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Human tubulin beta class IVa (TUBB4A) is a member of the β-tubulin family. In most normal tissues, expression of TUBB4A is little to none, but it is highly expressed in human prostate cancer. Here we show that high expression levels of TUBB4A are associated with aggressive prostate cancers and poor patient survival, especially for African-American men. Additionally, in prostate cancer cells, TUBB4A knockout (KO) reduces cell growth and migration but induces DNA damage through increased γH2AX and 53BP1. Furthermore, during constricted cell migration, TUBB4A interacts with MYH9 to protect the nucleus, but either TUBB4A KO or MYH9 knockdown leads to severe DNA damage and reduces the NF-κB signaling response. Also, TUBB4A KO retards tumor growth and metastasis. Functional analysis reveals that TUBB4A/GSK3β binds to the N-terminal of MYH9, and that TUBB4A KO reduces MYH9-mediated GSK3β ubiquitination and degradation, leading to decreased activation of β-catenin signaling and its relevant epithelial-mesenchymal transition. Likewise, prostate-specific deletion of Tubb4a reduces spontaneous tumor growth and metastasis via inhibition of NF-κB, cyclin D1, and c-MYC signaling activation. Our results suggest an oncogenic role of TUBB4A and provide a potentially actionable therapeutic target for prostate cancers with TUBB4A overexpression. The β-tubulin family protein TUBB4A is highly expressed in cancer but it’s molecular role is unclear. Here, the authors show that TUBB4A is required to protect the nucleus from genomic instability during migration and that it’s over expression promotes cancer progression.

Background The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurrence following surgery in localized ccRCC. Methods We morphologically identified and scored tumor infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) stained slides of patients with localized ccRCC (stage ≥T1b excluding stage IV). The University of Alabama at Birmingham (UAB) dataset ( n  = 159) was used to discover and the Fox Chase Cancer Center (FCCC) dataset ( n  = 198) was used to validate the results of morphologic immune cell analysis. We then performed gene expression analysis using the Immune Profile panel by NanoString in the UAB cohort and identified immune cells and pathways associated with recurrence, followed by validation in the Cancer Genome Atlas (TCGA) ccRCC dataset. Infiltrating immune cell types were identified by gene expression deconvolution. Results The presence of TILs identified by morphology correlated with higher T cell, Th1, CD8+ T and Treg gene signatures. Recurrence was associated with lower T cells and higher neutrophils. Higher Teffector (Teff)/Treg ratio correlated with lower rate of recurrence and was validated in the TCGA dataset. Genes associated with adaptive immune response were downregulated in tumors that recurred. Unsupervised hierarchical clustering identified a subset of patients with over-expression of adaptive response genes including CD8, CD3, GZMA/B, PRF1, IDO1, CTLA4, PDL1, ICOS and TIGIT. These patients had higher morphologic lymphocyte infiltration and T cell gene expression. Higher levels of TILs identified by morphology correlated with higher rates of recurrence in our discovery dataset but not in our validation set. Conclusions Recurrence of ccRCC following surgery was associated with lower T cell infiltrate, lower adaptive immune response and higher neutrophil gene expression. Presence of higher Teff/Treg ratio correlated with lower recurrence.

In the era of precision medicine the treatment options for cancer patients and subsequent outcomes are expected to improve. We present a review of patients enrolled in first-in-human Phase1 trials at University of Alabama at Birmingham. Between 1/2015–6/2017, 162 cancer patients (whole cohort, WC) were enrolled on phase1 studies receiving either targeted therapy (TT) or immuno-therapy (IOT). We assessed 90 day mortality (90DM) and time to treatment failure (TTF) to determine the predictors. Of the WC (122 (TT), 40 (IOT)), 90 (56%) received ≥ 2 prior therapies and 38 (24%) ⩾ 5 prior therapies. Overall, Grade 3 or 4 events were observed in 33% (WC) vs 31% (TT) vs 38% (IOT). The 90DM was 9.3% (WC) vs 7.4% (TT) vs 15% (IOT). The median TTF was 4.2 months vs 4.5 m vs 3.6 m. The number of lines of prior therapy and performance status were identified as outcome predictors. Our data reflects the new trend in precision oncology where majority received non-cytotoxic therapeutic interventions. The observation that number of lines of prior therapy and performance status predictive of PFS and 90DM emphasizes the need to consider phase1 trials earlier, preferably upon progression following definitive therapy.

