Identification and biological evaluation of fused tetrahydroisoquinoline derivatives as Wnt/ß-catenin signaling inhibitors to suppress colorectal cancer.

Colorectal cancer (CRC) has been becoming one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/ß-catenin signaling is a crucial hallmark of CRC, and suppressing it is a promising strategy to treat CRC. Herein, we reported our latest efforts in the discovery of novel fused tetrahydroisoquinoline derivatives with good anti-CRC activities by screening our in-house berberine-like library and further structure-activity relationship (SAR) studies, in which we identified compound 10 is a potent lead compound with significant antiproliferation potencies. By the biotinylated probe and LC-MS/MS study, Hsp90 was identified as its molecular target, which is a fully different mechanism of action from what we reported before. Further studies showed compound 10 directly engaged the N-terminal site of Hsp90 and promoted the degradation of ß-catenin, thereby suppressing the Wnt/ß-catenin signaling. More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/ß-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

Directly targeting BAX for drug discovery: Therapeutic opportunities and challenges.

For over two decades, the development of B-cell lymphoma-2 (Bcl-2) family therapeutics has primarily focused on anti-apoptotic proteins, resulting in the first-in-class drugs called BH3 mimetics, especially for Bcl-2 inhibitor Venetoclax. The pro-apoptotic protein Bcl-2-associated X protein (BAX) plays a crucial role as the executioner protein of the mitochondrial regulated cell death, contributing to organismal development, tissue homeostasis, and immunity. The dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death, such as cancer, neurodegeneration, and heart failure. In addition to conducting thorough investigations into the physiological modulation of BAX, research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX, as well as diverse all-molecule BAX modulators. This review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on BAX. Furthermore, it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX, offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation shows decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. METHODS: Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and the HCC clinical characteristics as well as anti-PD-1 response. Subcutaneous xenograft, orthotopic xenograft, Trp53Δhep/Δhep; MYC- as well as Ctnnboe; METoe- driven mouse models were adopted to validate GCDH effects on HCC suppression. RESULTS: GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDHhigh cells. These cells induced the infiltration of immune cells by the senescence-associated secretory cell phenotype (SASP) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDHlow population was sensitized to anti-programmed cell death protein 1 (PD-1) therapy. CONCLUSION: GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment by SASP. The GCDHlow population is vulnerable to anti-PD-1 therapy because more PD-1+CD8+ T cells are exhibited in GCDHlow population. IMPACT AND IMPLICATIONS: GCDH is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most of GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Therefore, studies on the correlation between GCDH and liver cancer would contribute to discovering the initiation and progression of hepatocellular carcinoma, of which over 70% of patients occupied >2-fold GCDH downregulation. Given that the GCDHlow and GCDHhigh HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.

The spectrum of pre-mRNA splicing in autism.

Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in pre-mRNA splicing. Abnormal splicing patterns have been identified in the brains of individuals with ASD, and mutations in splicing factors have been found to contribute to neurodevelopmental delays associated with ASD. Here we review studies that shed light on the importance of splicing observed in ASD and that explored the intricate relationship between splicing factors and ASD, revealing how disruptions in pre-mRNA splicing may underlie ASD pathogenesis. We provide an overview of the research regarding all splicing factors associated with ASD and place a special emphasis on five specific splicing factors-HNRNPH2, NOVA2, WBP4, SRRM2, and RBFOX1-known to impact the splicing of ASD-related genes. In the discussion of the molecular mechanisms influenced by these splicing factors, we lay the groundwork for a deeper understanding of ASD's complex etiology. Finally, we discuss the potential benefit of unraveling the connection between splicing and ASD for the development of more precise diagnostic tools and targeted therapeutic interventions. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Evolution and Genomics > Computational Analyses of RNA RNA-Based Catalysis > RNA Catalysis in Splicing and Translation.

Stereotactic body radiotherapy for primary renal cell carcinoma: a systematic review and practice guideline from the International Society of Stereotactic Radiosurgery (ISRS).

