SMARCB1 regulates the hypoxic stress response in sickle cell trait.

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.

An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway.

Pro-apoptotic BAX is a cell fate regulator playing an important role in cellular homeostasis and pathological cell death. BAX is predominantly localized in the cytosol, where it has a quiescent monomer conformation. Following a pro-apoptotic trigger, cytosolic BAX is activated and translocates to the mitochondria to initiate mitochondrial dysfunction and apoptosis. Here, cellular, biochemical, and structural data unexpectedly demonstrate that cytosolic BAX also has an inactive dimer conformation that regulates its activation. The full-length crystal structure of the inactive BAX dimer revealed an asymmetric interaction consistent with inhibition of the N-terminal conformational change of one protomer and the displacement of the C-terminal helix α9 of the second protomer. This autoinhibited BAX dimer dissociates to BAX monomers before BAX can be activated. Our data support a model whereby the degree of apoptosis induction is regulated by the conformation of cytosolic BAX and identify an unprecedented mechanism of cytosolic BAX inhibition.

Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.

BACKGROUND: Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication 'single autosomal recessive mutation in rare disease'. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic 'second-hit' variants. METHODS: To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity. RESULTS: Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2-6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. CONCLUSION: Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits.

Selective Neurectomy for Postfacial Paralysis Synkinesis: A Systematic Review.

Facial synkinesis is characterized by unintentional contractions of facial musculature secondary to aberrant facial nerve healing. The associated impairment in facial functioning results in a significant decrease in patients' quality of life. The mainstay treatment for postfacial paralysis synkinesis (PFPS) is chemodenervation and physiotherapy, which requires long-term maintenance neurotoxin injections. This can lead to treatment resistance. Selective neurectomy of the distal branches of the facial nerve has been suggested as an effective surgical treatment of PFPS. This study aims to provide a comprehensive systematic review evaluating the efficacy of selective neurectomy for patients presenting with PFPS. Ovid MEDLINE, Ovid Embase, PubMed, Web of Science, and CINAHL were searched from inception until July 2022. Studies that investigated postoperative outcomes of pediatric and/or adult patients who underwent selective neurectomy as a treatment for PFPS were included. The database search identified 1,967 studies, and 11 were ultimately included based on inclusion and exclusion criteria. These 11 studies represented 363 patients. Studies reported on outcomes following selective neurectomy with or without adjuvant therapies for patients with PFPS. The main outcome categories identified were clinician-reported outcomes and patient-reported outcomes. The studies that used clinician-reported outcomes found an improvement in both synkinesis and facial nerve paralysis (FNP) outcomes following selective neurectomy according to their respective grading systems. Three studies looked at patient-reported outcomes and found increased patient-reported quality of life and satisfaction following selective neurectomy. The most reported complications were upper lip contracture, uneven cheek surface, lagophthalmos, and temporary oral incompetence. Selective neurectomy has demonstrated stable or improved synkinesis, FNP, and quality of life outcomes in patients with PFPS. This approach should be considered for patients with PFPS, particularly for patients with refractory symptoms or those who are unable to undergo continued medical management.

Measuring Self-Esteem with Expanded Format in a Fraction of Time: ESE-S and ESE-US.

Despite the ubiquity of Likert format scales, they are not without problems-distorted dimensionality being one of the most serious. Zhang and Savalei proposed an alternative to Likert format called the Expanded format, in which each response option in the Likert scale is replaced with a series of complete statements. In response to their recent call, the purpose of the present study is to develop concise but valid Expanded format scales for the Rosenberg Self-Esteem Scale. Short (four-item) and ultra-short (two-item) scales were constructed, and their validity was examined in four studies. Results showed both new scales had good psychometric properties (dimensionality, reliability, and validity). Therefore, they would seem to be practical alternatives to the RSES for future research.

Diversifying the dental curriculum: A review of the Bachelor of Dental Surgery degree reading lists in a UK dental school.

