Breast/chest imaging findings and clinical considerations in transgender patients.

The transgender population, a historically marginalized group, is growing in size, visibility, and cultural acceptance. However, lack of provider knowledge contributes to the disparities and discrimination that this group continues to face in the healthcare setting. Special considerations for transgender individuals undergoing imaging for breast/chest care can improve health equity, including appropriate evidence-based screening, tailored protocols, and inclusive radiology facilities. This article will focus on the imaging findings that can be seen in transgender patients during the course of gender-affirming care, which may involve hormone therapy and/or surgery. Relevant examples of benign and malignant pathologies that can be seen in transgender patients will be highlighted, and their imaging on mammogram, ultrasound, and magnetic resonance imaging (MRI) will be reviewed.

Characterisation and mapping of a Globodera pallida resistance derived from the wild potato species Solanum spegazzinii.

KEY MESSAGE: A new resistance locus acting against the potato cyst nematode Globodera pallida was mapped to chromosome VI in the diploid wild potato species Solanum spegazzinii CPC 7195. The potato cyst nematodes (PCN) Globodera pallida and Globodera rostochiensis are economically important potato pests in almost all regions where potato is grown. One important management strategy involves deployment through introgression breeding into modern cultivars of new sources of naturally occurring resistance from wild potato species. We describe a new source of resistance to G. pallida from wild potato germplasm. The diploid species Solanum spegazzinii Bitter accession CPC 7195 shows resistance to G. pallida pathotypes Pa1 and Pa2/3. A cross and first backcross of S. spegazzinii with Solanum tuberosum Group Phureja cultivar Mayan Gold were performed, and the level of resistance to G. pallida Pa2/3 was determined in progeny clones. Bulk-segregant analysis (BSA) using generic mapping enrichment sequencing (GenSeq) and genotyping-by-sequencing were performed to identify single-nucleotide polymorphisms (SNPs) that are genetically linked to the resistance, using S. tuberosum Group Phureja clone DM1-3 516 R44 as a reference genome. These SNPs were converted into allele-specific PCR assays, and the resistance was mapped to an interval of roughly 118 kb on chromosome VI. This newly identified resistance, which we call Gpa VIlspg, can be used in future efforts to produce modern cultivars with enhanced and broad-spectrum resistances to the major pests and pathogens of potato.

SMRT-AgRenSeq-d in potato (Solanum tuberosum) as a method to identify candidates for the nematode resistance Gpa5.

Potato is the third most important food crop in the world. Diverse pathogens threaten sustainable crop production but can be controlled, in many cases, through the deployment of disease resistance genes belonging to the family of nucleotide-binding, leucine-rich-repeat (NLR) genes. To identify effective disease resistance genes in established varieties, we have successfully established SMRT-AgRenSeq in tetraploid potatoes and have further enhanced the methodology by including dRenSeq in an approach that we term SMR-AgRenSeq-d. The inclusion of dRenSeq enables the filtering of candidates after the association analysis by establishing a presence/absence matrix across resistant and susceptible varieties that is translated into an F1 score. Using a SMRT-RenSeq-based sequence representation of the NLRome from the cultivar Innovator, SMRT-AgRenSeq-d analyses reliably identified the late blight resistance benchmark genes Rpi-R1, Rpi-R2-like, Rpi-R3a, and Rpi-R3b in a panel of 117 varieties with variable phenotype penetrations. All benchmark genes were identified with an F1 score of 1, which indicates absolute linkage in the panel. This method also identified nine strong candidates for Gpa5 that controls the potato cyst nematode (PCN) species Globodera pallida (pathotypes Pa2/3). Assuming that NLRs are involved in controlling many types of resistances, SMRT-AgRenSeq-d can readily be applied to diverse crops and pathogen systems.

Using Immersive Virtual Reality Distraction to Reduce Fear and Anxiety before Surgery.

