind, phase II study.

BACKGROUND: We evaluated the efficacy of adjuvant durvalumab after neoadjuvant concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: This randomized, double-blind, phase II study included patients with ESCC who underwent curative surgery after neoadjuvant CCRT. Patients were randomized to receive either durvalumab (20 mg/kg/i.v. every 4 weeks for 12 months) or placebo in a 1:1 ratio and were stratified by age and pathologic tumor stage. The primary endpoint was disease-free survival (DFS). RESULTS: Between March 2016 and June 2018, 86 patients were randomized to the durvalumab (n = 45) or placebo (n = 41) arm. The median follow-up duration was 38.7 months. There was no difference in DFS [hazard ratio (HR) 1.18, 95% confidence interval (CI) 0.62-2.27, P = 0.61] or overall survival (HR 1.08, 95% CI 0.52-2.24, P = 0.85) between the two arms. Subgroup analysis was performed for patients for whom the post-CCRT programmed death-ligand 1 (PD-L1) expression profile could be assessed (n = 54). In the PD-L1-positive group, based on tumor proportion score ≥1%, durvalumab was associated with longer overall survival compared with the placebo (36-month survival rate: 94% versus 64%; HR 0.42, 95% CI 0.10-1.76), while in the PD-L1-negative group, it was associated with shorter overall survival (42% versus 55%; HR 1.53, 95% CI 0.48-4.83), showing the tendency of interaction between post-CCRT PD-L1 status and adjuvant durvalumab therapy for overall survival (interaction P = 0.18). CONCLUSIONS: We failed to demonstrate that adjuvant durvalumab improved survival after neoadjuvant CCRT in patients with ESCC. However, post-CCRT PD-L1 expression could predict the survival of patients who receive adjuvant durvalumab after neoadjuvant CCRT, which needs to be validated.

Multi-disciplinary assessment of the entrustable professional activities of surgery residents.

Purpose: Medicine is practiced in a collaborative and interdisciplinary manner. However, medical training and assessment remain largely isolated in traditional departmental silos. Two Entrustable Professional Activities (EPAs) developed by the American Board of Surgery are multidisciplinary in nature and offer a unique opportunity to study interdisciplinary assessment. Methods: EPA microassessments were collected from Surgery and Emergency Medicine (EM) faculty between July 2018 and May 2020. Differences in feedback provided by faculty were assessed using natural language processing (NLP) techniques, (1) automated algorithms; and (2) topic modeling. Summative content analysis was used to identify themes in text feedback. We developed automated coding algorithms for these themes using regular expressions. Topic modeling was performed using latent Dirichlet allocation. Results: 549 assessments were collected for two EPAs: 198 for GS Consultation and 351 for Trauma. 27 EM and 27 Surgery faculty provided assessments for 71 residents. EM faculty were significantly more likely than Surgery faculty to submit feedback coded as Communication, Demeanor, and Timeliness, (all chi-square test p-values < 0.01). No significant differences were found for Clinical Performance, Skill Level, or Areas for Improvement. Similarly, topic modeling indicated that assessments submitted by EM faculty focused on communication, timeliness, and interpersonal skills, while those submitted by Surgery faculty focused on the residents' abilities to effectively gather information and correctly diagnose the underlying pathology. Conclusions: Feedback from EM and Surgery faculty differed significantly based on NLP analyses. EPA assessments should stem from multiple sources to avoid assessment gaps and represent a more holistic picture of performance.

Neuropsychological adverse drug reactions of Remdesivir: analysis using VigiBase, the WHO global database of individual case safety reports.