Surgery is the standard of care for patients with primary renal cell carcinoma. Stereotactic body radiotherapy (SBRT) is a novel alternative for patients who are medically inoperable, technically high risk, or who decline surgery. Evidence for using SBRT in the primary renal cell carcinoma setting is growing, including several rigorously conducted prospective clinical trials. This systematic review was performed to assess the safety and efficacy of SBRT for primary renal cell carcinoma. Review results then formed the basis for the practice guidelines described, on behalf of the International Stereotactic Radiosurgery Society. 3972 publications were screened and 36 studies (822 patients) were included in the analysis. Median local control rate was 94·1% (range 70·0-100), 5-year progression-free survival was 80·5% (95% CI 72-92), and 5-year overall survival was 77·2% (95% CI 65-89). These practice guidelines addressed four key clinical questions. First, the optimal dose fractionation was 25-26 Gy in one fraction, or 42-48 Gy in three fractions for larger tumours. Second, routine post-treatment biopsy is not recommended as it is not predictive of patient outcome. Third, SBRT for primary renal cell carcinoma in a solitary kidney is safe and effective. Finally, guidelines for post-treatment follow-up are described, which include cross-axial imaging of the abdomen including both kidneys, adrenals, and surveillance of the chest initially every 6 months. This systematic review and practice guideline support the practice of SBRT for primary renal cell carcinoma as a safe and effective standard treatment option. Randomised trials with surgery and invasive ablative therapies are needed to further define best practice.

Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic "Cold"-"Hot" Tumor Transformations.

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.

DBU-catalyzed diastereoselective 1,3-dipolar [3+2] cycloaddition of trifluoroethyl amine-derived isatin ketimines with chalcones: synthesis of 5'-CF3-substituted 3,2'-pyrrolidinyl spirooxindoles.

A diastereoselective 1,3-dipolar cycloaddition reaction between trifluoroethyl amine-derived isatin ketimines and chalcones was successfully achieved in the presence of DBU. A series of 5'-CF3-substituted 3,2'-pyrrolidinyl spirooxindoles were efficiently synthesized with high yields and excellent diastereoselectivities (up to 89% yield, and >99 : 1 dr). The in vitro anticancer activities of these highly functionalized spiro[pyrrolidin-3,2'-oxindole] derivatives were evaluated.

Management of sporadic intracanalicular vestibular schwannomas: A critical review and International Stereotactic Radiosurgery Society (ISRS) practice guidelines.

BACKGROUND: The choice of an appropriate strategy for intracanalicular vestibular schwannoma (ICVS) is still debated. We conducted a systematic review and meta-analysis with the aim to compare treatment outcomes amongst management strategies (conservative surveillance (CS), microsurgical resection (MR), or stereotactic radiosurgery (SRS)) aiming to inform guideline recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2021 referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies or case series reporting a cohort of ICVS managed with CS, MR, or SRS. Primary outcome measures included tumor control, the need for additional treatment, hearing outcomes, and posttreatment neurological deficits. These were pooled using meta-analytical techniques and compared using meta-regression with random effect. RESULTS: Forty studies were included (2371 patients). The weighted pooled estimates for tumor control were 96% and 65% in SRS and CS series, respectively (P < .001). Need for further treatment was reported in 1%, 2%, and 25% for SRS, MR, and CS, respectively (P = .001). Hearing preservation was reported in 67%, 68%, and 55% for SRS, MR, and CS, respectively (P = .21). Persistent facial nerve deficit was reported in 0.1% and 10% for SRS and MR series, respectively (P = .01). CONCLUSIONS: SRS is a noninvasive treatment with at least equivalent rates of tumor control and hearing preservation as compared to MR, with the caveat of better facial nerve preservation. As compared to CS, upfront SRS is an effective treatment in achieving tumor control with similar rates of hearing preservation.

Multifunctional nano MOF drug delivery platform in combination therapy.