Presurgical anxiety is very common and is often treated with sedatives. Minimizing or avoiding sedation reduces the risk of sedation-related adverse events. Reducing sedation can increase early cognitive recovery and reduce time to discharge after surgery. The current case study is the first to explore the use of interactive eye-tracked VR as a nonpharmacologic anxiolytic customized for physically immobilized presurgery patients. Method: A 44-year-old female patient presenting for gallbladder surgery participated. Using a within-subject repeated measures design (treatment order randomized), the participant received no VR during one portion of her preoperative wait and interactive eye-tracked virtual reality during an equivalent portion of time in the presurgery room. After each condition (no VR vs. VR), the participant provided subjective 0-10 ratings and state-trait short form Y anxiety measures of the amount of anxiety and fear she experienced during that condition. Results: As predicted, compared to treatment as usual (no VR), the patient reported having 67% lower presurgical anxiety during VR. She also experienced "strong fear" (8 out of 10) during no VR vs. "no fear" (0 out of 10) during VR. She reported a strong sense of presence during VR and zero nausea. She liked VR, she had fun during VR, and she recommended VR to future patients during pre-op. Interactive VR distraction with eye tracking was an effective nonpharmacologic technique for reducing anticipatory fear and anxiety prior to surgery. The results add to existing evidence that supports the use of VR in perioperative settings. VR technology has recently become affordable and more user friendly, increasing the potential for widespread dissemination into medical practice. Although case studies are scientifically inconclusive by nature, they help identify new directions for future larger, carefully controlled studies. VR sedation is a promising non-drug fear and anxiety management technique meriting further investigation.

The Emerging Role of Virtual Reality as an Adjunct to Procedural Sedation and Anesthesia: A Narrative Review.

Over the past 20 years, there has been a significant reduction in the incidence of adverse events associated with sedation outside of the operating room. Non-pharmacologic techniques are increasingly being used as peri-operative adjuncts to facilitate and promote anxiolysis, analgesia and sedation, and to reduce adverse events. This narrative review will briefly explore the emerging role of immersive reality in the peri-procedural care of surgical patients. Immersive virtual reality (VR) is intended to distract patients with the illusion of "being present" inside the computer-generated world, drawing attention away from their anxiety, pain, and discomfort. VR has been described for a variety of procedures that include colonoscopies, venipuncture, dental procedures, and burn wound care. As VR technology develops and the production costs decrease, the role and application of VR in clinical practice will expand. It is important for medical professionals to understand that VR is now available for prime-time use and to be aware of the growing body in the literature that supports VR.

Utilization of Screening Mammography in Women Before 50: Cross-Sectional Survey Results from the National Health Interview Survey.

OBJECTIVE: While the American College of Radiology recommends annual screening mammography starting at age 40 years, the US Preventive Services Task Force (USPSTF) recommends that screening mammography in women younger than age 50 years should involve shared- decision making (SDM) between clinicians and patients, considering benefits and potential harms in younger women. Using a nationally representative cross-sectional survey, we aimed to evaluate patient-reported reasons and predictors of screening mammography utilization in this age group. METHODS: Respondents aged 40-49 years from the 2018 National Health Interview Survey (NHIS) without a history of breast cancer were included (response rate 64%). Participants reported sociodemographic variables and reasons they did not engage in mammography screening within the last two years. Multiple variable logistic regression analyses were performed to evaluate the association between sociodemographic characteristics and patient-reported screening mammography use, accounting for complex survey sampling design elements. RESULTS: 1,948 women between the ages of 40-49 years were included. Of this group, (758/1948) 46.6% reported receiving a screening mammogram within the last year, and 1196/1948 (61.4%) reported receiving a screening mammogram within the last two years. The most common reasons for not undergoing screening included: "No reason/never thought about it" 744/1948 (38.2%), "Put it off" 343/1948 (17.6%), "Didn't need it" 331/1948 (16.9%), "Doctor didn't order it" 162/1948 (8.3%), and "I'm too young" 63/1948 (5.3%). Multiple variable analyses demonstrated that lack of health insurance was the strongest predictor of mammography non-engagement (p< 0.001). CONCLUSION: Deficits in shared- decision-making in women younger than 50 years related to mammography utilization exist. Radiologists may be key in addressing this issue among ambulatory care providers and patients, educating about the benefits and harms of screening younger women, particularly in racial/ethnic minorities and uninsured patients, who experience additional barriers to care and SDM discussions.

Antiviral function and viral antagonism of the rapidly evolving dynein activating adaptor NINL.

Viruses interact with the intracellular transport machinery to promote viral replication. Such host-virus interactions can drive host gene adaptation, leaving signatures of pathogen-driven evolution in host genomes. Here, we leverage these genetic signatures to identify the dynein activating adaptor, ninein-like (NINL), as a critical component in the antiviral innate immune response and as a target of viral antagonism. Unique among genes encoding components of active dynein complexes, NINL has evolved under recurrent positive (diversifying) selection, particularly in its carboxy-terminal cargo-binding region. Consistent with a role for NINL in host immunity, we demonstrate that NINL knockout cells exhibit an impaired response to interferon, resulting in increased permissiveness to viral replication. Moreover, we show that proteases encoded by diverse picornaviruses and coronaviruses cleave and disrupt NINL function in a host- and virus-specific manner. Our work reveals the importance of NINL in the antiviral response and the utility of using signatures of host-virus genetic conflicts to uncover new components of antiviral immunity and targets of viral antagonism.