OBJECTIVE: Although remdesivir (GS-5734) has recently demonstrated clinical benefits against the pandemic outbreak of coronavirus disease 2019 (COVID-19), neuropsychological adverse reactions (ADRs) remain to be examined in real-world settings. Therefore, we aimed to identify and characterize the neuropsychological ADRs associated with remdesivir use. MATERIALS AND METHODS: We obtained data for this international pharmacovigilance cohort study from individual case safety reports (ICSRs) in a World Health Organization database (VigiBase) from the first report on remdesivir on February 17, 2020, until August 30, 2020 (n=1,403,532). ADRs reported to be relevant to remdesivir were compared with the full database by using a Bayesian neural network method to calculate the information component (IC). RESULTS: A total of 2,107 reported cases of neuropsychological ADRs suspected to be associated with remdesivir were identified from among all ICSRs in the database during the observation period. Although 108 neuropsychological ADRs (64 neurologic events and 44 psychologic events) were reported in association with the medication, no statistically significant pharmacovigilance signal could be detected; the IC025 value was negative for all of the neuropsychological dysfunctions (anxiety [n=13, 0.62%], seizures [n=12, 0.57%], lethargy [n=6, 0.28%], agitation [n=5, 0.25%], cerebral infarction [n=3, 0.14%], ischemic stroke [n=3, 0.14%], and hemiparesis [n=3, 0.14%]). CONCLUSIONS: Our study demonstrates that remdesivir, a novel drug applied to the treatment of COVID-19, does not have a significant association with adverse neurologic or psychiatric reactions in the real-world setting.

Longitudinal Outcomes of COVID-19-Associated Collapsing Glomerulopathy and Other Podocytopathies.

BACKGROUND: The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown. METHODS: We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2. RESULTS: The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1. Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected. CONCLUSIONS: Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy.

Association between PD-L1 expression and initial brain metastasis in patients with non-small cell lung cancer and its clinical implications.

BACKGROUND: Brain metastases frequently occur in patients with non-small cell lung cancer (NSCLC) resulting in a poor prognosis. Here, we investigated the association between PD-L1 expression and brain metastasis in patients with NSCLC and its clinical significance. METHODS: A total of 270 patients diagnosed with metastatic NSCLC who underwent PD-L1 testing on their tumor tissue between January 2017 and March 2019 were retrospectively reviewed. The VENTANA PD-L1 (SP263) assay was used, and positive PD-L1 expression was defined as staining in ≥1% of tumor cells. RESULTS: Positive PD-L1 expression was observed in 181 (67.0%) patients, and 74 (27.4%) patients had brain metastasis at diagnosis. Synchronous brain metastases were more frequently observed in PD-L1-positive compared with PD-L1-negative patients (31.5% vs. 19.1%, p = 0.045). Multiple logistic regression analysis identified positive PD-L1 expression (odds ratio [OR]: 2.24, p = 0.012) as an independent factor associated with synchronous brain metastasis, along with the histological subtype of nonsquamous cell carcinoma (OR: 2.84, p = 0.003). However, the incidence of central nervous system (CNS) progression was not associated with PD-L1 positivity, with a two-year cumulative CNS progression rate of 26.3% and 28.4% in PD-L1-positive and PD-L1-negative patients, respectively (log rank p = 0.944). Furthermore, positive PD-L1 expression did not affect CNS progression or overall survival in patients with synchronous brain metastasis (long rank p = 0.513 and 0.592, respectively). CONCLUSIONS: Initial brain metastases are common in NSCLC patients with positive PD-L1 expression. Further studies are necessary to understand the relationship between early brain metastasis and cancer immunity.

Prognosis of papillary thyroid carcinoma in relation to preoperative subclinical hypothyroidism.

INTRODUCTION: It has been established that thyroid-stimulating hormone (TSH) stimulates the growth and development of thyroid malignancy, and a higher serum TSH level is associated with the incidence of thyroid cancer and an advanced tumour stage. This study aimed to evaluate the association of preoperative subclinical hypothyroidism with the prognosis of papillary thyroid cancer (PTC). METHODS: A total of 466 patients who underwent surgery for PTC between December 2006 and June 2009 were enrolled. Among them, 44 patients had subclinical hypothyroidism, while 422 did not have subclinical hypothyroidism, as diagnosed using the preoperative thyroid function test. We compared the recurrence rate and association with clinicopathological features in the two groups. RESULTS: The median patient age was 46.9 years (17-74 years). There were 420 female and 46 male patients. The median follow-up duration was 81.4 months. There were no statistical differences between the two groups with respect to age, sex, tumour size, extrathyroidal extension, multifocality, lymph node metastasis, TNM stages, recurrence and disease-free survival, despite a significant difference in the average TSH concentrations of the two groups. CONCLUSIONS: Our results suggest that preoperative subclinical hypothyroidism was not associated with tumour aggressiveness and recurrence in PTC.

Kaiso (ZBTB33) subcellular partitioning functionally links LC3A/B, the tumor microenvironment, and breast cancer survival.