Recent preclinical and clinical studies have demonstrated that for cancer treatment, combination therapies are more effective than monotherapies in reducing drug-related toxicity, decreasing drug resistance, and improving therapeutic efficacy. With the rapid development of nanotechnology, the combination of metal-organic frameworks (MOFs) and multi-mode therapy offers a realistic possibility to further improve the shortcomings of cancer treatment. This article focuses on the latest developments, achievements, and treatment strategies of representative multifunctional MOF combination therapies for cancer treatment in recent years, which include not only bimodal combination therapies, but also multi-modal synergistic therapies, further demonstrating the effectiveness and superiority of the MOF drug delivery systems in cancer treatment.

Adverse Outcomes in Hospitalizations for Amyloid-Related Heart Failure.

Transthyretin amyloid cardiomyopathy is being increasingly recognized as an important cause of heart failure (HF). In this study, we looked at adverse outcomes in hospitalizations with amyloid-related HF. This study was a retrospective analysis of the National Inpatient Sample data, collected from 2016 to 2019. Patients ≥41 years of age and admitted for HF were included in the study. In these hospitalizations, amyloid-related HF was identified through the International Classification of Diseases, Tenth Revision, Clinical Modification codes for amyloidosis. The primary outcome of the study was in-hospital mortality, whereas secondary outcomes were prolonged length of stay, mechanical ventilation, mechanical circulatory support, vasopressors use, and dispositions other than home. From 2016 to 2019, there were 4,705,274 HF hospitalizations, of which 16,955 (0.4%) had amyloid cardiomyopathy. In all HF hospitalizations, amyloid-related increased from 0.26% in 2016 to 0.46% in 2019 (relative increase, 76.9%, P for trend <0.001). Amyloid-related HF hospitalizations were more common in older, male, and Black patients. The odds of in-hospital mortality (odds ratio [OR], 1.29; 95% confidence interval [CI]: 1.11 to 1.38), prolonged hospital length (OR, 1.61; 95% CI: 1.49 to 1.73) and vasopressors use (OR, 1.59; 95% CI: 1.23 to 2.05) were significantly higher for amyloid-related hospitalizations. Amyloid-related HF hospitalizations are increasing substantially and are associated with adverse hospital outcomes. These hospitalizations were disproportionately higher for older, male, and Black patients. Amyloid-related HF is rare and underdiagnosed yet has several adverse outcomes. Hence, healthcare providers should be watchful of this condition for early identification and prompt management.

Stereotactic body radiotherapy for Ultra-Central lung Tumors: A systematic review and Meta-Analysis and International Stereotactic Radiosurgery Society practice guidelines.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an effective and safe modality for early-stage lung cancer and lung metastases. However, tumors in an ultra-central location pose unique safety considerations. We performed a systematic review and meta-analysis to summarize the current safety and efficacy data and provide practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: We performed a systematic review using PubMed and EMBASE databases of patients with ultra-central lung tumors treated with SBRT. Studies reporting local control (LC) and/or toxicity were included. Studies with <5 treated lesions, non-English language, re-irradiation, nodal tumors, or mixed outcomes in which ultra-central tumors could not be discerned were excluded. Random-effects meta-analysis was performed for studies reporting relevant endpoints. Meta-regression was conducted to determine the effect of various covariates on the primary outcomes. RESULTS: 602 unique studies were identified of which 27 (one prospective observational, the remainder retrospective) were included, representing 1183 treated targets. All studies defined ultra-central as the planning target volume (PTV) overlapping the proximal bronchial tree (PBT). The most common dose fractionations were 50 Gy/5, 60 Gy/8, and 60 Gy/12 fractions. The pooled 1- and 2-year LC estimates were 92 % and 89 %, respectively. Meta-regression identified biological effective dose (BED10) as a significant predictor of 1-year LC. A total of 109 grade 3-4 toxicity events, with a pooled incidence of 6 %, were reported, most commonly pneumonitis. There were 73 treatment related deaths, with a pooled incidence of 4 %, with the most common being hemoptysis. Anticoagulation, interstitial lung disease, endobronchial tumor, and concomitant targeted therapies were observed risk factors for fatal toxicity events. CONCLUSION: SBRT for ultra-central lung tumors results in acceptable rates of local control, albeit with risks of severe toxicity. Caution should be taken for appropriate patient selection, consideration of concomitant therapies, and radiotherapy plan design.

