Nitrogen doped bimetallic sludge biochar composite for synergistic persulfate activation: Reactivity, stability and mechanisms.

As a recycling use of waste activated sludge (WAS), we used high-temperature pyrolysis of WAS to support bimetallic Fe-Mn with nitrogen (N) co-doping (FeMn@N-S), a customized composite catalyst that activates peroxysulphate (PS) for the breakdown of tetracycline (TC). First, the performance of TC degradation was evaluated and optimized under different N doping, pH, catalyst dosages, PS dosages, and contaminant concentrations. Activating PS with FeMn@N-S caused the degradation of 91% of the TC in 120 min. Next, characterization of FeMn@N-S by XRD, XPS and FT-IR analysis highlights N doping is beneficial to take shape more active sites and reduces the loss of Fe and Mn during the degradation reaction. As expected, the presence of Fe-Mn bimetallic on the catalyst surface increases the rate of electron transfer, promoting the redox cycle of the catalyst. Other functional groups on the catalyst surface, such as oxygen-containing groups, accelerated the electron transfer during PS activation. Free radical quenching and ESR analysis suggest that the main contributor to TC degradation is surface-bound SO4•-, along with the presence of single linear oxygen (1O2) oxidation pathway. Finally, the FeMn@N-S composite catalyst exhibits excellent pH suitability and reusability, indicating a solid practicality of this catalyst in PS-based removal of antibiotics from wastewater.

The effect of China's many-child policy on the number of births and the prevalence of serious teratogenic and disabling defects in Hunan Province.

BACKGROUND: To research the effect of China's many-child policy on the number of births and the prevalence of serious teratogenic and disabling defects (STDDs) in Hunan province. METHODS: We performed an observational study based on the Birth Defect (BD) Surveillance System of Hunan Province and chose STDD case cards. From 2012-2022, we defined the following 4 periods: the one-child policy (OCP) (2012.01-2013.12), partial two-child policy (PTCP) (2014.1-2015.12), universal two-child policy (UTCP) (2016.1-2020.12), and the early stage of the three-child policy (ETCP) (2021.1-2022.12). Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association of policy changes with STDDs. Crame'r's V was calculated to estimate the effect sizes. Joinpoint regression analysis and annual percent change (APC) were used for each segment of the trend. RESULTS: A total of 1,652,079 births were included in this analysis. Joinpoint regression analysis showed that the number of perinatal births increased from 2012 to 2017, with APC = 9.52 (95% CI: 7.2 to 11.8), and decreased from 2017 to 2022, with an APC = -10.04 (95% CI: -11.9 to -8.1). The number of mothers over 30 years old gradually increased, from 25.54% during the OCP period to 54.05% during the ETCP period (Ptrend < 0.001). With policy changes, the total prevalence of STDDs increased from 28.10 per 10,000 births during the period of OCP into 46.77 per 10,000 births during the ETCP period by 66.44%. The live birth prevalence of STDDs increased only during the ETCP period (PTCP: OR = 1.27, 95% CI: 0.99-1.24, p = 0.057, UTCP: OR = 1.22, 95% CI: 0.99-1.52, p = 0.067, ETCP: OR = 1.75, 95% CI: 1.37-2.24, p < 0.001). Over the past ten years, there was a decrease in the gestational age at diagnosis (*F = 772.520, p < 0.001), from 24.49 ± 5.65 weeks in 2012 to 20.77 ± 5.17 weeks in 2022. From 2012 to 2022, the percentage of deaths within 7 days decreased with APC = -18.85 (95% CI: -26.4- -10.5, P > 0.05). CONCLUSION: Many-child policies were associated with a moderate increase in fertility especially for women in urban areas and older women. However, they have lost the ability to control birth since 2017. The total prevalence of STDDs increased over the entire period, but the live birth prevalence increased only during the ETCP period. The gestational age at diagnosis decreased and the percentage of deaths within 7 days decreased.

ISEScan: automated identification of insertion sequence elements in prokaryotic genomes.

MOTIVATION: The insertion sequence (IS) elements are the smallest but most abundant autonomous transposable elements in prokaryotic genomes, which play a key role in prokaryotic genome organization and evolution. With the fast growing genomic data, it is becoming increasingly critical for biology researchers to be able to accurately and automatically annotate ISs in prokaryotic genome sequences. The available automatic IS annotation systems are either providing only incomplete IS annotation or relying on the availability of existing genome annotations. Here, we present a new IS elements annotation pipeline to address these issues. RESULTS: ISEScan is a highly sensitive software pipeline based on profile hidden Markov models constructed from manually curated IS elements. ISEScan performs better than existing IS annotation systems when tested on prokaryotic genomes with curated annotations of IS elements. Applying it to 2784 prokaryotic genomes, we report the global distribution of IS families across taxonomic clades in Archaea and Bacteria. AVAILABILITY AND IMPLEMENTATION: ISEScan is implemented in Python and released as an open source software at https://github.com/xiezhq/ISEScan. CONTACT: hatang@indiana.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Functional analysis of the distal region of the third intracellular loop of PROKR2.