The use of digital pathology for the histomorphologic profiling of pathological specimens is expanding the precision and specificity of quantitative tissue analysis at an unprecedented scale; thus, enabling the discovery of new and functionally relevant histological features of both predictive and prognostic significance. In this study, we apply quantitative automated image processing and computational methods to profile the subcellular distribution of the multi-functional transcriptional regulator, Kaiso (ZBTB33), in the tumors of a large racially diverse breast cancer cohort from a designated health disparities region in the United States. Multiplex multivariate analysis of the association of Kaiso's subcellular distribution with other breast cancer biomarkers reveals novel functional and predictive linkages between Kaiso and the autophagy-related proteins, LC3A/B, that are associated with features of the tumor immune microenvironment, survival, and race. These findings identify effective modalities of Kaiso biomarker assessment and uncover unanticipated insights into Kaiso's role in breast cancer progression.

Relationship between tumor cell infiltration and 5-aminolevulinic acid fluorescence signals after resection of MR-enhancing lesions and its prognostic significance in glioblastoma.

PURPOSE: This study investigated the degree of tumor cell infiltration in the tumor cavity and ventricle wall based on fluorescent signals of 5-aminolevulinic acid (5-ALA) after removal of the magnetic resonance (MR)-enhancing area and analyzed its prognostic significance in glioblastoma. METHODS: Twenty-five newly developed isocitrate dehydrogenase (IDH)-wildtype glioblastomas with complete resection both of MR-enhancing lesions and strong purple fluorescence on resection cavity were retrospectively analyzed. The fluorescent signals of 5-ALA were divided into strong purple, vague pink, and blue colors. The pathologic findings were classified into massively infiltrating tumor cells, infiltrating tumor cells, suspicious single-cell infiltration, and normal-appearing cells. The pathological findings were analyzed according to the fluorescent signals in the resection cavity and ventricle wall. RESULTS: There was no correlation between fluorescent signals and infiltrating tumor cells in the resection cavity (p = 0.199) and ventricle wall (p = 0.704) after resection of the MR-enhancing lesion. The median progression-free survival (PFS) and median overall survival (OS) were 12.5 (± 2.1) and 21.1 (± 3.5) months, respectively. In univariate analysis, the presence of definitive infiltrating tumor cells in the resection cavity and ventricle wall was significantly related to the PFS (p = 0.002) and OS (p = 0.027). In multivariate analysis, the absence of definitive infiltrating tumor cells improved PFS (hazard ratio: 0.184; 95% CI: 0.049-0.690, p = 0.012) and OS (hazard ratio: 0.124; 95% CI: 0.015-0.998, p = 0.050). CONCLUSIONS: After resection both of the MR-enhancing lesions and strong purple fluorescence on resection cavity, there was no correlation between remnant fluorescent signals and infiltrating tumor cells. The remnant definitive infiltrating tumor cells in the resection cavity and ventricle wall significantly influenced the prognosis of patients with glioblastoma. Aggressive surgical removal of infiltrating tumor cells may improve their prognosis.

Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death.

Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.

Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes.

Induced pluripotent stem cells (iPSCs) can be derived from differentiated cells, enabling the generation of personalized disease models by differentiating patient-derived iPSCs into disease-relevant cell lines. While genetic variability between different iPSC lines affects differentiation potential, how this variability in somatic cells affects pluripotent potential is less understood. We generated and compared transcriptomic data from 72 dermal fibroblast-iPSC pairs with consistent variation in reprogramming efficiency. By considering equal numbers of samples from self-reported African Americans and White Americans, we identified both ancestry-dependent and ancestry-independent transcripts associated with reprogramming efficiency, suggesting that transcriptomic heterogeneity can substantially affect reprogramming. Moreover, reprogramming efficiency-associated genes are involved in diverse dynamic biological processes, including cancer and wound healing, and are predictive of 5-year breast cancer survival in an independent cohort. Candidate genes may provide insight into mechanisms of ancestry-dependent regulation of cell fate transitions and motivate additional studies for improvement of reprogramming.

Anchor, Spacer, and Ligand-Modified Engineered Exosomes for Trackable Targeted Therapy.