Effect of Frailty on Hospital Outcomes Among Pediatric Cancer Patients in the United States: Results From the National Inpatient Sample.

BACKGROUND: Studies on frailty among pediatric patients with cancer are scarce. In this study, we sought to understand the effects of frailty on hospital outcomes in pediatric patients with cancer. METHODS: This retrospective study used data collected and stored in the Nationwide Inpatient Sample (NIS) between 2005 and 2014. These were hospitalized patients and hence represented the sickest group of patients. Frailty was measured using the frailty definition diagnostic indicator by Johns Hopkins Adjusted Clinical Groups. RESULTS: Of 187,835 pediatric cancer hospitalizations included in this analysis, 11,497 (6.1%) were frail. The average hospitalization costs were $86,910 among frail and $40,358 for nonfrail patients. In propensity score matching analysis, the odds of in-hospital mortality (odds ratio, 2.08; 95% CI, 1.71-2.52) and length of stay (odds ratio, 3.76; 95% CI, 3.46-4.09) were significantly greater for frail patients. The findings of our study suggest that frailty is a crucial clinical factor to be considered when treating pediatric cancer patients in a hospital setting. CONCLUSIONS: These findings highlight the need for further research on frailty-based risk stratification and individualized interventions that could improve outcomes in frail pediatric cancer patients. The adaptation and validation of a frailty-defining diagnostic tool in the pediatric population is a high priority in the field.

Sporadic hyperplastic polyp associated with above-average risk of developing metachronous colorectal cancer.

Post-colonoscopy surveillance interval for colorectal polyps depends on the size, number, and pathological classification of removed polyps. The risk of sporadic hyperplastic polyps (HPs) for developing colorectal adenocarcinoma remains debatable due to limited data. We aimed to evaluate the risk of metachronous colorectal cancer (CRC) in patients with sporadic HPs. A total of 249 patients with historical HP(s) diagnosed in 2003 were included as the disease group, and 393 patients without any polyp as the control group. All historical HPs were reclassified into SSA or true HP based on the recent 2010 and 2019 World Health Organization (WHO) criteria. Polyp size was measured under light microscope. Patients developed CRC were identified from the Tumor Registry database. Each tumor was tested for DNA mismatch repair proteins (MMR) by immunohistochemistry. Results showed that 21 (8%) and 48 (19%) historical HPs were reclassified as SSAs based on the 2010 and 2019 WHO criteria, respectively. The mean polyp size of SSAs (6.7 mm) was significantly larger than HPs (3.3 mm) (P<0.0001). For polyp size ≥5 mm, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing SSA was 90%, 90%, 46%, and 99%, respectively. Left-sided polyps with size <5 mm were 100% of HPs. Five of 249 (2%) patients developed metachronous CRC during the 14-year follow-up from 2003 to 2017, including 2 of 21 (9.5%) patients with SSA diagnosed at intervals of 2.5 and 7 years, and 3 of 228 (1.3%) patients with HP(s) at 7, 10.3, and 11.9 years. Two of 5 cancers showed MMR deficiency with concurrent loss of MLH1/PMS2. Based on the 2019 WHO criteria, the rate of developing metachronous CRC in patients with SSA (P=0.0116) and HP (P=0.0384) was significantly higher than the control group, and no significant difference was observed between patients with SSA and with HP (P=0.241) in this cohort. Patients with either SSA or HP also had higher risk of CRC than average-risk US population (P=0.0002 and 0.0001, respectively). Our data add a new line of evidence that patients with sporadic HP are associated with above-average risk of developing metachronous CRC. Post-polypectomy surveillance for sporadic HP may be adjusted in future practice given the low but increased risk of developing CRC.