INTRODUCTION: Analysis of the diversity of reading lists on courses offered by universities is one way to assess what is being taught and how it shapes our understanding of the world. Very little work has been carried out so far within dentistry on decolonising the curriculum. Existing work looks at the representation of women or ethnic minorities but not at the dental curriculum per se. This article starts to address this. METHODS: The reading lists within the 5 year Bachelor of Dental Surgery curriculum in a large UK dental school were collected and assessed. A data extraction spreadsheet was developed and journal articles on every course reading list across the 5 year curriculum were read in detail. Information on authorship and author affiliations, alongside patient and population representation within the article itself, were collected and collated. RESULTS: We found that there are 2.5 times more male authors than female authors, and almost three times more male lead authors in the articles evaluated. The majority of journal articles included in the reading lists are written by academics and/or clinicians affiliated with institutions in the United Kingdom and most articles are from the global north. In addition, 65% of articles do not specify the focus patient or population group studied. DISCUSSION: It is unlikely that current reading lists within dentistry fully reflect the composition of the profession itself, the variety of knowledge needed to provide evidence-based practice in a globalised oral health arena or the heterogeneous nature of the patient population.

Same-Day Discharge vs Inpatient Robotic-Assisted Radical Prostatectomy: Complications, Time-Driven Activity-Based Costing, and Patient Satisfaction.

PURPOSE: Historically, robotic-assisted radical prostatectomy is accompanied by an inpatient hospital admission. The COVID-19 pandemic necessitated a transition to same-day discharge robotic-assisted radical prostatectomy in some centers to free up critically needed inpatient beds. This study aims to compare complications, total health care costs, and patient satisfaction for same-day discharge vs inpatient robotic-assisted radical prostatectomy. MATERIALS AND METHODS: We compared 392 consecutive robotic-assisted radical prostatectomies performed as same-day discharge (n = 206) vs inpatient (n = 186) from February 2020 to November 2022 at 2 academic medical centers. We utilized propensity score analysis to assess the impact of same-day discharge vs inpatient robotic-assisted radical prostatectomy on 30-day complications (primary outcome). Time-driven activity-based costing analysis was applied to compare total costs of robotic-assisted radical prostatectomy care, and we administered a validated Patient Satisfaction Outcome Questionnaire to compare satisfaction scores. RESULTS: Inpatient robotic-assisted radical prostatectomy patients were more likely to be older, self-reported Black race or Hispanic ethnicity, and have higher American Society of Anesthesiologists classification. Complication rates were nonsignificantly lower for same-day discharge vs inpatient robotic-assisted radical prostatectomy (OR 0.87, 95% CI 0.35 to 2.21; P = .8). Same-day discharge vs inpatient robotic-assisted radical prostatectomy demonstrated a $2106 (19%) overall cost reduction. Median satisfaction survey scores were similar, and a clinically significant difference can be excluded. CONCLUSIONS: Same-day discharge robotic-assisted radical prostatectomy is cost-effective and should be the preferred approach in appropriately selected patients.

Interleukin-12 as an in situ cancer vaccine component: a review.

Interleukin-12 (IL-12) is a type I cytokine involved in both innate and adaptive immunity that stimulates T and natural killer cell activity and induces interferon gamma production. IL-12 has been identified as a potential immunotherapeutic component for combinatorial cancer treatments. While IL-12 has successfully been used to treat a variety of cancers in mice, it was associated with toxicity when administered systemically in cancer patients. In this review, we discuss the research findings and progress of IL-12 used in combination with other cancer treatment modalities. We describe different methods of IL-12 delivery, both systemic and local, and ultimately highlight the potential of an in situ vaccination approach for minimizing toxicities and providing antitumor efficacy. This review offers a basis for pursuing an in situ vaccine approach that may eventually allow IL-12 to be more readily integrated as an immunotherapy into the clinical treatment of cancers.

Developments in optimizing transperineal prostate biopsy.