Humans and viruses are locked in an evolutionary arms race. Viruses hijack cells, using their resources and proteins to build more viral particles; the cells fight back, calling in the immune system to fend off the attack. Both actors must constantly and quickly evolve to keep up with each other. This genetic conflict has been happening for millions of years, and the indelible marks it has left on genes can serve to uncover exactly how viruses interact with the organisms they invade. One hotspot in this host-virus conflict is the complex network of molecules that help to move cargo inside a cell. This system transports elements of the immune system, but viruses can also harness it to make more of themselves. Scientists still know very little about how viruses and the intracellular transport machinery interact, and how this impacts viral replication and the immune response. Stevens et al. therefore set out to identify new interactions between viruses and the transport system by using clues left in host genomes by evolution. They focused on dynein, a core component of this machinery which helps to haul molecular actors across a cell. To do so, dynein relies on adaptor molecules such as 'Ninein-like', or NINL for short. Closely examining the gene sequence for NINL across primates highlighted an evolutionary signature characteristic of host-virus genetic conflicts; this suggests that the protein may be used by viruses to reproduce, or by cells to fend off infection. And indeed, human cells lacking the NINL gene were less able to defend themselves, allowing viruses to grow much faster than normal. Further work showed that NINL was important for a major type of antiviral immune response. As a potential means to sabotage this defence mechanism, some viruses cleave NINL at specific sites and disrupt its role in intracellular transport. Better antiviral treatments are needed to help humanity resist old foes and new threats alike. The work by Stevens et al. demonstrates how the information contained in host genomes can be leveraged to understand what drives susceptibility to an infection, and to pinpoint molecular actors which could become therapeutic targets.

Exploiting breakdown in nonhost effector-target interactions to boost host disease resistance.

Plants are resistant to most microbial species due to nonhost resistance (NHR), providing broad-spectrum and durable immunity. However, the molecular components contributing to NHR are poorly characterised. We address the question of whether failure of pathogen effectors to manipulate nonhost plants plays a critical role in NHR. RxLR (Arg-any amino acid-Leu-Arg) effectors from two oomycete pathogens, Phytophthora infestans and Hyaloperonospora arabidopsidis, enhanced pathogen infection when expressed in host plants (Nicotiana benthamiana and Arabidopsis, respectively) but the same effectors performed poorly in distantly related nonhost pathosystems. Putative target proteins in the host plant potato were identified for 64 P. infestans RxLR effectors using yeast 2-hybrid (Y2H) screens. Candidate orthologues of these target proteins in the distantly related non-host plant Arabidopsis were identified and screened using matrix Y2H for interaction with RxLR effectors from both P. infestans and H. arabidopsidis. Few P. infestans effector-target protein interactions were conserved from potato to candidate Arabidopsis target orthologues (cAtOrths). However, there was an enrichment of H. arabidopsidis RxLR effectors interacting with cAtOrths. We expressed the cAtOrth AtPUB33, which unlike its potato orthologue did not interact with P. infestans effector PiSFI3, in potato and Nicotiana benthamiana. Expression of AtPUB33 significantly reduced P. infestans colonization in both host plants. Our results provide evidence that failure of pathogen effectors to interact with and/or correctly manipulate target proteins in distantly related non-host plants contributes to NHR. Moreover, exploiting this breakdown in effector-nonhost target interaction, transferring effector target orthologues from non-host to host plants is a strategy to reduce disease.

Incidence of ophthalmic involvement in Behçet's disease in the United Kingdom: a British Ophthalmic Surveillance Unit (BOSU) study.