Exosomes have been widely demonstrated as an effective anticancer therapeutic moiety. However, their clinical translation has been limited by the requirement of prohibitively high therapeutic doses due to their lack of specificity in delivery and, consequently, short systemic half-life. To overcome these challenges, we engineered a platform for modifying exosomes with an active targeting modality composed of membrane Anchor (BODIPY)-Spacer (PEG)-targeting Ligands (cyclic RGD peptide) (ASL). Herein, we show that the intramembrane incorporation of a trackable, targeting system renders ASL exosomes (AExs) a modular platform. AExs significantly overcome challenges associated with exosome modification, including potential damage for functionalization, or destabilizing interactions between dyes and drugs. ASL-modification not only enhanced stability in imparting active targeting but also introduced a built-in bioimaging modality. Our studies show that AExs target B16F10 melanoma tumor sites by the specific interaction of cyclic RGD and integrin. Doxorubicin encapsulated AExs (dAExs) significantly inhibited the growth of melanoma in vitro and in vivo. Thus, we conclude that ASL-modification allows exosomes to be transformed into a novel therapeutic vehicle uniquely integrating in vivo tracking and robust targeting with drug delivery. We anticipate that the therapeutic, targeting, and diagnostic modularity provided by ASL will potentiate translational applications of exosome-based vehicles beyond anticancer therapy.

Whole-Exome Profiling of NSCLC Among African Americans.

INTRODUCTION: Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States, especially among men. Although significant progress has been made profiling the genomic makeup of lung cancer in EAs, AAs continue to be underrepresented. Our objective was to chart the genome-wide landscape of somatic mutations in lung cancer tumors from AAs. METHODS: In this study, we used the whole-exome sequencing of 82 tumor and noninvolved tissue pairs from AAs. Patients were selected from an ongoing case-control study conducted by the National Cancer Institute and the University of Maryland. RESULTS: Among all samples, we identified 178 significantly mutated genes (p < 0.05), five of which passed the threshold for false discovery rate (p < 0.1). In lung adenocarcinoma (LUAD) tumors, mutation rates in STK11 (p = 0.05) and RB1 (p = 0.008) were significantly higher in AA LUAD tumors (25% and 13%, respectively) compared with The Cancer Genome Atlas EA samples (14% and 4%, respectively). In squamous cell carcinomas, mutation rates in STK11 (p = 0.002) were significantly higher among AA (8%) than EA tumors from The Cancer Genome Atlas (1%). Integrated somatic mutation data with CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) data analysis revealed LUAD tumors from AAs carrying STK11 mutations have decreased interferon signaling. CONCLUSIONS: Although a considerable degree of the somatic mutation landscape is shared between EAs and AAs, discrete differences in mutation frequency in potentially important oncogenes and tumor suppressors exist. A better understanding of the molecular basis of lung cancer in AA patients and leveraging this information to guide clinical interventions may help reduce disparities.

Distribution of bone thickness in the human mandibular ramus - a CBCT-based study.

BACKGROUND: The bone thickness of the human mandibular ramus is an important parameter in mandibular surgeries. The aim of this study was to systematically measure the bicortical bone thickness, the ramus dimensions and the position of the lingula. The measurements were tested on significant correlations to the patients' parameters. METHODS: Based on CBCT scans 150 rami were reconstructed as 3D polygon surfaces. An anatomical grid was adapted to the ramus surface to mark the bone thickness measurement points and to achieve comparability between the measurements on different mandibles. The bone thickness, ramus height, ramus width and the gonion angle were measured. A cluster analysis was performed with these parameters to identify clinically relevant groups with anatomical similarities. RESULTS: The median distribution of the bone thickness was calculated and visualized in a pseudo-colour map. The mean ramus height was 44.78 mm, the mean width was 31.31 mm and the mean gonion angle was 124.8°. The average distance from the lingula to the dorsal tangent was 53% of the total width and its distance to the caudal tangent was 65% of the total height. Significant correlations between the bone thickness and the ramus proportions could be identified. Age and sex had no significant influence on the mean bone thickness. The measured rami could be divided into two groups by cluster analysis. CONCLUSION: The dimensions of the human mandibular ramus can be determined from 3D reconstructed surface models from CBCT scans. Measurements could be made comparable by applying an anatomically oriented grid. A cluster analysis allowed the differentiation of two groups with different bone thickness distributions and geometries, which can be used for the optimization of osteosynthesis systems and their precision of adaptation to different ramus morphologies.

Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.

BACKGROUND AND PURPOSE: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. METHODS: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. RESULTS: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. CONCLUSION: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis.

mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.