PURPOSE OF REVIEW: Prostate biopsy is a very commonly performed office procedure leading to the diagnosis of the most prevalent solid-organ malignancy in American men. Although the transrectal technique for prostate biopsy remains the gold standard, there is increasing interest in the transperineal approach as it offers a clean, percutaneous approach that significantly decreases the risk for infection. In this review, we discuss emerging developments in transperineal prostate biopsy that may optimize the way biopsies are performed in clinical practice. RECENT FINDINGS: Similarly, to transrectal biopsy, the transperineal approach also allows for the performance of systematic and MRI-targeted biopsy cores. As transperineal biopsy obviates the translocation of rectal bacteria to the prostate or bloodstream, in contrast to transrectal biopsy, it is feasible to forgo peri-procedural antibiotics in accordance with professional guidelines. This may attenuate antimicrobial resistance that may be associated with augmented prophylaxis. In addition, although transperineal biopsy may be traditionally performed under general anesthesia using a template grid, it may also be performed freehand under local anesthesia or sedation. Avoiding prophylactic antibiotics and general anesthesia as well as reducing infections/hospitalizations for transperineal biopsy scaled nationally will likely result in significant healthcare savings. SUMMARY: Transperineal biopsy with combined systematic and MRI-targeted cores, offers several advantages over conventional transrectal biopsy. Transperineal biopsy under local anesthesia and without periprocedural antibiotic is emerging as a promising method for prostate cancer diagnosis and surveillance.

Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion.

Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.

Positive parenting, adolescent adjustment, and quality of adolescent diet in nine countries.

INTRODUCTION: We sought to understand the relation between positive parenting and adolescent diet, whether adolescents' internalizing and externalizing behaviors mediate relations between positive parenting and adolescent diet, and whether the same associations hold for both boys and girls and across cultural groups. METHODS: Adolescents (N = 1334) in 12 cultural groups in nine countries were followed longitudinally from age 12 to 15. We estimated two sets of multiple group structural equation models, one by gender and one by cultural group. RESULTS: Modeling by gender, our findings suggest a direct effect of positive parenting at age 12 on a higher quality diet at age 15 for males (ß = .140; 95% CI: 0.057, 0.229), but an indirect effect of positive parenting at age 12 on a higher quality diet at age 15 by decreasing externalizing behaviors at age 14 for females (ß = .011; 95% CI: 0.002, 0.029). Modeling by cultural group, we found no significant direct effect of positive parenting at age 12 on the quality of adolescent diet at age 15. There was a significant negative effect of positive parenting at age 12 on internalizing (ß = -.065; 95% CI: -0.119, -0.009) and externalizing at age 14 (ß = -.033; 95% CI: -0.086, -0.018). CONCLUSIONS: We founder gender differences in the relations among positive parenting, adolescents' externalizing and internalizing behaviors, and adolescent diet. Our findings indicate that quality of parenting is important not only in promoting adolescent mental health but potentially also in promoting the quality of adolescents' diet.

A game-theoretical analysis of poliomyelitis vaccination.

Poliomyelitis is a worldwide disease that has nearly been eradicated thanks to the Global Polio Eradication Initiative. Nevertheless, the disease is currently still endemic in three countries. In this paper, we incorporate the vaccination in a two age-class model of polio dynamics. Our main objective is to see whether mandatory vaccination policy is needed or if polio could be almost eradicated by a voluntary vaccination. We perform game theoretical analysis and compare the herd immunity vaccination levels with the Nash equilibrium vaccination levels. We show that the gap between two vaccination levels is too large. We conclude that the mandatory vaccination policy is therefore needed to achieve a complete eradication.

Overcome tumor heterogeneity-imposed therapeutic barriers through convergent genomic biomarker discovery: A braided cancer river model of kidney cancer.

Tumor heterogeneity, encompassing genetic, epigenetic, and microenvironmental variables, is extremely complex and presents challenges to cancer diagnosis and therapy. Genomic efforts on genetic intratumor heterogeneity (G-ITH) confirm branched evolution, support the trunk-branch cancer model, and present a seemingly insurmountable obstacle to conquering cancers. G-ITH is conspicuous in clear cell renal cell carcinoma (ccRCC), where its presence complicates identification and validation of biomarkers and thwarts efforts in advancing precision cancer therapeutics. However, long-term clinical benefits on targeted therapy are not uncommon in metastatic ccRCC patients, implicating that there are underlying constraints during ccRCC evolution, which in turn force a nonrandom sequence of parallel gene/pathway/function/phenotype convergence within individual tumors. Accordingly, we proposed a "braided cancer river model" depicting ccRCC evolution, which deduces cancer development based on multiregion tumor genomics of exceptional mTOR inhibitor (mTORi) responders. Furthermore, we employ an outlier case to explore the river model and highlight the importance of "Five NGS Matters: Number, Frequency, Position, Site and Time" in assessing cancer genomics for precision medicine. This mutable cancer river model may capture clinically significant phenotype-convergent events, predict vulnerability/resistance mechanisms, and guide effective therapeutic strategies. Our model originates from studying exceptional responders in ccRCC, which warrants further refinement and future validation concerning its applicability to other cancer types. The goal of this review is employing kidney cancer as an example to illustrate critical issues concerning tumor heterogeneity.

Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with pan-omics precision.

Over the past 20 years, classifications of kidney cancer have undergone major revisions based on morphological refinements and molecular characterizations. The 2016 WHO classification of renal tumors recognizes more than ten different renal cell carcinoma (RCC) subtypes. Furthermore, the marked inter- and intra-tumor heterogeneity of RCC is now well appreciated. Nevertheless, contemporary multi-omics studies of RCC, encompassing genomics, transcriptomics, proteomics, and metabolomics, not only highlight apparent diversity but also showcase and underline commonality. Here, we wish to provide an integrated perspective concerning the future 'functional' classification of renal cancer by bridging gaps among morphology, biology, multi-omics, and therapeutics. This review focuses on recent progress and elaborates the potential value of contemporary pan-omics approaches with a special emphasis on cancer genomics unveiled through next-generation sequencing technology, and how an integrated multi-omics approach might impact precision-based personalized kidney cancer care in the near future. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Recognition of Infantile Spasms Is Often Delayed: The ASSIST Study.

OBJECTIVES: To characterize and quantify diagnostic and treatment delay among children with infantile spasms, and to estimate the developmental impact of this delay. STUDY DESIGN: In this cohort study, we surveyed the parents of 100 patients with infantile spasms about their experiences with diagnosis and treatment, and ascertained medical and sociodemographic factors potentially related to care of these infants. We specifically determined the latency to first visit an "effective provider," defined as a provider who identified infantile spasms, and prescribed an appropriate first-line treatment, namely adrenocorticotropic hormone, corticosteroids, or vigabatrin. Time to the first visit to an effective provider was evaluated using Cox proportional hazards regression. RESULTS: The median time from the onset of infantile spasms to first visit with an effective provider was 24.5 days. Only 29% of patients were evaluated by an effective provider within 1 week of infantile spasms onset. The time to first effective provider visit was associated with parental language preference, but with no other sociodemographic characteristics. Parents' suspicions that "something is wrong" were often discounted by healthcare providers, and survey respondents frequently reported that pediatricians and neurologists were unfamiliar with infantile spasms. CONCLUSION: This study demonstrates that substantial delay (ie, >1 week) in appropriate care is common, and suggests that the poor awareness of infantile spasms among healthcare providers is at least partly responsible for preventable and potentially significant delays in treatment.

Deadly splicing: Bax becomes Almighty.

Activation of Bax and Bak by BH3-only molecules triggers mitochondrial apoptosis. In a recent issue of Molecular Cell, Fu et al. (2009) identify a constitutively active isoform of Bax, Baxbeta, whose activity is tightly controlled by the ubiquitin-proteasome system.

Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis.

While activation of BAX/BAK by BH3-only molecules (BH3s) is essential for mitochondrial apoptosis, the underlying mechanisms remain unsettled. Here we demonstrate that BAX undergoes stepwise structural reorganization leading to mitochondrial targeting and homo-oligomerization. The alpha1 helix of BAX keeps the alpha9 helix engaged in the dimerization pocket, rendering BAX as a monomer in cytosol. The activator BH3s, tBID/BIM/PUMA, attack and expose the alpha1 helix of BAX, resulting in secondary disengagement of the alpha9 helix and thereby mitochondrial insertion. Activator BH3s remain associated with the N-terminally exposed BAX through the BH1 domain to drive homo-oligomerization. BAK, an integral mitochondrial membrane protein, has bypassed the first activation step, explaining why its killing kinetics are faster than those of BAX. Furthermore, death signals initiated at ER induce BIM and PUMA to activate mitochondrial apoptosis. Accordingly, deficiency of Bim/Puma impedes ER stress-induced BAX/BAK activation and apoptosis. Our study provides mechanistic insights regarding the spatiotemporal execution of BAX/BAK-governed cell death.