BACKGROUND: Behçet's disease (BD) is a relapsing-remitting vasculitis, which can manifest in different organ systems including the eyes. There is currently limited published data describing the incidence of ophthalmic disease within the United Kingdom. The primary aim of this study was to survey the incidence and manifestations of ophthalmic BD prospectively, with a secondary aim of reviewing treatment modalities initiated in first-line therapy. METHODS: Using the British Ophthalmic Surveillance Unit reporting system between October 2016 and November 2018, we prospectively surveyed the number of cases of BD presenting to UK ophthalmologists. A total of 89 cases of ophthalmic manifestations of BD were reported and complete information was collected on 58 patients. RESULTS: 93 eyes of 58 patients were affected. The median age of reported cases was 31 years (range 13-55 years) who were born in 15 different countries. Most cases (n = 35, 60%) had bilateral involvement. Vitritis was the most common ocular manifestation (68%; n = 63) followed by anterior uveitis (46%; n = 43). The greatest causes of visual morbidity were cystoid macular oedema, vitritis and retinal ischaemia. Most patients were prescribed either topical or oral corticosteroids (59%; n = 34), with some given intravitreal or intravenous corticosteroids. Five patients (8.6%) were initiated on disease-modifying anti-rheumatic drugs and one given an anti-TNF monoclonal antibody. CONCLUSIONS: This is the first prospective study to analyse the incidence of ophthalmic involvement in BD over a 2-year period, finding an annual incidence of 0.04 per 100,000 individuals in the UK.

Running With Scissors: Evolutionary Conflicts Between Viral Proteases and the Host Immune System.

Many pathogens encode proteases that serve to antagonize the host immune system. In particular, viruses with a positive-sense single-stranded RNA genome [(+)ssRNA], including picornaviruses, flaviviruses, and coronaviruses, encode proteases that are not only required for processing viral polyproteins into functional units but also manipulate crucial host cellular processes through their proteolytic activity. Because these proteases must cleave numerous polyprotein sites as well as diverse host targets, evolution of these viral proteases is expected to be highly constrained. However, despite this strong evolutionary constraint, mounting evidence suggests that viral proteases such as picornavirus 3C, flavivirus NS3, and coronavirus 3CL, are engaged in molecular 'arms races' with their targeted host factors, resulting in host- and virus-specific determinants of protease cleavage. In cases where protease-mediated cleavage results in host immune inactivation, recurrent host gene evolution can result in avoidance of cleavage by viral proteases. In other cases, such as recently described examples in NLRP1 and CARD8, hosts have evolved 'tripwire' sequences that mimic protease cleavage sites and activate an immune response upon cleavage. In both cases, host evolution may be responsible for driving viral protease evolution, helping explain why viral proteases and polyprotein sites are divergent among related viruses despite such strong evolutionary constraint. Importantly, these evolutionary conflicts result in diverse protease-host interactions even within closely related host and viral species, thereby contributing to host range, zoonotic potential, and pathogenicity of viral infection. Such examples highlight the importance of examining viral protease-host interactions through an evolutionary lens.

The Genomic Impact of Selection for Virulence against Resistance in the Potato Cyst Nematode, Globodera pallida.

Although the use of natural resistance is the most effective management approach against the potato cyst nematode (PCN) Globodera pallida, the existence of pathotypes with different virulence characteristics constitutes a constraint towards this goal. Two resistance sources, GpaV (from Solanum vernei) and H3 from S. tuberosum ssp. andigena CPC2802 (from the Commonwealth Potato Collection) are widely used in potato breeding programmes in European potato industry. However, the use of resistant cultivars may drive strong selection towards virulence, which allows the increase in frequency of virulent alleles in the population and therefore, the emergence of highly virulent nematode lineages. This study aimed to identify Avirulence (Avr) genes in G. pallida populations selected for virulence on the above resistance sources, and the genomic impact of selection processes on the nematode. The selection drive in the populations was found to be specific to their genetic background. At the genomic level, 11 genes were found that represent candidate Avr genes. Most of the variant calls determining selection were associated with H3-selected populations, while many of them seem to be organised in genomic islands facilitating selection evolution. These phenotypic and genomic findings combined with histological studies performed revealed potential mechanisms underlying selection in G. pallida.

Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells.

Perturbations in insulin/IGF signaling and manganese (Mn2+) uptake and signaling have been separately reported in Huntington's disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn2+-responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn2+ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn2+ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn2+-dependent AKT signaling is predominantly mediated by direct Mn2+ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn2+ bioavailability. We examined the combined effects of IGF-1 and/or Mn2+ treatments on AKT signaling in multiple HD cellular models. Mn2+ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70-80% of Mn2+-associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn2+-induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn2+ and IGF-1. Lastly, Mn2+-induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn2+ supplementation. Our data demonstrate that Mn2+ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn2+ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.

Pediatric Stapes Surgery: Hearing and Surgical Outcomes in Endoscopic vs Microscopic Approaches.