Mutations in the G-protein-coupled receptor PROKR2 have been identified in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) manifesting with delayed puberty and infertility. Recently, the homozygous mutation V274D was identified in a man displaying KS with an apparent reversal of hypogonadism. The affected amino acid, valine 274, is located at the junction region of the third intracellular loop (IL3) and the sixth transmembrane domain (TM6). In this study, we first studied the effect of V274D and related mutations (V274A, V274T, and V274R) on the signaling activity and cell surface expression of PROKR2. Our data indicate that a charged amino acid substitution at residue 274 of PROKR2 results in low cell surface expression and loss-of-function. Furthermore, we studied the effects of two clusters of basic amino acids located at the proximal region of Val274 on the cell surface expression and function of PROKR2. The deletion of RRK (270-272) resulted in undetectable cell surface expression, whereas RKR (264-266)-deleted PROKR2 was expressed normally on the cell surface but showed loss-of-function due to a deficiency in G-protein coupling. Our data indicate that the distal region of the IL3 of PROKR2 may differentially influence receptor trafficking and G-protein coupling.

Enhanced degradation of micropollutants by visible light photocatalysts with strong oxygen activation ability.

Visible light photocatalysis is widely considered a sustainable approach to break down micropollutants without chemical addition. To promote the output of photogenerated carriers under visible light, a Z-scheme plasmonic photocatalyst Bi-CeO2/Ag0/BiO2 was designed and fabricated to activate dissolved oxygen in water for micropollutant degradation. The doped Bi not only improved the separation of electron-hole, but also narrowed the band gap of CeO2 to enhance its absorption of visible light. Notably, metallic silver (Ag0) works as an electronic transmission vehicle from Bi-CeO2 to BiO2 in a Z-scheme mechanism. Likewise, the surface plasmon resonance effect of Ag0 also enhanced the absorption of visible light. Furthermore, the Bi doping induced abundant surface oxygen vacancies on CeO2 for enhanced capability and selectivity towards O2 adsorption and activation, which favored the generation of O2•- by photogenerated electrons to degrade sulfamethoxazole, enrofloxacin, and bisphenol A. Theoretical calculation results also confirmed the O2•--driven degradation pathway for sulfamethoxazole. Therefore, the Z-scheme Bi-CeO2/Ag0/BiO2 not only extends the photocatalytic reactivity of CeO2-based catalysts to the visible light range, but also provides a chemical-free method to effectively degrade micropollutants.

Unintentional injury deaths among children under five in Hunan Province, China, 2015-2020.

Injury is the most common cause of preventable morbidity and death among children under five. This study aimed to describe the epidemiological characteristics of injury-related mortality rates in children under five and to provide evidence for future preventive strategies. Data were obtained from the Under Five Child Mortality Surveillance System in Hunan Province, China, 2015-2020. Injury-related mortality rates with 95% confidence intervals (CI) were calculated by year, residence, gender, age, and major injury subtype (drowning, suffocation, traffic injuries, falls, and poisoning). And crude odds ratios (ORs) were calculated to examine the association of epidemiological characteristics with injury-related deaths. The Under Five Child Mortality Surveillance System registered 4,286,087 live births, and a total of 22,686 under-five deaths occurred, including 7586 (which accounted for 33.44% of all under-five deaths) injury-related deaths. The injury-related under-five mortality rate was 1.77‰ (95% CI 1.73-1.81). Injury-related deaths were mainly attributed to drowning (2962 cases, 39.05%), suffocation (2300 cases, 30.32%), traffic injuries (1200 cases, 15.82%), falls (627 cases, 8.27%), and poisoning (156 cases, 2.06%). The mortality rates due to drowning, suffocation, traffic injuries, falls, and poisoning were 0.69‰ (95% CI 0.67,0.72), 0.54‰ (95% CI 0.51,0.56), 0.28‰ (95% CI 0.26,0.30), 0.15‰ (95% CI 0.13,0.16), and 0.04‰ (95% CI 0.03,0.04), respectively. From 2015 and 2020, the injury-related mortality rates were 1.78‰, 1.77‰, 1.60‰, 1.78‰, 1.80‰, and 1.98‰, respectively, and showed an upward trend (χ2trend = 7.08, P = 0.01). The injury-related mortality rates were lower in children aged 0-11 months than in those aged 12-59 months (0.52‰ vs. 1.25‰, OR = 0.41, 95% CI 0.39-0.44), lower in urban than rural areas (1.57‰ vs. 1.88‰, OR = 0.84, 95% CI 0.80-0.88), and higher in males than females (2.05‰ vs . 1.45‰, OR = 1.42, 95% CI 1.35-1.49). The number of injury-related deaths decreased with children's age. Injury-related deaths happened more frequently in cold weather (around February). Almost half (49.79%) of injury-related deaths occurred at home. Most (69.01%) children did not receive treatment after suffering an injury until they died, and most (60.98%) injury-related deaths did not receive treatment because it was too late to get to the hospital. The injury-related mortality rate was relatively high, and we have described its epidemiological characteristics. Several mechanisms have been proposed to explain these phenomena. Our study is of great significance for under-five child injury intervention programs to reduce injury-related deaths.

Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer.

Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.

Study on the Economic Burden of Neurodevelopmental Diseases on Patients With Genetic Diagnosis.

Objective: To study the burden of neurodevelopmental diseases (NDDs) via cost-of-illness analysis of Chinese patients with genetic diagnosis. Methods: We recruited NDD patients (0-18 years old) with genetic diagnosis (GD) from September 1, 2020 to January 30, 2021. We gathered basic information on the details of diagnosis, as well as the direct medical cost, direct non-healthcare cost and indirect cost before and after receiving GD. We corrected the cost for time biases by calculating the cost per day for each patient. Results: For the 502 patients with NDDs, the mean age was 4.08 ± 3.47. The household income was 0.6 (0.4, 1.0) 10,000 CNY per-month on average. The direct medical cost, direct non-healthcare cost and indirect cost were 12.27 (7.36, 22.23) 10,000 CNY, 1.45 (0.73, 2.69)10,000 CNY and 14.14(4.80, 28.25) 10,000 CNY per patient, respectively. Every patient received 1.20 (0.34, 3.60) 10,000 CNY on average (15.91%) from insurance. The daily total cost after receiving GD were ~62.48% lower than those before GD (191.59 CNY vs. 71.45 CNY). The descend range of lab cost (95.77%, P < 0.05) was the largest, followed by drugs (91.39%, P < 0.05), hospitalization (90.85%, P < 0.05), and consultation (57.41%, P < 0.05). The cost of rehabilitation kept slightly increasing but there were no significant differences (P > 0.05). The daily direct medical cost of each patient fell by 75.26% (P < 0.05) from 311.79 CNY to 77.14 CNY when the diagnostic age was younger than 1, and declined by 49.30% (P < 0.05) and 8.97% (P > 0.05) when the diagnostic age was 1-3 and older than 3, respectively. Conclusions: Early genetic diagnosis is crucial for to reducing the burden of disease because of the amount of money spent was lower when they are diagnosed at younger age. Patients with NDDs can incur a heavy economic burden, especially in rehabilitation cost and indirect cost, because the insurance coverage for patients is low, so it is urgent for governments to pay more attention to these issues.

Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance.

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK-STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK-STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK-STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.

Delafossite-alumina nanocomposite for enhanced catalytic wet peroxide oxidation of anionic pollutants.

Mass transfer efficiency and catalytic reactivity are the two major hurdles for heterogeneous catalytic wet peroxide oxidation (CWPO) technologies. To address these issues, nanocomposite CuFeO2/Al2O3 was synthesized and assessed as a novel catalyst for enhanced adsorption and oxidation of anionic pollutants (catechol and reactive red 195 (RR195)) in waters. With a positive charge on the nanocomposite by introducing Al2O3, the adsorption of anionic pollutants was promoted. The surface complexation reaction on CuFeO2/Al2O3, which fits well to the Langmuir isotherm, has engined the mass transfer of pollutants to the nanocatalyst that demonstrated 96.46% and 99.75% removal of catechol and RR195 at pH 3, respectively. CuFeO2/Al2O3 also showed good performance in various reaction media including binary pollutants system and real wastewaters. The hydroxyl radical in aqueous solution played a major role in the pollutants degradation. The CWPO, which followed the Haber-Weiss mechanism, has been accelerated by the Cu and Fe redox cycles. The robustness of the catalyst was verified by negligible amount of metal leaching from the catalysts along with stable catalytic performance after five cycles. Upon the observed results, CuFeO2/Al2O3 with the synergistic effect has shown to be a promising catalyst for removal and degradation of anionic pollutants in CWPO.

