In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer.

The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1b/HLA-E. Surprisingly, loss of tumor interferon-γ (IFNγ) signaling sensitizes many models to immunity. The immune inhibitory effects of tumor IFN sensing are mediated through two mechanisms. First, tumor upregulation of classical MHC class I inhibits natural killer cells. Second, IFN-induced expression of Qa-1b inhibits CD8+ T cells via the NKG2A/CD94 receptor, which is induced by ICB. Finally, we show that strong IFN signatures are associated with poor response to ICB in individuals with renal cell carcinoma or melanoma. This study reveals that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints can facilitate immune escape.

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

Targeting TBK1 to overcome resistance to cancer immunotherapy.

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

Single-cell genomic variation induced by mutational processes in cancer.

How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct 'foreground' mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells.

Ovarian cancer mutational processes drive site-specific immune evasion.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFß signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.

Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.

Therapeutic Peptides, Proteins and their Nanostructures for Drug Delivery and Precision Medicine.

Peptide and protein nanostructures with tunable structural features, multifunctionality, biocompatibility and biomolecular recognition capacity enable development of efficient targeted drug delivery tools for precision medicine applications. In this review article, we present various techniques employed for the synthesis and self-assembly of peptides and proteins into nanostructures. We discuss design strategies utilized to enhance their stability, drug-loading capacity, and controlled release properties, in addition to the mechanisms by which peptide nanostructures interact with target cells, including receptor-mediated endocytosis and cell-penetrating capabilities. We also explore the potential of peptide and protein nanostructures for precision medicine, focusing on applications in personalized therapies and disease-specific targeting for diagnostics and therapeutics in diseases such as cancer.

Molecular landscape of ERBB2/HER2 gene amplification among patients with gynecologic malignancies; clinical implications and future directions.

OBJECTIVE: Investigate the prevalence of ERBB2/HER2 gene amplification among patients with gynecologic malignancies. METHODS: The American Association of Cancer Research (AACR) Genomics Evidence of Neoplasia Information Exchange (GENIE) (version 13.1) database was accessed and patients with endometrial, ovarian, and cervical cancer were identified. Patients with available data on the presence of copy-number gene alterations were selected for further analysis. Incidence of ERBB2 amplification following stratification by tumor site and histology was evaluated. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine presence of pathogenic genomic alterations. RESULTS: A total of 6961 patients who met the inclusion criteria were identified: 49.1% with ovarian cancer, 45.2% with endometrial cancer and 5.7% with cervical cancer respectively. Overall incidence of ERBB2 amplification was 3.8%. Highest incidence of ERBB2 amplification was observed among patients with mucinous ovarian (14.4%), uterine serous (13.2%), uterine clear cell (9.4%), and uterine carcinosarcoma (7.9%). ERBB2 amplification was rare among patients with TP53 wild-type endometrioid endometrial cancer (0.4%). High incidence of mutations in genes of the PI3K pathway was observed among patients with ERBB2 amplified tumors. CONCLUSION: ERBB2 amplification is frequently encountered among patients with uterine serous carcinoma, and mucinous ovarian carcinoma. In addition, a high incidence was also observed among those with uterine clear cell carcinoma, and uterine carcinosarcoma. For patients with endometrioid endometrial carcinoma, incidence of ERBB2 amplification is low, especially in the absence of TP53 mutations.

The prognosis of stage IA cervical cancer: Subgroup analysis of the SCCAN study.