OBJECTIVE: To compare endoscopic and microscopic pediatric stapes surgery. STUDY DESIGN: Case series with chart review. SETTING: Two academic otology practices. SUBJECTS AND METHODS: Surgical and hearing outcomes were compared for consecutive children (<18 years) undergoing microscopic and endoscopic stapes surgery. The main outcome measure was closure of the air-bone gap (ABG) to ≤20 dB. RESULTS: Twenty-two endoscopic surgeries (17 stapedectomies, 4 stapedotomies, and 1 stapes mobilization) and 52 microscopic surgeries (30 stapedectomies, 19 stapedotomies, and 3 stapes mobilizations) were performed. Patient demographics, history of ipsilateral middle ear surgery, and revision stapes surgery status were similar. The most common diagnosis for the endoscopic group and microscopic group were congenital stapes footplate fixation (45.5%) and juvenile otosclerosis (46.2%), respectively. Preoperative ABGs in the endoscopic (37.7 dB) and microscopic (32.8 dB) groups (P = .170) were similar. There were no major complications, including facial nerve injury or anacusis, in the endoscopic group. Postoperative sensorineural hearing loss (>15 dB) did not occur in any patients in the endoscopic group but was present in 2 patients in the microscopic group (P = .546). Improvement in pure-tone average (25.9 dB vs 18.5 dB, P = .382) and ABG (21.7 dB vs 14.7 dB, P = .181) was similar, and postoperatively, the median ABG was 11.3 dB and 15.0 dB for endoscopic and microscopic cases (P = .703), respectively. ABG closure to ≤20 dB (72.7% vs 65.2%, P = .591) was also similar. CONCLUSION: Pediatric endoscopic stapes surgery is safe and hearing outcomes are similar to the microscopic approach when performed by experienced endoscopic ear surgeons.

Mapping the H2 resistance effective against Globodera pallida pathotype Pa1 in tetraploid potato.

KEY MESSAGE: The nematode resistance gene H2 was mapped to the distal end of chromosome 5 in tetraploid potato. The H2 resistance gene, introduced into cultivated potatoes from the wild diploid species Solanum multidissectum, confers a high level of resistance to the Pa1 pathotype of the potato cyst nematode Globodera pallida. A cross between tetraploid H2-containing breeding clone P55/7 and susceptible potato variety Picasso yielded an F1 population that segregated approximately 1:1 for the resistance phenotype, which is consistent with a single dominant gene in a simplex configuration. Using genome reduction methodologies RenSeq and GenSeq, the segregating F1 population enabled the genetic characterisation of the resistance through a bulked segregant analysis. A diagnostic RenSeq analysis of the parents confirmed that the resistance in P55/7 cannot be explained by previously characterised resistance genes. Only the variety Picasso contained functionally characterised disease resistance genes Rpi-R1, Rpi-R3a, Rpi-R3b variant, Gpa2 and Rx, which was independently confirmed through effector vacuum infiltration assays. RenSeq and GenSeq independently identified sequence polymorphisms linked to the H2 resistance on the top end of potato chromosome 5. Allele-specific KASP markers further defined the locus containing the H2 gene to a 4.7 Mb interval on the distal short arm of potato chromosome 5 and to positions that correspond to 1.4 MB and 6.1 MB in the potato reference genome.

Endoscopic Removal of an Epithelial Cyst of the Zygoma.

This study elaborates a brief overview of epithelial cysts in the bones of the skull and describes an unusual patient with an epidermoid cyst of the zygoma. This report focuses on an endoscopic preauricular infratemporal fossa approach for resection of a left epidermoid cyst of the zygoma. Preoperative magnetic resonance imaging and computed tomography imaging as well as intraoperative endoscopic images and movie were demonstrated. The epithelial cyst was successfully removed from the patient using a minimally invasive approach utilizing endoscopes. No complications were encountered. The possible causes of this rare presentation and minimal surgical removal utilizing endoscopes were discussed in this study. According to the authors, this is the first reported study of endoscopic removal of an epidermoid cyst from the zygomatic root. The patient's previous surgical history of a tympanoplasty could have contributed to the unusual location of the lesion.

Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line.