Prevalence and trends of perioperative major adverse cardiovascular and cerebrovascular events during cancer surgeries.

Major adverse cardiovascular and cerebrovascular events (MACCE) is an important cause of morbidity and mortality during perioperative period. In this study, we looked for national trends in perioperative MACCE and its components as well as cancer types associated with high rates of perioperative MACCE during major cancer surgeries. This study was a retrospective analysis of the National Inpatient Sample, 2005-2014. Hospitalizations for surgeries of prostate, bladder, esophagus, pancreas, lung, liver, colorectal, and breast among patients 40 years and greater were included in the analysis. MACCE was defined as a composite measure that included in-hospital all-cause mortality, acute myocardial infarction (AMI), and ischemic stroke. A total of 2,854,810 hospitalizations for major surgeries were included in this study. Of these, 67,316 (2.4%) had perioperative MACCE. Trends of perioperative MACCE showed that it decreased significantly for AMI, death and any MACCE, while stroke did not significantly change during the study period. Logistic regression analysis for perioperative MACCE by cancer types showed that surgeries for esophagus, pancreas, lung, liver, and colorectal cancers had significantly greater odds for perioperative MACCE. The surgeries identified to have greater risks for MACCE in this study could be risk stratified for better informed decision-making and management.

Difference in 30-Day Readmission Rates After Laparoscopic Sleeve Gastrectomy Versus Laparoscopic Roux-En-Y Gastric Bypass: a Propensity Score Matched Study Using ACS NSQIP Data (2015-2019).

PURPOSE: There are very few studies that have compared the short-term outcomes of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG). Among short-term outcomes, hospital readmission after these procedures is an area for quality enhancement and cost reduction. In this study, we compared 30-day readmission rates after LSG and LRYGB through analyzing a nationalized dataset. In addition, we identified the reasons of readmission. MATERIALS AND METHODS: The current study was a retrospective analysis of data from National Surgical Quality Improvement Program (NSQIP) All adult patients, ≥ 18 years of age and who had LSG or LRYGB during 2014 to 2019 were included. Current Procedural Terminology (CPT) codes were used to identify the procedures. Multivariate logistic regressions were used to calculate propensity score adjusted odds ratios (ORs) for all cause 30-day re-admissions. RESULTS: There were 109,900 patients who underwent laparoscopic bariatric surgeries (67.5% LSG and 32.5% LRYGB). Readmissions were reported in 4168 (3.8%) of the patients and were more common among RYGB recipients compared to LSG (5.6% versus 2.9%, P < 0.001). The odds of 30-day readmissions were significantly higher among LRYGB group compared to LSG group (AOR, 2.20; 95% CI; 1.83, 2.64). In addition, variables such as age, chronic obstructive pulmonary disease, hypertension, bleeding disorders, blood urea nitrogen, SGOT, alkaline phosphatase, hematocrit, and operation time were significantly predicting readmission rates. CONCLUSIONS: Readmission rates were significantly higher among those receiving LRYGB, compared to LSG. Readmission was also affected by many patient factors. The factors could help patients and providers to make informed decisions for selecting appropriate procedures.

Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties.

Direct activation of the pro-apoptotic protein BAX represents a potential therapeutic strategy to trigger apoptosis in cancer. Herein, structural optimization of the reported BAX trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the BAX activation cascade, promoting BAX insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and apoptosis. Furthermore, 6d showed significantly improved in vitro stability and CYPs profile compared to BTSA1. This work may lay a foundation to develop potent BAX trigger site activators for the treatment of BAX-expressing malignancies.

Impact of COVID-19 on Intracranial Meningioma Resection: Results from California State Inpatient Database.