OBJECTIVE: Patients with TNM T1a cervical cancer have excellent prognosis; however, the risk for recurrence remains an issue of concern and management guidelines are based on limited data. Here we performed subgroup analysis of the Surveillance in Cervical Cancer (SCCAN) consortium with the objective of defining the prognosis of T1a cervical cancer patients. METHODS: SCCAN was an international, multicentric, retrospective cohort study of patients with cervical cancer undergoing surgical treatment in tertiary centers. Inclusion criteria included: histologically confirmed cervical cancer treated between 2007 and 2016; TNM T1a; primary surgical management; and at least 1-year of follow-up data availability. Exclusion criteria included treatment with primary chemo-radiation, and missing treatment-related or clinical data. RESULTS: Out of 975 patients included, 554 (57 %) were T1a1 and 421 (43 %) T1a2. The majority had squamous-cell carcinoma (78 %). 79 patients (8.1 %) had lymphovascular space invasion (LVSI). 455 patients (47 %) underwent radical hysterectomy/ parametrectomy. Laparoscopic and open surgery was performed in 401 (41 %) and in 361 (37 %) patients, respectively. Adjuvant treatment was administered to 56 patients (5.7 %). Assessment of lymph nodes (LN) was performed in 524 patients (54 %), with LN involvement found in 15 (2.9 %). There were 40 (4.1 %) recurrences, occurring at a median of 26 months (4-106), out of which 33 (82.5 %) occurred in pelvis. Among T1a1 cases, there were 10 recurrences (2.0 %) if LVSI was negative, and 3 recurrences (6.7 %) if LVSI was positive. Among T1a2 cases, there were 23 recurrences (6.7 %) if LVSI was negative, and 4 recurrences (5.1 %) if LVSI was positive. There were 3 recurrences in the LN+ group (recurrence rate 20 %). CONCLUSIONS: The risk of recurrence in T1a cervical cancer was 4.1 % corresponding to the rates seen in patients with FIGO 1B cancer in recently published prospective trials. LN involvement represents a risk factor for disease recurrence. Our results indicate that stage T1a cervical cancer, apart from T1a1 LVSI negative disease, should follow the same principles in the management as that of FIGO stage 1B cancer.

Role of systematic lymphadenectomy at the time of interval debulking surgery for patients with advanced-stage epithelial ovarian carcinoma who achieved complete gross resection.

OBJECTIVE: To evaluate the role of systematic lymphadenectomy at the time of interval cytoreductive surgery for patients with advanced-stage epithelial ovarian carcinoma who achieved complete gross resection. METHODS: The National Cancer DataBase was accessed, and patients diagnosed between 2010 and 2015 with advanced-stage ovarian carcinoma who underwent interval cytoreductive surgery and achieved complete gross resection were identified. Patients who did not undergo lymphadenectomy and those who underwent systematic lymphadenectomy (defined as at least 20 lymph nodes removed) were selected for further analysis. Median overall survival was compared with the log-rank test and controlled for a priori selected confounders. RESULTS: A total of 1060 patients were identified. Systematic lymphadenectomy was performed for 125 (11.8%) patients with a median of 29 lymph nodes (range 20-72) removed. Rate of lymph node metastasis was 62.4%. Patients who underwent systematic lymphadenectomy had higher rate of unplanned readmission (8.9% vs 1.6%, p<0.001), and median hospital stay (6 vs 4 days, p<0.001). Median overall survival for patients who did and did not undergo systematic lymphadenectomy was 44.2 and 40.4 months, respectively, p=0.40. After controlling for confounders, performance of systematic lymphadenectomy was not associated with better survival (HR=0.98, 95% CI 0.80 to 1.19). CONCLUSION: Systematic lymphadenectomy is rarely performed at the time of interval cytoreductive surgery and not associated with a survival benefit for patients who achieved complete gross resection.

Oncologic outcomes based on lymphovascular space invasion in node-negative FIGO 2009 stage I endometrioid endometrial adenocarcinoma: a multicenter retrospective cohort study.

BACKGROUND: The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system includes lymphovascular invasion quantification as a staging criterion for endometrioid endometrial carcinomas; no lymphovascular invasion and focal invasion (≤4 vessels involved) are grouped as one category, and substantial invasion as another. OBJECTIVE: To assess the association between lymphovascular invasion and oncologic outcomes. METHODS: We retrospectively identified patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with total hysterectomy and lymph node assessment at two tertiary care centers between January 1, 2012, and December 31, 2019. Lymphovascular space invasion was categorized as focal (<5 vessels involved), substantial (≥5 vessels involved), and no lymphovascular invasion using WHO criteria. RESULTS: Of 1555 patients included, 65 (4.2%) had substantial, 119 (7.7%) had focal, and 1371 (88.2%) had no lymphovascular invasion. Median age was 64 years (range 24-92). Thirty-five patients (53.8%) with substantial, 44 (37%) with focal, and 115 (8.4%) with no lymphovascular invasion had stage IB disease (p<0.001); 21 (32.3%) with substantial, 24 (20.2%) with focal, and 91 (6.6%) with no lymphovascular invasion had grade 3 disease (p<0.001). Thirty-six patients (55.4%) with substantial, 80 (67.2%) with focal, and 207 (15.1%) with no lymphovascular invasion received adjuvant treatment (p<0.001). Median follow-up was 61.5 months (range 0.8-133.9). Five-year progression-free survival rates were 68.7% (substantial), 70.5% (focal), and 90.7% (no invasion) (p<0.001). On multivariate analysis, any lymphovascular invasion was associated with increased risk of progression/death (adjusted HR (aHR)=1.84 (95% CI 1.73 to 1.96) for focal; 2.17 (95% CI 1.96 to 2.39) for substantial). Compared with focal, substantial lymphovascular invasion was associated with an aHR for disease progression of 1.18 (95% CI 1.00 to 1.39). CONCLUSIONS: Focal and substantial lymphovascular invasion were associated with increased risk of disease progression and do not appear to be prognostically distinct. Focal versus no lymphovascular invasion have different prognostic outcomes and should not be combined into one category.