In a recent study, we found that blocking the protein kinase ataxia telangiectasia mutated (ATM) with the small molecule inhibitor (SMI) KU-55933 can completely abrogate Mn-induced phosphorylation of p53 at serine 15 (p-p53) in human induced pluripotent stem cell (hiPSC)-differentiated striatal neuroprogenitors. However, in the immortalized mouse striatal progenitor cell line STHdhQ7/Q7, a concentration of KU55933 far exceeding its IC50 for ATM was required to inhibit Mn-induced p-p53. This suggested an alternative signaling system redundant with ATM kinase for activating p53 in this cell line- one that was altered by KU55933 at these higher concentrations (i.e. mTORC1, DNApk, PI3K). To test the hypothesis that one or more of these signaling pathways contributed to Mn-induced p-p53, we utilized a set of SMIs (e.g. NU7441 and LY294002) known to block DNApk, PI3K, and mTORC1 at distinct concentrations. We found that the SMIs inhibit Mn-induced p-p53 expression near the expected IC50s for PI3K, versus other known targets. We hypothesized that inhibiting PI3K reduces intracellular Mn and thereby decreases activation of p53 by Mn. Using the cellular fura-2 manganese extraction assay (CFMEA), we determined that KU55933/60019, NU7441, and LY294002 (at concentrations near their IC50s for PI3K) all decrease intracellular Mn (∼50%) after a dual, 24-h Mn and SMI exposure. Many pathways are activated by Mn aside from p-p53, including AKT and mTOR pathways. Thus, we explored the activation of these pathways by Mn in STHdh cells as well as the effects of other pathway inhibitors. p-AKT and p-S6 activation by Mn is almost completely blocked upon addition of NU7441(5µM) or LY294002(7µM), supporting PI3K's upstream role in the AKT/mTOR pathway. We also investigated whether PI3K inhibition blocks Mn uptake in other cell lines. LY294002 exposure did not reduce Mn uptake in ST14A, Neuro2A, HEK293, MEF, or hiPSC-derived neuroprogenitors. Next, we sought to determine whether inhibition of PI3K blocked p53 phosphorylation by directly blocking an unknown PI3K/p53 interaction or indirectly reducing intracellular Mn, decreasing p-p53 expression. In-Cell Western and CFMEA experiments using multiple concentrations of Mn exposures demonstrated that intracellular Mn levels directly correlated with p-p53 expression with or without addition of LY294002. Finally, we examined whether PI3K inhibition was able to block Mn-induced p-p53 activity in hiPSC-derived striatal neuroprogenitors. As expected, LY294002 does not block Mn-induced p-p53 as PI3K inhibition is unable to reduce Mn net uptake in this cell line, suggesting the effect of LY294002 on Mn uptake is relatively specific to the STHdh mouse striatal cell line.

HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia.

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11-Rad51-DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair 'addiction' and provide an effective therapeutic option for Ph+ B-cell precursor ALL.

Isolated endogenous Fusarium endophthalmitis in an immunocompetent adult after a thorn prick to the hand.

PURPOSE: To report the case of an immunocompetent adult presenting with endogenous Fusarium endophthalmitis. OBSERVATIONS: A woman in her thirties presented with symptoms and signs of a unilateral anterior uveitis. After initial improvement with topical corticosteroids, she continued to develop a panuveitis with an associated drop in vision to counting fingers. A vitreous biopsy confirmed Fusarium solani by 18S rRNA fungal gene detection and PCR sequencing. Despite treatment with pars plana vitrectomy, intravitreal amphotericin B and systemic voriconazole her visual outcome was poor. Detailed review of her antecedent history revealed the route of acquisition to be a thorn prick to the hand two weeks prior to presentation. CONCLUSIONS AND IMPORTANCE: This patient's endophthalmitis most likely resulted from cutaneous inoculation of Fusarium solani with subsequent hematogenous spread. Endogenous Fusarium endophthalmitis is well recognized in the immunocompromised but is very rarely seen in the immunocompetent. This case highlights the importance of thorough history-taking and consideration of fungal endophthalmitis in the differential diagnosis of a treatment-refractory uveitis.

Rethinking the traditional full-mouth rehabilitation by applying minimal prosthetic dentistry for maximum patient benefit.

The field of dentistry is an ever-evolving discipline. A marked rise in the use of endosseous implants, adhesive ceramic bonding, and composite resins, as well as continued patient desire for minimally invasive procedures, has created a new conservative era in the practices of many restorative dentists. These trends, coupled with the significant financial impact associated with the reconstruction of failing, worn, and esthetically compromised dentitions, have facilitated a paradigm shift in the way that individual patient cases are being treatment planned today. Applying restraint to conventional practices involving the unnecessary gross removal of hard tooth structure is both a skill that needs to be cultivated as well as an evident obligation to the patient. A case report demonstrates the utilization of multiple restorative materials to provide a minimally invasive definitive treatment that was biomechanically, esthetically, and financially satisfactory for the patient.