The Differences of Population Birth Defects in Epidemiology Analysis between the Rural and Urban Areas of Hunan Province in China, 2014-2018.

OBJECTIVES: To compare the differences of epidemiology analysis in population birth defects (BDs) between the rural and urban areas of Hunan Province in China. METHODS: The data of population-based BDs in Liuyang county (rural) and Shifeng district (urban) in Hunan Province for 2014-2018 were analyzed. BD prevalence rates, percentage change, and annual percentage change (APC) by sex and age were calculated to evaluate time trends. Risk factors associated with BDs were assessed using simple and multiple logistic regression analyses. RESULTS: The BD prevalence rate per 10,000 perinatal infants (PIs) was 220.54 (95% CI: 211.26-230.13) in Liuyang and 181.14 (95% CI: 161.18-202.87) in Shifeng. Significant decreasing trends in BD prevalence rates were noted in the female PIs (APC = -9.31, P = 0.044) and the total BD prevalence rate in Shifeng (APC = -14.14, P = 0.039). Risk factors for BDs were as follows: rural area, male PIs, PIs with gestational age < 37 weeks, PIs with birth weight < 2500 g, and migrant pregnancies. CONCLUSIONS: We should focus on rural areas, reduce the prevalence of premature and low birth weight infants, and provide maternal healthcare services for migrant pregnancies for BD prevention from the perspective of population-based BD surveillance.

Effects of pre-pregnancy body mass index on pregnancy and perinatal outcomes in women based on a retrospective cohort.

To investigate the prevalence of underweight, overweight and obesity as defined by pre-pregnancy body mass index (BMI) and the relationship between pre-pregnancy BMI and pregnancy and perinatal outcomes in women based on a retrospective cohort. Women registered via the Free Pre-pregnancy Health Check (FPHC) program from 2017 to 2019 in Hunan Province, China, were included to the study cohort. The data regarding maternal characteristics, pregnancy outcomes, and infant characteristics were retrieved from the surveillance system of the FPHC program. Logistic regressions were performed to calculate odds ratios (ORs) and adjusted odds ratios (AORs) with 95% confidence intervals (95% CIs) to assess the associations between pre-pregnancy BMIs and the outcomes. Among a total of 398,368 women, 54,238 (13.62%) were underweight (BMI < 18.5 kg/m2), 51,251 (12.87%) were overweight (24.0 kg/m2 ≤ BMI < 28.0 kg/m2), and 10,399 (2.61%) were obese (BMI ≥ 28.0 kg/m2). Underweight occurred more commonly in the 20-24 years old (17.98%), Han Chinese (13.89), college-educated (16.09%), rural (13.74%), and teacher/public servant/office clerk (16.09%) groups. Obesity occurred more often in the older than 35-year-old (4.48%), minority (3.64%), primary school or below (4.98%), urban (3.06%), and housewife (3.14%) groups (P < 0.001). Compared with the normal BMI group, underweight was associated with increased risk of low birth weight (LBW) (AOR = 1.25) and small-for-gestational age (SGA) (AOR = 1.11), but protected against gestational hypertensive disorder (GHD) (AOR = 0.85), gestational diabetes mellitus (GDM) (AOR = 0.69), macrosomia (AOR = 0.67), post-term pregnancy (AOR = 0.76), and cesarean-section (AOR = 0.81). Overweight and obesity were associated with increased risk of GHD (AOR = 1.28, 2.47), GDM (AOR = 1.63, 3.02), preterm birth (AOR = 1.18, 1.47), macrosomia (AOR = 1.51, 2.11), large-for-gestational age (LGA) (AOR = 1.19, 1.35), post-term pregnancy (AOR = 1.39, 1.66), and cesarean- section (AOR = 1.60, 2.05). Pre-pregnancy underweight is relatively common in Hunan Province, China. Pre-pregnancy underweight to some extent is associated with better maternal outcomes, but it has certain adverse effects on neonatal outcomes. Pre-pregnancy overweight, especially obesity, has a substantial adverse effect on pregnancy and perinatal outcomes.

Determinants of renal cell carcinoma invasion and metastatic competence.