ARIA II: a randomized controlled trial of near-infrared Angiography during RectosIgmoid resection and Anastomosis in women with ovarian cancer.

BACKGROUND: Ovarian cancer with extensive metastatic disease involving pelvic structures often requires rectosigmoid resection for complete gross resection; however, it is associated with increased surgical morbidity. There are limited data, and none in ovarian cancer, on near-infrared assessment of perfusion in rectosigmoid resections with anastomosis. PRIMARY OBJECTIVE: To compare the rate of pelvic complications (pelvic abscesses, anastomotic leaks, and infections) within 30 days of surgery with and without near-infrared assessment of perfusion at time of rectosigmoid resection and re-anastomosis in patients undergoing cytoreductive surgery for ovarian cancer. STUDY HYPOTHESIS: We hypothesize the use of near-infrared technology (intravenous indocyanine green and endoscopic near-infrared fluorescence imaging), compared with standard intra-operative assessment, to evaluate anastomotic perfusion at time of rectosigmoid resection and re-anastomosis will result in lower rates of post-operative pelvic complications. TRIAL DESIGN: This is a planned multicenter randomized controlled trial. Patients who undergo rectosigmoid resection as part of their ovarian cytoreductive surgery will be randomized 1:1 to standard assessment of anastomosis with the surgeon's usual technique (control arm) or assessment with near-infrared angiography using indocyanine green and endoscopic fluorescence imaging (experimental arm). Randomization will occur after rectosigmoid resection has been completed and the surgeon declares their plan to create a diverting ostomy. Randomization will be stratified by plan for diverting ostomy. MAJOR INCLUSION/EXCLUSION CRITERIA: Main inclusion criteria include patients with primary or recurrent ovarian, fallopian tube, or primary peritoneal cancer who are scheduled for cytoreductive surgery with suspected need for low-anterior rectosigmoid resection. PRIMARY ENDPOINT: Rate of 30-day post-operative pelvic complications. SAMPLE SIZE: 310 (155 per arm) ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Q2 2027 and Q4 2027, respectively. TRIAL REGISTRATION: NCT04878094.

Association between psoriasis and cardiometabolic comorbidities in a racially and ethnically diverse low-income primary care population.

Psoriasis is associated with cardiometabolic comorbidities, including obesity, diabetes, hyperlipidaemia and hypertension. Many studies that established these associations originated from primarily White and/or relatively affluent populations. To evaluate whether there is a differential risk for cardiometabolic comorbidities in racial/ethnic minorities, we performed a cross-sectional analysis comparing cardiometabolic comorbidities between those with and without psoriasis in a racially and ethnically diverse population of 56 987 low-income patients, stratified by race/ethnicity, and assessed whether race/ethnicity acts as an effect modifier for cardiometabolic comorbidities. We found that psoriasis was statistically significantly associated with obesity, diabetes, hyperlipidaemia and hypertension. The association of psoriasis with comorbidities did not differ significantly by race/ethnicity; thus, we did not find evidence of effect modification. However, our diverse, low-income population had an extremely high baseline prevalence of cardiometabolic comorbidities compared with previous populations studied. Our results suggest education and intervention regarding modifiable risk factors are particularly important among vulnerable populations.

TISMO: syngeneic mouse tumor database to model tumor immunity and immunotherapy response.