PURPOSE: To assess the effects of COVID-19 on hospitalizations for intracranial meningioma resection using a large database. METHODS: We conducted a retrospective analysis of the California State Inpatient Database (SID) 2019 and 2020. All adult (18 years or older) hospitalizations were included for the analysis. The primary outcomes were trends in hospitalization for intracranial meningioma resection between 2019 and 2020. Secondary outcomes were Clavien-Dindo grade IV complications, in-hospital mortality, and prolonged length of stay, which was defined as length of stay ≥75 percentile. RESULTS: There were 3,173,333 and 2,866,161 hospitalizations in 2019 and 2020, respectively (relative decrease, 9.7%), of which 921 and 788 underwent intracranial meningioma resection (relative decrease, 14.4%). In 2020, there were 94,114 admissions for COVID-19 treatment. Logistic regression analysis showed that year in which intracranial meningioma resection was performed did not show significant association with Clavien-Dindo grade IV complications and in-hospital mortality (OR, 1.23, 95% CI: 0.78-1.94) and prolonged length of stay (OR, 1.05, 95% CI: 0.84-1.32). CONCLUSION: Our findings show that neurosurgery practice in the US successfully adapted to the unforeseen challenges posed by COVD-19 and ensured the best quality of care to the patients.

Patterns of structural variation define prostate cancer across disease states.

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 531 localized and 143 metastatic prostate cancers profiled by whole genome sequencing, 125 metastatic samples of which were also profiled via whole transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined 9 subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.

Development of a series of novel Mcl-1 inhibitors bearing an indole carboxylic acid moiety.

The B cell lymphoma protein 2 (Bcl-2) family proteins regulate cell apoptosis by participating in the endogenous apoptosis pathway. As an important anti-apoptotic protein, Myeloid cell leukemia 1 (Mcl-1) is overexpressed in a variety of tumor cells, and targeting this protein has been a promising strategy for cancer therapy. Herein, based on the 1H-indole-5-carboxylic acid structure previously discovered, we have developed a series of novel compounds with increased affinities and selectivity toward Mcl-1 through structure-based drug design. Among those compounds, 26 exerted relatively better affinity and selectivity for Mcl-1 with moderate inhibition in HL-60 cells. Mechanism studies showed that compound 26 could induce cancer cells apoptosis in an Mcl-1-dependent manner. It also exhibited good microsomal and plasma stability with acceptable pharmacokinetics profiles. Furthermore, treatment with target compound in a 4T1 xenograft mouse model significantly suppressed the tumor growth. Overall, the small molecule described herein represents a promising Mcl-1 inhibitor for further study.

Designing hierarchical iron doped nickel-vanadium hydroxide microsphere as an efficient electrocatalyst for oxygen evolution reaction.

Exploring highly active and inexpensive electrocatalysts for oxygen evolution reaction (OER) is considered to be one of the preconditions for the development of energy and environment-related technologies. Nickel-based layered double hydroxides (LDHs) are extensively-studied OER electrocatalysts, but they still require relatively high overpotentials to achieve threshold current densities. In this work, iron-doped nickel-vanadium hydroxide microspheres (Fe-doped NiV HMS) were synthesized by doping iron ions into the NiV HMS through a facile cation-exchange method. The Fe-doped NiV HMS are hollow hierarchical structure stacked by high-density perpendicularly-lying nanosheets, which provide enough space for electrolyte penetration and diffusion. Owing to optimized composition and hollow hierarchical structure, the Fe-doped NiV HMS exhibits excellent electrocatalytic performance, which possessed a very low running overpotential (255 mV at 10 mA cm-2) and a smallest Tafel slope (56 mV dec-1) compared with hierarchical NiV HMS toward OER. Electrochemical results and density functional theory (DFT) manifest that Fe doping could regulate the electronic structure of NiV HMS, thus improving its electrical conductivity and electron transfer rate, and thus enhancing its catalytic activity. This research provides a convenient way to prepare Ni-based hydroxides as promising OER catalysts.