Metastasis is the principal cause of cancer related deaths. Tumor invasion is essential for metastatic spread. However, determinants of invasion are poorly understood. We addressed this knowledge gap by leveraging a unique attribute of kidney cancer. Renal tumors invade into large vessels forming tumor thrombi (TT) that migrate extending sometimes into the heart. Over a decade, we prospectively enrolled 83 ethnically-diverse patients undergoing surgical resection for grossly invasive tumors at UT Southwestern Kidney Cancer Program. In this study, we perform comprehensive histological analyses, integrate multi-region genomic studies, generate in vivo models, and execute functional studies to define tumor invasion and metastatic competence. We find that invasion is not always associated with the most aggressive clone. Driven by immediate early genes, invasion appears to be an opportunistic trait attained by subclones with diverse oncogenomic status in geospatial proximity to vasculature. We show that not all invasive tumors metastasize and identify determinants of metastatic competency. TT associated with metastases are characterized by higher grade, mTOR activation and a particular immune contexture. Moreover, TT grade is a better predictor of metastasis than overall tumor grade, which may have implications for clinical practice.

Protein sumoylation sites prediction based on two-stage feature selection.

Protein sumoylation is one of the most important post-translational modifications. Accurate prediction of sumoylation sites is very useful for the analysis of proteome. Though the putative motif Psi K XE can be used, optimization of prediction models still remains a challenge. In this study, we developed a prediction system based on feature selection strategy. A total of 1,272 peptides with 14 residues from SUMOsp (Xue et al. [8] Nucleic Acids Res 34:W254-W257, 2006) were investigated in this study, including 212 substrates and 1,060 non-substrates. Among the substrates, only 162 substrates comply to the motif Psi K XE. First, 1,272 substrates were divided into training set and test set. All the substrates were encoded into feature vectors by hundreds of amino acid properties collected by Amino Acid Index Database (AAIndex, http://www.genome.jp/aaindex ). Then, mRMR (minimum redundancy-maximum relevance) method was applied to extract the most informative features. Finally, Nearest Neighbor Algorithm (NNA) was used to produce the prediction models. Tested by Leave-one-out (LOO) cross-validation, the optimal prediction model reaches the accuracy of 84.4% for the training set and 76.4% for the test set. Especially, 180 substrates were correctly predicted, which was 18 more than using the motif Psi K XE. The final selected features indicate that amino acid residues with two-residue downstream and one-residue upstream of the sumoylation sites play the most important role in determining the occurrence of sumoylation. Based on the feature selection strategy, our prediction system can not only be used for high throughput prediction of sumoylation sites but also as a tool to investigate the mechanism of sumoylation.

Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

Lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical targets of the host antitumor immune response, and their presence correlates with the efficacy of immunotherapy treatment. Many studies involving assessment of tumor neoantigens principally focus on total neoantigen load, which simplistically treats all neoantigens equally. Neoantigen load has been linked with treatment response and prognosis in some studies but not others. We developed a Cauchy-Schwarz index of Neoantigens (CSiN) score to better account for the degree of concentration of immunogenic neoantigens in truncal mutations. Unlike total neoantigen load determinations, CSiN incorporates the effect of both clonality and MHC binding affinity of neoantigens when characterizing tumor neoantigen profiles. By analyzing the clinical responses in 501 treated patients with cancer (with most receiving checkpoint inhibitors) and the overall survival of 1978 patients with cancer at baseline, we showed that CSiN scores predict treatment response to checkpoint inhibitors and prognosis in patients with melanoma, lung cancer, and kidney cancer. CSiN score substantially outperformed prior genetics-based prediction methods of responsiveness and fills an important gap in research involving assessment of tumor neoantigen burden.

Pancreatic tropism of metastatic renal cell carcinoma.

Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.

HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.

PURPOSE: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1ß, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. PATIENTS AND METHODS: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. RESULTS: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. CONCLUSIONS: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors.

By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors.Significance: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis. Cancer Discov; 8(9); 1142-55. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.

OPMSP: A Computational Method Integrating Protein Interaction and Sequence Information for the Identification of Novel Putative Oncogenes.

Oncogenes are genes that have the potential to cause cancer. Oncogene research can provide insight into the occurrence and development of cancer, thereby helping to prevent cancer and to design effective treatments. This study proposes a network method called the oncogene prediction method based on shortest path algorithm (OPMSP) for the identification of novel oncogenes in a large protein network built using protein-protein interaction data. Novel putative genes were extracted from the shortest paths connecting any two known oncogenes. Then, they were filtered by a randomization test, and the linkages among them and known oncogenes were measured by protein interaction and sequence data. Thirty-seven new putative oncogenes were identified by this method. The enrichment analysis of the 37 putative oncogenes indicated that they are highly associated with several biological processes related to the initiation, progression and metastasis of tumors. Six of these genes-ESR1, CDK9, SEPT2, HOXA10, LMX1B, and NR2C2-are extensively discussed. Several lines of evidence indicate that they may be novel oncogenes.