Syngeneic mouse models are tumors derived from murine cancer cells engrafted on genetically identical mouse strains. They are widely used tools for studying tumor immunity and immunotherapy response in the context of a fully functional murine immune system. Large volumes of syngeneic mouse tumor expression profiles under different immunotherapy treatments have been generated, although a lack of systematic collection and analysis makes data reuse challenging. We present Tumor Immune Syngeneic MOuse (TISMO), a database with an extensive collection of syngeneic mouse model profiles with interactive visualization features. TISMO contains 605 in vitro RNA-seq samples from 49 syngeneic cancer cell lines across 23 cancer types, of which 195 underwent cytokine treatment. TISMO also includes 1518 in vivo RNA-seq samples from 68 syngeneic mouse tumor models across 19 cancer types, of which 832 were from immune checkpoint blockade (ICB) studies. We manually annotated the sample metadata, such as cell line, mouse strain, transplantation site, treatment, and response status, and uniformly processed and quality-controlled the RNA-seq data. Besides data download, TISMO provides interactive web interfaces to investigate whether specific gene expression, pathway enrichment, or immune infiltration level is associated with differential immunotherapy response. TISMO is available at http://tismo.cistrome.org.

Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Measuring early adolescents' prosocial behavior toward diverse others: Considering multiple social identities.

INTRODUCTION: In a diverse society, individuals often need to make prosocial decisions toward others who vary on a range of intertwined social identities. Adolescence is a prime time to promote intergroup prosociality due to identity salience during this developmental stage. In this study, our goal was to develop and provide initial validation, of a novel measure on intergroup prosocial behavior considering gender and race/ethnicity. METHOD: We used two independent samples of early adolescents (N1 = 118, Mage = 12.21 years, 55% boys, 59% White collected nationally in the United States.; N2 = 133, Mage = 12.77, 51.1% boys, 77% White collected locally in Arizona). RESULTS: Using the data from Sample 1, Exploratory Factor Analyses revealed a two-factor solution capturing intergroup prosociality and personal distress. Confirmatory Factor Analyses with data from Sample 2 confirmed the factor structure. The reliability of intergroup prosociality was acceptable. Prosociality subscale was positively correlated with adolescents' empathy, sympathy, compliant, emotional, dire, and anonymous prosocial behaviors indicating convergent validity and negatively correlated with adolescents' public prosocial behavior indicating discriminant validity. Further, we examined whether youth engage in differential intergroup prosocial behavior using both variable-centered and person-centered approaches, combining data from Samples 1 and 2. While adolescents did not engage in differential intergroup prosocial behavior, Latent Profile Analyses revealed five distinct profiles of early adolescents' intergroup prosociality. Overall, this study advances research on youth's intergroup prosociality across two intersectional social identities, moving beyond the conceptualization of single social identities in intergroup research.

NPC1 deficiency impairs cerebellar postnatal development of microglia and climbing fiber refinement in a mouse model of Niemann-Pick disease type C.

Little is known about the effects of NPC1 deficiency in brain development and whether these effects contribute to neurodegeneration in Niemann-Pick disease type C (NPC). Degeneration of cerebellar Purkinje cells occurs at an earlier stage and to a greater extent in NPC; therefore, we analyzed the effect of NPC1 deficiency on microglia and on climbing fiber synaptic refinement during cerebellar postnatal development using the Npc1nmf164 mouse. Our analysis revealed that NPC1 deficiency leads to early phenotypic changes in microglia that are not associated with an innate immune response. However, the lack of NPC1 in Npc1nmf164 mice significantly affected the early development of microglia by delaying the radial migration, increasing the proliferation and impairing the differentiation of microglia precursor cells during postnatal development. Additionally, increased phagocytic activity of differentiating microglia was observed at the end of the second postnatal week in Npc1nmf164 mice. Moreover, significant climbing fiber synaptic refinement deficits along with an increased engulfment of climbing fiber synaptic elements by microglia were found in Npc1nmf164 mice, suggesting that profound developmental defects in microglia and synaptic connectivity might precede and predispose Purkinje cells to early neurodegeneration in NPC.

A differential diagnosis between uterine leiomyoma and leiomyosarcoma using transcriptome analysis.