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.

Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

•HCUP-NIS is a large database of more than 39 million all-payer inpatient care visits recorded across 1000 hospitals.•We conducted a 3 tiered matching between African American patients and White patients who had similar demographic, clinical or treatment characteristics.•Even after matching for above characteristics, length of stay and mortality was higher in African American patients compare to White patients. This paper aims to determine whether racial disparities exist in hospitalization outcomes among African-American and White hospitalized prostate cancer patients in the United States. We evaluated racial differences among matched groups of patients in post-operative complications, hospital length of stay and in-hospital mortality. We identified a total of 183,856 men aged 40 years and older with a primary diagnosis of prostate cancer, of which 58,701 underwent prostatectomy, through the Nationwide Inpatient Sample, and matched all African-American patients with White patients on: 1) Demographics, 2) Demographics+Clinical presentation and 3) Demographics+Clinical presentation+Treatment. Multivariable regression analyses were conducted in SAS and estimates were reported with 95% confidence intervals. African-American patients were more likely to be admitted with metastatic disease (24.8%) compared with White patients matched on demographics (17.9%), and demographics+presentation (23.6%). However, 23.9% of African-American patients received surgery compared with 38.2% and 34.2% of Whites matched on demographics and demographics+presentation, respectively. White patients had lower in-hospital mortality compared with African-American patients matched on demographics (OR: 0.72, 95% CI: 0.66-0.79), demographics+presentation (OR: 0.88, 95% CI: 0.81-0.96), but was no longer significantly lower when matched on demographics, presentation and treatment (OR: 0.92, 95% CI: 0.85–1.00). There were significant racial differences in outcomes among prostate cancer patients within the inpatient setting, even after accounting for demographic and presentation differences.

Following publication of the original article [1], the author reported that the current funding section “Kidney Cancer Association Young Investigator Grant provided funding for this project” should be replaced with “Kidney Cancer Association Young Investigator Grant and Bucks County Board provided funding for this project.”

Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030. Bill & Melinda Gates Foundation.

BackgroundBariatric surgery offers effective treatment for morbid obesity and associated medical comorbidities, with excellent short- and long-term outcomes. Although it has been well documented that racial minority bariatric patients have worse outcomes than White patients, it remains unclear whether this recognition has led to improvement. Herein, we assess recent trends in bariatric surgery among Black and White patients and compare early postoperative outcomes by race.MethodsPrimary sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) patients from 2015 to 2021 reported to the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program were studied. Bariatric patients were stratified by race (Black and White) and perioperative outcomes were compared between matched Black and White patients. Primary outcome was 30-day mortality. Secondary outcomes included hospital readmissions, hospital length of stay (LOS), reoperation, and postoperative complications.ResultsOverall, there were 193,071 Black and 645,224 White primary bariatric patients, with a higher volume of SG and RGYB performed among White patients. A total of 219,566 Black and White bariatric patients were matched and included in the case–control. Black patients were found to have higher rates of 30-day mortality (0.02% vs. 0.01%; p = 0.03) and readmissions (3.68% vs. 2.65%; p < 0.001). There were no significant differences in LOS, reoperations, or overall postoperative complications. However, there was a higher postoperative pulmonary thromboembolism rate (0.16% vs 0.08%; p < 0.001).). The differences in perioperative outcomes stratified by race persisted over the study period (Fig. 1).ConclusionBlack bariatric surgery patients continue to have worse perioperative outcomes compared with their White counterparts. Further work must be done to determine contributing factors in order to effect improvement in outcomes in bariatric surgical care for racial minority patients.