BACKGROUND: The objective of this study was to estimate the accuracy of transcriptome-based classifier in differential diagnosis of uterine leiomyoma and leiomyosarcoma. We manually selected 114 normal uterine tissue and 31 leiomyosarcoma samples from publicly available transcriptome data in UCSC Xena as training/validation sets. We developed pre-processing procedure and gene selection method to sensitively find genes of larger variance in leiomyosarcoma than normal uterine tissues. Through our method, 17 genes were selected to build transcriptome-based classifier. The prediction accuracies of deep feedforward neural network (DNN), support vector machine (SVM), random forest (RF), and gradient boosting (GB) models were examined. We interpret the biological functionality of selected genes via network-based analysis using GeneMANIA. To validate the performance of trained model, we additionally collected 35 clinical samples of leiomyosarcoma and leiomyoma as a test set (18 + 17 as 1st and 2nd test sets). RESULTS: We discovered genes expressed in a highly variable way in leiomyosarcoma while these genes are expressed in a conserved way in normal uterine samples. These genes were mainly associated with DNA replication. As gene selection and model training were made in leiomyosarcoma and uterine normal tissue, proving discriminant of ability between leiomyosarcoma and leiomyoma is necessary. Thus, further validation of trained model was conducted in newly collected clinical samples of leiomyosarcoma and leiomyoma. The DNN classifier performed sensitivity 0.88, 0.77 (8/9, 7/9) while the specificity 1.0 (8/8, 8/8) in two test data set supporting that the selected genes in conjunction with DNN classifier are well discriminating the difference between leiomyosarcoma and leiomyoma in clinical sample. CONCLUSION: The transcriptome-based classifier accurately distinguished uterine leiomyosarcoma from leiomyoma. Our method can be helpful in clinical practice through the biopsy of sample in advance of surgery. Identification of leiomyosarcoma let the doctor avoid of laparoscopic surgery, thus it minimizes un-wanted tumor spread.

Peptide Hydrogels and Nanostructures Controlling Biological Machinery.

Peptides are versatile building blocks for the fabrication of various nanostructures that result in the formation of hydrogels and nanoparticles. Precise chemical functionalization promotes discrete structure formation, causing controlled bioactivity and physical properties for functional materials development. The conjugation of small molecules on amino acid side chains determines their intermolecular interactions in addition to their intrinsic peptide characteristics. Molecular information affects the peptide structure, formation, and activity. In this Perspective, peptide building blocks, nanostructure formation mechanisms, and the properties of these peptide materials are discussed with the results of recent publications. Bioinstructive and stimuli-responsive peptide materials have immense impacts on the nanomedicine field including drug delivery, cellular engineering, regenerative medicine, and biomedicine.

Facility level variation in the utilization of neoadjuvant chemotherapy is associated with higher surgical morbidity for patients with advanced stage epithelial ovarian carcinoma.

OBJECTIVE: Investigate outcomes for advanced stage epithelial ovarian cancer (EOC) patients based on facility-level utilization of neoadjuvant chemotherapy (NACT). METHODS: Stage III-IV EOC patients diagnosed between 2010 and 2016 were identified in the National Cancer Database. Percentage of patients managed with NACT was calculated for facilities, reporting ≥120 patients. Facilities with lowest and highest quartile of NACT rate comprised the low and high-utilizing groups. Clinico-pathological characteristics were collected, and appropriate statistical analysis performed. RESULTS: High- and low-utilizing facilities managed on average 54.1% and 25.4% of patients with NACT respectively. Patients managed at high-utilizing facilities were significantly more likely to be >65 (p = 0.029), have stage IV disease (p < 0.001) and comorbidities (p < 0.001). Patients managed with primary debulking surgery (PDS) at low-utilizing facilities were significantly more likely to be >65, have stage IV disease, and have comorbidities (all, p < 0.001). Patients undergoing PDS at low-utilizing facilities were significantly less likely to achieve complete gross resection (p < 0.001), and were significantly more likely to experience 90-day mortality (p < 0.001), and unplanned 30-day readmission (p < 0.001). After controlling for age, comorbidities, race, insurance status, stage, grade and histology, high-utilizing facilities trended towards better overall survival (OS) (HR: 0.92, 95% CI: 0.85-0.99). Overall, patients undergoing PDS had better OS compared to those who had NACT (median 42 vs 27 months, p < 0.001). CONCLUSIONS: Despite treating an EOC population with more advanced disease and comorbidities, high-utilizing facilities have lower surgical morbidity and mortality with no detrimental impact on long-term survival. Careful patient selection to minimize the morbidity and mortality associated with PDS is pivotal.